22nd Century Medical Center Donation Course
Department of Ischemic Circulatory Physiology, Kaatsu
Training, University of Tokyo
University of Tokyo, 7-3-1
Hongo, Bunkyo-ku,
Tokyo, Japan
Donation company: Kaatsu Japan Co., Ltd

Course opened：October 2004 ～ September 2014 (10-year maturity)◆Donation course name
Ischemic Circulatory Physiology, Kaatsu Training◆Donation course instructor
Toshiaki Nakajima Associate Professor
Tomohiro Yasuda Special Lecturer
Toshihiro Morita Assistant Professor

1◆Purpose of course establishment
The course carries out multifaceted examination and verification research on
innovative exercise methods represented by KAATSU training. Based on the results, we
promote health maintenance and promotion activities in Japan, and widely advocate amodel for reducing medical expenses as a social contribution.

◆Research
It goes without saying that prolonging healthy life span is a social issue in Japan,
where the aging of society is rapidly progressing. Under the keywords of healthpromotion, disease prevention, and long-term care prevention, it is urgent that industry,
government, and academia work together to reduce social security burden. It is a socialrole that is required for all organizations in the health and medical field. In such asituation, the usefulness of exercise is high from the medical point of view of prevention
and treatment, and development and diffusion of a science-based exercise method withstrong intention more than ever is strongly desired.
KAATSU training is performed by pressurizing the lower limbs or upper limbs
with a pneumatic pressure band, and exercise with moderate blood flow restriction is
expected to have a muscle hypertrophic effect even under short-term and light loads. It
is a rehabilitation method suitable for society. In addition, since the endocrine system is
activated, including growth hormone, depending on the type of disease, a direct
improvement effect is expected. Furthermore, the pooling action of the lower extremity
blood by pressurization has the same standing stimulation effect as lower body negative
pressure (LBNP), so it seems to have the cardiovascular system deconditioning
preventing effect for astronauts and long-term bedridden patients. As a result, muscle
hypertrophy effect (improvement of disuse atrophy) is expected in patients with various
diseases as well as healthy people. Furthermore, this method can be widely used in
sports, nursing prevention, clinical and space medicine in Japan. It is also expected to be
applied to cardiac rehabilitation muscle strength training and orthostatic dysregulation(OD) patients.
Animal experiments are also conducted to elucidate the mechanism of KAATSU
training. As its underlying mechanism, promotion of muscle protein synthesis, andsuppression of degradation systems have been reported, but the details are unknown.
Therefore, we aim to elucidate the molecular mechanism of the effect of this method.
We also examined the chronic effects and their molecular mechanisms. KAATSU
ttraining was considered to be a useful method in measures against sarcopenia in theelderly.

◆ 22nd Century Medical Center (Excerpt from Tokyo University
Hospital website)
At the University of Tokyo Hospital, a variety of initiatives aimed at advanced
medical research and development are underway. As part of that, in order to research
2and develop new clinical medicine or medical related services in the field of the
University of Tokyo Hospital, the establishment of a 22nd century medical center isplanned in 2002. In 2004, the course was opened and activities started, and in April
2006, it was officially launched as the center of the University of Tokyo Hospital. The
Central Medical Center 2 is the base of activities from September 2006, and consists ofa donation course and a social cooperation course.
Research activities include the development of new diagnostic methods andtreatments, the spread and verification of therapeutic methods, preventive medicine,
medical policy, medical equipment and facilities provided through actual clinics andservices. These research activities occupy a position close to practical use and social
return among medical and medical research, and play a central role in translational
research promoted by the University of Tokyo Medical School and Medical School at
the Hongo Campus. In addition, by promoting industry-academia collaboration andvarious joint research, it plays a role to improve the global presence.

Major clinical achievements
Ｉ．About the effect and safety of KAATSU training● Because KAATSU muscle training promotes secretion of growth hormone in acute exercise
and is a special training method called blood flow restriction, we examined the influence on
hemodynamics during training.
Takano H, Morita T, Iida H, Asada K, Kato M, Uno K, Hirose K, Matsumoto A, Takenaka K,
Hirata Y, Eto F, Nagai R、SatoY、Nakajima T 2005. Hemodynamic and hormonal responses toa short-term low-intensity resistance exercise with the reduction of muscle blood flow. Eur J
Appl Physiol. 95: 65-73.
We investigated the hemodynamic and hormonal responses to a short-term low-intensity
resistance exercise (STLIRE) with the reduction of muscle blood flow. Eleven untrained men
performed bilateral leg extension exercise under the reduction of muscle blood flow of theproximal end of both legs pressure-applied by a specially designed belt (a banding pressure of
1.3 times higher than resting systolic blood pressure, 160-180 mmHg), named as Kaatsu. The
intensity of STLIRE was 20% of one repetition maximum. The subjects performed 30
repetitions, and after a 20-seconds rest, they performed three sets again until exhaustion. The
superficial femoral arterial blood flow and hemodynamic parameters were measured by using
the ultrasound and impedance cardiography. Serum concentrations of growth hormone (GH),vascular endothelial growth factor (VEGF), noradrenaline (NE), insulin-like growth factor(IGF)-1, ghrelin, and lactate were also measured. Under the conditions with Kaatsu, the arterial
flow was reduced to about 30% of the control. STLIRE with Kaatsu significantly increased GH(0.11+/-0.03 to 8.6+/-1.1 ng/ml, P < 0.01), IGF-1 (210+/-40 to 236+/-56 ng/ml, P < 0.01), andVEGF (41+/-13 to 103+/-38 pg/ml, P < 0.05). The increase in GH was related to neither NE nor
lactate, but the increase in VEGF was related to that in lactate (r = 0.57, P < 0.05). Ghrelin did
not change during the exercise. The maximal heart rate (HR) and blood pressure (BP) in
STLIRE with Kaatsu were higher than that without Kaatsu. Stroke volume (SV) was lower due
to the decrease of the venous return by Kaatsu, but, total peripheral resistance (TPR) did notchange significantly. These results suggest that STLIRE with Kaatsu significantly stimulates the3exercise-induced GH, IGF, and VEGF responses with the reduction of cardiac preload during
exercise, which may become a unique method for rehabilitation in patients with cardiovasculardiseases.
Pub med is the first dissertation to be searched first in KAATSU, and so far more than
100 citations have been seen.
● Research to verify the safety of KAATSU traininga) Research from national questionnaire survey
Nakajima T et al. 2006. Use and safety of KAATSU training: Results of a national survey. Int J
KAATSU Training Res 2: 5-14.
KAATSU training is a novel training, which is performed under conditions of restrictedblood flow. It can induce a variety of beneficial effects such as increased muscle strength, and it
has been adopted by a number of facilities in recent times. The purpose of the present study is toknow the present state of KAATSU training in Japan and examine the incidence of adverse
events in the field. The data were obtained from KAATSU leaders or instructors in a total of
105 out of 195 facilities where KAATSU training has been adopted. Based on survey results,
12,642 persons have received KAATSU training (male 45.4%, female 54.6%). KAATSU
training has been applied to all generations of people including the young ( 80 years old). The
most popular purpose of KAATSU training is to strengthen muscle in athletes and to promote
the health of subjects, including the elderly. It has been also applied to various kinds of physicalconditions, cerebrovascular diseases, orthopedic diseases, obesity, cardiac diseases,
neuromuscular diseases, diabetes, hypertension and respiratory diseases. In KAATSU training,
various types of exercise modalities (physical exercise, walking, cycling, and weight training)are used. Most facilities have used 5-30 min KAATSU training each time, and performed it 1-3
times a week. Approximately 80% of the facilities are satisfied with the results of KAATSU
training with only small numbers of complications reported. These results indicate that the
KAATSU training is a safe and promising method for training athletes and healthy persons, andcan also be applied to persons with various physical conditions.
b) Examination about influence of KAATSU training on coagullaion, and fibrinolytic system
The following studies were conducted to further confirm the safety. Although the subject
was a healthy person, the study was added under several conditions. Conducted as a joint
research with Japan Aerospace Exploration Agency (JAXA).
Nakajima T, et al 2007. Effects of KAATSU training on haemostasis in healthy subjects. Int J
KAATSU Training Res 3: 11-21.
Purposes: The KAATSU training is performed under the reduction of muscle blood flowby a specially designed belt (KAATSU belt), which induces blood pooling in capacitancevessels by restricting venous return. However, no prior studies have examined the effects of
KAATSU training on haemostasis. The purpose of the present study was to investigate acuteeffects of KAATSU training on haemostasis including fibrinolytic responses in healthy subjects.
Methods: Two protocols have been performed. (1) 6 healthy men (mean age= 48 ± 5 yr)
performed KAATSU (160 mmHg) of both thighs for 15 minutes and then KAASTU training
combined with low-intensity leg and foot aerobic exercises for ∼ 10 minutes in hypobaric
chamber, which mimics 8000 feet in airflight. (2) Another 7 men (mean age=30 ± 4 yr)
4performed leg press exercises (30 % 1 RM) with and without KAATSU of both thighs 24 h after
bed rest. Blood samples were taken at rest, immediately after KAATSU, and exercises with orwithout KAATSU, and after exercise. For the investigation of blood fibrinolysis, determinationsof tissue-type plasminogen activator (tPA) activity or antigen, plasminogen activator inhibitor(PAI)-1 activity or antigen, fibrin degradation product (FDP) and D-dimer were used.
Prothrombin time (PT) and platelet counts were also measured. Results: (1) In hypobaric
chamber, KAATSU by itself significantly increased tPA activity, while PAI-1 activity was
unchanged. Furthermore, immediately after the exercise, tPA activity increased significantly. (2)During the exercises combined with KAATSU 24 h after bed rest, tPA antigen significantly
increased, compared with control exercises, but PAI-1 antigen was unchanged. In both cases,
KAATSU training did not induce fibrin formation as assessed by fibrin D-dimer and FDP.
Conclusions: This study indicates that potentially favorable changes occur in fibrinolytic factors
after KAATSU and KAATSU training in healthy subjects.
●Examination of influence of hemodynamics by KAATSU training of lower limbs
The above-mentioned study revealed the effect of KAATSU on venous blood pooling in
the lower limbs. This led to the following study. In outer space, weightlessness causes the bloodto shift to the head and body center, which is responsible for the deconditioning of thecirculatory system. Therefore, we examined the effects of KAATSU on hemodynamics and theeffects on various hormones. As a result, depending on the applied pressure, blood
accumulation in the lower limbs is observed, and at 150 mmHg or more, accumulation in thelower limbs occurs more than standing stimulation, and hemodynamically standing stimulation
is given in the prone position.
Iida H, Kurano M, Takano H, Oonuma H, Imuta H, Kubota N, Morita T, Meguro K, Sato Y,
Abe T, Yamazaki Y, Nakajima T. 2006. Can KAATSU be used for an orthostatic stress inastronauts?: A case study. Int J KAATSU Training Res 2: 45-52.
The application of an orthostatic stress such as lower body negative pressure (LBNP)
during exercise has been proposed to minimize the effects of weightlessness on the
cardiovascular system and subsequently to reduce the cardiovascular deconditioning. The
KAATSU training is a novel method for strength training to induce muscle strength andhypertrophy. KAATSU induces venous pooling of blood in capacitance vessels by restricting
venous blood flow. Therefore, to investigate whether KAATSU can be used as an orthostatic
stress, we examined the effects of KAATSU on the hemodynamic, autonomic nervous andhormonal parameters in one subject. The several parameters were measured by impedance
cardiography; heart rate (HR), mean blood pressure (mBP), stroke volume (SV), cardiac output(CO), total peripheral resistance (TPR), and heart rate variability (HRV). These data wereobtained before (pre), during and after (post) pressurization (50 and 200 mmHg) on both thighswith KAATSU mini belts, and compared with those in standing. The serum concentration ofnoradrenaline (NA) and vasopressin (ADH), and plasma rennin activity (PRA) were alsomeasured. The application of 200 mmHg KAATSU decreased SV, which was almost equal tothe value in standing. HR and TPR increased in a similar manner as standing with slight change
of mBP. High frequency (HFRR), a marker of parasympathetic nervous activity, decreased
during both 200 mmHg KAATSU and standing, while LFRR/HFRR, a quantitative marker of
sympathetic nervous activity, increased significantly. During KAATSU and standing, NA, PRA
5

and ADH increased. These results indicate that the application of KAATSU on both thighs
simulates systemic cardiovascular effects of orthostasis in one gravity (1G), and that KAATSU
training appears to be a useful method for potential countermeasure like lower body negative
pressure (LBNP) against orthostatic intolerance in space flight as well as strength training to
induce muscle strength and hypertrophy.
Iida H, Kurano M, Takano H, Kubota N, Morita T, Meguro K, Sato Y, Abe T, Yamazaki Y,
Uno K, Takenaka K, Hirose K, Nakajima T. 2007. Hemodynamic and neurohumoral responses
to the restriction of femoral blood flow by KAATSU in healthy subjects. Eur J Appl Physiol
100: 275-285.
The application of an orthostatic stress such as lower body negative pressure (LBNP) has
been proposed to minimize the effects of weightlessness on the cardiovascular system andsubsequently to reduce the cardiovascular deconditioning. The KAATSU training is a novel
method to induce muscle strength and hypertrophy with blood pooling in capacitance vessels by
restricting venous return. Here, we studied the hemodynamic, autonomic nervous and hormonal
responses to the restriction of femoral blood flow by KAATSU in healthy male subjects, using
the ultrasonography and impedance cardiography. The pressurization on both thighs induced
pooling of blood into the legs with pressure-dependent reduction of femoral arterial blood flow.
The application of 200 mmHg KAATSU significantly decreased left ventricular diastolicdimension (LVDd), cardiac output (CO) and diameter of inferior vena cava (IVC). Similarly,
200 mmHg KAATSU also decreased stroke volume (SV), which was almost equal to the value
in standing. Heart rate (HR) and total peripheral resistance (TPR) increased in a similar manner
to standing with slight change of mean blood pressure (mBP). High-frequency power (HF(RR))
decreased during both 200 mmHg KAATSU and standing, while low-frequency/high-frequency
power (LF(RR)/HF(RR)) increased significantly. During KAATSU and standing, theconcentration of noradrenaline (NA) and vasopressin (ADH) and plasma renin activity (PRA)
increased. These results indicate that KAATSU in supine subjects reproduces the effects ofstanding on HR, SV, TPR, etc., thus stimulating an orthostatic stimulus. And, KAATSU
training appears to be a useful method for potential countermeasure like LBNP against
orthostatic intolerance after spaceflight.
● Examination about the usefulness as a training of astronauts
Thus, KAATSU was considered to have new application as a training method for
astronauts, including the prevention of muscle atrophy in space. Therefore, joint research with
two JAXA was conducted.
a) Examination about influence on hemodynamics and various hormones of leg press by thepresence or absence of KAATSU in environment simulating weightlessness 24 hours after -6
degrees bed rest
Kubota N, Takano H, Tsutsumi T, Kurano M, Iida H, Yasuda T, Meguro K, Morita T, Sato Y,
Kawashima S, Yamazaki Y, Ohshima H, Tachibana S, Ishii N, Abe T, Nakajima T.2008.
Resistance exercise combined with KAATSU during simulated weightlessness Int J KAATSU
Training Res 4:9-15.
The application of a gravity-specific stress (e.g. LBNP), in combination with exercise,prevents cardiovascular deconditioning in space flight. KAATSU training is a method to induce
blood pooling in capacitance vessels by restricting venous return (as with LBNP) and which
6when combined with low-intensity resistance (RE) exercise produces remarkable muscle massand muscle strength gains. The purpose of this study was to investigate the hemodynamic andneurohumonal responses induced by KAATSU in combination with leg RE (30 % 1 RM),
during simulated weightlessness (6°head-down tilt for 24 h, n=7). Following 24 h bed rest 6°
head-down tilt, body mass was decreased from 75.3 ± 3.9 to 73.3 ± 3.8 Kg (P<0.01). Blood
volume (BV) and plasma volume (PV) were reduced by −4.4 ± 1.4% and −7.9 ± 2.5%,
respectively. During RE, BV and PV were significantly decreased; the changes with KAATSU
induced a lower-body venous pooling, resulting in a sustained decrease in stroke volume (SV;from 77.0 ± 4.4 ml to 55.9 ± 5.1 ml; P<0.01) that was comparable to resting SV while standing.
Consequently, RE heart rate (HR) was greater with KAATSU. The serum concentrations ofplasma renin activity (PRA), vasopressin (ADH), noradrenaline (NOR), and lactate were alsosignificantly elevated during RE with KAATSU as compared to control RE. These
hemodynamic and neurohumoral responses following head-down tilt and during RE closely
approximate the gravity-specific stress observed with LBNP. Thus, when used in combination
with RE, KAATSU may be a useful countermeasure in microgravity
Nakajima T et al. 2008. Hemodynamic responses to simulated weightlessness of 24-h
head-down bed rest and KAATSU blood flow restriction. Eur J Appl Physiol. 104: 727-737.
The KAATSU training is a unique method of muscle training with restricting venous
blood flow, which might be applied to prevent muscle atrophy during space flight, but theeffects of KAATSU in microgravity remain unknown. We investigated the hemodynamic
responses to KAATSU during actually simulated weightlessness (6 degrees head-down tilt for
24 h, n = 8), and compared those to KAATSU in the seated position before bed rest. KAATSU
was applied to the proximal ends of both the thighs. In the seated position before bed rest,
sequential incrementing of KAATSU cuff pressure and altering the level of blood flow
restriction resulted in a decrease in stroke volume (SV) with an increase in heart rate (HR).
KAATSU (150-200 mmHg) decreased SV comparable to standing. Following 24-h bed rest,
body mass, blood volume (BV), plasma volume (PV), and diameter of the inferior vena cava
(IVC) were significantly reduced. Norepinephrine (NOR), vasopressin (ADH), and plasma renin
activity (PRA) tend to be reduced. A decrease in SV and CO induced by KAATSU during thesimulated weightlessness was larger than that in the seated position before bed rest, and one ofeight subjects developed presyncope due to hypotension during 100 mmHg KAATSU.
High-frequency power (HF(RR)) decreased during KAATSU and standing, while
low-frequency/high-frequency power (LF(RR)/HF(RR)) increased significantly. NOR, ADH
and PRA also increased during KAATSU. These results indicate that KAATSU blood flow
restriction reproduces the effects of standing on HR, SV, NOR, ADH, PRA, etc., thus
stimulating a gravity-like stress during simulated weightlessness. However, syncope due tolower extremity blood pooling and subsequent reduction of venous return may be induced
during KAATSU in microgravity as reported in cases of lower-body negative pressure.
b. Examination of the effect on aerobic capacity and muscle hypertrophy by KAATSU
ergometer
In space, an ergometer exercise lasting two and a half hours is performed to prevent
muscle atrophy, but it has been found that even such long-term exercise does not sufficiently
prevent muscle atrophy. Therefore, a study was conducted on the effect of aerobic exercise and7

muscle hypertrophy with and without KAATSU by bicycle ergometer exercise for 2 months.
Abe T, Fujita S, Nakajima T, Sakamaki M, Ozaki H, Ogasawara R, Sugaya M, Kudo M,
Kurano M, Yasuda T, Sato Y, Ohshima H, Mukai C, Ishii N. Effects of low-intensity cycle
training with restricted leg blood flow on thigh muscle volume and VO2max in young men.
Journal of Sports Science and Medicine 2010; 9, 452-458.
Concurrent improvements in aerobic capacity and muscle hypertrophy in response to asingle mode of training have not been reported. We examined the effects of low-intensity cycle
exercise training with and without blood flow restriction (BFR) on muscle size and maximum
oxygen uptake (VO2max). A group of 19 young men (mean age ± SD: 23.0 ± 1.7 years) wereallocated randomly into either a BFR-training group (n=9, BFR-training) or a non-BFR control
training group (n=10, CON-training), both of which trained 3 days/wk for 8 wk. Training
intensity and duration were 40% of VO2max and 15 min for the BFR-training group and 40%of VO2max and 45 min for the CON-training group. MRI-measured thigh and quadriceps
muscle cross-sectional area and muscle volume increased by 3.4-5.1% (P < 0.01) and isometricknee extension strength tended to increase by 7.7% (p < 0.10) in the BFR-training group. There
was no change in muscle size (~0.6%) and strength (~1.4%) in the CON-training group.
Significant improvements in VO2max (6.4%) and exercise time until exhaustion (15.4%) wereobserved in the BFR-training group (p < 0.05) but not in the CON-training group (-0.1 and 3.
9%, respectively). The results suggest that low-intensity, short-duration cycling exercise
combined with BFR improves both muscle hypertrophy and aerobic capacity concurrently inyoung men. Key pointsConcurrent improvements in aerobic capacity and muscle hypertrophy inresponse to a single mode of training have not been reported.In the present study, low-intensity(40% of VO2max) cycle training with BFR can elicit concurrent improvement in muscle
hypertrophy and aerobic capacity.
● Examination about the influence on muscle activity and metabolic system by KAATSU
training
Under KAATSU training (12 healthy people), despite the low intensity load, muscle
activity and blood pH and lactic acid production comparable to high intensity are observed,
which is thought to be one of the mechanisms of muscle hypertrophy effect.
Yasuda T, Fujita T, Miyagi Y, Kubota Y, Sato Y, Nakajima T, Bemben MG, Abe T. 2006.
Electromyographic responses of arm and chest muscle during bench press exercise with andwithout KAATSU. Int J KAATSU Training Res 2: 15-19.
The purpose of this study was to compare the EMG activity of blood flow restricted(limb) and nonrestricted (trunk) muscles during multi-joint exercise with and without KAATSU.
Twelve (6 women and 6 men) healthy college students [means (SD) age: 24.1 (3.5) yrs]
performed 4 sets (30, 15, 15, and 15 reps) of flat bench press exercise (30% of a predetermined
one repetition maximum, 1-RM) during two different conditions [with KAATSU and without
KAATSU (Control)]. In the KAATSU condition, a specially designed elastic cuff belt (30 mmwide) was placed at the most proximal position of the upper arm and inflated to a pressure of
100% of individual's resting systolic blood pressure. Surface EMG was recorded from themuscle belly of the triceps brachii (TB) and pectoralis major (PM) muscles, and mean integrated
EMG (iEMG) was analyzed. During 4 sets of the exercise, gradual increases in iEMG were8

observed in both TB and PM muscles for the KAATSU condition. The magnitude of theincreases in iEMG in the TB and PM muscles were higher (P<0.05) with KAATSU comparedto the Control condition. In the first set, the mean exercise intensity from normalized iEMG wasapproximately 40% of 1-RM in both Control and KAATSU conditions. However, the mean
exercise intensity of both muscles were 60-70% of 1-RM for the KAATSU condition and only
about 50% of 1-RM for the Control condition, respectively, during the fourth set. We concluded
that increases in iEMG in the trunk muscle during KAATSU might be an important factor for
KAATSU training-induced trunk muscle hypertrophy.
Yasuda T, Abe T, Brechue WF, Iida H, Takano H, Meguro K, Kurano M, Fujita S, Nakajima T.
Venous blood gas and metabolite response to low-intensity muscle contractions with externallimb compression. Metabolism. 2010 Oct;59(10):1510-9. doi: 10.1016/j.metabol.2010.01.016.
Epub 2010 Mar 4.
The effect of low-intensity resistance exercise with external limb compression (100[EC100] and 160 [EC160] mm Hg) on limb blood flow and venous blood gas-metabolite
response was investigated and compared with that of high-intensity resistance exercise (noexternal compression). Unilateral elbow flexion muscle contractions were performed at 20% (75repetitions, 4 sets, 30-second rest intervals) and 70% of 1-repetition maximum (1-RM; 3 sets,
each set was until failure, 3-minute rest intervals). Precontraction brachial arterial blood flow
(Doppler ultrasound) was reduced with EC100 or EC160 (56% and 39% of baseline value,
respectively) compared with no external compression (control). At 20% 1-RM, brachial arterial
blood flow increased after contractions performed with EC160 (190%), but not with the others.
Decreases in venous oxygen partial pressure (P(v)O(2)) and venous oxygen saturation(S(v)O(2)) were greater during EC100 and EC160 than control (mean [SE]: P(v)O(2), 28 [3] vs26 [2] vs 33 [2] mm Hg; S(v)O(2), 41% [5%] vs 34% [4%] vs 52% [5%], respectively).
Changes in venous pH (pH(v)), venous carbon dioxide partial pressure (P(v)CO(2)), and venous
lactate concentration ([L(-)](v)) were greater with EC160 than EC100 and/or control (pH(v),7.19 [0.01] vs 7.25 [0.01] vs 7.27 [0.02]; P(v)CO(2), 72 [3] vs 64 [2] vs 60 [3] mm Hg; [L(-)](v),5.4 [0.6] vs 3.7 [0.4] vs 3.0 [0.4] mmol/L, respectively). Seventy percent 1-RM contractions
resulted in greater changes in pH(v) (7.14 [0.02]), P(v)CO(2) (91 [5] mm Hg), and [L(-)](v) (7.0[0.5] mmol/L) than EC100 and EC160, but P(v)O(2) (30 [4] mm Hg) and S(v)O(2) (40% [3%])were similar. In conclusion, changes in pH(v), P(v)CO(2), and [L(-)](v), but not in P(v)O(2) andS(v)O(2), are sensitive to changes in relative, "internal" intensity of low-intensity muscle
contractions caused by reduced blood flow (EC160) or high-intensity muscle contractions.
Given the magnitude of the changes in pH(v), P(v)CO(2), and [L(-)](v), it appears plausible thatthey may be involved in stimulating the observed increase in muscle activation via group III and
IV afferents
Yasuda T, Fukumura K, Fukuda T, Iida H, Imuta H, Sato Y, Yamasoba T, Nakajima T. Effectsof low-intensity, elastic band resistance exercise combined with blood flow restriction on
muscle activation. Scand J Med Sci Sports. 2014 Feb;24(1):55-61. doi:
10.1111/j.1600-0838.2012.01489.x. Epub 2012 Jun 27.
We examined the effects of blood flow-restricted, low-intensity resistance exercise(termed kaatsu) using an elastic band for resistance on muscle activation. Nine men performed
triceps extension and biceps flexion exercises (four sets respectively) using an elastic band for9resistance with blood flow restriction (BFR) or CON (unrestricted blood flow). During a BFR
session, subjects wore pressure cuffs inflated to 170-260 mmHg on the proximal region of botharms. Surface electromyography (EMG) was recorded from the triceps brachii and biceps
brachii muscles, and mean integrated EMG (iEMG) was analyzed. Blood lactate concentration
was obtained before (Pre) and immediately after two exercises (Post). During triceps extension
and biceps flexion exercises, muscle activation increased progressively (P < 0.05) under BFR(46% and 69%, respectively) but not under CON (12% and 23%, respectively). Blood lactate
concentration at Post was higher (P < 0.05) under BFR than under CON (3.6 and 2.1 mmol/L,
respectively). Blood lactate concentration at Post was significantly correlated with increased
iEMG in both triceps extension (r = 0.65, P < 0.01) and biceps flexion exercises (r = 0.52,
P < 0.05). We conclude that kaatsu training using elastic bands for resistance enhances muscle
activation and may be an effective method to promote muscle hypertrophy in older adults or
patients with a low level of activity.

II. Application to patients with various diseases
The KAATSU training is performed for patients with various diseases centering on heartdisease, and the effects as rehabilitation, direct or secondary effects on diseases are comparedwith the effects of conventional rehabilitation methods. Although over 1000 cases in total of
KAATSU training have been conducted since March 2007, no serious side effects have been
observed, and it has been found to be safe for patients with disease.
● Effects of low-intensity KAATSU resistance training on skeletal muscle size/strength andendurance capacity in patients with ischemic heart disease
T. Nakajima, M. Kurano, F. Sakagami, H. Iida, K. Fukumura, T. Fukuda, H. Takano, H.
Madarame, T. Yasuda, T. Nagata, Y. Sato, T. Yamasoba, T. Morita. Effects of low-intensity
KAATSU resistance training on skeletal muscle size/strength and endurance capacity in patientswith ischemic heart disease. Int J KAATSU Training Res 2010; 6: 1-7
KAATSU training induces muscle hypertrophy and strengthens muscle in athletes andhealthy subjects through short-term and low-intensity exercise. However, it remains
uninvestigated whether lowintensity KAATSU resistance training (LIKRT) induces muscle
strength and hypertrophy in patients with cardiovascular diseases. We examined the effects of
LIKRT on skeletal muscle size/strength and endurance capacity in patients with ischemic heartdisease (IHD). Seven male patients with stable IHD performed three kinds of resistance
exercises (leg press, leg curl and leg extension) with their femoral muscle blood flow restricted
by KAATSU belt two times/week for three months. We measured one RM (1-RM) in eachresistance exercises, and evaluated muscle cross-sectional areas (CSA) by MRI before training
and after the training. We used cardiopulmonary examinations to measure endurance capacity(Peak VO2 (VO2peak), VO2 at anaerobic threshold (VO2AT)). We performed blood sampling
to measure resting plasma level of insulin growth factor-1 (IGF-1) and serum high-sensitive
C-reactive protein (hsCRP). LIKRT significantly increased leg press (15%), leg curl (18%) andleg extension (17%) 1-RM strength. Increases of muscle CSA in quadriceps femoris at theproximal lower leg (30%), the mid-thigh (50%), and the proximal lower leg (70%) were 5.1%,
4.6% and 10.4%, respectively. Similarly, hamstring and adductor CSA were also increased by
LIKRT. LIKRT significantly increased VO2peak and VO2AT by 10.7% and 10.9%,10respectively. IGF-1 and hsCRP were not altered before or after the training. These results
suggest that LIKRT increases muscle strength/mass and endurance capacity in patients with
IHD. LIKRT appears to be a promising and effective resistance method in cardiac rehabilitation.

● Study on the influence of KAATSU walking on venous compliance
Iida H, Nakajima T, Kurano M, Yasuda T, Sakamaki M, Sato Y, Yamasoba T, Abe T. Effects ofWalking with Blood Flow Restriction on Limb Venous Compliance in Elderly Subjects. Clin
Physiol Funct Imaging. 2011 Nov;31(6):472-476.
Venous compliance declines with age and improves with chronic endurance exercise.
KAATSU, an exercise combined with blood flow restriction (BFR), is a unique training method
for promoting muscle hypertrophy and strength gains by using low-intensity resistance exercises
or walking. This method also induces pooling of venous blood in the legs. Therefore, wehypothesized that slow walking with BFR may affect limb venous compliance and examined theinfluence of 6 weeks of walking with BFR on venous compliance in older women. Sixteen
women aged 59-78 years were partially randomized into either a slow walking with BFR group(n=9, BFR walk group) or a non-exercising control group (n=7, control group). The BFR walkgroup performed 20-min treadmill slow walking (67 m min(-1) ), 5 days per week for 6 weeks.
Before (pre) and after (post) those 6 weeks, venous properties were assessed using strain gauge
venous occlusion plethysmography. After 6 weeks, leg venous compliance increased
significantly in the BFR walk group (pre: 0·0518 ± 0·0084, post: 0·0619 ± 0·0150 ml 100
ml(-1) mmHg(-1) , P<0·05), and maximal venous outflow (MVO) at 80 mmHg also increased
significantly after the BFR walk group trained for 6 weeks (pre: 55·3 ± 15·6, post: 67·1 ± 18·9
ml 100ml(-1) min(-1) , P<0·01), but no significant differences were observed in venous
compliance and MVO in the control group. In addition, there was no significant change in arm
compliance in the BFR walk group. In conclusion, this study provides the first evidence that 6
weeks of walking exercise with BFR may improve limb venous compliance in untrained elder
female subjects.
● Evaluation of hemodynamics of dizziness-associated with orthostatic hypotension andexamination of effectiveness of KAATSU training
2009-2011 Challenging sprouting research representative Tatsuya Yamasoba (share Toshiaki
Nakajima)
Evaluation of hemodynamics of dizziness-associated with orthostatic hypotension andtreatment by KAATSU trainin
Dizziness and balance disorder associated with orthostatic hypotension is a frequentdisease at the Otorhinolaryngology and Cardiovascular Internal Medicine Departments, but its
diagnosis is measurement of blood pressure and pulse rate at supine and standing positions(Sherong test). It is not based on a detailed and accurate diagnosis of the hemodynamics, andthe cause has not been sufficiently evaluated. Moreover, the treatment for this disease issymptomatic, such as administration of a hypertensive agent, and no radical treatment has been
performed. In this study, diagnosis and evaluation focused on hemodynamics were performedon cases diagnosed with orthostatic hypotension and visited for dizziness. At the same time,muscle training under blood flow restriction (KAATSU training) is performed, and it isdetermined whether orthostatic hypotension can be improved by increasing the muscle mass of11

the lower leg called the second heart, and circulation The influence on the behavior was also
examined. Although some showed improvement trends, it seemed necessary to conduct
large-scale prospective research in the future.
● Elucidation of molecular mechanism of skeletal muscle hypertrophy by KAATSU training
and application to elderly people sarcopenia
2012-2015 Grant-in-Aid for Scientific Research (B) Toshiaki Nakajima (Representative)
Elucidation of molecular mechanism of skeletal muscle hypertrophy by KAATSU training andapplication to elderly sarcopenia
This study aimed to elucidate the molecular mechanism of muscle hypertrophy in
KAATSU training using the rat KAATSU model as well as the effects on muscle hypertrophy
and muscle strengthening in elderly people with KAATSU training. We examined muscle
strengthening and muscle hypertrophy in low-intensity KAATSU training in elderly people. As
a result of training of upper or lower limbs and loading method, a machine or an elastic band
was used. Furthermore, the rat KAATSU model was used to investigate the effect of acuteblood flow restriction on muscle oxygen partial pressure and the effect on muscle protein
synthesis system. We also examined the chronic effects and their molecular mechanisms.
KAATSU ttraining was considered to be a useful method in measures against sarcopenia in theelderly.
Nakajima T, Koide S, Yasuda T, Hasegawa T, Yamasoba T, Obi S, Toyoda S, Nakamura F,
Inoue T, Poole DC, Kano Y. Muscle hypertrophy following blood flow-restricted, low-force
isometric electrical stimulation in rat tibialis anterior: role for muscle hypoxia. J Appl Physiol(1985). 2018 Jul 1;125(1):134-145. doi: 10.1152/japplphysiol.00972.2017. Epub 2018 Mar 22.
Low-force exercise training with blood flow restriction (BFR) elicits muscle hypertrophy
as seen typically after higher-force exercise. We investigated the effects of microvascularhypoxia [i.e., low microvascular O2 partial pressures (P mvO2)] during contractions on muscle
hypertrophic signaling, growth response, and key muscle adaptations for increasing exercise
capacity. Wistar rats were fitted with a cuff placed around the upper thigh and inflated to restrict
limb blood flow. Low-force isometric contractions (30 Hz) were evoked via electricalstimulation of the tibialis anterior (TA) muscle. The P mvO2 was determined byphosphorescence quenching. Rats underwent acute and chronic stimulation protocols. Whereas
P mvO2 decreased transiently with 30 Hz contractions, simultaneous BFR induced severe
hypoxia, reducing P mvO2 lower than present for maximal (100 Hz) contractions. Low-force
electrical stimulation (EXER) induced muscle hypertrophy (6.2%, P < 0.01), whereas control
group conditions or BFR alone did not. EXER+BFR also induced an increase in muscle mass
(11.0%, P < 0.01) and, unique among conditions studied, significantly increased fibercross-sectional area in the superficial TA ( P < 0.05). Phosphorylation of ribosomal protein S6
was enhanced by EXER+BFR, as were peroxisome proliferator-activated receptor gamma
coactivator-1α and glucose transporter 4 protein levels. Fibronectin type III domain-containing
protein 5, cytochrome c oxidase subunit 4, monocarboxylate transporter 1 (MCT1), and clusterof differentiation 147 increased with EXER alone. EXER+BFR significantly increased MCT1
expression more than EXER alone. These data demonstrate that microvascular hypoxia duringcontractions is not essential for hypertrophy. However, hypoxia induced via BFR may
potentiate the muscle hypertrophic response (as evidenced by the increased superficial fiber
12

cross-sectional area) with increased glucose transporter and mitochondrial biogenesis, which
contributes to the pleiotropic effects of exercise training with BFR that culminate in an
improved capacity for sustained exercise. NEW & NOTEWORTHY We investigated the effectsof low microvascular O2 partial pressures (P mvO2) during contractions on muscle
hypertrophic signaling and key elements in the muscle adaptation for increasing exercise
capacity. Although demonstrating that muscle hypoxia is not obligatory for the hypertrophic
response to low-force, electrically induced muscle contractions, the reduced P mvO2 enhanced
ribosomal protein S6 phosphorylation and potentiated the hypertrophic response. Furthermore,
contractions with blood flow restriction increased oxidative capacity, glucose transporter, andmitochondrial biogenesis, which are key determinants of the pleiotropic effects of exercise
training.
Nakajima T, Yasuda T, Koide S, Yamasoba T, Obi S, Toyoda S, Sato Y, Inoue T, Kano Y.
Repetitive restriction of muscle blood flow enhances mTOR signaling pathways in a rat
model.Heart Vessels. 2016 Oct;31(10):1685-95. doi: 10.1007/s00380-016-0801-6. Epub 2016
Feb 1.
Skeletal muscle is a plastic organ that adapts its mass to various stresses by affecting
pathways that regulate protein synthesis and degradation. This study investigated the effects ofrepetitive restriction of muscle blood flow (RRMBF) on microvascular oxygen pressure(PmvO2), mammalian target of rapamycin (mTOR) signaling pathways, and transcripts
associated with proteolysis in rat skeletal muscle. Eleven-week-old male Wistar rats underanesthesia underwent six RRMBF consisting of an external compressive force of 100 mmHg for
5 min applied to the proximal portion of the right thigh, each followed by 3 min rest. During
RRMBF, PmvO2 was measured by phosphorescence quenching techniques. The total RNA andprotein of the tibialis anterior muscle were obtained from control rats, and rats treated with
RRMBF 0-6 h after the stimuli. The protein expression and phosphorylation of various
signaling proteins were determined by western blotting. The mRNA expression level wasmeasured by real-time RT-PCR analysis. The total muscle weight increased in rats 0 h after
RRMBF, but not in rats 1-6 h. During RRMBF, PmvO2 significantly decreased (36.1 ± 5.7 to
5.9 ± 1.7 torr), and recovered at rest period. RRMBF significantly increased phosphorylation of
p70 S6-kinase (p70S6k), a downstream target of mTOR, and ribosomal protein S6 1 h after the
stimuli. The protein level of REDD1 and phosphorylation of AMPK and MAPKs did notchange. The mRNA expression levels of FOXO3a, MuRF-1, and myostatin were notsignificantly altered. These results suggested that RRMBF significantly decreased PmvO2, andenhanced mTOR signaling pathways in skeletal muscle using a rat model, which may play arole in diminishing muscle atrophy under various conditions in human studies.
● Elucidation of muscle hypertrophy mechanism of KAATSU training and its application2013 Young Scientist Research Program (B) Yasuda T Elucidation of muscle hypertrophymechanism of KAATSU training and its application: Comparison of shortening andextensibility contraction● Development of a muscle strength improvement program that takes advantage of KAATSU
training● 2011-2012 fiscal year research program young research (B) Yasuda T Development of a13

muscle strength improvement program that takes advantage of KAATSU training
Yasuda T, Fukumura K, Uchida Y, Koshi H, Iida H, Masamune K, Yamasoba T, Sato Y,
Nakajima T. Effects of Low-Load, Elastic Band Resistance Training Combined with Blood
Flow Restriction on Muscle Size and Arterial Stiffness in Older Adults. J Gerontol A. Biol Sci
Med Sci. 2015 Aug;70(8):950-8. doi: 10.1093/gerona/glu084. Epub 2014 Jun 10.
Yasuda T, Nakajima T. Response to the Letter "Blood Flow Restricted Training in Older
Adults: Consider Standardized Methodology for Future Investigations?". J Gerontol A Biol Sci
Med Sci. 2016 May;71(5):620-1. doi: 10.1093/gerona/glv178. Epub 2015 Oct 15.
We examined the effect of low-load, elastic band resistance training with blood flow
restriction (BFR) on muscle size and arterial stiffness in older adults. Healthy older adults (aged61-85 years) were divided into BFR training (BFR-T, n = 9) or non-BFR training (CON-T, n =8) groups. Both groups performed low-load arm curl and triceps down exercises (four sets, total
75 repetitions for each) using an elastic band, 2 d/wk for 12 weeks. The BFR-T group wore
inflated pneumatic elastic cuffs (120-270 mm Hg) on both arms during training. Magnetic
resonance imaging-measured muscle cross-sectional area of the upper arm, maximum voluntaryisometric contraction of the elbow flexors and extensors, cardio-ankle vascular index testing,and ankle-brachial pressure index were measured before and 3-5 days after the final training
session. Muscle cross-sectional area of the elbow flexors (17.6%) and extensors (17.4%)
increased, as did elbow flexion and elbow extension maximum voluntary isometric contraction(7.8% and 16.1%, respectively) improved (p < .05) in the BFR-T group, but not in the CON-T
group. In cardio-ankle vascular index and ankle-brachial pressure index testing, there were nochanges between pre- and post-results in either group. In conclusion, elastic band BFR-T
improves muscle cross-sectional area as well as maximal muscle strength but does notnegatively affect arterial stiffness in older adults.
Yasuda T, Fukumura K, Fukuda T, Uchida Y, Iida H, Meguro M, Sato Y, Yamasoba T,
Nakajima T. Muscle size and arterial stiffness after blood flow-restricted low-intensity
resistance training in older adults. Scand J Med Sci Sports. 2014 Oct;24(5):799-806. doi:
10.1111/sms.12087. Epub 2013 Jun 3.
Previous studies have shown that blood flow-restricted low-intensity resistance training(BFR-RT) causes muscle hypertrophy while maintaining arterial function in young adults. We
examined the effects of BFR-RT on muscle size and arterial stiffness in older adults. Healthy
subjects (ages 61-84 years) were divided into BFR-RT (n = 9) or non-training control (CON;n = 10) groups. The BFR-RT group performed 20% and 30%, respectively, of one-repetition
maximal (1-RM) knee extension and leg press exercises, 2 days/wk for 12 weeks. The BFR-RT
group wore elastic cuffs (120-270 mmHg) on both legs during training. Magnetic resonanceimaging-measured muscle cross-sectional area (CSA), 1-RM strength, chair stand (CS) test, andcardio-ankle vascular index testing (CAVI), an index of arterial stiffness, were measured before
and 3-5 days after the final training session. Muscle CSA of the quadriceps (8.0%), adductors(6.5%), and gluteus maximus (4.4%), leg extension and leg press 1-RM strength (26.1% and33.4%), and CS performance (18.3%) improved (P < 0.05) in the BFR-RT group, but not in the
CON group. In CAVI testing, there were no changes in both two groups. In conclusion,
BFR-RT improves muscle CSA as well as maximal muscle strength, but does not negatively
affect arterial stiffness or humeral coagulation factors in older adults.
14

Yasuda T, Fukumura K, Iida H, Nakajima T. Effects of detraining after blood flow-restricted
low-load elastic band training on muscle size and arterial stiffness in older women. Springerplus.
2015 Jul 15;4:348. doi: 10.1186/s40064-015-1132-2. eCollection 2015.
BACKGROUND: We examined the effects of detraining after blood flow-restricted (BFR)
low-load elastic band training on muscle size and arterial stiffness in older women.
FINDINGS: Fourteen women were divided into BFR training (BFR-T) or non-BFR training(CON-T). Each group participated in 12 weeks of arm curl and press down training using anelastic band either with (BFR-T) or without BFR (CON-T). Muscle cross-sectional area (CSA)
and maximum voluntary isometric contraction (MVIC) for upper arms and cardio-ankle
vascular index (CAVI) were evaluated before and after the 12-week training period and also
after 12 weeks of detraining. CSA and MVIC were higher at post and detraining (CSA: 16.3%(p < 0.01) and 6.9% (p < 0.01) for elbow flexion and 17.1% (p < 0.01) and 8.7% (p > 0.05) for
elbow extension; MVIC: 7.3 and 3.9% (both p > 0.05) for elbow flexion and 17.6 and 15.1%(both p < 0.01) for elbow extension) than at pre for the BFR-T, but not for the CON-T. There
was no change in CAVI for the two groups.
CONCLUSIONS: Increased muscle strength/size following 12 weeks of elastic band BFR-T
was well maintained with a low risk of arterial stiffness after 12 weeks of detraining in older
women.
● Application of KAATSU muscle training in respiratory rehabilitation of COPD patients
2009-2011 Grant-in-Aid for Scientific Research (C) Nakaga T ((Representative) (Shared
Nakajima T, H21-23) Application of KAATSU Muscle Training in Respiratory Rehabilitation
for COPD Patients
In COPD patients, the effects of arm curl exercise with free weights on muscle activity
were examined. The application of blood flow restriction enhanced muscle activity on theelectromyography and increased blood lactate concentration and Borg scale, but did not reduce
SpO2. The KAATSU training was considered to enhance muscle activity safely and effectively
in COPD patients, even with low strength and easy exercise modes such as using free weights
and rubber bands. Finally, the chronic effects of KAATSU training were examined in COPD
patients. Leg extension under KAATSU confirmed the improvement of QOL and the increaseof muscle strength and muscle mass, and also the maximum inspiratory pressure (PImax) andthe maximum expiratory pressure (PEmax) were also improved. Not only COPD but also old
age is important as a cause of COPD patients causing sarcopenia. Therefore, in the elderly, theeffects of KAATSU walk (walk under KAATSU) on QOL, muscle strength, etc. were examined.
The KKATSU training sgnificantly increased muscle strength, and improved function of timed
up & go and chair stand test was also observed. In COPD patients with sarcopenia, pressure
walks may also be a safe and effective strength training. In the future, it seems necessary to
study more cases.

● Case report papers
1) H. Iida, M. Kurano, H. Takano, H. Oonuma, H. Imuta, N. Kubota, T. Morita, K. Meguro, Y.
Sato, T. Abe, Y. Yamazaki, T. Nakajima. Can KAATSU be used for an orthostatic stress in15

astronauts?: A case study. Int J KAATSU Training Res 2, 45-52, 2006.
The application of an orthostatic stress such as lower body negative pressure (LBNP)
during exercise has been proposed to minimize the effects of weightlessness on the
cardiovascular system and subsequently to reduce the cardiovascular deconditioning. The
KAATSU training is a novel method for strength training to induce muscle strength andhypertrophy. KAATSU induces venous pooling of blood in capacitance vessels by restricting
venous blood flow. Therefore, to investigate whether KAATSU can be used as an orthostatic
stress, we examined the effects of KAATSU on the hemodynamic, autonomic nervous andhormonal parameters in one subject. The several parameters were measured by impedance
cardiography; heart rate (HR), mean blood pressure (mBP), stroke volume (SV), cardiac output(CO), total peripheral resistance (TPR), and heart rate variability (HRV). These data wereobtained before (pre), during and after (post) pressurization (50 and 200 mmHg) on both thighswith KAATSU mini belts, and compared with those in standing. The serum concentration ofnoradrenaline (NA) and vasopressin (ADH), and plasma rennin activity (PRA) were alsomeasured. The application of 200 mmHg KAATSU decreased SV, which was almost equal tothe value in standing. HR and TPR increased in a similar manner as standing with slight change
of mBP. High frequency (HFRR), a marker of parasympathetic nervous activity, decreased
during both 200 mmHg KAATSU and standing, while LFRR/HFRR, a quantitative marker of
sympathetic nervous activity, increased significantly. During KAATSU and standing, NA, PRA
and ADH increased. These results indicate that the application of KAATSU on both thighs
simulates systemic cardiovascular effects of orthostasis in one gravity (1G), and that KAATSU
training appears to be a useful method for potential countermeasure like lower body negative
pressure (LBNP) against orthostatic intolerance in space flight as well as strength training to
induce muscle strength and hypertrophy.
2) Madarame H, Kurano M, Takano H, Iida H, Sato Y, Ohshima H, Abe T, Ishii N, Morita T
and Nakajima T. Effects of low-intensity resistance exercise with blood flow restriction on
coagulation system in healthy subjects. Clinical Physiology and Functional Imaging 2010
May;30(3):210-3.
Churg-Strauss syndrome (CSS) is an eosinophilic vasculitis, which involves multiple
organ systems, including the lungs, heart, skin and neuromuscular system. Since CSS is an
inflammatory disease, administration of systemic glucocorticoids has been a standard therapy
for the disease. However, even if the inflammation has been controlled by glucocorticoids,
neuromuscular disorders often do not improve. Thus, we aimed in this study to evaluate theefficacy of low-intensity exercise with blood flow restriction (BFR) on CSS-induced muscle
atrophy and weakness. A 40-year-old female ballet dancer with CSS-induced muscle atrophy in
her right lower leg underwent a 14-wk training program, which consisted of low-intensity
resistance exercise (plantar flexion, leg extension and leg curl) and walking exercise with BFR.
To measure cross-sectional area (CSA) of lower leg muscles, magnetic resonance images (MRI)of both lower legs were obtained before and after the 14-wk training period. After the 14-wk
training period, muscle CSA of the right lower leg showed 29.1% increase, though it was still
23.4% smaller than that of the left side. In conclusion, this case study showed that low-intensity
exercise with BFR induced muscle hypertrophy in a female ballet dancer with CSS. It issuggested that low-intensity exercise with BFR can be a valuable rehabilitation tool for patientswith CSS to counteract muscle atrophy and weakness.
163) Uchida Y, Morita T, Fukumura K, Otsuka T, Fukuda T, sato Y, Nakajima T. Effects of
KAATSU training on a patient with benign fasciculation syndrome. Int J KAATSU Training
Res 2012; 8: 9-12.
[Objective] Benign fasciculation syndrome (BFS) is a neurological disorder characterized
by involuntary and repeated contractions of synergetic muscles and commonly occurs in theeyelids, arms and legs. BFS is also associated with pain, which may interfere with everyday
activities. This report describes the case of a BFS patient who performed KAATSU exercise, atype of exercises performed under the conditions of restricting muscle blood flow. [Methods]
The patient performed KAATSU exercise of the bilateral upper and lower extremities at afrequency of twice a week for 3 months. Knee extensor strength as measured with a hand-helddynamometer (HHD), QOL scores as assessed by the SF-36v2 questionnaire form, and bilateralfemoral muscle mass as measured by MRI were compared before and after exercise. [Results]
After a 3-month KAATSU exercise program, the right and left knee extensor strength asmeasured with a HHD increased by about 26% from 30.9 to 38.8 kgf and by about 44% from
39.9 to 57.4 kgf, respectively, and the bilateral femoral muscle mass as measured by MRI
increased by about 23% from 8,730 to 10,709 cc. Overall improvement in QOL was also
observed, as assessed by the SF-36v2 questionnaire form. [Conclusion] For patients withneurological disorders with pain, such as the present patient, active introduction of
KAATSU-based exercise is likely to result in improved health-related QOL, as well as increased
muscle mass and strength.
4) Iwashita H, Morita T, Sato Y, Nakajima T. KAATSU training in a case of patients withperiventricular leukomalacia (PVL). International Jouranal of KAATSU Training Research
2014; 10: 7-11.
[Objective] The effectiveness of KAATSU training has been reported in wide-ranging
fields from sports medicine to rehabilitation, and KAATSU training has been clinically applied.
However, there have been only limited reports on pediatric cases. We performed KAATSU
training in a pediatric patient with periventricular leukomalacia (PVL) and examined its
effectiveness and safety for cerebral palsy. We report here the results of this examination.
[Methods]KAATSU training was performed on a PVL patient on an outpatient basis. This
training was performed once a week for 14 weeks and involved mainly three specified motionsof the upper and lower limbs. Evaluation was performed using the Gross Motor Function
Measure (Gross Motor Function Classification System: GMFM) and videos. In this report, theeffectiveness of short-term KAATSU training was compared with that of intensive physicaltherapy using data in the literature. [Results]QOL improved due to short-term reduction ofmuscle tonus and increased acquired movements resulting from KAATSU training.
[Conclusion]The results of this report suggest that KAATSU training can be effective in PVL
patients. Further examination is necessary with increased cases and evaluation methods.
5) Nakajima T, Yasuda T, Fukumura K, Kurano M, Imanishi T, Morita T, Sato Y, Hiraizumi Y.
KAATSU training as a new exercise therapy for femoral head avascular necrosis: A case study.
Int J KAATSU Training Res 2015;11:1-6.
Femoral head avascular necrosis is a condition in which part of the femoral head
undergoes necrosis due to decreased blood flow. The femoral head gradually disintegrates
17causing pain and even today, there are no effective rehabilitation methods other thansymptomatic treatment such as decreasing the load on the hip joints with the use of a cane orwalker. We herein describe our insights into this condition based on our experience with a caseof femoral head avascular necrosis caused by steroid use in which KAATSU training was foundto be highly effective. The patient was a 34-year-old woman (154 cm tall and weighing 50 kg, aradiologist). Since the age of 23, this patient had been receiving steroid treatment to control her
refractory asthma. She later developed pain in her right hip and gradually suffered hip joint
deformation, restricted range of motion, and difficulty in walking. MRI revealed Association
Research Circulation Osseous (ARCO) stage IV disease. She suffered marked pain of the right
hip joint every time she walked, occasionally falling and required a cane to walk. At thepatientʼs own request, she received KAATSU training including KAATSU walking over a
period of 3 months (total 28 sessions). Various assessments were carried out before and after
training to determine the effects of KAATSU training. QOL was determined by SF–36v2, andmarked improvement of role physical, body pain, general health, vitality, and social functioning
were noted. Before training, the Japanese Orthopaedic Association (JOA) hip scores for pain
were 10 (right), 40 (left), walking ability 16 (right), 20 (left), while 3 months after training,these scores were markedly improved in the affected side. Furthermore, not only did muscle
strength on the affected side show marked improvement, but the MRI also revealed a tendency
for improvement of the right femoral head avascular necrosis. DEXA showed signs of a clear
increase in bone mineral density. Based on the above, these results suggest that KAATSU
training is extremely useful as a rehabilitation method in patients with femoral head avascularnecrosis. But, further larger scale investigations should be carried out in the future to support
our findings.
6) Hiraizumi Y, Nakajima T, Sato Y, Imanishi T. KAATSU training as a new effective exercise
therapy in a case of femoral medical condyle osteonecrosis. Int J KAATSU Training Res
2016;12:1-4
Idiopathic osteonecrosis of the medial condyle of the femur, a relatively common disease
among Japanese women 60 years or older, is often progressive and requires surgical treatment.
In this paper, we report on a case where KAATSU training was effective for a 71-year-old
woman with bone necrosis in the left femoral medial condyle revealed by magnetic resonanceimaging (MRI). At the first visit, the patient was suffering severe pain, and unable to walkwithout a cane. After 1 to 2 months of KAATSU training, her pain was mitigated and in about 3
months she was able to walk without a cane. In 6 months she could go upstairs and downstairs
using the handrails and about 2 to 3 months later, she no longer needed to use the handrails.
MRI revealed marked shrinkage (to 10 mm x 15 mm) of the necrotized region as a result ofbone tissue remodeling. From these results, KAATSU training seems to be useful as a new
method of rehabilitation for patients with idiopathic osteonecrosis of the medial condyle of thefemur.
7) Yasuda T, Oosumi S, Sugimoto S, Morita T, Sato Y, Ishii M, Nakajima T. Effect of
KAATSU training on thigh muscle size and potential safety for a patient with knee
meniscectomy over 3 years. Int J KAATSU Training Res 2017;13:11-14.
[Objective] It is well known that knee meniscectomy is one of the major knee surgeries,
which induces thigh muscle atrophy. However, it is unclear whether thigh muscle size after knee18meniscectomy can be improved with KAATSU training. We examined effect of KAATSU
training on thigh muscle size and safety for a patient with knee meniscectomy. [Methods] Thepatient was a 57-year-old woman (standing height 159 cm and body weight 52 kg). The
KAATSU training composed of 7 types of resistance exercise and one type of cycling exercise
was provided for a total of 125 sessions over approximately 3 years. Transverse scans werecarried out for mid-thigh length. Thigh muscle cross-sectional area (CSA) in affected-leg andunaffected-leg was measured by the CT scan before, 63 weeks, and 152 weeks after the training.
[Results] Thigh muscle CSA was highly increased for affected-leg, and the attained level was
exactly similar for both legs after the 152 weeks training period. [Conclusion] The long-term
KAATSU exercises were a highly safe and effective training method for a patient with knee
meniscectomy8) Ooshima A, Ishizaka Y, Katayanagi S, Arakawa C, Takahashi R, Nozawa N, Mizushima Y,
Matsumoto K, Sawaguchi T, Haruyama A, Toyoda S, Ogawa H, Shibasaki I, Yagi H,
Yamaguchi S, Uematsu A, Yasuda T, Sato Y, Fukuda H, Inoue T, Nakajima T. Combination of
KAATSU training® and BCAA intake for a patient after aortic valve replacement surgery: A
case study. Int J KAATSU Training Res 2018;12:1-4。
We report a case in which a favorable course was obtained by using KAATSU training®
and BCAA intake early after aortic valve replacement surgery. The patient was a 43-year-old
male with low cardiac function who underwent aortic valve replacement surgery. Heart failureand hypotension persisted while waiting for surgery. He tended to line on a bed all day, so that
disuse muscular atrophy advanced. Therefore, in addition to the postoperative rehabilitation
program, KAATSU training and BCAA intake were performed postoperatively and continued
in outpatient rehabilitation. The KAATSU training was performed using knee extension twiceor three times a week. For BCAA intake (2.5 g), one pack of jelly containing BCAA
(Reha-Time Jelly, Clinico Co., Ltd.) was taken within 30 minutes after the training. About 3
months later, the thigh circumference (+ 7.3 cm), the maximum voluntary isometric contractionof knee extension (+ 20 kgf), the quadriceps muscle thickness (+ 1 cm) evaluated by a B-mode
ultrasound, the muscle mass of the lower limb (+ 1 kg), and a marked increase in thigh muscle
cross-sectional area as measured by CT scan were observed. No deterioration of circulatory
hemodynamics and side effects were observed during the course. In conclusion, the combined
use of KAATSU training and BCAA intake early after cardiac operation seems to be a safe andeffective way to obtain muscle hypertrophy and muscle strengthening, but further studies areneeded to clarify it.

19

●Paper presentation (English)
1. Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J, Hara K, Omata M, Nagai R, Takizawa H,
Nagase T, Nakajima T: Voltage-gated sodium channel expressed in cultured human smoothmuscle cells: involvement of SCN9A. FEBS Lett., 567, 339-343, 2004.
2. Toyo-oka T, Kawada T, Nakata J, Xie H, Urabe M, Masui F, Ebisawa T, Tezuka A, Iwasawa
K, Nakajima T, Uehara Y, Kumagai H, Kostin S, Schaper J, Nakazawa T, Ozawa K:
Translocation and cleavage of myocardial dystrophin as a common pathway to advanced heart
failure: a scheme for the progression of cardiac dysfunction. Proc Natl Acad Sci U S A. 101,
7381-7385, 2004.
3. Ma J, Iida H, Jo T, Takano H, Oonuma H, Morita T, Toyo-Oka T, Omata M, Nagai R, Okuda
Y, Yamada N, Nakajima T. Ursodeoxycholic acid inhibits endothelin-1 production in humanvascular endothelial cells. Eur J Pharmacol. 28, 67-74, 2004.
4. Kato M, Matsumoto A, Nakajima T, Hirose K, Iwasawa K, Takenaka K, Yamashita H,
Sugiura S, Hirata Y, Nagai R. Amlodipine increases nitric oxide production in exhaled air during
exercise in patients with essential hypertension. Am J Hypertens.17, 729-733, 2004.
5. Takano H, Morita T, Iida H, Kato M, Uno K, Hirose K, Matsumoto A, Takenaka K, Hirata
Y,Furuichi T, Eto F, Nagai R, Sato Y, Nakajima T: Effects of low-intensity “KAATSU”
resistance exercise on hemodynamic and growth hormone responses: Int. J. Kaatsu Training Res.
1, 13-18, 2005.
7. Jo T, Iida H, Kishida S, Imuta H, Oonuma H, Nagata T, Hara H, Iwasawa K, Soma M, Sato Y,
Nagase T, Nagai R, Nakajima T. Acute and chronic effects of eicosapentaenoic acid on
voltage-gated sodium channel expressed in cultured human bronchial smooth muscle cells.
Biochem Biophys Res Commun. 331, 1452-1459, 2005.
8. Iida H, Jo T, Iwasawa K, Morita T, Hikiji H, Takato T, Toyo-oka T, Nagai R, Nakajima T.
Molecular and pharmacological characteristics of transient voltage-dependent K+ currents incultured human pulmonary arterial smooth muscle cells. Br J Pharmacol. 46, 49-59, 2005.
9. Iida H, Takano H, Meguro K, Asada K, Oonuma H, Morita T, Kurano M, Sakagami F, Uno K,
Hirose K, Nagata T, Takenaka K, Suzuki J, Hirata Y, Furuichi T, Eto F, Nagai R, Sato Y,
Nakajima T. Hemodynamic and autonomic nervous responses to the restriction of femoral bloodflow by KAATSU. Int J KAATSU Training Res 1, 57-64, 2005.
10. Tomaru T, Kawano H, Tsujiuchi Y, Suzuki J, Nakajima T, Uchida Y: Mechanism ofantithrombotic effect of heparin and antithrombin in balloon-injured arteries: Life Sci 77,
2611-2625, 2005.
11. Takano H, Morita T, Iida H, Asada K, Kato M, Uno K, Hirose K, Matsumoto A, Takenaka K,
Hirata Y, Eto F, Nagai R, Sato Y, Nakajima T Hemodynamic and hormonal responses to ashort-term low-intensity resistance exercise with the reduction of muscle blood flow. Eur J Appl
Physiol. 95, 65-73, 2005.
12. Kishida S, Nakajima T, Ma J, Jo T, Imuta H, Oonuma H, Iida H, Takano H, Morita T, Nagai
R. Amiodarone and N-desethylamiodarone enhance endothelial nitric oxide production inhuman endothelial cells. Int Heart J. 47, 85-93, 2006.
13. J. Ma, S. Kishida, G.Q. Wang, K. Meguro, H. Imuta, H. Oonuma, H. Iida, T. Jo, H. Takano,
T. Morita, R. Nagai, T. Nakajima. Comparative Effects of Azelnidipine and Other Ca2+-Channel
Blockers on the Induction of Inducible Nitric Oxide Synthase in Vascular Smooth Muscle Cells.
20

J Cardiovasc Pharmacol 47, 314-321, 2006.
14. H. Iida, M. Kurano, H. Takano, H. Oonuma, H. Imuta, N. Kubota, T. Morita, K. Meguro, Y.
Sato, T. Abe, Y. Yamazaki, T. Nakajima. Can KAATSU be used for an orthostatic stress inastronauts?: A case study. Int J KAATSU Training Res 2, 45-52, 2006.
15. T. Yasuda, T. Fujita, Y. Miyagi, Y. Kubota, Y. Sato, T. Nakajima, M.G. Bemben, T. Abe.
Electromyographic responses of arm and chest muscle during bench press exercise with andwithout KAATSU. Int J KAATSU Training Res 2, 15-19, 2006.
16. T. Nakajima, M. Kurano, H. Iida, H. Takano, H. Oonuma, T. Morita, K. Meguro, Y. Sato, T.
Nagata, Kaatsu Training Group. Use and safety of KAATSU training: Results of a national
survey. Int J KAATSU Training Res 2, 5-14, 2006.
17. K. Kusuhara, T. Fujita, T. Yasuda, T. Nakajima, Y. Sato, Y. Miyagi, Y. Murakami, T. Abe.
Effects of knee xtension exercise with KAATSU on forehead cutaneous blood flow in healthy
young and middle-aged women. Int J KAATSU Training Res 2, 29-34, 2006.
18. Nishimura S, Kawai Y, Nakajima T, Hosoya Y, Fujita H, Katoh M, Yamashita H, Nagai R,
Sugiura S. Membrane potential of rat ventricular myocytes responds to axial stretch in phase,
amplitude and speed-dependent manners. Cardiovasc Res. 72:403-411, 2006.
19. Sahara M, Takahashi T, Imai Y, Nakajima T, Yao A, Morita T, Hirata Y, Nagai R. New
insights in the treatment strategy for pulmonary arterial hypertension. Cardiovasc Drugs Ther20, 377-386, 2006.
20. Nakajima T, Takano H, Kurano M, Iida H, Kubota N, Yasuda T, Kato M, Meguro K, Sato Y,
Yamazaki Y, Kawashima S, Ohshima H, Tachibana S, Nagata T, Ishii N, Morita T. (2007)
Effects of KAATSU training on haemostasis in healthy subjects. Int J KAATSU Training Res 3,
11-21, 2007.
21. Iida H, Kurano M, Takano H, Kubota N, Morita T, Meguro K, Sato Y, Abe T, Yamazaki Y,
Uno K, Takenaka K, Hirose K, Nakajima T. Hemodynamic and neurohumoral responses to therestriction of femoral blood flow by KAATSU in healthy subjects. Eur J Appl Physiol 100,275-285, 2007.
22. Nakajima T, Jo T, Meguro K, Oonuma H, Ma J, Kubota N, Imuta H, Takano H, Iida H,
Nagase T, Nagata T. Effect of dexamethasone on voltage-gated Na+ channel in cultured humanbronchial smooth muscle cells. Life Sci. 82:1210-1215, 2008.
23. N. Kubota, H. Takano, T. Tsutsumi, M. Kurano, H. Iida, T. Yasuda, K. Meguro, T. Morita,
Y. Sato, Sino Kawashima, Yoshihisa Yamazaki, H. Ohshima, S. Tachibana, N. Ishii, T. Abe, T.
Nakajima. Resistance exercise combined with KAATSU during simulated weightlessness Int J
KAATSU Training Res 4, 9-15, 2008.
24. Nakajima T, Iida H, Kurano M, Takano H, Morita T, Meguro K, Sato Y, Yamazaki Y,
Kawashima S, Ohshima H, Tachibana S, Ishii N, Abe T. Hemodynamic responses to simulated
weightlessness of 24-h head-down bed rest and KAATSU blood flow restriction. Eur J Appl
Physiol. 104, 727-737, 2008.
25. T Nakajima, N Kubota, T Tsutsumi, A Oguri, H Imuta, T Jo, H Oonuma, M Soma, K
Meguro, H Takano, T Nagase, T Nagata. Eicosapentaenoic acid inhibits voltage-gated sodium
channels and invasiveness in prostate cancer cells. Br J Pharmacol 156, 420-431, 2009.
26. K Meguro, H Iida, H Takano, T Morita, M Sata, R Nagai, T Nakajima. Function and Role ofVoltage-Gated Sodium Channel (NaV1.7) Expressed in Aortic Smooth Muscle Cells. Am J
Physiol Heart Circ Physiol 2009. 296:H211-H219.
27. Ogawa S, Yamashita T, Yamazaki T, Aizawa Y, Atarashi H, Inoue H, Ohe T, Ohtsu H,
21

Okumura K, Katoh T, Kamakura S, Kumagai K, Kurachi Y, Kodama I, Koretsune Y, Saikawa
T, Sakurai M, Sugi K, Tabuchi T, Nakaya H, Nakayama T, Hirai M, Fukatani M, Mitamura H;
J-RHYTHM Investigators.Collaborators (224) Optimal treatment strategy for patients withparoxysmal atrial fibrillation: J-RHYTHM Study. Circ J. 2009 Feb;73(2):242-8.
28. Matsuyama N, Tsutsumi T, Kubota N, Nakajima T, Suzuki H, Takeyama Y. Direct action ofan angiotensin II receptor blocker on angiotensin II-induced left atrial conduction delay inspontaneously hypertensive rats. Hypertens Res. 2009; 32: 721-26.
29. Abe T, Sakamaki M, Fujita S, Ozaki H, Sugaya M, Sato Y, Nakajima T. Effects of
low-intensity walk training with restricted leg blood flow on muscle strength and aerobic
capacity in elderly subjects. J Geriatr Phy Ther 2010, Jan-Marc 33:34-40.
30. Madarame H, Kurano M, Takano H, Iida H, Sato Y, Ohshima H, Abe T, Ishii N, Morita T
and Nakajima T. Effects of low-intensity resistance exercise with blood flow restriction on
coagulation system in healthy subjects. Clinical Physiology and Functional Imaging 2010
May;30(3):210-3.
31. Fukuda T, Maegawa T, Matsumoto A, Komatsu Y, Nakajima T, Nagai R, Kawahara T.
Effects of Acute Hypoxia at Moderate Altitude on Stroke Volume and Cardiac Output During
Exercise. Int Heart J. 2010 May;51(3):170-5
32. Yasuda T, Abe T, Brechue WF, Iida H, Takano H, Meguro K, Kurano M, Fujita S, Nakajima
T. Venous blood gas and metabolite response to low-intensity muscle contractions with externallimb compression. Metabolism. 2010; 59:1510-1519.
33. Oguri A, Tanaka T, Iida H, Meguro K, Takano H, Oonuma H,Nishimura S, Morita T,
Yamasoba T, Nagai R, Nakajima T. Involvement of CaV3.1 T-type calcium channels on cellproliferation in mouse preadipocytes. Am J Physiol Cell Physiol . 2010 Jun;298(6):C1414-423.
34. Sahara M, Sata M, Morita T, Nakajima T, Hirata Y, Nagai R. A Phosphodiesterase-5
Inhibitor Vardenafil Enhances Angiogenesis Through a Protein Kinase G-Dependent
Hypoxia-Inducible Factor-1/Vascular Endothelial Growth Factor Pathway. Arterioscler Thromb
Vasc Biol. 2010 Jul;30(7):1315-24.
35. Endo A, Kohsaka S, Suzuki S, Atarashi H, Kamakura S, Sakurai M, Nakaya H, Fukatani M,
Mitamura H, Yamazaki T, Yamashita T, Ogawa S; J-RHYTHM Investigators. Impact of drug
alteration to maintain rhythm control in paroxysmal atrial fibrillation. Subanalysis from
J-RHYTHM study. Circ J. 2010 Apr 23;74(5):870-5. Epub 2010 Apr 3.
36. T. Nakajima, M. Kurano, F. Sakagami, H. Iida, K. Fukumura, T. Fukuda, H. Takano, H.
Madarame, T. Yasuda, T. Nagata, Y. Sato, T. Yamasoba, T. Morita. Effects of low-intensity
KAATSU resistance training on skeletal muscle size/strength and endurance capacity in patientswith ischemic heart disease. Int J KAATSU Training Res 2010; 6: 1-7
37. Ozaki H, Miyauchi M, Nakajima T, Abe T. Muscle volume and strength and arterial
compliance after walk training with blood flow restriction in elederly women. J Am Geriatr Soc.
2010 Aug;58(8):1597-1598.
37. Nakajima T, Kurano M, Hasegawa T, Takano H, Iida H, Yasuda T, Fukuda T, Madarame H,
Uno K, Meguro K, Shiga T, Sagara M, Nagata T, Maemura K, Hirata Y, Yamasoba T, Nagai R.
Pentraxin3 and hsCRP are independent inflammatory markers released during high-intensity
exercise. Eur J Appl Physiol 2010; 110: 905-913.
38. Abe T, Fujita S, Nakajima T, Sakamaki M, Ozaki H, Ogasawara R, Sugaya M, Kudo M,
Kurano M, Yasuda T, Sato Y, Ohshima H, Mukai C, Ishii N. Effects of low-intensity cycle
training with restricted leg blood flow on thigh muscle volume and VO2max in young men.
22

Journal of Sports Science and Medicine 2010; 9, 452-458.
39. Madarame H, Takano H, Iida H, Hashida H, Morita T and Nakajima T. Blood Flow
restricted exercise in a ballet dancer with Churg-Strauss syndrome. Gazzetta Medica Italiana
2011; 170: 63-67.
40. Ozaki H, Miyachi M, Nakajima T, Abe T. Effects of 10- Weeks Walk Training With Leg
Blood Flow Reduction on Carotid Arterial Compliance and Muscle Size in the Elderly Adults.
Angiology. 2011: 62; 81-86.
41. Ozaki H, Sakamaki M, Yasuda T, Fujita S, Ogasawara R, Sugaya M, Nakajima T, Abe T.
Increases in Thigh Muscle Volume and Strength by Walk Training with Leg Blood Flow
Reduction in Older Participants. J Gerontol A Biol Sci Med Sci. 2011; 66: 257-263.
42. Tanaka T, Ikeda K, Yamamoto Y, Iida H, Kikuchi H, Morita T, Yamasoba T, Nagai R,
Nakajima T. Effects of serum amyloid A and lysophosphatidylchoilne on intracellular calcium
concentration in human coronary smooth muscle cells. Int Heart J 2011;52: 185-193.
43. Tsutsumi T, Takano N, Matsuyama N, Higashi Y, Iwasawa K, Nakajima T. High frequency
powers hidden within QRS complex as an additional predictor of lethal ventricular arrhythmias
to ventricular late potential in post-myocardial infarction patients Heart Rhythm 2011;
8:1509-1515.
44. Iida H, Nakajima T, Kurano M, Yasuda T, Sakamaki M, Sato Y, Yamasoba T, Abe T. Effectsof Walking with Blood Flow Restriction on Limb Venous Compliance in Elderly Subjects. Clin
Physiol Funct Imaging. 2011 Nov;31(6):472-476.
45. Nakajima T, Morita T, Sato Y. Key considerations when conducting KAATSU training. Int J
KAATSU Training Res 2011; 7: 1-6.
46. Fukuda T, Fukumura K, Uchida Y, Ootsuka T, Yasuda T, Iida H, Morita T, Nagata T, Sato Y,
Nakajima T. A case of dementia presenting remarkable improvement in activities of daily living
through KAATSU training. Int J KAATSU Training Res 2011; 7: 13-17.
47. Nakajima T, Yasuda T, Sato Y, Morita T, Yamasoba T. Effects of Exercise and Anti-Aging.
Anti-Aging Medicine 2011; 8: 92-102.
48. Fukuda T, Kurano M, Iida H, Takano H, Tanaka T, Yamamoto Y, Ikeda K, Nagasaki M,
Monzen K, Uno K, Kato M, Shiga T, Maemura K, Matsuda N, Yamashita Y, Hirata Y, Nagai R,
Nakajima T. Cardiac rehabilitation decreases plasma pentraxin 3 in patients with cardiovasculardiseases.Eur J Prev Cardiol. 2012 Dec;19(6):1393-400.
49. Iwasaki S, Nakajima T, Chihara Y, Inoue A, Fujimoto C, Yamasoba T. Developmental
changes in the expression of Kv1 potassium channels in rat vestibular ganglion cells. Brain
Research 2012;1429:29-35.
50. Takano NK, Tsutsumi T, Suzuki H, Okamoto Y, Nakajima T. Time frequency power profile
of QRS complex obtained with wavelet transform in spontaneously hypertensive rats. Comput
Biol Med. 2012 Feb;42(2):205-212.
51. Nakajima T, Kurano M, Hasegawa T, Iida H, Takano H, Fukuda T, Madarame H, Fukumura
K, Sato Y, Yasuda T, Morita T. The effects of low-intensity KAATSU resistance exercise on
intracellular neutrophil PTX3 and MPO. Int J KAATSU Training Res 2012; 8: 1-8.
52. Fukuda T, Matsumoto A, Kurano M, Takano H, Iida H, Morita T, Yamashita H, Hirata Y,
Nagai R, Nakajima T. Cardiac output response to exercise in chronic cardiac failure patients.:
Role of stroke volume. Int Heart J 2012; 53: 293-298.
53. Uchida Y, Morita T, Fukumura K, Otsuka T, Fukuda T, sato Y, Nakajima T. Effects of
KAATSU training on a patient with benign fasciculation syndrome. Int J KAATSU Training Res
23

2012; 8: 9-12.
54. Minami Y, Kaneda H, Inoue M, Ikutomi M, Morita T, Nakajima T. Endothelial dysfunction
following drug-eluting stent implantation: A systematic review of the literature. International
Journal of Cardiology 2013; 165(2): 222-228.
55. Madarame H, Kurano M, Fukumura K, Fukuda T, Nakajima T. Hemostatic andinflammatory responses to blood flow-restrcited exercise in patients with ischemic heartdiseases: a pilot study. Clin Physiol Funct Imaging. 2013; 33: 11-7.
56. Yamamoto Y, Morita T, Tanaka T, Ikeda K, Kikuchi H, Oguri G, Nakamura F, Nakajima T,
Nagai R. Amiodarone inhibits tissue factor expression in monocytic THP-1 cells. Eur J
Pharmacol. 2013 Feb 15;701(1-3):14-19.
57. Ikeda K, Nakajima T, Yamamoto Y, Takano N, Tanaka T, Kikuchi H, Oguri G, Morita T,
Nakamura F, Komuro I. Roles of transient receptor potential canonical (TRPC) channels andreverse-mode Na+/Ca2+ exchanger on cell proliferation in human cardiac fibroblasts: Effects oftransforming growth factor β1. Cell Calcium 2013 Sep;54(3):213-225.
58. Fukuda T, Kurano M, Fukumura K, Yasuda T, Iida H, Morita T, Yamamoto Y, Takano N,
Komuro I, Nakajima T. Cardiac rehabilitation increases exercise capacity with a reduction ofoxidative stress. Korean Circ J. 2013 Jul;43(7):481-487.
59. Fukuda T, Yasuda T, Fukumura K, Iida H, Morita T, Sato Y, Nakajima T. Low-intensity
kaatsu resistance exercise using an lelastic band enhances muscle activation in patients withcardiovascular diseases. Int J KAATSU Training Res 2013; 9: 1-5.
60. Eshima H, Tanaka Y, Sonobe T, Inagaki T, Nakajima T, Poole DC, Kano Y. In vivo imaging
of intracellular Ca2+ after muscle contractions and direct Ca2+ injection in rat skeletal muscle indiabetes. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology
2013 Sep 15;305(6):R610-618.
61. Sahara M, Ikutomi M, Morita T, Minami Y, Nakajima T, Hirata Y, Nagai R, Sata M.
Deletion of Angiotensin-converting Enzyme 2 Promotes the Development of Atherosclerosis
and Arterial Neointima Formation. Cardiovasc Res. 2014; 101: 236-246.
62. Yasuda Y, Fukumura K, Fukuda T, Uchida Y, Iida H, Meguro M, Sato Y, Yamasoba T,
Nakajima T. Muscle size and arterial stiffness after blood flow-restricted low-intensity
resistance training in older adults. Scand J Med Sci Sports 2014; 24: 799-806.
63. Yasuda T, Fukumura K, Fukuda T, Iida H, Imuta H, Sato Y, Yamasoba T, Nakajima T.
Effects of low-intensity, elastic band resistance exercise combined with blood flow restriction
on muscle activation. Scandinavian Journal of Medicine and Science in Sports 2014; 24: 55-61.
64. Inoue A, Iwasaki S, Fujimori C, Nakajima T, Yamasoba T. Developmental changes in theprotective effect of exogenous brain-derived neurotrophic factor and neurotrophin-3 against
ototoxic drugs in cultured rat vestibular ganglion neurons. Cell and Tissue Res 2014; 356:
299-308.
65. Yasuda T, Fukumura K, Sato Y, Yamasoba T, Nakajima T. Effects of detraining after bloodflow restricted low-intensity training on muscle size and strength in older adults. Aging Clinicaland Experimental Research 2014; 26: 561-564.
66. Tsutsumi T, Okamoto Y, Takano NK, Wakatsuki D, Suzuki H, Sezaki T, Iwasawa K,
Nakajima T. Time-frequency analysis of the QRS complex in patients with ischemic
cardiomyopathy and myocardial infarction. International Jouranal of Cardiology Heart &Vessels 2014; 4: 177-187.
67. Oguri G, Nakajima T, Yamamoto Y, Takano N, Tanaka T, Kikuchi H, Morita T, Nakamura F,
24

Yamasoba T, Komuro I. Effects of methylglyoxal on human cardiac fibroblasts: Roles oftransient receptor potential ankyrin 1 (TRPA1) channels. Am J Physiol Heart Circ Physiol
2014;307:H1339-H1352.
68. Yoshimoto R, Iwasaki S, Takago H, Nakajima T, Sahara R, Kitamura K. Developmental
increase in hyperpolarization-activated current regulates intrinsic firing properties in rat
vestibular ganglion cells. Neuroscience 2015;284:632-642.
69. Iwashita H, Morita T, Sato Y, Nakajima T. KAATSU training in a case of patients withperiventricular leukomalacia (PVL). International Jouranal of KAATSU Training Research
2014; 10: 7-11.
67. Yasuda T, Fukumura K, Uchida Y, Koshi H, Iida H, Masamune K, Yamasoba T, Sato Y,
Nakajima T. Effects of low-load, elastic band resistance training combined with blood flow
restriction on muscle size and arterial stiffness in older adults. J Gerontol A Biol Sci Med Sci.
2015 Aug;70(8):950-958.
68. Yasuda T, Fukumura K, Iida H, Nakajima T. Effect of low-load resistance exercise with andwithout blood flow restriction to volitional fatigue on muscle swelling. Eur J Appl Physiol. 2015
May;115(5):919-926.
69. Takano N, Takano H, Fukuda T, Kikuchi H, Oguri G, Fukumura K, Iwasawa K, Nakajima T.
Relationship between chronotropic incompetence and β-blockers based on changes inchronotropic response during cardiopulmonary exercise testing. International Journal of
Cardiology Heart & Vessels 2015; 6: 12-18.
70. Minami Y, Nakajima T, Ikutomi M, Morita T, Komuro I, Sata M, Sahara M. Angiogenic
potential of early and late outgrowth endothelial progenitor cells is dependent on the time of
emergence. Int J Cardiol 2015: 186: 305-314.

● English Report
1. Abe T, Ozaki H, Sugaya M, Fujita S, Sakamaki M, Sato Y, Bembem MG, Nakajima T. Effectsof 42 weeks walk training with blood flow reduction on muscle size and strength in the elderly.
Proceedings of the ICSES, pp336-341, 2009.
2. Ozaki H, Kusuhara K, Sato Y, Brechue WF, Ogita F, Nakajima T, Abe T. Cardiovascular andmetabolic responses to walking with and without leg blood flow reduction. Proceedings of the
ICSES, pp342-347, 2009.

25

(textbook of KAATSU training in Japanese)26

● Internationa conferences
1. Kusuhara K, Fujita T, Yasuda T, Nakajima T, Sato Y, Miyagi Y, Murakami Y, Abe T. Foreheadcutaneous blood flow in response to unloaded kaatsu leg exercise: 2324: board #3 june 1 3:30
PM -5:00 PM. Med Sci Sports Exerc. 2007 May;39(5 Suppl):S426.
2. Abe T, Kusuhara K, Fujita T, Brechue WF, Sato Y, Nakajima T. Cardiovascular response to
low-intensity walking with restricted leg muscle blood flow: 2334: board #13 june 1 3:30 PM-5:00 PM. Med Sci Sports Exerc. 2007 May;39(5 Suppl):S428.
3. Yasuda T, Abe T, Kurano M, Takano H, Meguro K, Brechue W.F. Nakajima T. Venous bloodchanges with low-intensity muscle contractions and blood flow restriction. The 55th American
College of Sports Medicine, 2008 May 28-31 (Indianapolis, USA)
4. Nakajima T, Iida H, Kurano M, Yasuda T, Takano H, Morita T, Meguro K, Sato Y, Abe T,
Ishii, N Ohshima H. Hemodynamic and neurohumoral responses to simulated weightless and
KAATSU blood flow restriction. The 55th American College of Sports Medicine, 2008 May
28-31 (Indianapolis, USA)
5. Nakajima T. Master Physicians Class in New Respiratory Pathologies for Pneumologists(Tokyo: 2009.3.5) New perspectives in the treatment of pulmonary disease: Respiratory
KAATSU rehabilitation.
6. Nakajima T, Kurano M, Iida H, Takano H, Yasuda T, Fujita S, Morita T, Sato Y, Yamasoba T,
Abe T. The 56th American College of Sports Medicine (Seattle, Washington, USA:
2009/5/27-30) Effects of 6-week Kaatsu walking on limb venous compliance in elderly subjects.
7. Takano H, Nakajima T, Kurano M, Kubota N, Iida H, Yasuda T, Sato Y, Ohshima H, Abe T,
Ishii N, Morita T. The 56th American College of Sports Medicine (Seattle, Washington, USA:
2009/5/27 -30) Effecst of Kaatsu training on haemostasis in healthy subjects.
8. Oguri A, Tanaka T, Iida H, Meguro K, Takano H, Oonuma H, Nishimura S, Morita T, Nagai
R, Nakajima T. The Scientific Sessions, American Heart Association 2009 (Orlando, Florida,
USA: 2009/11/15-17) α1G T-Type Calcium Channels in Mouse Preadipocytes: A Role on Cell
Proliferation.
9. Nakajima T, Iida H, Kurano M, Takano H, Yasuda T, Fujita S, Morita T, Sato Y, Yamasoba T,
Abe T. The Scientific Sessions, American Heart Association 2009 (Orlando, Florida, USA:
2009/11/15-17) 6-week Blood Flow Restricted Walking Training Improves Limb Venous
Compliance in Elderly Subjects.
10. Nakajima T, Kurano M, Iida H, Takano H, Fukuda T, Nagasaki M, Monzen K, Uno K, Kato
M, Meguro K, Shiga T, Maemura K, Masuda N, Hirata Y, Nagai R. The Scientific Sessions,
American Heart Association 2009 (Orlando, Florida, USA: 2009/11/15-17) Improvement of
Plasma Pentraxin3 Following Cardiac Rehabilitation in Patients With Cardiovascular Diseases.
11. Abe T, Ozaki H, Sugaya M, Fujita S, Sakamaki M, Sato Y, Bemben MG, Nakajima T. The 1st
International Conference on Sports and Exercise Science (Bangkok, Thailand: 2009/12/1-3)
EFFECTS OF 42 WEEKS WALK TRAINING WITH BLOOD FLOW REDUCTION ON
MUSCLE SIZE AND STRENGTH IN THE ELDERLY.
12. Ozaki H, Kusuhara K, Sato Y, Brechue WF, Ogita F, Nakajima T, Abe T. The 1st
International Conference on Sports and Exercise Science (Bangkok, Thailand: 2009/12/1-3)
CARDIOVASCULAR AND METABOLIC RESPONSES TO WALKING WITH ANDWITHOUT LEG BLOOD FLOW REDUCTION
27

13. Haruhiko Madarame, Miwa Kurano, Haruhito Takano, Haruko Iida, Yoshiaki Sato, Hiroshi
Ohshima, Takashi Abe, Naokata Ishii, Toshihiro Morita, Toshiaki Nakajima. The 57th American
College of Sports Medicine (Baltimore, Maryland, USA: 2010/6/1-5) Low-intensity resistance
exercise with blood flow restriction does not activate coagulation system in young men.
14. Hayao Ozaki, Mikako Sakamaki, Riki Ogasawara, Masato Suguya, Tomohiro Yasuda,
Yoshiaki Sato, Toshiaki Nakajima, Takashi Abe. The 57th American College of Sports Medicine(Baltimore, Maryland, USA: 2010/6/1-5) Low-intensity walk training with blood-flow reduction
concurrently improved VO2peak and musclular function in elderly women.
15. Takashi Abe, Satoshi Fujita, Toshiaki Nakajima, Mikako Sakamaki, Hayao Ozaki, Riki
Ogasawara, Masato Sugiya, Maiko Kudo, Miwa Kurano, Tomohiro Yasuda, Yoshiaki Sato,
Hiroshi Ohshima, Chaiki Mukai, Naokata Ishii. The 57th American College of Sports Medicine(Baltimore, Maryland, USA: 2010/6/1-5) Concurrent improvement in muscle vlolume andVO2max in respsonse to blood flow restricted cycle tyraining.
16. Toshiaki Nakajima, Miwa Kurano, Haruko Iida, Haruhito Takano, Haruhiko Madarame,
Tomohiro Yasuda, Yoshiaki Sato, Toshihiro Morita. The 57th American College of Sports
Medicine (Baltimore, Maryland, USA: 2010/6/1-5) Effects of low-intensity KAATSU resistancetraining on skeletal muscle size and muscle strength/endurance capacity in patients withischemic heart diseases.
17. Toshiaki Nakajima, Miwa Kurano, Haruhito Takano, Haruko Iida, Taira Fukuda, Kentaro
Meguro, Taro Shiga, Mina Sagara, Koji Maemura, Yasunobu Hirata, Tatsuya Yamasoba, Ryozo
Nagai. The Scientific Sessions, American Heart Association 2010 (Chicago, Ilinois
2010/11/13-17) Acute high-intensity exercise releases myeloperoxidase and pentraxin3 fromperipheral neutrophils in healthy subjects.
18. Toshiaki Nakajima, Miwa Kurano, Takaaki Hasegawa, Haruhito Takano, Haruko Iida, Taira
Fukuda, Haruhiko Madarame, Kazuya Fukumura, Yoshiaki Sato, Toshihiro Morita. The 58th
American College of Sports Medicine (Denver, Colorado, USA: 2011/5/31-6/4) Effects of
low-intensity resistance exercise with restricting muscle blood flow (KAATSU) on intracellular
PTX3 and MPO in neutrophils
19. Nakajima T, Kurano M, Takano H, Yasuda T, Takano N, Iida H, Fukuda T, Fukumura K,
Sato Y, Morita T, Yamasoba T. The 59th American College of Sports Medicine (San Fransisco,
CA, USA, 2012/5/29-6/2) Blood Flow Restriction Enhances Oxidant Stress and Anti-oxidant
Capacity during Aerobic Exercise in Healthy Subjects.
20. The 59th American College of Sports Medicine (San Fransisco, CA, USA, 2012/5/29-6/2)
Effects of blood-flow restricted low-intensity muscle contractions using elastic band on muscle
activation. Yasuda T, Fukumura K, Otsuka T, Fukuda T, Uchida Y, Iida H, Chujo Y, Sato Y,
Yamasoba T, Nakajima T.
21. Minami Y, Sahara M, Nakajima T, Ikutomi M, Morita T, Yamashita H, Hirata Y, Nagai R,
sata M. The Scientific Sessions, American Heart Association 2012 (Los Angeles, USA,
2012/11/13-17) Real Angiogenic Potential of Early or Late Outgrowth Endothelial Progenitor
Cells is Rigorously Dependent on the Time of Emergence
22. Yasuda T, Fukumura K, Fukuda T, Uchida Y, Iida H, Ohtsuka T, Chujo Y, Meguro M, Sato Y,
Nakajima T. The 60th American College of Sports Medicine (Indianapolis, Indiana, USA,
2013/5/8-6/1) Muscle size and arterial compliance after blood flow-restricted low-intensity
resistance training in olderly adults.
23. Nakajima T, Yasuda T, Koide S, Takano N, Sato Y, Kano T. The 60th American College of28

Sports Medicine (Indianapolis, Indiana, USA, 2013/5/8-6/1) Repetitive restriction of muscle
blood flow enhances mTOR signaling pathways in rat Kaatsu model.
24. Nakajima T, Yasuda T, Koide S, Sato Y, Takano N, Yamasoba T, Komuro I, Kano Y. The
Scientific Sessions, American Heart Association 2013 (Dallas, Texas, USA, 2013/11/16-11/20)
Repetitive restriction of muscle blood flow enhances mTOR signaling pathways in a rat
model.
25. Nakajima T, Yasuda T, Koide S, Sato Y, Morita T, Tomaru T, Kano Y. International Academyof Cardiology Annual Scientific Sessions 2014 19th World Congrss on Heart Disease (Boston,
MA, USA. July 25-28, 2014) Skeletal Muscle Hypertrophy Induced by Novel KAATSU
Rehabilitation and Prevention of Sarcopenia (Invited Lecture).
26. Nakajima T, Yasuda T, Koide S, Sato Y, Tomaru T, Kano Y. International Academy ofCardiology Annual Scientific Sessions 2014 19th World Congrss on Heart Disease (Boston, MA,
USA. July 25-28, 2014) Repetitive Application of Restriction of Muscle Blood Flow Enhances
mTOR Signaling Pathways in a Rat Model.

◆ Acknowledgments
After 10 years of course opening, we were able to reach a high tide for a term after being
supported by many associates and teachers. For the past 10 years, we have been leading theworld and researching various effects related to KAATSU training, in particular, muscle
hypertrophy, rehabilitation effect and secondary beneficial effects. KAATSU training is
considered to contribute to sports, nursing prevention, clinical, space medicine and a wide rangeof other fields. We thanked all staffs, which had been supported for 10 years, as well as
long-term donations and support for research. We also thank KAATSU Japan Co., Ltd. (Dr.
Yoshiaki Sato).

31/July/2019 Toshiaki Nakajima

29

Received: Sep. 26, 2011
Accepted: Oct. 19, 2011
Published online: Dec. 28, 2011

Review Article

Effects of Exercise and Anti-Aging
Toshiaki Nakajima 1), Tomohiro Yasuda 1), Yoshiaki Sato 2), Toshihiro Morita 1), Tatsuya Yamasoba 3)1) Department of Ischemic Circulatory Physiology, KAATSU Training, Graduate School of Medicine, The University of Tokyo
2) Kaatsu International University3) Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo

Abstract
As demographic aging continues in Japan, the number of very elderly individuals aged 75 years or older is increasing rapidly,
as is the number of bedridden, elderly individuals, with ramifications extending to economic problems such as health care costs andinsurance for long-term care. Consequently, there is a great importance to questions of how to prevent age-related loss of muscle(sarcopenia) to prevent bedridden states, and further to improve quality of life (QOL) and maintain active lifestyles. Exercise
is the most effective means for preventing and addressing sarcopenia. Regular exercise is also reported to prevent progressionof arteriosclerosis, prevent lifestyle diseases, and delay onset of dementia. However, the effects of exercise are known to differ
substantially for different types of exercise. Regular walking and other aerobic exercise improves cardiovascular endurance, but
among the elderly, loss of muscular strength, muscular atrophy, and other diminished physical functions have implications for fallingand fractures, and it is not uncommon to see a consequent aggravation of disuse syndrome due to inactivity, leading to a bedridden
state. In this light, strength training is also important for elderly individuals, to increase muscular strength and muscle mass. It is also
highly important for elderly individuals to eat a diet, particularly amino acids, that enhances the effects of exercise. Here we present
an overview of aerobic exercise, resistance training, and “kaatsu training” (i.e., training under pressure-restricted blood flow to theextremities) representing anti-aging exercise methods. We likewise discuss the importance of diet for exercise.

KEY WORDS: Kaatsu training, anti-aging, resistance exercise, amino acids, sarcopenia

Introduction

lower than that of strength training. In contrast, resistance(muscular strength) training has a stronger effect than aerobic
exercise on enhancing muscular strength and muscle size andlikewise acts strongly to increase bone density. Resistancetraining also elevates basal metabolism. Each type of exercise
has an apparently similar effect of improving glucose
metabolism and fat metabolism, and both are reputedly usefulfor improving insulin resistance, in particular, decreasing
insulin response to glucose loading.
American College of Sports Medicine (ACSM) guidelines
report that elderly individuals show sarcopenia and diminishedmuscle strength in nearly all cases and state that resistancetraining is needed to enhance muscle strength and maintainmuscle mass. Strength training is also seen to improve insulin
resistance, increase bone density, and improve QOL and isrecommended for progressive, age-related osteoporosis, acause of fractures. However, the guidelines also state thatelderly individuals should not engage in high-intensity strength
training with weights. While muscle strength and muscle mass
clearly diminish with age, peak oxygen uptake is also known
to decrease. Myers et al. studied the association between peakoxygen uptake and prognosis by comparing individuals withpeak oxygen uptake at or lower than 5 METS with those at
higher levels; they reported a distinct difference in long-term
prognosis both among healthy individuals free from obvious
disease and among patients with cardiovascular disease 2) .
Recently, the incidence of dementia has also increased rapidly,
and after 10 years, 10% of those age 65 years or older are said

Muscular strength and muscle mass are well known todecline with age. This phenomenon is called sarcopenia.
When an individual passes age 30, muscle mass decreases
approximately 0.3-0.5% every year, and after age 60, the rate ofdecrease is very substantial. At age 80, muscle mass is thought
to decrease to 50% or lower than during the prime years. In
bed, muscles also decrease by 0.6% per day. Consequently,
hospital admission for cerebrovascular accident, fracture, orother such reasons can lead, in 3 weeks of bed rest, to evena 12% reduction in muscle mass, and particularly for elderly
individuals or sarcopenia patients, such an instance often leads
to a bedridden state or disuse syndrome. Additionally, agerelated sarcopenia not only increases the risk of falling; it canalso be a factor in decreased independence or frailty of theelderly due to insulin resistance or glucose metabolism disorderassociated with decreased muscle mass. Routine measures
to maintain muscular strength and muscle mass and prevent
sarcopenia are therefore highly important.
In gross distinction, exercise can be divided into strength
training versus aerobic exercise such as walking (treadmill)and bicycling (ergometer) 1). Fig. 1 presents differences in theeffects of aerobic exercise versus strength training. The effects
of aerobic exercise are more apparent than those from strength
training in terms of peak oxygen uptake, extension of exercise
endurance time, and other improvements in cardiovascular
endurance. However, aerobic exercise does not increase muscle
mass, and its effect of increasing bone density is reputedly
Anti-Aging Medicine 8 (7) : 92-102, 2011(c) Japanese Society of Anti-Aging Medicine

92

Prof. Akira Kawada, M.D., Ph.D.
Department of Dermatology, Kinki University Faculty of Medicine
377-2 Ohno-Higashi, Osaka-Sayama City, Osaka 589-8511, Japan
Tel:+81-72-366-0221 / Fax: +81-72-368-2120 / E-mail: kawada@med.kindai.ac.jp

Effects of Exercise and Anti-Aging

Fig. 1. Comparative effects of aerobic exercise and strength training (cf. Reference 1)

reported effects include decreased blood pressure at rest andduring exercise, decreased heart rate, decreased myocardial
oxygen consumption during exercise, increased mass of active
muscles, and increased muscular mitochondrial activity. In
this light, routine aerobic exercise is also useful for preventing
progression of arteriosclerosis, preventing lifestyle disease, andat the same time improving QOL of the elderly.
Actual aerobic exercise is often prescribed by determining
load intensity using a treadmill or bicycle (ergometer) 7,8). The
effects of exercise are closely related to exercise intensity,and the effect of an increase in peak oxygen uptake (an index
of exercise endurance) increases with increasing exercise
intensity. In general, improvement in aerobic capacity requires
exercise at an intensity of 50-80% of peak oxygen uptake(VO2max) for 20 min. or longer, 3-5 times per week. However,for considerations of safety among elderly and other suchindividuals, the load intensity used is, for example, 40-60%
of peak oxygen uptake and 50-70% of maximum heart rate
as measured by an exercise load tester, and AT as prescribed(intensity of 70-80% AT or 1 minute prior to AT). Exercise
with a somewhat challenging target value (Borg scale 13) as a
subjective symptom is often pursued for 20-60 min. per day,2-5 days per week. The effects of exercise are also manifest
more readily at low levels of physical capability and activity. In
a study of the effect of cardiac rehabilitation (aerobic exercise)on peak oxygen uptake among patients participating in cardiac
rehabilitation at our facility 9), a mean 15% increase in peakoxygen uptake was observed after 3 months of 40 minutes ofaerobic exercise (ergometer) performed 2-3 times per week.
The patients involved were age 34-85 years and thus included
very elderly individuals. In this respect, ongoing, appropriate
aerobic exercise is regarded as a safe means of exercise pursued
actively even among elderly individuals. Recent reports statethat repetitive training alternating between high and low loads,
i.e., interval training and hypoxic training involving exercise
in a low-oxygen environment 10), increases cardiopulmonary
endurance more than ordinary aerobic exercise, and futureapplications are also anticipated.

to develop dementia. In contrast, routine exercise is reported
to improve QOL in dementia 3), and results from a prospective
cohort study state that routine exercise may also delay onset ofdementia 4). In this light, anti-aging exercise is the joint pursuitof both types of exercise to manifest their independent effects:
aerobic exercise to improve peak oxygen uptake and impartendurance, and strength training to improve muscle strength,
and this regimen is also recommended for its anticipatedcomplementary effects.
Here we provide an overview of aerobic exercise, resistancetraining, and kaatsu training, together representing anti-aging
exercise. Kaatsu training is a new training method reported
to increase muscle size and muscular strength even with lowintensity loading, in a manner not achieved by conventional
resistance training. We also discuss diet, and particularly aminoacid intake, highly important elements for enhancing the effectof exercise in elderly individuals.

I. Aerobic exercise and strength training
Ia. Aerobic exercise
Aerobic exercise (e.g., wal king, t read mill, bicycle
ergometer) known to improve cardiopulmonary endurance
is f u ndamental to exercise therapy. Evidence as to its
multifaceted effects proves the usefulness of exercise therapy
5,6). In particular, 1) improved exercise endurance is shown byimproved anaerobic threshold (AT) and peak oxygen uptake,which increases patient QOL. 2) Symptomatic improvement in
identical ADL tasks and 3) improved life expectancy are shownby numerous meta-analyses indicating that cardiovasculardeath and total deaths decrease by 20-30%. 4) Improved
lipid metabolism and glucose metabolism and improvementin obesity are demonstrated by further improvement withconcomitant dietary guidance and weight loss. 5) Decreasedsmoking rates and 6) improved psychosocial satisfaction
and decreased stress are psychological improvements. Other93

Effects of Exercise and Anti-Aging

Ib. Strength training

IIa. About kaatsu training

As described, appropriate aerobic exercise is useful for
improving cardiopulmonary endurance even in the elderly.
However, sarcopenia and diminished muscular strength areseen in virtually all elderly individuals, and resistance trainingis also needed to enhance muscular strength and increase
muscle mass. Strength training is also known to have effects
of improving insulin resistance, increasing bone density, andimproving QOL. Strength training is therefore recommended
as an anti-aging measure to increase muscular strength andmuscle mass 7) . Resistance training is strength-enhancing
exercise of the extremities or trunk using free weights, rubberbands, or machines and is performed with careful setting ofloads for each exercise. The recommended resistance exercise
regimen is 2-3 times per week, and for the most part, 2 times
per week is used. The procedures used come from a strength
training menu of several categories (8 categories) for the
major muscle groups and include chest press, shoulder press,
triceps extension, biceps curl, pull-down (upper back), lower
back extension, abdominal crunch/curl-up, leg extension orleg press, leg curls (hamstrings), and calf raises, with loadintensity at 40-60% of 1RM. In strength training using training
machines, the load intensity is preferably 30-40% for upper
extremity exercise and 40-50% for lower extremity exercise.
In most cases, 1 set comprises 8-15 repetitions, and 1-2 sets are
performed. However, effective improvement of the structureand function of skeletal muscle, for example, to increase muscle
size and muscular strength, generally requires a high intensity
exceeding 70% of maximum weight lift potential (1RM), to thepoint of muscular fatigue, i.e., 3 sets, 2-3 times per week. In asystematic review of the literature published to date concerning
the sarcopenia-improving effect of strength training, Michiya
et al.11) reported that even moderate intensity could have theeffect of increasing muscular strength, but high-intensity
training is required to increase muscle mass. Accordingly,
conventional strength training pursued at an intensity of 4060% 1RM often simply does not produce increases in muscle
size. However, high-intensity loading entails a risk of injury to
the moving organs or circulatory system in elderly individuals.
High-intensity strength training studied in healthy, young
subjects is also reported to increase arterial stiffness, an index
of arteriosclerosis 12-14), and among elderly individuals too,high-intensity strength training is often not recommended due
to increased stress on the joints.

Kaatsu training is strength training in which specialized
pressure-applying belts are used to apply pressure at the base of
the extremities, and training is performed in a state of restrictedblood flow 15,16,19-23). The training is distinctive for producing
increases in muscle size and strength through short-duration,
low load-intensity training. While there is considerable researchon the load intensity used in ordinary strength training and its
principal effects, load intensity, essentially, mechanical stress,is thought to be the most crucial element for effecting increases
in muscle size. In ordinary exercise procedures, a load intensityof 65-70% 1RM or greater is needed to increase muscle strengthand size; however, an intensity of 65% 1RM or greater is often
difficult for elderly individuals and patients presenting muscularatrophy. In addition, resistance training at high-intensity
raises blood pressure, and due care is required. In contrast,
because one characteristic of kaatsu training is production ofincreased muscle size and strength at low load-intensity thatcannot be realized through conventional resistance training,larger muscle size and greater strength are produced evenat the low intensity of 20%-40% 1RM, i.e., nearly a routine
level of activity. Takarada, Ishii, et al.20) studied the effects ofkaatsu training (30%-50% 1RM, 3 sets, 2×/week, 4 months) of
upper arm flexors among subjects comprising healthy femalesof mean aged 60 years old, and reported in their results thatboth cross-sectional area and muscle strength of the biceps
brachii increased by a mean of approximately 20.3%, an effectequivalent to training at an intensity of 80% 1RM. Conversely,
there was virtually no observed effect in the same training at
an intensity of 30%-50% 1RM when kaatsu pressure was notapplied, suggesting that the effect of increased muscle size wasattributable to kaatsu pressure. Ishii et al.23) also stated that leg
extension kaatsu training (20-30 RM [sic], 5 sets, 2×/week, for 2
months) among top athletes also produced an approximate meanof 10% increase in muscle size and 15% increase in strength,
but muscle size and strength did not increase in training at thesame intensity without kaatsu pressure. These results suggestthat kaatsu training has a substantial effect without regard to
the age or training history of the subject, and that the primaryfactor in such effects is kaatsu pressure itself. Wernorm 24)
recently studied the domestic and foreign literature concerning
high-intensity strength training and low-intensity training underrestricted blood flow and reported that the relative increase inquadriceps size from leg extension exercise was similar in eachcase. In high-intensity strength training (80% 1RM, 3-4 sets,
6-10 repetitions, 60-120 second pause), the increase was 0.030.26%/day and 1-7%/month; in the low-intensity training underrestricted blood flow (20-50% 1RM, 3-4 sets, 15-30 repetitions,30-60 second pause), the increase was 0.04-0.22%/day and 1.26%/month.
In high-intensity strength training, muscle fatigue alsoprecludes consecutive-day training for healthy individuals
who are non-athletes, and patients as well, but the use of lowintensity loading in kaatsu training allows consecutive-day
training. Yasuda et al. reported that muscle cross-sectional area
increased approximately 8% in the short duration of 2 weeks
when kaatsu training (intensity approximately 20% 1RM) was
performed twice per day (morning and evening) every day
by healthy individuals using the lower extremities 25). Kaatsu
training is also not limited to resistance training using strengthmachines and can also be applied in aerobic exercise such as
walking or ergometer use 26,27). Abe et al.26) reported observing
increased lower limb strength and muscle size in young, healthy
individuals after 3 weeks of walking at a normal pace (walking
at approximately 20% of peak oxygen uptake). In this fashion,

II. Kaatsu training
In ordinary resistance training, muscle size is known not
to increase unless loading is applied at an intensity of 65-70%
1RM or higher, and a rehabilitation technique with the effect ofincreasing muscle size safely at low intensity would represent
a highly revolutionary training method with application forpatients with various diseases, including the elderly. Kaatsu
training is a new strength training method which stimulates
numerous muscle fibers and can produce increased muscle sizeand strength even with low-intensity loading 15,16). At present,
kaatsu training is used by persons such as healthy individuals
and athletes to increase strength, but the training has also
been applied in rehabilitation to increase strength among
patients with various diseases 17,18). Here we briefly describekaatsu training and its mechanism and also summarize actual
applications.
94Effects of Exercise and Anti-Aging

Abe et al. reported that increased muscle size was observedin a research study concerning kaatsu-walk training conductedwith elderly individuals 30,31). High-intensity strength training
has been reported to increase arterial stiffness, an index ofarteriosclerosis 12,13) , but in kaatsu-walk training, arterial
stiffness was instead seen to improve 32,33). Venous stiffness
as well as arterial stiffness has been reported to increase withaging, and we studied the effects of kaatsu-walk training byelderly individuals on venous stiffness. In the results, wereported that kaatsu-walk training by elderly individuals also
improved venous stiffness 34). This series of results suggeststhat in kaatsu-walk training, an effect of increased muscle
size is observed even among elderly individuals only with low
intensity loads at which conventional training does not produce
such an effect, and likewise, that vascular compliance may
be improved, and that progression of arteriosclerosis may be
prevented.

kaatsu training can also be applied in aerobic training methods
and can be performed ordinarily by anyone, and the training canalso be adjusted according to individual abilities. By inducing
effects of increased muscle strength and size at a low intensityof 20% 1RM, kaatsu resistance training allows development of
individual muscle groups without use of special machines, andif machines are used, even more effective strength training canbe accomplished.
There are several recent reports concerning the effectsof kaatsu training among elderly individuals. One concerning
research using strength training machines reports that increased
muscle strength akin to that in high-intensity strength training
was observed 28). We likewise studied the effects of kaatsu
strength training on muscle strength and size among 7 patientswith stable ischemic heart disease (52±4 years, 5 pPCI, 2
pCABG) 29). The low-load strength training was performed withlower leg extremity only (leg extension, leg press, leg curl) at
20-30% 1RM, 4 sets. The interval between sets was 30 seconds,
and the training duration was 2×/week for 3 months. Fig. 2
presents the effects of kaatsu training with regard to increased
muscle size and strength. After kaatsu training, effects of asignificant increase in muscle size (A) and muscle strength (B)were observed. Additionally, during the training, no particular
problematic adverse effects were observed.

IIb. Muscle growth mechanism of kaatsu training
Th rough var ious mechanisms, kaatsu t raining canincrease muscle size and strength effectively 16,19) . Kaatsu
training involves exercising while pressure is applied to thebase of the extremities with specialized pressure-application

Fig. 2. Effect of kaatsu training on ischemic heart disease patients (cf. Reference 29)
A: Change in muscle cross-section after kaatsu training. Relative increase in size of separate muscle
groups, thigh region, according to MRI. Relative increase in cross-section versus pre-training value forseparate muscle groups 30% down from top of thigh region, at central 50%, and 70% down from top ofthigh region. Quadriceps femoris (QF), hamstring (HAM), adductor (ADD).
B: Relative increase in 1 RM for various strength training exercises (leg extension, leg press, leg curl).
p < 0.05 vs. control.

95Effects of Exercise and Anti-Aging

muscular glycogen. Myostatin in particular is a factor whichstrongly restricts muscular growth, and the fact that this change
is regarded as a factor accelerating muscular growth means thatthe changes in such local factors due to kaatsu pressure may
cause muscle growth.

belts to restrict primarily venous blood flow in the muscles(intramuscular blood pooling) 21,22) . Oxygen supply to themuscles is then reduced and clearance of lactic acid and othermetabolic products is obstructed. As a result, it is thought thata large number of motor units are mobilized during exercise
in order to maintain strength 16). This mobilization of a large
number of motor units during exercise is regarded as one causeof the increase in muscle size, and in reality, kaatsu training
under low-intensity load has been shown to accelerate protein
synthesis 35). Fujita et al. also carried out leg extension exercise
at 20% 1RM and reported that muscle protein synthesis was
stimulated by a change in the mRNA translation initiation
system 35). A report 36) based on electromyogram analysis also
states that activity in a large number of muscle fibers has also
been observed under kaatsu pressure, as in high-intensity
training, in spite of the light load applied.
Ohta et al. studied the effect of kaatsu training on muscle
fibers and reported that both Type I (slow-twitch fibers) andType II fibers (fast-twitch fibers) each demonstrated a trendof increased size in muscle biopsy performed after 8 weeks ofkaatsu rehabilitation following reconstruction of the anterior
cruciate ligament 37,38) . Type II fibers are also reported toincrease in size in kaatsu training by healthy individuals 25). In
general, it is Type II fibers that show conspicuous enlargement
due to muscle training. Consequently, the muscle-enlarging
effect of kaatsu training is thought to result mainly fromenlargement of fast-twitch fibers, but further studies to include
the effect on slow-twitch fibers are needed. As fast-twitch fibers
also decrease markedly with aging, and this phenomenon isclosely related to decreased muscular strength in the elderly,
kaatsu training may be effective for increasing muscle size andstrength in elderly individuals.
Growth hormone (GH) and other such humoral factors
are said to contribute to muscle growth through resistancetraining. One mechanism of the muscle size-increasing effectof kaatsu training is thought to be the role of increased growth
hormone secretion. GH is secreted by the pituitary gland, is an
import growth factor affecting the muscles, bones, and othereffectors, and is known to have various functions. Secretionof GH pursuant to exercise depends on the intensity, type, andduration of exercise and other related factors and requires atleast 10 minutes of high-intensity exercise or exercise exceeding
the anaerobic threshold (AT); at lower loading, distinct
secretion does not occur. In low-intensity kaatsu training (20%1RM) studied in the thigh muscles, the level of GH in blood
was reported to increase markedly immediately after exercise39). Our investigation also found distinct secretion under kaatsupressure, at low-intensity resistance loading of 20% 1RM 40).
This effect was observed not only with resistance loading of theextremities, but also in ordinary walking 26). In kaatsu training,
accumulation of lactic acid and other such substances stimulates
multifunctional afferent nerves distributed in skeletal muscle,
and triggers a metabolic reflex mediated by the hypothalamicpituitary system, which is considered to play a crucial role insecretion of G.H.
Localized mechanisms may also contribute to the overallmechanism of muscle growth. These include growth factor
secreted by muscle fibers or their surrounding cells. In an
experiment using a kaatsu animal model (rat with surgicallyinduced selective blocking of veins from muscles of theposterior extremities), Kawada et al.41) reported that fasttwitch muscle fibers were selectively enlarged approximately
10 days after restriction of blood flow. These enlarged muscles
demonstrated characteristics including 1) decreased myostatin
expression, 2) increased active hepatocyte growth factor (HGF),
3) increased nitric oxide synthase (NOS-1), and 4) increased

IIc. Effect of kaatsu training on trunk muscles
Like the lower extremities, the trunk muscles are known
as skeletal muscles readily susceptible to sarcopenia 42,43) .
Sarcopenia in these muscles, which play a crucial role in daily
activities and walking, can lead to diminishment of bodilyfunctions required for activities of daily living. We therefore
summarize the effects of kaatsu training on the trunk muscles.
Investigation of the effect of kaatsu training at 30%
1RM on the trunk muscles using primarily the bench press, amultiarticular exercise, showed that the amount of muscular
activity in the pectoral muscles and triceps brachii duringkaatsu exercise increased in both muscle groups as the numberof lifting repetitions increased, and at the last stage of the
final set, activity reached a high value of 110-120% versus thestart of exercise in both muscle groups. Kaatsu exercise also
produced a significantly higher level of muscular activity than
exercise without kaatsu pressure 44). This finding represented
results similar to those in single-articular exercise moving only
the limbs, and in low-intensity kaatsu bench press exercise,large mechanical stress in excess of the loading weight lifted
was found to bear on the muscles of the trunk, not merely on
those of the arms 45,46). The stimulation from kaatsu trainingis thus regarded to substantially affect even the trunk muscles,
where blood flow is not restricted.
Changes in muscle thickness have also been observedin the triceps and pectoral muscles during 2-week kaatsu
training performed 2×/day (morning and afternoon, Fig. 3) 47).
Typically, muscle thickness at these locations demonstrates
an extremely high correlation with muscle cross-sectional
area and muscle volume, therefore, any changes in muscle
thickness can be a primary indication of changes in muscle
mass. Muscle thickness of the pectorals measured prior to themorning training increased approximately 11% in the first
1-week period, did not decrease even with the interruption of abreak on Sunday, and was observed to increase approximately
6% further in Week 2. These changes in muscle thickness
did not decline even 3 weeks after the completion of training.
However, virtually no changes in muscle thickness wereobserved throughout the 2-week period in training without
kaatsu pressure. Such changes in muscle thickness were also
observed in the triceps, and the limbs and trunk demonstrated
similar changes. Next, to determine whether any changes incross-sectional area of the pectorals would be observed underordinary training conditions, the effects of kaatsu training wereobserved during 6 weeks (3×/week) of bench press exercise.
As a result, muscle cross-sectional area measured by MRI
showed an approximate 5% increase in the triceps muscle
and an approximate 8% enlargement of the pectoral muscles
48,49) . These results therefore show that kaatsu training may
also enlarge the muscles of the trunk. As stated previously,
a marked increase in muscular activity was observed in the
pectorals, and not only the triceps, during low-intensity benchpress exercise with kaatsu pressure. It is possible that whenkaatsu pressure fatigues the muscle groups of the arms, thethoracic muscle groups, as cooperative muscles, compensate
and work more actively than usual, and that this stimulation is
one important factor causing an increase in the size of the trunk
muscles. Dramatic activation of the endocrine system has also
been observed in kaatsu exercise, and in conjunction, effects
96Effects of Exercise and Anti-Aging

Fig. 3. Change in muscle thickness in triceps brachii and pectoralis major after 2 weeks of kaatsu training(bench press, cf. Reference 47).

IId. Potential effect of kaatsu training on muscularatrophyoutside the local area where blood flow is restricted have also
been reported (i.e., effect migration), which may be anothersubstantial factor 50).
Because pressure is applied at the base of the extremities inkaatsu training, it is readily but incorrectly thought that perhaps
only the extremities grow. But in reality, as such purely local
enlargement occurs, a similar response has also been found tooccur in muscles of the trunk which contribute to motion of theshoulder joints and hip joints 47-49,51,52). Consequently, kaatsu
training performed at low intensity can also enlarge the musclesof the trunk, and not only those of the extremities, indicatingthat this training is extremely effective for frail and elderly
individuals and may hold substantial promise as a supportive
method to correct sarcopenia in particular.

Cachexia and sarcopenia are k nown as par ticularly
conspicuous states of muscular atrophy. Sarcopenia refers to
a decrease in muscle size leading to a distinct reduction inmuscle strength. The diseases engendering this state are mostoften chronic obstructive pulmonary disease (COPD) andheart failure but also include senility, rheumatoid arthritis,and cancer. Various factors contribute to cause sarcopenia,
including degeneration of muscle fibers, inflammation due toincreased levels of tumor necrosis factor (TNF)-α and othercytokines, nutrition, and disuse. Resistance training, as wellas aerobic exercise, are useful in preventing muscular atrophy,
but improvement is often slow. Here we present an actual
case where kaatsu training proved useful for such a patient.
A 39-year-old female experienced decreased muscle strengthand muscular atrophy in the lower limbs due to allergic
97Effects of Exercise and Anti-Aging

III. Exercise and nutritional intervention forcorrection of sarcopenia

granulomatous angiitis, making plantar f lexion and dorsal
flexion impossible in this case. Before training started, lower
limb circumference at the distal portion was 26.9 cm in theright leg and 31.7 cm in the left leg, showing clear atrophy on
the right side. Kaatsu training was performed 2 times per weekwith an attachment pressure of 40 mmHg applied to the lower
limbs, and setting pressures of 200 mmHg and 150 mmHg
applied to the right and left legs respectively at the beginningof the training. Training comprised light, low-load exercise
including plantar flexion and dorsal flexion of the hands andfeet (3-point set), non-loaded leg extensions (alternating), nonloaded squats, and kaatsu-walk training. The fact that evenpressures of 200-300 mmHg do not cause hemostasis is aparticular feature of the specialized kaatsu belts used, though
individual differences and setting pressures produce different
results. Training was then changed to lower limb-only exercise,and the exercise level was raised with increased loads. The
22nd training comprised kaatsu exercise of the lower limbs
only. The attachment pressure used was 45 mmHg, and settingpressures were 300 mmHg and 180 mmHg for the right andleft legs respectively. Three-point sets of leg extensions with a
5 kg load and leg curls with a 14 kg load applied deliberately
to the right leg were performed, followed by calf raises underkaatsu pressure and kaatsu-walk training. Fig. 4 presents MRI
findings for the lower limbs before inception of kaatsu training
and 3 months later. The individual also perceived an increasein muscle strength and muscle size, and plantar flexion anddorsal flexion also became possible. Kaatsu training was thus
determined to have a clearly effective improvement, even in apatient presenting muscular atrophy 53).
As stated above, recent investigations of the effect ofkaatsu training on muscle strength and mass among elderly
individuals have reported a distinct effect 28-33).

Measures have been studied to maintain muscle mass andprevent atrophy in occurrences of sarcopenia, a phenomenon
among the elderly in which muscular atrophy leads to decreased
muscle mass, resulting in impaired mobility. In particular,
nutritional intake and consumption of essential amino acids
including branched chain amino acids (BCAA) are crucial for
rapidly increasing synthesis of skeletal muscle proteins. The
amount of muscle proteins present is determined by the balanceof muscle protein synthesis and decomposition. Fig. 5 presents
the effects of exercise (resistance exercise) and diet (aminoacid intake) on muscle protein synthesis and decomposition54). Muscle proteins are continually and repeatedly synthesizedand decomposed, and at rest, decomposition of muscle
proteins outweighs synthesis, and the net balance of muscle
protein addition and subtraction produces no increase. At
the same time, muscle protein synthesis is regulated byamino acid concentrations in the blood, and when suchconcentrations decline, muscle protein synthesis decreases
rapidly; conversely, when such concentrations increase,muscle protein synthesis also increases. Consequently, whenamino acids are administered at rest, muscle protein synthesis
increases (Fig. 5). In addition, when amino acids are consumed
after exercise, muscle protein synthesis is accelerated, while
muscle protein decomposition caused by exercise is inhibited,moving the net balance of muscle proteins distinctly toward
increase and improvement. However, when amino acids are notadministered, decomposition of muscle proteins is not inhibited,
and the balance does not become positive. Thus, consumptionof BCAA is thought to decrease the amount of amino acids
liberated from muscle proteins, inhibit decomposition ofmuscle proteins, and in this way incline the balance toward an

Fig. 4. Effect of kaatsu training in a case of decreased strength and muscular atrophy, lower
extremities, due to allergic angiitis (cf. Reference 53).
MRI findings before/after kaatsu training shown. Clearly atrophied right lower thigh muscle isperceptibly larger after kaatsu training.

98Effects of Exercise and Anti-Aging

Fig. 5. Effect of amino acid (AA) administration at rest and during exercise on muscle protein synthesis and decomposition(from Reference 54)
FO.M. (intracellular amino acid utilization (protein synthesis)), FM.O. (intracellular amino acid appearance (proteolysis)), N.B.
(net amino acid balance across the leg (negative numbers indicate net release)). Muscle protein synthesis at rest is increased
by administration of amino acids. In exercise, amino acid administration makes that balance positive, and synthesis ofmuscle proteins overcomes decomposition. See reference for details.

An adequate supply of amino acids in the blood is also crucial
for stimulation of muscle protein synthesis by insulin. In sum,
nutritional intervention is regarded as an extremely importantfactor for increasing muscle size.
Many factors are regarded as causes of sarcopenia
among the elderly, including age-related changes in endocrine
secretion function, inactivity, and inadequate nutrition,
particularly inadequate amino acid intake. Irregular meals
or amino acid intake and inactivity is theorized to lead to anegative balance of muscle protein addition and subtraction
and cause muscle atrophy. However, resistance training has
been proven to accelerate synthesis of skeletal muscle proteinseven among the elderly, just as in young individuals 56,57). Volpi
et al.58) investigated muscle protein metabolism as a functionof amino acid intake among elderly individuals. Their results
showed that the accelerating effect on muscle protein synthesis
was equivalent when complete amino acids were provided
and when essential amino acids were provided, and essential
amino acids produced a muscle protein synthesis-accelerating
effect even among elderly individuals 58). Thus, exercise andnutritional intervention are regarded as useful for correctionof sarcopenia even among elderly individuals, just as among
younger individuals.

increase in muscle proteins. As a result, if strength training
is performed on an empty stomach, unless the acceleration ofmuscle protein synthesis exceeds the rate of decomposition, it isdifficult to trigger an increase in muscle size. The combinationof extrinsic BCAA and resistance training are thus considered
as an important, complementary relationship moving thebalance of muscle proteins toward a net increase, and habitual
exercise (resistance training) in combination of extrinsic
BCAA is thought to induce increases in muscle size. In thisacceleration of muscle protein synthesis by amino acids, leucine,which is categorized as branched-chain amino acid (BCAA), plays
an important and unique role as compared to other essential aminoacids 55). BCAA have been shown to accelerate synthesis of muscle
proteins by increasing the translation rate of mRNA (Fig. 6).
Consuming a regular meal and then before exercise
consuming a large amount of proteins and amino acids isreportedly effective for enhancing the effect of amino acids.
Further, in young individuals, the addition of sugars to aminoacids increases the rate of protein synthesis synergistically.
Consumption of sugars together with proteins elevates
insulin secretion, and insulin is a hormone with a proteinassimilating effect which stimulates muscle protein synthesis
by incorporating amino acids in the blood into muscle tissue
and changing the transcription initiation system of mRNA.
99

Effects of Exercise and Anti-Aging

Fig. 6. Effect on 70-kDa S6 protein kinase (p70S6K) Ser424/Thr421 phosphorylation in skeletal muscle from administration of
essential amino acids (BCAA) at rest and during exercise. Phosphorylation at 1 and 2 hours after exercise isdistinctly increased by administration of BCAA versus non-administration (from Reference 55).

Conversely, Volpi et al.59) investigated the effects ofamino acids and sugars on muscle protein assimilation among
elderly individuals, and reported that protein assimilation
produced by amino acids alone was clearly lowered whensugar was consumed. This effect is deemed related to factors
such as insulin resistance 60), but it can also be assumed thatthe capability for dietary-based protein synthesis is reduced
among the elderly. Fujita et al.61) also reported that increase in
intramuscular blood flow is highly important for acceleration ofmuscle protein synthesis by insulin. Consequently, when insulin
resistance or other such factors preclude increase in muscularblood flow, muscle protein synthesis is also thought to decline.
In the elderly, such nutritional deficiency may contributeto sarcopenia, and further study of effective nutritional
intervention for the elderly is needed.

Conclusion
As societal aging continues, questions of how to prevent
age-related muscle loss (sarcopenia) to prevent bedridden
states, and further to improve QOL and maintain active
lifestyles are crucial issues. Exercise therapy is highly useful inthese respects. Our paper discusses aerobic exercise, strength
training, and kaatsu training in particular as anti-aging
exercise. Diet that enhances the effects of exercise, and aminoacid intake in particular, are regarded as extremely importantmeasures to correct sarcopenia among the elderly. Further
study is needed on prevention and improvement of sarcopenia
through multifaceted programs combining exercise and dietaryintervention.

100Effects of Exercise and Anti-Aging

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102

CASE REPORTKAATSU training® as a new exercise therapy forfemoral head avascular necrosis: A case study
T. Nakajima, T. Yasuda, K. Fukumura, M. Kurano, T. Imanishi, T. Morita, Y. Sato, Y. Hiraizumi
Int. J. KAATSU Training Res. 2015; 11: 1-6

Correspondence to:
Toshiaki Nakajima, Heart
Center, Dokkyo Medical
University HospitalProf. Toshiaki Nakajima, M.D.
Heart Center, Dokkyo Medical
University Hospital, 880
Kitakobayashi, Mibu-machi,
Shimotsuga-gun, Tochigi, 3210293, Japan
nakat@dokkyomed.ac.jp
See end of article forauthors’ affiliations

Introduction

Femoral head avascular necrosis is a condition in which part of the femoral head undergoes necrosis
due to decreased blood flow. The femoral head gradually disintegrates causing pain and even today,
there are no effective rehabilitation methods other than symptomatic treatment such as decreasing theload on the hip joints with the use of a cane or walker. We herein describe our insights into thiscondition based on our experience with a case of femoral head avascular necrosis caused by steroid
use in which KAATSU training was found to be highly effective. The patient was a 34-year-old woman(154 cm tall and weighing 50 kg, a radiologist). Since the age of 23, this patient had been receiving
steroid treatment to control her refractory asthma. She later developed pain in her right hip andgradually suffered hip joint deformation, restricted range of motion, and difficulty in walking. MRI
revealed Association Research Circulation Osseous (ARCO) stage IV disease. She suffered marked
pain of the right hip joint every time she walked, occasionally falling and required a cane to walk. At
the patientʼ s own request, she received KAATSU training including KAATSU walking over a period of
3 months (total 28 sessions). Various assessments were carried out before and after training todetermine the effects of KAATSU training. QOL was determined by SF–36v2, and marked
improvement of role physical, body pain, general health, vitality, and social functioning were noted.
Before training, the Japanese Orthopaedic Association (JOA) hip scores for pain were 10 (right), 40(left), walking ability 16 (right), 20 (left), while 3 months after training, these scores were markedly
improved in the affected side. Furthermore, not only did muscle strength on the affected side show
marked improvement, but the MRI also revealed a tendency for improvement of the right femoral headavascular necrosis. DEXA showed signs of a clear increase in bone mineral density. Based on theabove, these results suggest that KAATSU training is extremely useful as a rehabilitation method inpatients with femoral head avascular necrosis. But, further larger scale investigations should be
carried out in the future to support our findings.
Key words: Femoral head avascuar necrosis, KAATSU training, Bone density, Pain, Rehabilitation

Femoral head avascular necrosis is a condition inwhich part of the femoral head suffers necrosis due toa decrease in blood flow. Although the cause remains
unknown, possibilities include thrombosis due toabnormalities in the blood coagulation system, andinjuries of the vascular endothelium (Chang et al.,1993). Risk factors include the administration ofsteroids (Weinstein, 2011). Steroid administration
leads to decreases in blood flow due to increases in theinternal pressure of the femoral head resulting fromhypertrophy and proliferation of adipocytes. Together
with decrease in blood flow, it has been reported that
direct inhibition of osteoblasts and osteocytes may also
be involved (Cruess, 1976; Kerachian et al., 2009;
Ding et al., 2015). Pain occurs as the femoral headdisintegrates, and other than symptomatic treatment
such as using canes and walkers to reduce weightbearing stress upon the hip joint, there are no effective
rehabilitation methods (Wang et al., 2014). Muscle

strength training is often used in the rehabilitation
exercises but there are cases where pain will make it
impossible to exercise while weight-bearing is notpossible and so this is often ineffective. Therefore,
even today, it is difficult to prevent the progressionof disease with conservative treatment alone, andprognosis is poor so that surgery is eventually required.
KAATSU training (Takarada et al., 2000; Sato et al.,2007) allows for muscle growth when blood flow isrestricted, even with low stress training, and major
increases in muscle mass can be achieved. It is indeed
a useful rehabilitation method for patients withvarious diseases and our aging society (Nakajima,
2010; Abe et al., 2010; Ozaki et al., 2011; Nakajima
et al., 2011; Yasuda et al., 2014). Exercise methods
include no load, elastic band (Yasuda et al., 2015), andin addition to free weight, walking (Abe et al., 2006),
and ergometer (Abe et al., 2010). In this way KAATSU
training is being featured as a method of rehabilitationin cases where high exercise loads are to be avoided.

2

KAATSU training® as a new exercise therapy for femoral head avascular necrosis: A case study

In addition, KAATSU training with restricted bloodflow causes decreases in the intramuscular oxygen
partial pressure during exercise and hypoxemia. With
active refilling of vasculature in response to belt
release, reactive hyperemia develops and vascularendothelial growth factor (VEGF) and nitric oxide(NO) production are enhanced (Takano et al., 2005;
Horiuchi and Okita, 2012) and this may lead to
improvements in both endothelial function andcirculation. In this way, KAATSU training appears tobe effective as a rehabilitation method in patients withfemoral head avascular necrosis, but there are few
reports regarding the effects of KAATSU training inthese patients until now.
We experienced a case of femoral head avascularnecrosis in one patient and would like to report ourfindings.

1. Case introduction

Case report: A 34-year-old woman (height 154 cm,
weight 50 kg, profession radiologist)
Diagnosis: femoral head avascular necrosis
Chief complaint: pain of the hip joint during
ambulation, gait disturbance.
Family history: no notable findings.
History of present illness: bronchial asthma with an
onset during youth. Since experiencing a severe
attack of aspirin-induced asthma at age 15, the patient
became dependent on steroids and repeatedly required
hospitalization because of poor control and had
continued to take a large dose of steroids. As of age 23,
HOT was introduced, and since age 25, as soon as her
clinical rotations started, pain in the right hip joint
began to manifest. Thereafter, deformation of the right
hip joint progressed until at age 33, and she developed
femoral head avascular necrosis (OA). Gradually, thehip joint pain worsened with the limitations in her
range of motion (ROM), and abduction externalrotation contracture appeared. The patient suffered
extreme pain in the right pelvis during walking and inorder to reduce the joint load during walking had
been using a cane. She presented at our hospital
hoping to receive exercise treatment with KAATSU
training. The patient had been taking prednisolone 3
mg/day, theophylline, montelukast sodium, andsalmeterol/fluticasone.
This research was approved by the Institutional
Review Board at the University of Tokyo andperformed after receiving patient consent.

2. KAATSU training protocol

A KAATSU belt is wrapped around the base of thethigh and a KAATSU Master device (KAATSU Japan,
Co., Ltd) was used. KAATSU training was provided
for a total of 28 sessions over 3 months. Base pressure
was 45 – 50 SKU. The optimal pressure started at 100– 140 SKU and while repeatedly pressurizing anddepressurizing, it gradually increased in 20 SKU
increments, until an optimal pressure was reached.
The training menu was as follows. 1) 3 point set: Toecurls, ankle dorsiflexion, and ankle plantar flexion. 2)
KAATSU walk: gradually increased distance toapproximately 150 to 300m during each session until
a comfortable walking speed was achieved. 3) NonKAATSU walk: belts were removed and the patient
was allowed to walk for 75m to check for symptoms.
In late stage intervention, calf-raises and squats wereadded, and the patient extended her comfortable
walking distance to approximately 300m. Calf raises
and squats were performed standing and bearing oneʼs
own weight. The KAATSU side in the early stage ofintervention was the affected leg only, starting with a
KAATSU pressure of 300-320 SKU. In the latter stages,
in addition to the affected right thigh, the healthy left
thigh (160-300 SKU) exercise therapy under KAATSU
condition was also conducted.

3. Evaluation

The following evaluations were conducted before
and after training.
1) Magnetic resonance imaging (MRI)2) Life functioning: 36-item short form health survey(SF–36v2).
The effect of training on life functioning wasinvestigated using the SF-36v2 evaluation survey.
Role physical, body pain, general health, vitality,
social functioning, role emotional, and mental
health were assessed.
3) Muscle strength evaluation using Cybex
Measurements were taken with the subject seatedin a chair with the trunk and thighs immobilized.
Exercise involved bending the knee joint 90°, froma flexed position to extension and flexion. Bilaterallower limb muscle strength (isomeric knee extension
strength: knee joint 75°, isokinetic knee extension
and flexion muscle strength: 30°/sec, 90°/sec, 180°/sec) was determined.
4) Functional analysis of the hip joint by Japanese
Orthopaedic Association (JOA) hip scores as shownin Table 1 (Takatori et al., 2010)5) Dual energy x-ray absorbed absorptiometry (DEXA)
bone mineral density measurement device.

4. Results and clinical course

MRI findings before training are shown in Fig. 1A(left). T1 and T2 weighted images of the right femoral
head weight-bearing areas revealed areas of low
intensity signals. The surrounding areas showed highsignals in the T2 weighted image, suggesting bone
necrosis and an edematous change of the surrounding
marrow. Her right hip joint showed joint space
narrowing and formation of bone spurs, while thefemoral head showed signs of flattening leading to

T. Nakajima, T. Yasuda, K. Fukumura., et al.

3

Table 1. JOA scores for the hip joint (From Takatori et al., 2010)

I. Painpoint
No complaints regarding the hip joint
40
Indefinite complaints (feeling strange, fatigue) present but no pain
35
No pain during walking (however at the start of walking or after walking for long distances there is sometimes pain) 30
No spontaneous pain. Pain during walking, but disappears with short rests
20
Spontaneous pain is sometimes present. Pain during walking but alleviates with rest
10
Continuous spontaneous pain or nocturnal pain0
II. Range of motion assessment
Flexion: Joint angle counted in 10° intervals, one point per 10°. However, all points beyond 120° are counted
as 12 points (if joint contracture is present this is subtracted and evaluations based on movable range).
Abduction: Joint angles are measured in 10° increments and each 10° is counted as 2 points.
However any angle over 30° is counted as 8 points
III. Walking ability
Absolutely no complaints regarding the joint
40
Indefinite complaint (feeling strange, fatigue), no pain
35
No pain during walks (however there may be pain at the start of the walk or after walking long distances)
30
No spontaneous pain. Pain during walks disappears after short rests.
20
Spontaneous pain is sometimes present. Pain present during walks but is relieved after rest.
10
Continuous or spontaneous pain or nocturnal pain.
0
IV. Activities of daily living (ADL)
Evaluationeasy
difficult
impossible
Knee blankets
420Standing work (includes housework) (continues for about 30 minutes).
4
2
0
If rests are required, it is considered “difficult”. In cases where exercise
can only be continued for 5 minutes, it is considered “impossible”.
Squatting and standing (those who require assistance: consider it “difficult”)
4
2
0
Climbing up and down stairs (those who require a railing: consider it “difficult”)
4
2
0
Getting on and off cars and buses
4
2
0

Figure 1. A: MRI findings before and after KAATSU training. Before training (left), after training (right) B: Dual-energy x-ray
absorptiometry (DEXA) scan bone mineral density findings before and after KAATSU training. After training, bone mineraldensity in the right leg (affected side) was clearly increased, compared with the left leg (healthy side).

4

KAATSU training® as a new exercise therapy for femoral head avascular necrosis: A case study

Figure 2. Efficacy of KAATSU training in a patient with femoral head avascular necrosis. A: Effect on JOA score. a: JOA score(total, comprehensive), b: Pain, c: Walking, d: ROM (range of motion), B: SF-36v2. Role physical, Body pain, General health,
Vitality, Social functioning, Role emotional, Mental healtha case of secondary arthrosis. Surrounding areas
included a small high-signal intensity subchondralbone cyst. The other hip joint showed no signs ofabnormally high intensity areas. Based on these MRI
findings, the patient was diagnosed with Association
Research Circulation Osseous (ARCO) stage IV rightfemoral head avascular necrosis and secondary hiparthrosis.
Before and after training, several evaluations werecarried out. Fig. 2A shows the effectiveness of KAATSU
training on JOA hip scores. JOA (pain, b) scores
were 10 (right), 40 (left); while the JOA (walk, c)scores were 16 (right), 20 (left); and JOA (score,comprehensive, a) was 55 (right), 84 (left). After
training, all scores showed marked improvement in
the right affected leg compared to the left healthy leg.
JOA (ROM (range of motion), d) revealed no signs ofimprovement on the affected side. In the latter half oftraining, pain of the hip joint during walking dissipated
so that the patient no longer required a cane to walk.
In addition, there was a clear improvement in thepatientʼs walking style.
Fig. 2B shows the effect on SF–36v2 before andafter KAATSU training. Role physical, body pain,
general health, vitality, social functioning, roleemotional, and mental health were evaluated. Physicalfunction, role physical, body pain, general health,vitality, social functioning all improved after KAATSU
training
Figure 3 shows the effects of KAATSU training onlower limb muscle strength (extension and flexion).
Muscle strength during extension and flexion wasmarkedly improved in the right leg on the affectedside, compared to the healthy left leg.
Fig. 1B shows the efficacy of using KAATSU training
on bone mineral density measured by DEXA. There
was a clear increase in right affected leg bone mineraldensity from 0.798 to 0.836. On the other hand, theleft healthy leg went from 0.857 to 0.868 with no clear
signs of improvement. Furthermore, MRI findings
after KAATSU training shown in Fig. 1A (right)
showed a tendency for the right femoral head necrosis
to improve.

T. Nakajima, T. Yasuda, K. Fukumura., et al.

5

Figure 3. Effect of KAATSU training on lower limb muscle strength (knee extension, knee flexion) measured by Cybex.

5. Discussion

We treated a patient with femoral head avascularnecrosis for 3 months with KAATSU training andnoted the following improvements. 1) After KAATSU
training, the JOA score of the hip joint and the JOA
pain score both improved markedly. 2) Together with
an apparent improvement in gait, femoral muscle
strength improvement was noted while bone mineraldensity of the lower limbs had clearly increased in
the affected side. 3) MRIs showed a tendency for
improvement of the right femoral head necrotic site.
In this patient, SF–36v2 was evaluated. Of the life
functions, physical function, role physical, general
health, vitality, social functioning, and walking ability
based on the Japan Orthopedic Association hip score(JOA hip score) (Takatori et al., 2010) had all improved.
Furthermore, muscle strength on the affected side had
increased, proving that muscle strength improvementwith KAATSU training can lead to improved walking
ability and have a major impact on enhancing QOL.
This meant that in the latter half of the training, thepatient became able to walk without a cane. In
addition, the affected limb could support weight
without use of a cane, and it is believed that there wasa clear increase in bone mineral density on the affectedside.
The mechanism for this effect of KAATSU training
includes a characteristic of KAATSU training (Takaradaet al., 2000; Sato et al., 2007) which is that exercise
under restricted muscle blood flow conditions leads toincreased muscle strength and muscle growth after
only a short period of low stress exercise. In this case,
we observed a clear increase in muscle strength with
only 3 months of KAATSU training. KAATSU training
is just the right rehabilitation method for patients withvarious diseases and our aging society (Nakajima,
2010; Abe et al., 2010; Ozaki et al., 2011; Nakajima etal., 2011; Yasuda et al., 2014). Loading included nonweight bearing, elastic band (Yasuda et al., 2015), a

dumbbell, walking (Abe et al., 2006), and ergometer(Abe et al., 2010) loads. In this way, KAATSU training
is an extremely useful rehabilitation method foruse in patients in whom excessive stress would beinappropriate. In our case, we added squats and calf
raises to the KAATSU walking schedule, carrying out
various forms of exercise in a way that the femoral
head would not have to bear any weight. As a result,patient ADLs improved markedly. However, the ROM
did not improve. Therefore, in the future we believe a
longer investigation is warranted.
Furthermore, after KAATSU training, pain scoresbased on the SF–36v2 and JOA hip scores showed
clear signs of improvement. With improvement ofher pain, the patient no longer required a cane andwe believe her quality of life has been greatly
improved because she regained the ability to walk.
The mechanism responsible for improving pain in
KAATSU training is still unknown, but increased
muscle strength, muscle growth and alleviation of theweight-bearing on the hip joints are believed to play arole. On the other hand, KAATSU training leads to adecrease in intramuscular partial O2 pressure andhypoxemia during exercise under restricted blood
flow. Reactive hyperemia develops and vascularendothelial growth factor (VEGF), and nitric oxide(NO) production is enhanced (Takano et al., 2005;
Horiuchi and Okita, 2012) in response to vascularrefilling after the belts are released, leading to
improvements in endothelial function and blood
flow. We propose these improvements in blood flow
helped to heal the necrosis in the femoral head.
Animal models of femoral head avascular necrosis
caused by steroids have actually shown that as bloodflow into the femoral head decreases, both VEGF
protein and mRNA decrease (Wang et al., 2010).
However, the improvement of MRIs in the present
study for 3 months was minor so the effects should befurther confirmed in a long-term study. In addition,

6

KAATSU training® as a new exercise therapy for femoral head avascular necrosis: A case study

investigations into elucidating the mechanism behind
pain relief with KAATSU training are warranted.
Conservative treatment for femoral head avascularnecrosis should be instituted carefully to avoid
crushing the femoral head, and there are currently
no effective rehabilitation methods other thansymptomatic treatment such as using a cane or walker
to reduce placing weight on the affected hip joint.
From the present study, KAATSU training may be auseful rehabilitation method to treat femoral headavascular necrosis.

Summary

We reported our experience with a patient who
developed femoral head avascular necrosis while onsteroid therapy who was successfully treated withKAATSU training. We believe further clinical research
will be necessary.
<Nakajima T, Yasuda T, Fukumura K, and Morita T
have participated in seminars until September 2014
donated by KAATSU Japan.>

References
1) Abe T, Fujita S, Nakajima T, Sakamaki M, Ozaki H, Ogasawara R,
Sugaya M, Kudo M, Kurano M, Yasuda T, Sato Y, Ohshima H, Mukai
C, Ishii N (2010) Effects of low-intensity cycle training with restrictedleg blood flow on thigh muscle volume and VO2max in young men. J
Sports Sci Med. 9:452-458.
2) Abe T, Kearns CF, Sato Y (2006) Muscle size and strength are
increased following walk training with restricted venous blood flowfrom the leg muscle, KAATSU-walk training. J Appl Physiol.
100:1460-1466.
3) Abe T, Sakamaki M, Fujita S, Ozaki H, Sugaya M, Sato Y, Nakajima
T (2010) Effects of low-intensity walk training with restricted leg bloodflow on muscle strength and aerobic capacity in elderly subjects. J
Geriatr Phy Ther. 33:34-40.
4) Chang CC, Greenspan A, Gershwin ME (1993) Osteonecrosis:
current perspectives on pathogenesis and treatment. Semin Arthritis
Rheum. 23:47-69.
5) Cruess RL (1976) Steroid-induced avascular necrosis of the head of
the humerus. Natural history and management. J Bone Joint Surg Br.
58:313-317.
6) Ding H, Wang T, Xu D, Cha B, Liu J, Li Y (2015) Dexamethasoneinduced apoptosis of osteocytic and osteoblastic cells is mediated by
TAK1 activation. Biochem Biophys Res Commun. 460:157-163.
7) Horiuchi M, Okita K (2012) Blood flow restricted exercise andvascular function. Int J Vasc Med. 2012:543218.
8) Kerachian MA, Séguin C, Harvey EJ (2009) Glucocorticoids inosteonecrosis of the femoral head: a new understanding of themechanisms of action. J Steroid Biochem Mol Biol. 114:121-128.
9) Nakajima T (2010) KAATSU training and thickening of the muscle.
In: Kozuki M et al. (Eds.) Latest Rehabilitation Medicine for
Rehabilitation Physicians and Healthcare Professionals (in Japanese),
Advanced Medical Series 40, Advanced Medical Technology Institute,Japan, pp292-297.
10) Nakajima T, Yasuda T, Sato Y, Morita T, Yamasoba T (2011) Effectsof Exercise and Anti-Aging. Anti-Aging Medicine 8:92-102.

11) Ozaki H, Sakamaki M, Yasuda T, Fujita S, Ogasawara R, Sugaya
M, Nakajima T, Abe T (2011) Increases in Thigh Muscle Volume andStrength by Walk Training with Leg Blood Flow Reduction in Older
Participants. J Gerontol A Biol Sci Med Sci. 66:257-263.
12) Sato Y, Ishii N, Nakajima T, Abe T (2007) Theory and Practice of
KAATSU Training, Kodansha.
13) Takano H, Morita T, Iida H, Asada K, Kato M, Uno K, Hirose K,
Matsumoto A, Takenaka K, Hirata Y, Eto F, Nagai R, Sato Y,
Nakajima T (2005) Hemodynamic and hormonal responses to ashort-term low-intensity resistance exercise with the reduction ofmuscle blood flow. Eur J Appl Physiol. 95:65-73.
14) Takatori Y, Ito K, Sofue M, Hirota Y, Itoman M, Matsumoto T,
Hamada Y, Shindo H, Yamada H, Yasunaga Y, Ito H, Mori S, Owan I,
Fujii G, Ohashi H, Mawatari T, Iga T, Takahira N, Sugimori T,
Sugiyama H, Okano K, Karita T, Ando K, Hamaki T, Hirayama T,
Iwata K, Matsuura M, Jingushi S (2010) Investigation Group into
Coxarthrosis and Acetabular Dysplasia in Japan. Analysis ofinterobserver reliability for radiographic staging of coxarthrosis andindexes of acetabular dysplasia: a preliminary study. J Orthop Sci.
15:14-19.
15) Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000) Effects of resistance exercise combined with moderatevascular occlusion on muscular function in humans. J Appl Physiol.
88:2097-2106.
16) Wang C, Peng J, Lu S (2014) Summary of the various treatments forosteonecrosis of the femoral head by mechanism: A review. Exp Ther
Med. 8:700-706.
17) Wang G, Zhang CQ, Sun Y, Feng Y, Chen SB, Cheng XG, Zeng BF(2010) Changes in femoral head blood supply and vascularendothelial growth factor in rabbits with steroid-induced
osteonecrosis. J Int Med Res. 38:1060-1069.
18) Weinstein RS (2011) Glucocorticoid-induced bone disease. (2011)
N Engl J Med. 365:62-70.
19) Yasuda T, Fukumura K, Fukuda T, Uchida Y, Iida H, Meguro M,
Sato Y, Yamasoba T, Nakajima T (2014) Muscle size and arterial
stiffness after blood flow-restricted low-intensity resistance training inolder adults. Scand J Med Sci Sports. 24:799-806.
20) Yasuda T, Fukumura K, Uchida Y, Koshi H, Iida H, Masamune K,
Yamasoba T, Sato Y, Nakajima T (2015) Effects of Low-Load, Elastic
Band Resistance Training Combined With Blood Flow Restriction on
Muscle Size and Arterial Stiffness in Older Adults. J Gerontol A Biol
Sci Med Sci. 70:950-958.

Authorʼs affiliations
T. Nakajima, Heart Center, Dokkyo Medical University Hospital,
Tochigi, JapanT. Yasuda, School of Nursing, Seirei Christopher University, Shizuoka,
Japan
K. Fukumura, Kanto Central Hospital of the Mutual Aid Association of
Public School Teachers, Tokyo, Japan
M. Kurano, Jumonji University, Research Institute of Food and Nutrition
and Health, Tokyo, Japan
T. Imanishi, Medical Affairs, Kyokushin-Kaikan, Kanagawa, Japan
T. Morita, Y. Sato, KAATSU International University, Sri Lanka
Y. Hiraizumi, Department of Orthopaedic Surgery, Showa University
School of Medicine, Tokyo, JapanThe use of KAATSU Training or the term “KAATSU Training”
in the body text are registered trademarks of KAATSU JAPANCo., Ltd.
©2015 KAATSU JAPAN Co., Ltd.

Case Report

KAATSU training as a new effective exercise therapy
in a case of femoral medial condyle osteonecrosis
Yutaka Hiraizumi1*), Toshiaki Nakajima2), Yoshiaki Sato3), Toshihiko Imanishi4)
Int. J. KAATSU Training Res. 2016; 12: 1-4*Correspondence to:
Yutaka Hiraizumi, Department of Orthopaedic Surgery,Showa University School of
Medicine
1-5-8, Hatanodai,
Shinagawa-ku, Tokyo,
142-8555 Japane-mail: hiraizum@med.
showa-u.ac.jp
See end of article forauthors’ affiliations

Introduction

Idiopathic osteonecrosis of the medial condyle of the femur, a relatively common disease among
Japanese women 60 years or older, is often progressive and requires surgical treatment. In thispaper, we report on a case where KAATSU training was effective for a 71-year-old woman withbone necrosis in the left femoral medial condyle revealed by magnetic resonance imaging (MRI).
At the first visit, the patient was suffering severe pain, and unable to walk without a cane. After 1
to 2 months of KAATSU training, her pain was mitigated and in about 3 months she was able towalk without a cane. In 6 months she could go upstairs and downstairs using the handrails andabout 2 to 3 months later, she no longer needed to use the handrails. MRI revealed marked
shrinkage (to 10 mm x 15 mm) of the necrotized region as a result of bone tissue remodeling.
From these results, KAATSU training seems to be useful as a new method of rehabilitation for patients with idiopathic osteonecrosis of the medial condyle of the femur.

Osteonecrosis (ON) of the medial condyle of the femur
may develop as a secondary condition associated with theprolonged use of steroids. However, idiopathic ON of themedial condyle of the femur is relatively common among
women 60 years or older. In the early stages, the disease isdifficult to distinguish from knee osteoarthritis by radiography and sometimes it is accompanied by severe pain.
The patients may be followed up after conservative treatment. In many cases, however, surgical treatments such asarthroplasty are unavoidable because progression cannot
be suppressed by conservative treatment alone1,2).
KAATSU training3,4) is expected to be effective for increasing muscle volume and muscle power, even with low
loads by training under blood flow restriction. KAATSU
training represents a method of rehabilitation suitable forpatients with various diseases and this aged society5-9). The
exercises include load-free exercises, elastic bands 10), andfree weights, as well as walking11) and ergometers12). As
such, KAATSU training is attracting much attention as amethod of rehabilitation which avoids high physical loads.
We recently reported a case in which KAATSU training
was effective in a patient with steroid-induced osteonecrosis of the femoral head13). In this paper, we report a patientwith idiopathic ON of the medial condyle of the femur
who achieved remarkable improvement of the disease by
KAATSU training.

1. Case review

Patient: A 71-year-old woman (157 cm in height,
weighing 70 kg)
Diagnosis: Idiopathic osteonecrosis of the medial condyle of the femur
Chief complaint: Left medial knee pain on walking
Family history of illness: Non-contributory.
History of present illness:
In 2014, the patient presented with left medial knee
pain at a nearby orthopedic clinic. She was diagnosed withknee osteoarthritis, and underwent ambulatory treatment
for several months. Since her symptoms did not remit,
and the pain worsened, she visited another medical institution in November 2014. The diagnosis of osteonecrosisof the medial portion of the medial condyle of the left femur was established. In January 2015, MRI findings suggested further exacerbation. KAATSU training was started
in March 2015. One year 3 months later, in June 2016,
the outcome was good with marked shrinkage of the necrotized region and improved activities of daily living.

2. KAATSU training protocol

KAATSU training was performed using the KAATSU
MASTER equipment (KAATSU Japan Co., Ltd.). Taking
into account the fact that the patient was an elderly woman, the wearing pressure was set at low levels (20-30
SKU). In March to April 2015, at the start of training,
KAATSU training was performed for the leg on the dis-

1) Department of Orthopaedic Surgery, Showa University School of Medicine2) Heart Center, Dokkyo Medical University Hospital3) Chairman, Center for KAATSU Research at Harvard Medical School4) KAATSU Medical Training Center

2

KAATSU training as a new effective exercise therapy in a case of femoral medial condyle osteonecrosis

CR; November 19, 2014

CR; January 21, 2015

CR; June 22, 2016 CR

MRI; November 19, 2014

MRI; February 18, 2015

MRI; June 22, 2016

Figure 1. Bone x-ray and MRI images taken before and after KAATSU training.

eased side (left) only. Drills which were performed exclusively on the diseased side of the lower half of the body included the following: 1) compression and decompression,2) three point set: Toe curls, ankle dorsiflexion, and ankle
plantar flexion. 3) leg extensions, and 4) leg curls. In April
to May 2015, the patient became accustomed to unilateralleg pressurization and switched to bilateral pressurization.
In addition to the unilateral program, quarter squats wereadded. Bilateral sessions for the lower half of the body included the following: 1) compression and decompression,2) quarter squats, 3) diseased-side leg extensions, 4) diseased-side leg curls, and 5) bilateral pressurized walking(KAATSU walking). In June 2015, a set of sessions for theupper half of the body was newly included in the training
program. Bilateral sessions for the upper half of the bodyconsisted of the following: 1) compression and decompression, 2) three point set: Toe curls, ankle dorsiflexion,

and ankle plantar flexion, 3) stiff shoulder course, and 4)
dumbbell curls (1 kg). Bilateral sessions for the lower halfof the body included: 1) compression and decompression,2) quarter squats, 3) high-knee drills, 4) diseased-side leg
extensions, 5) diseased-side leg curls, and 6) bilateral pressurized walking (KAATSU walking). Equipment pressure
was increased step by step with gradual adaptation, and it
was finally set at 320 SKU for unilateral application, and
280 SKU for bilateral application.

3. Course of symptoms

At the first visit, the patient was suffering severe pain,
and was unable to walk without a cane. After 1 to 2
months of KAATSU training, her pain was remarkably
mitigated and in about 3 months she was able to walkwithout a cane. In 6 months she was able to go upstairs
and downstairs using handrails and about 2 to 3 months

Yutaka Hiraizumi, Toshiaki Nakajima, Yoshiaki Sato, Toshihiko Imanishi

later, she no longer needed the use of handrails.

4. Bone X-ray and MRI findings (see Figure 1)

November 19, 2014
CR showed a mild regression of bone cortex, suspectedof being bone necrosis in the load-exerted portion of theleft femoral medial condyle; MRI revealed a 10 mm x 40
mm necrotized bone region at the same site.
February 18, 2015
The necrotized region was found to have expanded.
June 22, 2016
MRI revealed marked shrinkage of the necrotized region (to 10 mm x 15 mm) as a result of bone tissue remodeling, with mild regression persisting on the load-exerted surface of the medial condyle at the necrotized bone.

Discussion

Idiopathic femoral osteonecrosis develops mainly in the
medial condyle of the femur, the anatomical site on whichmuch of human body weight is exerted. Therefore, patients may undergo conservative treatments, including
symptom relief by the reduction of stress on the affected
portion with the use of, for example, a cane, and enhancement of lower limb function by training of the quadriceps
femoris muscle. In many cases, however, surgical treatments such as arthroplasty are unavoidable because theprogression cannot be suppressed by conservative treatment alone. Surgical treatments for idiopathic osteonecrosis of the medial condyle of femur include unilateral knee
arthroplasty (UKA), total knee arthroplasty (TKA), andopening wedge high tibial osteotomy (OWHTO) 14). In
particular, OWHTO sometimes leads to bone regeneration via drilling following curettage of the necrotized portion.
In the present case of osteonecrosis of the medial condyle of femur, KAATSU training was found to be effective; it produced bone regeneration, without surgical maneuvers. The patient achieved marked mitigation of painin 1 to 2 months after the start of KAATSU training. Although the mechanisms for this pain mitigation by
KAATSU training remains unknown, muscle strengthening and building by KAATSU training3,4) might lessen thephysical load on the patient’s knees. KAATSU training
may be described as a method of rehabilitation suitable forpatients with various diseases and for this aged society5-9).
The available means of applying training burdens include
load-free exercises, elastic bands10), dumbbells, walking11),
and ergometers12); KAATSU training is considered quite a
useful method of rehabilitation for patients who do notwish to undergo heavy physical loads. In the present case,the patient undertook pressurized walking, squatting,self-weighted leg extensions, leg curls, and other exercises
in a way such that the femoral head would not bear a highload.
On the other hand, it remains unclear as to the mecha-

3nism of bone regeneration through KAATSU training
without surgical treatment. In addition to its effects on
muscle strengthening and building, and the endocrine system, including growth hormones 15), KAATSU training
may increase the production of vascular endothelial
growth factor (VEGF), nitric oxide (NO), and other substances by decreasing muscular oxygen tension and hypoxia in the muscles during exercises, and by inducing vascular reactive hyperemia following belt release16,17), and hence
it improves endothelium function and blood circulation,
which in turn may lead to the amelioration of the necrosis.
In conclusion, KAATSU training is potentially highly
useful as a new method of rehabilitation for patients with
idiopathic osteonecrosis of the medial condyle of the femur. Further investigation is expected to elucidate themechanism of the onset of the effects of this non-invasive
method with slight physical burden.

References
1) Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien
SJ (1998) Osteonecrosis of the knee: current clinical concepts. Knee
Surg Sports Traumatol Arthrosc. 6: 2-11.
2) Karim AR, Cherian JJ, Jauregui JJ, Pierce T, Mont MA (2015) Osteonecrosis of the knee: review. Ann Transl Med. 3:6. doi: 10.3978/
j.issn.2305-5839.2014.11.13.
3) Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000) Effects of resistance exercise combined with moderate vascular occlusion on muscular function in humans. J Appl Physiol 88:
2097-2106.
4) Sato Y, Ishii N, Nakajima T, Abe T. (2007) Theory and Practice of
KAATSU training (in Japanese), Kodansaha.
5) Nakajima T, Yasuda T, Sato Y, Morita T, Yamasoba T (2011) Effectsof Exercise and Anti-Aging. Anti-Aging Medicine 8: 92-102.
6) Abe T, Sakamaki M, Fujita S, Ozaki H, Sugaya M, Sato Y, Nakajima
T (2010) Effects of low-intensity walk training with restricted leg
blood flow on muscle strength and aerobic capacity in elderly subjects. J Geriatr Phy Ther 33: 34-40.
7) Ozaki H, Sakamaki M, Yasuda T, Fujita S, Ogasawara R, Sugaya M,
Nakajima T, Abe T (2011) Increases in Thigh Muscle Volume andStrength by Walk Training with Leg Blood Flow Reduction in Older
Participants. J Gerontol A Biol Sci Med Sci. 66: 257-263.
8) Nakajima T (2010) KAATSU training and thickening of the muscle.
In; Kouki M, et al. (Eds.) Latest Rehabilitation Medicine for Rehabilitation Physicians and Healthcare Professionals (in Japanese), Advanced Medical Series 40, Advanced Medical Technology Institute,Japan, pp292-297.
9) Yasuda T, Fukumura K, Fukuda T, Uchida Y, Iida H, Meguro M, SatoY, Yamasoba T, Nakajima T (2014) Muscle size and arterial stiffness
after blood flow-restricted low-intensity resistance training in older
adults. Scand J Med Sci Sports. 24: 799-806.
10) Yasuda T, Fukumura K, Uchida Y, Koshi H, Iida H, Masamune K,
Yamasoba T, Sato Y, Nakajima T (2015) Effects of Low-Load, Elastic
Band Resistance Training Combined With Blood Flow Restriction on
Muscle Size and Arterial Stiffness in Older Adults. J Gerontol A Biol
Sci Med Sci. 70: 950-958.
11) Abe T, Kearns CF, Sato Y (2006) Muscle size and strength are increased following walk training with restricted venous blood flowfrom the leg muscle, KAATSU-walk training. J Appl Physiol 100:
1460-1466.

4

KAATSU training as a new effective exercise therapy in a case of femoral medial condyle osteonecrosis12) Abe T, Fujita S, Nakajima T, Sakamaki M, Ozaki H, Ogasawara R,
Sugaya M, Kudo M, Kurano M, Yasuda T, Sato Y, Ohshima H, Mukai C, Ishii N (2010) Effects of low-intensity cycle training with restricted leg blood flow on thigh muscle volume and VO2max inyoung men. J Sports Sci Med. 9; 452-458.
13) Nakajima T, Yasuda T, Fukumura K, Kurano M, Imanishi T, Morita
T, Sato Y, Hiraizumi Y (2015) KAATSU training as a new exercise
therapy for femoral head avascular necrosis: A case study. Int J
KAATSU Training Res 11: 1-6.
14) Horiuchi T (2015) Examinations of postoperative clinical performance and endoscopic findings of opening wedge high tibial osteotomy in idiopathic osteonecrosis of femoral head (in Japanese)
JOKAS 40: 766-770.
15) Takarada Y, Nakamura Y, Aruga S, Onda T, Miyazaki S, Ishii N(2000) Rapid increase in plasma growth hormone after low-intensity resistance exercise with vascular occlusion. J Appl Physiol 88: 6165.

16) Takano H, Morita T, Iida H, Asada K, Kato M, Uno K, Hirose K,
Matsumoto A, Takenaka K, Hirata Y, Eto F, Nagai R, Sato Y, Nakajima T (2005) Hemodynamic and hormonal responses to a shortterm low-intensity resistance exercise with the reduction of muscle
blood flow. Eur J Appl Physiol 95: 65-73.
17) Horiuchi M, Okita K (2012) Blood flow restricted exercise and vascular function. Int J Vasc Med 2012: 543218.
Author’s affiliations
T. Nakajima, Heart Center, Dokkyo Medical University Hospital, Tochigi, Japan
T. Imanishi, KAATSU Medical Training Center, Tokyo, Japan
Y. Hiraizumi, Department of Orthopaedic Surgery, Showa University
School of Medicine, Tokyo, Japan
Y. Sato, Center for KAATSU Research at Harvard Medical School, Boston, U.S.ACASE REPORT

Effect of KAATSU training on thigh muscle size andsafety for a patient with knee meniscectomy over 3
years
Tomohiro Yasuda1,2), Seiya Oosumi3), Shinpei Sugimoto3), Toshihiro Morita3), Yoshiaki Sato4),
Masanori Ishii3,5), Toshiaki Nakajima2,6).
Int. J. KAATSU Training Res. 2017; 13: 11-14

Correspondence to:Tomohiro Yasuda, PhD.
School of Nursing, Seirei
Christopher University
3453, Mikatahara, Kita-Ku,
Hamamatsu, Shizuoka,
433-8558, Japan
E-Mail: tomohiro-y@seirei.ac.jp
Phone: +81-53-439-1417
Fax: +81-53-439-1406
See end of article forauthors’ affiliations

Introduction[Objective] It is well known that knee meniscectomy is one of the major knee surgeries, which induces thigh muscle atrophy. However, it is unclear whether thigh muscle size after knee meniscectomy can be improved with KAATSU training. We examined effect of KAATSU training on thighmuscle size and safety for a patient with knee meniscectomy.
[Methods] The patient was a 57-year-old woman (standing height 159 cm and body weight 52kg). The KAATSU training composed of 7 types of resistance exercise and one type of cycling exercise was provided for a total of 125 sessions over approximately 3 years. Transverse scans werecarried out for mid-thigh length. Thigh muscle cross-sectional area (CSA) in affected-leg and unaffected-leg was measured by the CT scan before, 63 weeks, and 152 weeks after the training.
[Results] Thigh muscle CSA was highly increased for affected-leg, and the attained level was exactly similar for both legs after the 152 weeks training period.
[Conclusion] The long-term KAATSU exercises were a highly safe and effective training method fora patient with knee meniscectomy.
Key words: knee meniscectomy, muscle hypertrophy, thigh muscle, long duration, rehabilitation.

It is well known that knee meniscectomy is one of the
major knee surgeries, which induces thigh muscle atrophy(Akima and Furukawa, 2005; Ericsson et al., 2006). In
general, traditional high-intensity exercise training (≥ 70%
1-repetition maximum: 1RM) improves skeletal muscle
morphology and function (ACSM, 2009), but it appears
that this method is not practical and may even be dangerous in patients with knee meniscectomy. On the other
hand, KAATSU training (≤ 30% 1RM) can produce muscle hypertrophy and does not decrease vascular function(Ozaki et al., 2013; Yasuda et al., 2015; Yasuda et al.,2016). Additionally, recent studies (Nakajima et al., 2015;
Hiraizumi et al., 2016) reported that KAATSU training isquite useful as a rehabilitation method in disorder of bone
(femoral head avascular necrosis, femoral medial condyle
osteonecrosis). However, it is unclear whether thigh muscle size after knee meniscectomy can be improved withKAATSU training.
Thus, the purpose of this study was to examine effect of
KAATSU training on thigh muscle size and safety for apatient with knee meniscectomy.

1. Case review

Patient: A 57-year-old woman (standing height 159 cm,
body weight 52 kg), a physical education teacher
Diagnosis: knee meniscectomy
Chief complaint: Left knee joint pain on walking.
Family history of illness: No notable findings.
History of present illness & course of symptoms: On 15
October, 2014, she received meniscectomy implementation of the left knee under arthroscopy, and visited Okamoto-Ishii Hospital for receiving rehabilitation. At the first
visit, the patient was suffering from strong leg swelling,heat sensation, and severe pain for left knee and was unable to walk without a cane. The KAATSU training started
from October 30. At the start of rehabilitation, after performing pressurization / depressurization, exercises of isometric contraction without joint movement were performed. After that, she received icing. The pain gradually
decreased, and she could raise the stairs with crutches. After 1 month of KAATSU training, her pain was remark-1) School of Nursing, Seirei Christopher University, Shizuoka, Japan
2) Department of Cardiovascular Medicine, School of Medicine, Dokkyo Medical University, Tochigi, Japan
3) Okamoto-Ishii Hospital, Shizuoka, Japan4) Center for KAATSU Research at Harvard Medical School, Massachusetts, USA.
5) Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Japan.
6) Heart Center, School of Medicine, Dokkyo Medical University Hospital, Tochigi, Japan12

Effect of KAATSU training on thigh muscle size and safety for a patient with knee meniscectomy over 3 years

Figure 1. Pictures show 7 types of KAATSU resistance training.

ably mitigated and she was able to walk without cane. On
January, 2015, the pain was abolished. After 9 months, she
was able to go upstairs and downstairs, and began to run alittle without pain. She noticed the increase of muscle
power and mass. After that, she also began to climb thestairs without problems, and could run through the hallway, and jump rope in physical education class. At present,
she is doing mountain climbing at her elementary school
excursions. On September 2017, she has received KAATSU training for approximately three years. Any side effects
have not been occurred during the long-term training.
The principles of the World Medical Association Declaration of Helsinki and the American College of Sports
Medicine Guidelines for Use of Human Subjects were adopted in this stady. The study was approved by the Ethics
Committee, and informed assent consent was obtained
from the patient.

2. KAATSU training protocol

During the KAATSU training sessions, a patient wore a
specially designed pneumatic cuff (50 mm width, KAATSU Master, KAATSU Japan Co., Ltd., Tokyo, Japan)
around the most proximal portion of both thighs. KAATSU training was provided for a total of 125 sessions overapproximately 3 years (from October 2014 to September
2017, 152 weeks). Basically, the cuffs were set at 40 SKU

Figure 2. KAATSU training protocols for each session.
Exercise

Menu
Intensity
6 setsLower leg weight
Unilateral knee extension(30, 30, 20, 20, 10, 10 reps) + 1.5 kg weight
6 setsBody weight
Bilateral calf raise(30, 30, 20, 20, 10, 10 reps) + 3.0 kg weight
Go up and down
6 setsBody weightwith one step
(30, 30, 20, 20, 10, 10 reps) + 1.5 kg weight
6 setsLower leg weight
Unilateral knee flexion(30, 30, 20, 20, 10, 10 reps) + 1.5 kg weight
6 set
Hip adduction
Lower leg weight(30, 30, 20, 20, 10, 10 reps)
3 setsHip extension
Lower body weight(30, 20, 10)
3 setsHip flexion
Lower body weight(30, 20, 10)
Bicycle ergometer
30 min65-70 wattand air pressure was inflated to 200 SKU. The training
protocol (7 types of resistance exercise and one type of cycling exercise) was shown as Figure 1 and 2. Eight exercises over 60 min were performed each session.

3. Computed tomographic (CT) finding

Subjects rested quietly in the body coil in a supine position with their legs extended and relaxed. Transverse scans
were carried out for mid-thigh length (from the top edge

T. Yasuda , S. Oosumi, S. Sugimoto, T. Morita , Y. Sato, M. Ishii, T. Nakajima

13

session) compared to unaffected-leg after the 63 weeks
training period. Taken together, KAATSU training using
body weight can induce large improvement in thigh muscle size for a patient with knee meniscectomy over thelong period.
In the present study, heart rate and ratings of perceived
exertion during 7 types of KAATSU resistance exercises(90-129 BPM and 11-16, respectively) and KAATSU cycling exercise (～127 BPM and ～11, respectively) were
not high level (data not shown). These results are similar
to that reported in previous KAATSU training studies forhealthy subjects (Yasuda et al., 2014; Kim et al., 2016; Yasuda et al., 2016). Thus, it appears that these KAATSU
exercises were a highly safe and effective training method
for a patient with knee meniscectomy.
In conclusion, KAATSU training is potentially highly
useful as a new method of rehabilitation for a patient withknee meniscectomy.

Acknowledgement

Figure 3. Thigh muscle cross-sectional area (CSA) in affected-leg and unaffected-leg before, 63 weeks, and 152 weeks after
training.

of the great trochanter to the lateral condyle of femur).
From the cross-sectional image, outlines of the thigh muscles were traced, and digitized by using a personal computer (MacBook, Apple, Tokyo, Japan) for analysis using
image analysis software (Image J 1.5, NIH, USA), andmuscle CSA was calculated. The CT scan was measured at
October 9, 2014, December 24, 2015, and September 9,2017. Thigh muscle CSA was highly increased for affected-leg, and the attained level was exactly similar for bothlegs at September 9, 2017 (Figure 3).

Discussion

The improvement of intrinsic morphology for the thighmuscles is important in exercise training for patients withknee injury and knee surgery. To the best of our knowledge, this is the first study to investigate the effect of
KAATSU training on muscle strength and function for apatient with knee meniscectomy. The primary finding of
this study was that KAATSU training remarkably increased the thigh muscle CSA for affected-leg, which wascomparable with the unaffected-leg after the long-term
period for 152 weeks.
Our findings show that KAATSU training after 63
weeks produces a hypertrophic potential of 0.33% per session for unaffected-leg, which is similar to that observed
following KAATSU training after 12 weeks using weightmachines (0.33% per session, Yasuda et al. 2014). Thissuggests that this training protocol is enough method for
improving thigh muscle size for unaffected-leg over a long
period. Additionally, the increase in thigh muscle CSA isapproximately 2-fold higher in for affected-leg (0.61% perThis study was supported, in part, by Grant-in-aid(#15K01553) from the Japan Ministry of Education, Culture, Sports, Science, and Technology.
Yasuda T, Morita T and Nakajima T belonged to thedepartment of Ischemic Circulatory Physiology (up to
September 2014) at Universiry of Tokyo, which was funded by KAATSU Japan Coy Ltd.

References
1) Akima H, Furukawa T (2005) Atrophy of thigh muscles after meniscal lesions and arthroscopic partial menisectomy. Knee Surg Sports
Traumatol Arthrosc. 13: 632-637.
2) American College of Sports Medicine (1998) American College ofSports Medicine position stand. Exercise and physical activity for
older adults. Med Sci Sports Exerc 30: 992-1008.
3) Ericsson YB, Roos EM, Dahlberg L (2006) Muscle strength, functional performance, and self reported outcomes four years after arthroscopic partial meniscectomy in middle-aged patients. Arthritis
Rheum. 55: 946-952.
4) Hiraizumi Y, Nakajima T, Sato Y, Imanishi T (2016) KAATSU training
as a new effective exercise therapy in a case of femoral medial condyle osteonecrosis. Int J KAATSU Training Res. 12: 1-4.
5) Kim D, Singh H, Loenneke JP, Thiebaud RS, Fahs CA, Rossow LM,
Young K, Seo DI, Bemben DA, Bemben MG (2016) Comparative
Effects of Vigorous-Intensity and Low-Intensity Blood Flow Restricted
Cycle Training and Detraining on Muscle Mass, Strength, and Aerobic Capacity. J Strength Cond Res. 30: 1453-1461.
6) Nakajima T, Yasuda T, Fukumura K, Kurano M, Imanishi T, Morita T,
Sato Y, Hiraizumi Y (2015) KAATSU training® as a new exercise
therapy for femoral head avascular necrosis: A case study. Int J
KAATSU Training Res. 11: 1-6.
7) Ozaki H, Yasuda T, Ogasawara R, Sakamaki-Sunaga M, Naito H,
Abe T (2013) Effects of high-intensity and blood flow-restricted
low-intensity resistance training on carotid arterial compliance: roleof blood pressure during training sessions. Eur J Appl Physiol. 113:
167-174.
8) Thiebaud RS, Loenneke JP, Fahs CA, Rossow LM, Kim D, Abe T, Anderson MA, Young KC, Bemben DA, Bemben MG (2013) The effects

14

Effect of KAATSU training on thigh muscle size and safety for a patient with knee meniscectomy over 3 yearsof elastic band resistance training combined with blood flow restriction on strength, total bone-free lean body mass and muscle thickness in postmenopausal women. Clin Physiol Funct Imaging. 33:
344-352.
9) Yasuda T, Fukumura K, Fukuda T, Uchida Y, Iida H, Meguro M, SatoY, Yamasoba T, Nakajima T (2014) Muscle size and arterial stiffness
after blood flow-restricted low-intensity resistance training in older
adults. Scand J Med Sci Sports. 24: 799-806.

10) Yasuda T, Fukumura K, Uchida Y, Koshi H, Iida H, Masamune K,
Yamasoba T, Sato Y, Nakajima T (2015) Effects of Low-Load, Elastic
Band Resistance Training Combined With Blood Flow Restriction on
Muscle Size and Arterial Stiffness in Older Adults. J Gerontol A Biol
Sci Med Sci. 70: 950-958.
11) Yasuda T, Fukumura K, Tomaru T, Nakajima T (2016) Thigh muscle size and vascular function after blood flow-restricted elastic
band training in older women. Oncotarget. 7: 33595-225607.

Case Report

Combination of KAATSU training® and BCAA intake for apatient after aortic valve replacement surgery: A case study
Ooshima A1), Ishizaka Y1), Katayanagi S1), Arakawa C1), Takahashi R1), Nozawa N1), Mizushima Y1),
Matsumoto K1), Sawaguchi T2), Haruyama A2), Toyoda S2), Ogawa H3), Shibasaki I3), Yagi H4), Yamaguchi S4), Uematsu A6), Yasuda T5), Sato Y7), Fukuda H3), Inoue T2), Nakajima T2)
Int. J. KAATSU Training Res. 2018; 14: 1-5

Correspondence to Dr.
Toshiaki Nakajima, Heart
Center, Dokkyo Medical
University, 880 Kitakobayashi, Mibu, Tochigi, Japan
321-0293
E-mail: nakat@dokkyomed.
ac.jp
Running head: KAATSU
training and BCAA
See end of article forauthors’ affiliations

Introduction

Abstract
We report a case in which a favorable course was obtained by using KAATSU training® and BCAA
intake early after aortic valve replacement surgery. The patient was a 43-year-old male with low
cardiac function who underwent aortic valve replacement surgery. Heart failure and hypotension
persisted while waiting for surgery. He tended to line on a bed all day, so that disuse muscular atrophy advanced. Therefore, in addition to the postoperative rehabilitation program, KAATSU training and BCAA intake were performed postoperatively and continued in outpatient rehabilitation.
The KAATSU training was performed using knee extension twice or three times a week. For BCAA
intake (2.5 g), one pack of jelly containing BCAA (Reha-Time Jelly, Clinico Co., Ltd.) was taken
within 30 minutes after the training. About 3 months later, the thigh circumference (+ 7.3 cm), themaximum voluntary isometric contraction of knee extension (+ 20 kgf), the quadriceps muscle
thickness (+ 1 cm) evaluated by a B-mode ultrasound, the muscle mass of the lower limb (+ 1kg), and a marked increase in thigh muscle cross-sectional area as measured by CT scan wereobserved. No deterioration of circulatory hemodynamics and side effects were observed during
the course. In conclusion, the combined use of KAATSU training and BCAA intake early after cardiac operation seems to be a safe and effective way to obtain muscle hypertrophy and muscle
strengthening, but further studies are needed to clarify it.
Key word: KAATSU training, cardiac surgery, muscle hypertrophy, muscle strength, BCAA

Rehabilitation for patients with heart disease is basedon aerobic exercise to improve cardiopulmonary function
and resistance training for increasing muscle strength andmass. However, excessive exercise load may increase therisk of arrhythmia and heart failure exacerbation1). Therefore, aerobic exercise based on exercise prescription underanaerobic threshold (AT) is usually performed. For a kindof aerobic exercise, an ergometer or a treadmill is used,
and its strength is determined by cardiopulmonary exercise testing (CPX). On the other hand, resistance exercise
more than 67% of 1 repetition maximum (1 RM) is required for improving muscle strength and mass2). But, it isrecommended to start from a load of 50-60% in the lower
limbs, taking safety into consideration3,4). For that reason,

the improvement of muscle strength and an increase inmuscle mass are not observed in several cases.
KAATSU training is a method that inventor Dr. Yoshiaki Sato repeatedly have conducted research for over 47
years. It is a novel exercise under the conditions with therestricted muscle blood flow, by binding the proximal portion of lower or upper extremities with a specially-designed belt. This training has been reported to inducemuscle hypertrophy and strengthen muscle in athletes andhealthy subjects, by using a short-term low-intensity exercise5-7). Until now, several clinical studies using KAATSU
training have been also reported to promote muscle hypertrophy in patients with cardiovascular diseases including ischemic heart disease7,8).
In addition to resistance training, the effect of ingesting1) Department of Rehabilitation, Dokkyo Medical University, Tochigi, Japan
2) Department of Cardiovascular Medicine, School of Medicine, Dokkyo Medical University, Tochigi, Japan
3) Department of Cardiovascular Surgery, School of Medicine, Dokkyo Medical University, Tochigi, Japan
4) Department of Department of Cardiology and Nephrology, Dokkyo Medical University, Tochigi, Japan.
5) School of Nursing, Seirei Christopher University, Shizuoka, Japan
6) Department of Health and Sport Sciences, Premedical Sciences, Dokkyo Medical University, Tochigi, Japan
7) Chaiman, Center for KAATSU Research at Harvard Medical School, U.S.A

2

Combination of KAATSU training® and BCAA intake for a patient after aortic valve replacement surgery: A case study

a beverage containing branched-chain amino acid (BCAA)
has been attracted attention. BCAA is considered to induce an increase of the muscle mass by enhancing the synthesis of muscle protein9) and preventing the degradationof muscle protein10).
Here, we report a case with low cardiac function inwhich a marked improvement of muscle strength andmass were obtained by using KAATSU training ® and
BCAA intake early after aortic valve replacement surgery.

Materials and method
1. Subjects

The patient was a 43-year-old male (173.0 cm, 66.3 kg,
BMI 22.2 kg / m2). He was urgently introduced to our
hospital with suspected heart failure from a nearby doctor.
He had no medical history, and coronary risk factors including dyslipidemia, hyperuricemia, and hypertension.
At the time of admission, plasma brain natriuretic peptide(BNP) level was 2566 pg / ml. The cardiac ultrasound examination showed thinner heart wall, and prominent left
ventricular enlargement (left ventricular (LV) end-diastolic
diameter (LVDd) 72.1 mm, left ventricular end-systolic
diameter (LVDs) 57.8 mm, left ventricular end-diastolic
interventricular septum (IVS) thickness (IVST) 7.5 mm,
left ventricular end-diastolic posterior wall thickness(LVPWT) 9.2 mm, left atrial diameter (LAD) 47 mm).
The left ventricular ejection fraction (LVEF) was 34%. He
was diagnosed as severe aortic regurgitation, and firstly received medication treatment. Cardiac rehabilitation started from the 7th disease day. However, the circulatory hemodynamics was unstable, and the exacerbation of heart
failure was observed on the 16th disease day. Symptoms ofhypotension also persisted and he became lying bed, so
systemic marked waste muscle atrophy was recognized.
Postoperative rehabilitation was resumed on the 42th day(Postoperative day 4: POD 4) after aortic valve replacement by thoracotomy on the 38th disease day. Since he
was young, muscle recovery was desired for social reintegration. For that reason, KAATSU training and BCAA intake were introduced from the 49th disease day (POD11), and outpatient rehabilitation continued even after
discharge.
This study has been approved by the ethics committeeof Dokkyo Medical University Hospital

2. Method

In the preoperative evaluation, only body composition
analysis (see below) was carried out in consideration of
hypotension and risk. On the 44th disease day (POD 6),
the thigh circumference, the maximum voluntary isometric contraction (MVC) of knee extension, body composition analysis, quadriceps muscle thickness measured by a
B-mode ultrasound and thigh muscle cross-sectional area
was measured by CT scan. The KAATSU training started
on the 49th disease day (POD 11) and reassessment was
performed on the 66th disease day before discharge (POD28). After discharge from the hospital, he received outpa-

tient rehabilitation at a frequency of twice or three times aweek and clinical evaluation was performed approximately
every month.
The apparatus named KAATSU NANO (KAATSU JAPAN Co., Ltd) was used for KAATSU training and a pressure cuff was attached to the base of both thighs. The set
pressure was gradually increased to a proper pressure (100to 200 SKU) at a mounting pressure of 15 ~ 25 SKU. Under the restriction of muscle blood flow, knee extension
exercise (OG wellness company, GX-320) was performed.
At the first time, the knee extension was done from a setof load of 20-30 % of 1 RM × 1 time of 20 repetitions.
Number of times and set number increased stepwise, andfinally 30 repetitions 3 sets (time between sets 30 seconds)
was carried out. The frequency of KAATSU training was
performed twice or three times a week. The KAATSU
training was conducted under the guide of a medical doctor who was qualified as a KAATSU instructor. The bloodpressure measurement, electrocardiogram monitoring, andsubjective strength measurements (Borg scale) were performed according to the rehabilitation guideline for cardiovascular diseases11). The BCAA (Reha-Time Jelly, Clinico Co., Ltd., Japan) was applied within 30 minutes after
the KAATSU training. The protein content was 10 g /120 g, and the total BCAA content was 2.5 g / 120 g with
800 I.U. (20 µg) vitamin D / 120 g. The BCAA composition (per 120 g of a bag) was isoleucine 0.63 nmol / ml
(0.6 g / 120 g), leucine 1.44 nmol / ml (1.4 g / 120 g),
and valine 0.47 nmol / ml (0.5g / 120 g).

3. Clinical Evaluation

The thigh circumference was measured at the midpointof the thigh length at the supine position. Hand Held Dynamometer (ANIMA Corporation, μTas F-1) was used formeasuring MVC of knee extension. In measurements,
limb position was a sitting posture with the trunk in thevertical position. The hip and the knee joint were bent 90
degrees and the upper limbs were assembled with the front
chest. The position of the sensor was the distal part of thelower leg, and the fixing belt was attached so as to be perpendicular to the direction in which the force was applied.
The measurement was performed twice on each side andthe maximum value was adopted as MVC of knee extension.
The quadriceps muscle thickness was measured at the
midpoint of the thigh length using an ultrasonic tomography apparatus (GE Healthcare Japan, Ltd., LOGIQ e Premium) as previously described12). It was measured at supine position, and the measurement was performed twice
at each side of the thigh, and the average value was adopted.
Body composition analysis was measured in the supine
position using a body composition analyzer (Inbody Japan, Body Composition Analyzer Inbody S10) as shown
previously12). The muscle mass of left and right leg wasevaluated.
The femoral muscle cross-sectional area was obtained by

Ooshima A, Ishizaka Y, Katayanagi S., et al3reconstructing the range from the upper edge of the greater trochanter to the upper edge of the patella with a slit of
1.5 mm with a 320-row CT apparatus (Canon Inc., Aquilion ONE). It was measured using Ziostation software.
The image data was opened by 3D analysis. The cine wascreated by re-saving the cine and enlarging the right thighwith the midpoint from the upper edge of the greater trochanter to the upper edge of the patella as the measurement point of the axial image. The rescued right femoral
region image was opened with the protocol of body fat
measurement. The CT value of the subcutaneous fat ofthigh part was 50 ~150 Hounsfield Unit (HU), and theCT value of the visceral fat of 0 ~ 80 HU was changed tomuscle CT value and measured. Bones were excluded, andthe outer periphery of the thigh muscles was finely adjusted to measure the cross sectional area of the thigh muscle.
For nutritional evaluation, CONUT (controlling nutritional status) modified method13) using three items, serum
albumin (Alb), peripheral total lymphocyte count (TLC)
and hemoglobin (Hb), was used. In the measurement ofserum BCAA concentration, blood was collected in con-trol without taking breakfast (control) and 60 and 120
minutes after one bottle of jelly containing BCAA (2.5 g,Reha -ime Jelly, Clinico Co. Ltd., Japan).

4. Result

After the KAATSU training plus BCAA intake, thethigh circumference, the MVC of knee extension, quadriceps muscle thickness, and lower limb muscle mass gradually increased (Table 1). At 80 days after starting the training, the thigh circumference was + 7.3 cm, and the MVC
of knee extension was about + 20 kgf for both left andright, compared with the control level before the training.
The quadriceps muscle thickness increased about + 1 cm,
and the lower limb muscle mass increased about + 1 kg in
both left and right (Table 1). Also, in the femoral CT image after 100 days of the training, there was a marked increase in femoral muscle cross-sectional area of 56.9 cm2on the right and 55.9 cm2 on the left, compared with thecontrol level (Table 1, Figure 1).
Table 2 shows changes in body weight and the nutrition
states before and after KAATSU training combined with

Table 1. Changes of each evaluation before and after KAATSU training combined with BCAA intake
Days
after KAATSU training

Femoral circumference (cm)Right knee extension muscle force (kgf )left knee extension muscle force (kgf )Quadriceps muscle thickness (cm)Muscle mass of right lower limb (kg)Muscle mass of left lower limb (kg)Femoral muscle cross-sectional area (left) (cm2)
Femoral muscle cross-sectional area (right) (cm2)

Before7 days later17 days later29 days later52 days later

80 days later 100 days later

44th
disease day

56th
disease day

66th
disease day

78th
disease day

101th
disease day

129th
disease day

38.2
40.4

39.0
38.5
31.7
2.4
7.2
7.1

39.5
38.9
34.0
2.4
7.4
7.3

39.8
39.8
37.7
2.6
7.7
7.7

44.3
53.7
44.5
2.8
7.8
7.7

45.5
64.0
53.8
3.1
7.9
7.9

2.1
6.7
6.7
61.6
62.2

Figure 1. Comparison of femoral CT scan images before (A) and 100 days after KAATSU training (B) combined with BCAA intake

149th
disease day

117.5
119.1

Combination of KAATSU training® and BCAA intake for a patient after aortic valve replacement surgery: A case study

4

Table 2. Changes in body weight and nutrition before and after KAATSU training combined with BCAA intake
Days
after KAATSU training

Body weight (kg)Modified CONUT score (point)
Alb (g/dl)
TLC (μL)
Hb (mg/dl)

Before7 days later17 days later29 days later52 days later

80 days later

44th
disease day

56th
disease day

66th
disease day

78th
disease day

101th
disease day

129th
disease day

58.7
3
3.3
2101.6
10.9

59.0
4
3.1
1387.5
10.4

59.4
1
3.5
1929.6
11.6

61.0
0
3.9
1795.5
13.7

63.5

65.9
4.3

2037.6
13.9

14.8

Alb: Serum albumin, TLC: Peripheral total lymphocyte count, Hb: Hemoglobin
Table 3. Changes in blood BCAA concentration before and after BCAA (2.5 g) intake
Amino acids

ValineIsoleucine

leucineTotal BCAA

Reference value (nmol/ml)

147.8〜307.0

43.0〜112.8

76.6〜171.3

265.8〜579.1

Before60 minutes
120 minutes

236.9
333.7
296.3

86.5
187.8
116.6

146.9
329.8
231.4

470.3
851.3
644.3

BCAA: Branched Chain Amino Acids

BCAA intake. The modified CONUT score showed 3
points at the start of the training, and decreased to 0 point
after 29 days of the training. Eighty days after the training, he recovered to almost the weight before the operation (Table 2).
Table 3 shows the changes of serum BCAA concentration before and 120 and 180 minutes after the BCAA intake. The serum concentration of BCAA showed a remarkable increase in numerical value at 60 minutes after
BCAA intake, and maintained a high level at 120 minutes,
compared to the control level (Table 3).

5. Discussion

This case was a patient with low cardiac function andprominent left ventricular enlargement. However, there
was no appearance of any arrhythmia and side effects
during the training even early after the cardiac operation.
Furthermore, by performing the combined KAATSU
training and BCAA administration immediately after the
training, the marked muscle strength improvement andmuscle hypertrophy could be obtained.
Rehabilitation intervenes during the perioperative period. Resistance training is frequently necessary to improve
the reduction of muscular strength and muscle mass due
to surgical invasion and waste syndrome due to decreased
activity. However, lower limb resistance training for patients after cardiac surgery begins with low load exercise at
the level of daily living behavior in the early postoperative
period. Subsequently, the resistance exercise with load is
recommended to start 5 weeks after surgery14). For thatreason, the improvement of muscle strength and an increase in muscle mass are not recognized in several cases.
In addition, in this case, the preoperative bedtime period
due to exacerbation of heart failure and hypotension waslong, and the severe muscle weakness and atrophy devel-

oped. However, the KAATSU training can be conductedfrom a low load. The ordinary resistance training mobilizes from small slow muscle fibers of the movement unit according to the principle of size. As the exercise intensity
rises, large fast muscle fibers of the exercise units can bemobilized. Therefore, at a low intensity of 20-30% of 1
RM, fast muscle fibers are hardly mobilized and it is difficult to recognize muscle hypertrophy and muscle strength
improvement. On the other hand, in KAATSU training,hypoxia caused by restricted muscle blood flow promotes
recruitment of fast muscle fibers as well as muscle activityof slow muscle fibers5,15). Therefore, it can expect muscle
hypertrophy and muscle strengthening similar to normal
high-intensity training 5-7, 15), even by using low-intensity
load. In fact, we have already reported that KAATSU
training was a useful method for improving muscle
strengthening and muscle mass in patients with ischemic
heart disease8). In this study, we performed the KAATSU
training in a young cardiac surgery patient with low cardiac function early after aortic valve replacement surgery.
Since a low load at an intensity of 20-30% of 1 RM canbe used during the KAATSU training, we started thetraining early after the operation. In addition, in terms ofnutrition, resistance training under malnutrition is predominant in protein degradation, making it difficult toincrease muscle mass17). Before the KAATSU training, nutritional status was bad in this case with blood albumin of
3.3 g / dl and CONUT score 3 points. Therefore, BCAA
administration was concomitantly used for the training.
As a result, the marked increase in muscle strengthening
and muscle hypertrophy could be observed after the intervention. During the training, the nutritional state also improved, and the CONUT score decreased to 0 point after
29 days of the training. From these observations, in addition to the effects of KATTSU training, it is most likely

Ooshima A, Ishizaka Y, Katayanagi S., et althat protein synthesis has become dominant by ingesting
BCAA immediately after exercise. Protein synthesis is considered to increase rapidly after 1 to 2 hours after exercise18). Looking at the trend of BCAA in this case, serum
BCAA concentration was about twice higher than thecontrol level before taking BCAA. Therefore, it is likelythat considering the resistance training and intake time of
BCAA was effective for efficient muscle strengthening andmuscle hypertrophy in this patient.
In this study, the KAATSU training was conducted under a medical doctor who was qualified as a KAATSU instructor. And, according to the rehabilitation guidelines
for cardiovascular disease11), blood pressure measurement,
electrocardiogram monitoring, and subjective strength
measurements (Borg scale) were carried out. No side effects as previously described16) were observed during thetraining. The most common side effects in KAATSU
training are petechia as described previously16). This patient received warfarin therapy, but no petechia had occurred during the training.

6. Conclusion

By using KAATSU training together with BCAA intake, a marked improvement in muscle strength and muscle hypertrophy was obtained in a patient with low cardiac
function early after aortic valve replacement surgery. The
combined use of KAATSU training and BCAA intake early after cardiac operation seems to be a safe and effective
way to obtain muscle hypertrophy and muscle strength
increase, but further studies are needed to clarify it.

Acknowledgments

I thank Clinico Co., Ltd. for providing the supplementof BCAA (Reha-Time Jelly) in this research.

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Earle RW, eds. Essentials of Strength Training and Conditioning.
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3) Japan Cardiovascular Society, Japan Congenital Disease Association, Japan Chest Surgery Association, and others: Guidelines on
Diagnosis and Treatment of Cardiovascular Disease (Report of the
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rehabilitation in cardiovascular disease (2012 revised edition). 30.
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6) Nakajima T, Yasuda T, Sato Y, Morita T, Yamasoba T (2011) Effectsof Exercise and Anti-Aging. Anti-aging Medicine 8: 92-102.
7) Nakajima T (2010) KAATSU training and thickening of the muscle.

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In; Kouki M, et al. (Eds.) Latest Rehabilitation Medicine for Rehabilitation Physicians and Healthcare Professionals (in Japanese), Advanced Medical Series 40, Advanced Medical Technology Institute,Japan, pp292-297.
8) Nakajima T, Kurano M, Sakagami F, et al (2010) Effects of low-intensity KAATSU resistance training on skeletal muscle size/strengthand endurance capacity in patients with ischemic heart disease. International Journal of KAATSU Training Research 6: 1-7.
9) Layman DK (2002) Role of leucine in protein metabolism during exercise and recovery. Appl Physiol Nutrit Metab 27: 646-662.
10) Matsumoto K, Mizuno M, Mizuno T, et al. (2007)Branched-chainamino acids and arginine supplementation attenuates skeletal muscle proteolysis induced by moderate exercise in young individuals.
Int J Sports Med 28: 531-538.
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Diagnosis and Treatment of Cardiovascular Disease (Report of the
Joint Research Group of 2011) (2012 in Japanese) Guidelines on
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12) Yasuda T, Nakajima T, Sawaguchi T, et al. (2017) Short Physical
Performance Battery for cardiovascular disease inpatients: implications for critical factors and sarcopenia. Sci Rep. 12;7(1):17425.
doi: 10.1038/s41598-017-17814-z.
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748-752.
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18) Miyashita M (2012) Making muscle - involvement of genes. Healthnetwork (in Japanese) 8-10.
Indication of KAATSU training and “KAATSU training” in the text areregistered as trademarks of KAATSU JAPAN Co., Ltd.
Authors’ affiliations
Ooshima A, Ishizaka Y, Katayanagi S, Arakawa C, Takahashi R, Nozawa N, Mizushima Y, Matsumoto K, Department of Rehabilitation,
Dokkyo Medical University, Tochigi, Japan
Nakajima T, Sawaguchi T, Haruyama A, Toyoda S, Inoue T, Department of Cardiovascular Medicine, School of Medicine, Dokkyo
Medical University, Tochigi, Japan
Ogawa H, Shibasaki I, Fukuda H, Department of Cardiovascular Surgery, School of Medicine, Dokkyo Medical University, Tochigi, Japan
Yagi H, Yamaguchi S, Department of Department of Cardiology and
Nephrology, Dokkyo Medical University, Tochigi, Japan.
Yasuda T, School of Nursing, Seirei Christopher University, Shizuoka,
Japan
Uematsu A, Department of Health and Sport Sciences, Premedical Sciences, Dokkyo Medical University, Tochigi, Japan
Sato Y, Chaiman, Center for KAATSU Research at Harvard Medical
School, U.S.A.

ORIGINAL ARTICLE

Effect of knee extension exercise with KAATSU on
forehead cutaneous blood flow in healthy young andmiddle-aged women
K. Kusuhara, T. Fujita, T. Yasuda, T. Nakajima, Y. Sato, Y. Miyagi, Y. Murakami, T. Abe
Int. J. KAATSU Training Res. 2006; 2: 29-34

Correspondence to:Dr. T Abe, Graduate School of
Frontier Sciences, The
University of Tokyo, 5-1-5
Kashiwa-no-ha, Kashiwa,
Chiba 277-8561, Japan
E-mail: abe@k.u-tokyo.ac.jp
See end of article forauthor’s affiliations

Dynamic exercise induces changes in the redistribution of whole-body organ-tissue blood circulation,
including cutaneous blood circulation. We hypothesized that limb exercise combined with therestriction of muscular blood flow (KAATSU) may influence cutaneous blood flow redistribution. To
examine this hypothesis, forehead (supraorbital) cutaneous blood flow was compared in women
performing exercises with and without KAATSU. Ten young and middle-aged female subjects in thesupine position performed three sets of 15 repetitions of unloaded unilateral knee extension exercises(30-s rest between sets). Blood flow was calculated from blood velocity and red blood cell mass
(blood flow = velocity * mass) determined by laser blood flowmetry. While exercise without KAATSU
did not induce alterations in velocity and mass (hence, no alterations in blood flow) throughout theentire exercise series, exercise with KAATSU induced increases (P<0.05) in blood flow owing toincreases in velocity. These increases were not eliminated during the rest periods between exercise
sets. Heart rate (HR) increased (P<0.05) with the second and third sets of exercises with KAATSU
compared with HR before exercise initiation, and was higher than the HR resulting from acorresponding set of exercises without KAATSU. There were no changes in blood lactate andhematocrit in both types of exercises. Norepinephrine increased (P<0.05) at the completion of theexercise sets. These results suggest that forehead cutaneous blood circulation was increased byunloaded KAATSU leg exercise.
Key words: cutaneous blood flow, laser blood flowmetry, knee extension exercise, norepinephrine

INTRODUCTION
Whole-body circulation during physical exercise ishighly organized. Exercise-induced activation of
sympathetic nerve activity leads to increased heart
rate (HR), cardiac output (Q), and stroke volume(SV). At the same time, dynamic exercise induceschanges in the redistribution of whole-body blood
circulation; blood flow into working muscles to meetoxygen demand precedes flow into inactive regions. It
has been suggested that cutaneous circulation iscontrolled by sympathetic nerve activity, which
regulates vasoconstriction and the active vasodilation
tone system (Kellogg et al, 1991, Kellogg, 2006,
Johnson et al 1986).
Exercise combined with the restriction of muscularblood flow (KAATSU) is a distinctive type of exercise
training that results in obvious hypertrophy andincreased muscle strength. KAATSU is extremely low
intensity and is characterized by its short training
duration (Abe et al, 2005, 2006, Takarada et al, 2000)
One of the most striking characteristics of this training
method is the restriction of blood flow in theexercising limbs using a restriction cuff belt during
exercise, which leads to alteration in circulation

dynamics. It has been proposed that exercise withKAATSU may lead to acidic and anaerobic
intramuscular states, while restriction-induced
elevation in metabolites, such as lactate and growth
hormone, might stimulate hypertrophy (Takano, etal, 2005b).
KAATSU has been suggested to induce alterationsin hemodynamic parameters, such as Q and SV, aswell as changes in HR and blood pressure (BP), bothat rest and during exercise. Iida et al (2005)
demonstrated that application of a KAATSU belt toboth legs during rest restricted venous blood flow andcaused venous blood pooling in the legs distal to thebelt, resulting in pressure-dependent reduction ofarterial blood flow. Consequently, decreases in Q andSV, a slight increase in HR, and no change in BP were
demonstrated. In exhaustive knee extension exercise
with KAATSU, HR and BP as well as Q have been
demonstrated to increase; on the other hand, SV
decreased (Takano et al, 2005a). These studies suggestthat these parameters play a role in controllingwhole-body circulation in response to KAATSU withand without exercise.
In the aforementioned studies (Iida et al, 2005,

30

Effect of exercise with KAATSU on cutaneous blood flow

Takano et al, 2005b), blood pooling in the exercisinglimbs has been clearly demonstrated. On the other
hand, it is unknown how circulation in other parts ofthe body responds to KAATSU in the exercisinglimbs. In the present study, we investigated the
response of cutaneous circulation in the forehead(suparorbital region) to knee extension exercise
combined with KAATSU-induced blood flow
restriction.

METHODS
Subjects

Ten healthy female aged 23 to 47 years (mean age,
34.5 (SD 10.0) years) volunteered to participate in
the study (Table 1). All subjects led active lives, with 8of 10 participating in KAATSU training for the last 2
years. All subjects were informed of the procedures,risks, and benefits of the study, and signed an
informed consent document before participation. The
study was approved by the Ethics Committee for
Human Experiments, The University of Tokyo.
Exercise protocol

The subjects assumed a supine position andperformed three sets of knee extension exercises
following a warm-up period, with a 30-s rest period
between sets (Figure 1). In each set, subjects
performed 15 repetitions of left knee extension
exercises at 12 repetitions per minute, taking
approximately 75 s to perform the entire set. The
subjects performed this three-set series of exercises
twice – for the first time without KAATSU, and forthe second time with KAATSU. The KAATSU belt
(Kaatsu-Master, Sato Sports Plaza, Tokyo, Japan) was
placed around the most proximal portion of thesubject’s left leg. Before starting the exercise with the
KAATSU belt, the air pressure in the belt, ranging
from an initial 140 mm Hg to the a final pressure of
200 mm Hg, was repeatedly held for 30 s and thenreleased for 10 s. The final restriction pressure of 200
mm Hg was selected for its ability to serve as an

occlusive stimulus, as described previously (Abe et al,2006). Before starting to exercise with the final
restriction pressure, subjects rested for 1 min. The
restriction of muscular blood flow was maintained
throughout the second exercise set, including the 30s rest periods. The belt pressure was released
immediately upon completion of the session.
Cutaneous blood flow measurement.

Cutaneous blood flow in the forehead (supraorbital
region) was measured using laser blood flowmetry(Omega Wave, Tokyo, Japan), multiplying blood
velocity (the velocity of red blood cells) by mass (thenumber of red blood cells passing through a given
surface area in a specific unit time). The laser probe
was placed in the middle of the region, and thecirculation at ~1 mm in depth was measured (Figure2.). Facial skin thickness varies from 0.4 to 1.4 mm(epidermis + dermis) depending on the region; thelaser beam is able to penetrate to the dermis. Bloodflow measurement was performed at the beginning of
the rest period (with and without KAATSU) andlasted through the entire exercise series, both withand without KAATSU. The data obtained for the last
30 s were used for analysis.
Blood sampling and biochemical analysis

Venous blood samples were obtained four times
from nine subjects in a supine position before andimmediately after exercise both with and without
KAATSU. All blood samples were processed to plasma
before storage at -20ºC. Blood lactate (LA)Exercise without Kaatsu
Blood flow and HR measurement
2.5min

75sec

75sec

75sec

2min
Rest

W-up

Ex1
Ex2
Ex3
Rest1
Rest2

Table 1. Descriptive characteristics of subjects.

n10Age, y34.5 (10.0)

Standing height, cm

161.1 (5.8)

Body mass, kg

51.3 (4.3)

BMI, kg/m

2Midthigh girth, cm

19.8 (1.3)

Exercise with Kaatsu
Blood flow and HR measurement
1min 75sec

75sec

75sec

2~2.3minRepeating pressure
Reststarted From 140 mmHg

Ex1
Ex2
Ex3
Rest1
Rest2

46.9 (3.3)

Values are means (SD); BMI, body mass index.

Rest: rest at final pressure restriction, ↑: blood sampling
Figure 1. Experimental protocol.

K. Kusuhara, T. Fujita, T. Yasuda, et al.

31

on changes in cutaneous blood flow and in blood
parameters over time (pre- and postexercise) were
tested by a two-factor ANOVA for repeatedmeasurement. Further analysis used Student’s pairedt test, if interaction, KAATSU x group was significant.
Statistical significance was set at P<0.05.

Epidermis

Dermis

0.4~1.4mm

Probe

RESULTS
Forehead cutaneous blood flow

Subcutaneous tissue

Figure 3 shows changes in mass, velocity, andblood flow. Exercise without KAATSU did not show
any changes in mass, velocity, and blood flow for all
three measurements. On the other hand, exercise
with KAATSU increased (P<0.05) the velocity andblood flow in all exercise sets compared with thevelocity and blood flow measurements made before
the start of exercise. Significantly, these KAATSUinduced increases in both velocity and blood flow
were not eliminated following the 30-s rest period
between sets.

Laser beam irradiation area
Figure 2. Structure of face skin and measurement of

cutaneous blood flow. Laser beam captures bloodflow in capillary blood vessels or arterioles.

concentrations were determined using a portable
analyzer (Lactate Pro, Arkray, Kyoto Primary Science,
Kyoto, Japan), and hematocrit was measured in
duplicate by microcentrifugation. Plasma
norepinephrine (NE) concentration was measured at
SRL, Inc. (Tokyo, Japan). HR during exercise wasmeasured using a finger probe (Onyx, Nonin Medical,
MN, USA). The data obtained from the last 30 s wereused for analysis.

Heat rate and blood parameters

HR increased significantly (P<0.05) at the second
and third exercise sets with KAATSU compare withpre-exercise HR without KAATSU (Figure 4). Also,
HR is significantly higher than HR measurements
made during the corresponding exercise sets without
KAATSU.
Table 2 shows changes in plasma NE concentration.
NE increased (P<0.05) from 0.21 (SD 0.08) ng/mL atrest to 0.30 (SD 0.15) ng/mL at the end of exercise

Statistical analysis

Results are expressed as mean ± standard deviation(SD) for all values. The effects of exercise withKAATSU compared with exercise without KAATSU

1.4

Panel A: Velocity
With Kaatsu
＊

1.2

＊
＊

＊

＊

(＊ )

Without Kaatsu
1.0
Con(Rest without
Kaatsu)1.4

Rest with
KaatsuEx1

Panel B: Blood flow

Rest1

Ex2

Rest2

＊

＊

＊

With Kaatsu
＊

Ex3

＊

1.2
Without Kaatsu
1.0
Con(Rest without
Kaatsu)Figure 3.

Rest with
Kaatsu

Ex1

Rest1

Ex2

Rest2

Ex3

Effect of exercise with blood flow restriction (Kaatsu) on
cutaneous circulation in the forehead. The samples are expressed relative
to Con (rest without Kaatsu). Panel A: Velocity, Panel B: Blood flow,*: significantly different from Con, P<0.05. (*): tends to be different from
Con, 0.05<P<0.10

Heart rate (beats/min)

32

Effect of exercise with KAATSU on cutaneous blood flow

Table 2.

72
70
68
66

Blood norepinephrine and lactate concentration, andhematocrit in response to low-intensity knee extension exercise withand without KAATSU.

*
With Kaatsu

*

64

*

*

62
60
58
56
Ex1

Ex2

Kaatsu-Exercise

Pre

Pre

n

Without Kaatsu

PreControl-Exercise

Ex3

Post

Post

9

9

9

9

NE (pg/mL)

0.23 (0.16)

0.19 (0.09)

0.21 (0.08)

0.30 (0.15)*

Hematocrit (%)

39.3 (2.4)

38.3 (2.3)

38.4 (3.0)

39.3 (2.7)

Lactate (mM)

0.82 (0.04)

0.81 (0.03)

0.82 (0.04)

0.81 (0.03)

NE, norepinephrine
Figure 4. Effect of exercise with blood flow

* Significantly higher than preexercise in the same exercise style (P<0.05).

DISCUSSION
The main findings of the present study are as
follows: 1) Unloaded knee extension exercise withKAATSU significantly stimulated cutaneous
circulation in peripheral regions; an elevation inblood flow mainly due to increased velocity wasobserved. Further, this increase was maintained
during rest periods between exercising. 2) Exercise
with KAATSU increased HR and circulating NE. 3) No
alterations were found in plasma LA and hematocrit
values in exercise both with and without KAATSU.
In the present study, subjects performed free extraload knee extension exercises. In spite of its
extremely low intensity, exercise with KAATSU
resulted in changes in cutaneus circulation, with anelevation in NE secretion, suggesting that exercise
with KAATSU stimulates sympathetic nerve activity
and cutaneous circulating dynamics.
Although a significant elevation in velocity andblood flow in response to exercise with KAATSU was
observed in almost all subjects, in some subjects theincrease was very slight, as illustrated in Figure 5.
Subjects who did not show a clear elevation also
showed a sluggish increase in NE concentration(<0.04 ng/mL). This suggests that even if exercise
with KAATSU is performed in the same way by all
subjects, there might be differences among subjects intheir sensitivity to these stimuli. In other words, insubjects who showed clear increases in velocity andblood flow, those increases might relate to NE
elevation.
In addition to increasing cutaneous circulation
dynamics, KAATSU exercise had a potent effectduring the rest periods. The exercise-induced increasein velocity and blood flow was maintained during rest
periods (rest 1 and rest 2), and there were no
significant differences in these parameters during

Cutaneous blood flow
(relative to control)with KAATSU. There were no changes in either blood
LA or hematocrit values (Table 2).

1.4

Cutaneous blood flow
(relative to control)

restriction (Kaatsu) on heart rate. *: P<0.05

1.4

Subject A

1.3
Blood flow
Velocity
Mass

1.2
1.1
1.0
Con
1.3

Ex1

Ex2

Ex3

Ex1

Ex2

Ex3

Subject B

1.2
1.1
1.0
Con

Figure 5.

Typical pattern of cutaneous blood flow in
response to exercise with blood flow restriction (Kaatsu).
Increases in velocity and blood flow in response to
exercise with Kaatsu were more obvious in subject A thansubject B.

exercise and at rest. In addition, during the rest
period before the start of the first exercise set withKAATSU, velocity was already showing a tendency toincrease (Figure 3). The main factor behind theincrease in velocity and blood flow is currently
unknown. If the impact of KAATSU on cutaneous
circulation dynamics precedes the impact of exercise,the effect of the extremely low exercise intensity
might be obscured by the effect of the blood flow
restriction itself.
The KAATSU-induced increase in venous blood
pooling has been demonstrated in both legs distal to
the KAATSU belt during rest (Iida et al, 2005). This
restriction resulted in decreases in Q and SV, a slightincrease in HR, and no change in BP. On the other
hand, during exhaustive leg extension exercises in aseated position, an increase in Q, HR, and BP and a

K. Kusuhara, T. Fujita, T. Yasuda, et al.

decrease in SV have been demonstrated (Takano et al,
2005a). Both studies suggest that KAATSU induces adecrease in SV owing to decreased venous return
during both rest and exercise. Further, as Takano et al(2005a) elucidated, an increase in Q during exercise iscontrolled mainly by an increase in HR. In thepresent study, a slight but significant increase in HR,
possibly induced by elevation of NE, was found in
exercise with KAATSU. Thus, the increase in HR
might be a response to decreased SV to satisfy bloodflow for increasing Q demand. However,measurement of Q, SV, and BP was not done in thepresent study, so precise interaction of theseparameters in response to KAATSU is still uncertain.
Additionally, postural effect on the hemodynamic
system during exercise with KAATSU also should beconsidered when evaluating the interaction of theseparameters because unlike in previous studies,
exercise in the present study was performed in thesupine position. In this position, the reducedhydrostatic pressure causes a shifting of blood volume
toward the heart, thereby increasing SV and Q. Leyk
et al (1994) have demonstrated that in the supine
position, Q increased further in response to right ormoderate cycle exercise, and this increase was mainly
mediated by an increase in SV but not HR. In thepresent study, a shifting of blood volume toward theheart might also have occurred, and thus Q might
increase too. However, because of KAATSU, HR
might increase instead of SV as a compensatory
response to increased Q. It is therefore necessary tounderstand that in interpreting the response of thehemodynamic system to exercise with KAATSU, theincrease in HR in the present study might beinfluenced by both postural effect and an exerciseinduced NE increase.
The mechanism that induced an increase in bloodflow via an increase in velocity in response to exercise
with KAATSU is unidentified. In a previous paper(Takano et al, 2005a), BP has been demonstrated toincrease in response to exercise with KAATSU. In thepresent study, if an increase in BP occurs in the sameway during exercise with KAATSU, peripheral
vascular resistance is expected to increase. Also, it islogically assumed that the pooling of blood in one
part of the body leads to a shortage of blood flow
through the rest of the body, even though blood
continues to circulate. Therefore, it seems unlikelythat cutaneous blood flow in peripheral regions
would increase via acceleration of velocity inresponse to exercise with KAATSU. A possible
explanation of accelerated velocity might be found inchanges in vessel diameter. If a signal leading tovasodilation is activated independently from BP
modulation, peripheral vascular resistance would
decrease and blood flow might increase, with apossible combined increase in velocity. NE has also

33

been suggested to be related to both vasoconstriction
and vasodilation regulation (Kellogg, 2006).
Elucidation of the vasodynamic system inconjunction with BP alteration in response to exercise
with and without KAATSU is required.
There was a wide range in the ages (23-47 years) of
the subjects in the present study. Since all subjects
had an active life with no symptoms demonstrating
decreased circulatory function due to aging, such as
hypertension or arteriosclerosis, it seems that theeffect of age on the hemodynamic system in response
to exercise with KAATSU may be minor. However, if
KAATSU is to be applied to people of different ages or
people with different health conditions, further
examination to clarify the effect of KAATSU onwhole-body hemodynamics is required.
In conclusion, unloaded knee extension exercise
with KAATSU increased forehead cutaneous blood
flow. HR increased owing to elevation of NE in
response to exercise with KAATSU, possibly
influenced by modulation of cutaneous circulation
dynamics.

ACKNOWLEDGEMENTS
We would like to thank the subjects who
participated in this study and Nancy Coker for her
assistance with the preparation of this manuscript.
The authors wish to thank Dr. Tetsuji Hirao, ShiseidoLife Science Research Center, Yokohama, Japan, for
his technical expertise with the laser blood flowmetry
data collection and interpretation. The study was
supported, in part, by research grants from the Japan
Kaatsu Training Society.

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Effect of exercise with KAATSU on cutaneous blood flow

Authors’ affiliations
K. Kusuhara, Y. Sato, T. Abe, Department of Human andEngineered Environment, Graduate School of Frontier Science, The
University of Tokyo, 5-1-5 Kashiwa-no-ha, Kashiwa, Chiba, Japan,
T. Fujita, T. Yasuda, Department of Exercise and Sport Science, Tokyo
Metropolitan University, Hachioji, Tokyo, Japan
T. Nakajima, Y. Sato, Department of Ischemic Circulatory Physiology,
The University of Tokyo, Hongo, Tokyo, Japan
Y. Miyagi, Y. Murakami, BodybyVital Research Laboratory, Yoyogi,
Tokyo, Japan.

Journal of Gerontology: BIOLOGICAL SCIENCES
Cite journal as: J Gerontol A Biol Sci Med Sci. 2011 March;66A(3):257–263
doi:10.1093/gerona/glq182

© The Author 2010. Published by Oxford University Press on behalf of The Gerontological Society of America.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Advance Access published on October 25, 2010

Increases in Thigh Muscle Volume and Strength by Walk
Training with Leg Blood Flow Reduction in Older
Participants

1Graduate School of Frontier Sciences, Department of Human and Engineered Environmental Studies, University of Tokyo, Kashiwa, Japan.
2Graduate School of Medicine, Department of Ischemic Circulatory Physiology, University of Tokyo, Tokyo, Japan.

Address correspondence to Hayao Ozaki, Department of Human and Engineered Environmental Studies, Graduate School of Frontier Sciences, The
University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, Japan. Email: ozaki.hayao@gmail.com

We examined the effects of walk training combined with leg blood flow reduction (BFR) on muscle hypertrophy as wellas on peak oxygen uptake (VO2peak) in older individuals. Both the BFR walk training (BFR-Walk, n = 10, age; 64 ± 1
years, body mass index [BMI]; 22.5 ± 0.9 kg/m2) and control walk training (CON-Walk, n = 8, age; 68 ± 1 years, BMI;
23.2 ± 1.0 kg/m2) groups performed 20 minutes of treadmill walking at an exercise intensity of 45% of heart rate reserve,
4 days per week, for 10 weeks. The BFR-Walk group wore pressure belts (160–200 mm Hg) on both legs during training.
After the training, magnetic resonance imaging–measured thigh muscle cross-sectional area (3.1%, p < .01) and muscle
volume (3.7%, p < .01) as well as maximal isometric (5.9%, p < .05) and isokinetic (up to 22%, p < .01) strength increased in the BFR-Walk group, but not in the CON-Walk group. Estimated VO2peak during a bicycle graded exercise test
increased (p < .05) and correlated with oxygen pulse in both groups. In conclusion, BFR walk training improves bothmuscle volume and strength in older women.
Key Words: Walking—Aerobic capacity—Muscle hypertrophy—Occlusion.
Received March 25, 2010; Accepted September 16, 2010
Decision Editor: Rafael de Cabo, PhD

A

N age-related decline of cardiovascular fitness (eg,maximal oxygen uptake [VO2max]) has been attributedin part to changes in body composition, particularly a lossof skeletal muscle mass, and referred to as “senile sarcopenia” (1). Sarcopenia leads to an increased risk of developing
osteoporosis, insulin resistance, type 2 diabetes, and obesity(2), as well as reduced levels of daily activity and physicalfunction. Additionally, it has been reported that a low agerelated VO2max level is a risk factor for both cardiovasculardisease and all-causes mortality in middle-aged and elderly
populations (3). Based on existing evidence, cardiovascular
fitness and muscular strength must be maintained in an optimal range to minimize the potential risks of age-relateddiseases.
To improve muscular strength and cardiovascular fitness
in middle-aged and elderly populations, several societies(4,5) have published guidelines that recommend combining
training intensity, volume, and frequency to optimize muscle hypertrophy and strength gains as well as improveVO2max. In general, the magnitude of the acquired training
adaptation is proportional to the training stimulus, depending on the individual’s training experience and/or initialphysical fitness level. For instance, a training intensityof more than 65% of one repetition maximum (1-RM) is

considered the minimum intensity required to achieve muscle hypertrophy and strength gains (6). On the other hand,normally, the magnitude of change in VO2max induced followed a training increases as exercise intensity is raised
above 50% VO2max. The minimum stimulus necessary to
evoke change is more than 40% or 50% of VO2max. In fact,a few studies (7,8) have reported an increase in VO2max after
training at intensity as low as 45% of VO2max. The guidelines also recommend a training frequency of 3–5 days per
week for aerobic training and 2–3 days per week for resistance training (4). Because the typical duration of thesetraining sessions is approximately 60 minutes, including
warm-up and cool down, about 300–480 minutes (5–8
hours) per week would be needed to complete the program.
However, the vigorous training intensity and/or high training frequency might constitute major hindrance, preventing
middle-aged and elderly populations from participating in
the training programs.
Muscular blood flow reduction (BFR) during resistancetraining has been shown to elicit muscle hypertrophy andstrength gains similar to those elicited by traditional highintensity resistance training (HI-RT), but with much lower
exercise intensities (9,10). An intensity as low as thatassociated with walking, when combined with BFR, can257

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Hayao Ozaki,1 Mikako Sakamaki,1 Tomohiro Yasuda,1 Satoshi Fujita,1 Riki Ogasawara,1 Masato Sugaya,1
Toshiaki Nakajima,2 and Takashi Abe1

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Methods

Participants
A total of 18 sedentary women, aged 57–73 years, volunteered to participate in the present study. The participants
were recruited through printed advertisements and by wordof mouth and had not participated in a regular exercise program for at least the previous 3 years. All participants were
free of overt chronic disease as assessed by medical history,
physical examination, and complete blood chemistry andhematologic evaluation. Candidates who had smoked in theprevious 4 years or were taking medications or female hormone supplements were excluded. All participants were informed of the methods, procedures, and risks, and signed an
informed consent document before participating in the
study. The study was conducted according to the Declaration of Helsinki and was approved by the Ethics Committee
for Human Experiments of the University of Tokyo, Japan.
Participants were subsequently divided into either BFR
walk training group (BFR-Walk, n = 10) or a walk training
group without BFR (CON-Walk, n = 8) in random order but
balanced the participants to match anthropometric variables
between groups.

Training Protocol
The participants in both the BFR-Walk and CON-Walkgroups performed 20 minutes of treadmill walking at a predetermined exercise intensity of 45% of heart rate reserve(HRR). This training was performed under the close supervision of those with technical knowledge in BFR training.
One week before the start of the training study, walking
speed and grade were adjusted for each participant during asubmaximal walking test, and the exercise load condition ofeach participant was determined and remained constantthroughout the training period. The mean treadmill speed
and grade were 4.5 ± 0.0 km/h and 1.6 ± 0.4 degrees in the
BFR-Walk group and 4.4 ± 0.1 km/h and 1.5 ± 0.5 degrees
in the CON-Walk group. Age-predicted maximum heart
rate (HRmax; 220 – age) was used to determine the HRR foreach participant. Training sessions were conducted 4 days
per week for 10 weeks. During all training sessions, HR
was recorded at the 5th minute, 10th minute, and 15th minute for both the CON-Walk and BFR-Walk groups. Ratingsof perceived exertion were also recorded every 5 minutes
during the session.
Blood Flow Restriction and Its Safety
Participants in the BFR-Walk group wore elastic cuffs (5cm wide) (Kaatsu-Master system; Sato Sports Plaza, Tokyo,
Japan) on the most proximal portion of each leg during thetraining sessions. Before the training sessions, the participants were seated on a chair, and the upper thigh-mounted
cuff was inflated at 120 mm Hg (the approximate systolicblood pressure at heart level for each participant) for 30 seconds, and then the pressure was released. The air pressure
was increased by 20 mm Hg, held for 30 seconds, and thenreleased for 10 seconds before the next occlusive stimulation was performed. This process was repeated until a final
occlusion pressure for each training day was reached. On
the first day of training, the final cuff air pressure was 140
mm Hg. As participants adapted to the occlusive stimulus
during the early phase of the training, the air pressure wasincreased by 10 mm Hg each week until a final cuff pressureof as much as 200 mm Hg was reached. Because of significant muscle fatigue experienced by participants during thetraining sessions, only five participants got to 160–180 mm
Hg. The air pressure of 140–200 mm Hg was selected for
the BFR stimulus based on a review of the data in elderly
participants (12). Blood flow to the leg muscles was reduced
during each training session in the BFR-Walk group, andthe cuff air pressure was released immediately upon completion of the session.
To ascertain the safety of BFR walk training in theseolder women, seven participants in the BFR-Walk groupperformed a treadmill walk test with and without BFR on
two separate days, with an interval of more than 2 days between the two tests. The exercise protocol was the same as
the predetermined individual training protocol (45% HRR).

Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/66A/3/257/599635 by guest on 16 December 2018lead to significant improvements in knee joint strength andleg muscle size (11,12). Improvements in leg muscle size
and aerobic capacity using a single exercise of BFR walktraining may warrant the use of this training method in the
broader population, including the frail and elderly population. During exercise with BFR, the decline in venous return to the heart from blood flow–restricted limb muscles
results in a decreased stroke volume (SV) and an increased
heart rate (HR) while maintaining cardiac output (13).
Consequently, the increased HR at the same systolic bloodpressure during exercise with BFR may produce high mechanical stress on the heart, as indicated by a greater ratepressure product (14). In addition, the increases in muscle
activation (15) and oxygen uptake (11) observed during
BFR exercise may be the result of an increased arterial andmixed venous blood oxygen (a-v) O2 difference because
cardiac output during exercise with and without BFR isthe same (13). The increase in the (a-v) O2 difference may
stimulate adaptations in the mitochondria, the myoglobin
content of muscles, and/or muscle capillarization. We hypothesized that the potential benefits of BFR walk training
could include not only an anabolic response by the muscular system but also improvements in the cardiovascularsystem. However, there are few published studies documenting concurrent improvements in VO2max and muscle
hypertrophy using a single exercise training for older participants (16,17). Thus, the purpose of this study was toinvestigate the effects of BFR walk training on muscle sizeand function as well as aerobic capacity in the older
women.

BFR WALK TRAINING UPS VO2PEAK, THIGH VOLUME

Muscle Cross-sectional Area and Muscle Volume
Magnetic resonance images were prepared using a General Electric Yokogawa Signa 0.2-T scanner (GE Yokogawa,Tokyo, Japan). A T1-weighted, spin-echo, axial plane sequence
was performed with a 520-millisecond repetition time anda 20-millisecond echo time. To avoid an influence of fluid
shifts within the muscle, magnetic resonance imaging(MRI) procedure was performed around the same time before and 3 days after the final exercise. Prior to all scans, theparticipants rested quietly in the magnet bore in a supine
position, with their legs extended. The great trochanter wasused as origin point and continuous transverse images with
1.0-cm slice thickness (0-cm interslice gap) were obtained
from the great trochanter to the lateral condyle of the femur
for each participant. All MRI data were transferred to a personal computer for analysis using specially designed image
analysis software (Tomo Vision, Montreal, Canada). For
each slice, skeletal muscle tissue cross-sectional area (CSA)
was digitized, and the muscle tissue volume (cm3) per slice
was calculated by multiplying muscle tissue area (cm2) byslice thickness (cm). Muscle volume of the leg muscle wasdefined as the sum of the slices of muscle. An average value
for the right side of the body was used. We had previously
determined that the coefficient of variation of this measurement was less than 1% (21).
Maximum Isometric and Isokinetic Strength
Maximum voluntary isokinetic strength of the knee extensors and flexors was determined using a Biodex System
3 dynamometer (Biodex Medical Systems, Shirley, NY).
Participants were carefully familiarized with the testingprocedures of voluntary force production for the thigh muscles during several submaximal and maximal performances
about 1 week before testing. Each participants was seatedon a chair with the hip joint angle positioned at 85°. The
center of rotation of the knee joint was visually aligned withthe axis of the dynamometer’s lever arm, and the ankle of

the right leg was firmly attached to the lever arm with astrap. Several warm-up contractions were performed before
testing. Participants were then instructed to perform maximal isometric knee extension at a fixed knee joint angle of75° followed by maximal isokinetic knee extensions andflexions, from 0° to 90°, at 30° and 180° per second. A knee
joint angle of 0° corresponded to full extension of the knee.
Whole muscle–specific tension was also calculated by dividing maximum isometric knee extension strength by mid
thigh muscle CSA.
Estimation of Peak Oxygen Uptake
Oxygen uptake (VO2) was measured during a bicycle
graded exercise test (GXT) using an automated breath-bybreath mass spectrometry system (Aeromonitor AE-300S;
Minato Medical Science, Tokyo, Japan). For this test, thepedaling rate was maintained constant at 60 revolutions per
minute. The load was initially set at 40 W and increased by
5 W every minute until the participants reached approximately 80% of their age-predicted HRmax. Each participant’s
electrocardiograph was monitored throughout and used tomeasure HR at intervals of 60 seconds. Peak oxygen uptake(VO2peak) was estimated by fitting the age-predicted maximum HR value into the linear regression equation computedfrom the individual VO2 and HR value during GXT. Oxygen
pulse (O2 pulse) was calculated by dividing VO2 by HR ateach submaximal exercise load.
Functional Ability Tests
Two tests were used to assess functional abilities for eachparticipant before and after the training program. The Up &Go test measured the time it took for participants to standup from a chair without the use of their arms, walk 2.4 m,turn around, walk back to the chair, and return to a seatedposition. The second functional test, the chair-stand test, required participants to stand up from a seated position, as
many times as possible, within 30 seconds (22).
Statistical Analyses
Results are expressed as means and standard error for all
variables. Statistical analyses were performed by a two-way
analysis of variance (ANOVA) with repeated measures[Group (BFR-Walk and CON-Walk) × Time (pre- and posttesting)]. Post hoc testing was performed using a pairedt test when appropriate. All baseline differences and percent
changes between the BFR-Walk and CON-Walk groups
were evaluated with one-way ANOVA. Statistical significance was set at p < .05.
Results
Before training, there were no significant differences between the two groups for age and anthropometric variables

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We confirmed that BFR walk exercise has no impact onblood clotting as assessed by changes in fibrin d-dimer(before BFR walk training, 0.17 ± 0.02 mg/mL; immediately after BFR walk training, 0.55 ± 0.44 mg/mL; 15 minutes after BFR walk training, 0.20 ± 0.05 mg/mL) and fibrin
degradation products. These were in accordance with theresults of a previous study in young men (18). In addition,
previous studies have reported that unlike complete bloodflow occlusion and reperfusion, moderate restriction ofblood flow while performing low-intensity exercise does
not affect the production of reactive oxygen species, as assessed by plasma lipid peroxide (19), blood glutathione status, and plasma protein carbonyls (20). These findings
together support the notion that BFR walk training does notpose any immediate health concerns in older individuals.

259

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Table 1. Changes in Anthropometric Variables, Skeletal Muscle Size, and Volume After 10 Weeks of BFR-Walk or CON-Walk Training
BFR-Walk
Pre

Post

%

Pre

Post

%

Time Effect52.8 (2.1)
22.9 (1.0)
48.2 (1.3)
33.8 (0.9)

–1.2
–1.2
–0.3
0.2

p < .01p < .0164 (1)
1.54 (0.02)
53.5 (1.4)
22.5 (0.9)
47.1 (0.8)
33.8 (0.3)

53.1 (1.3)
22.4 (0.8)
47.5 (0.8)
34.3 (0.4)*

−0.8
−0.8
0.8
1.4†

68 (1)
0.52 (0.02)
53.4 (2.8)
23.2 (1.0)
48.3 (1.3)
33.7 (1.0)

96.4 (3.5)
43.2 (1.7)

99.3 (2.9)*,‡44.5 (1.5)*,‡

3.1‡
3.0‡

93.9 (4.8)
43.6 (1.8)

93.9 (4.5)
42.9 (1.9)

0.1
–1.6

1335 (44)612 (23)1384 (40)*628 (22)*

3.7‡
2.7‡

1329 (63)620 (28)1327 (64)616 (28)

–0.1
–0.6

p < .05

p < .01p < .05

Notes: Data are given as mean (±SE). BFR-Walk = BFR walk training; BMI = body mass index; CON-Walk = control walk training; CSA = cross-sectional area.
*p < .01, Pre versus Post; † p < .05, ‡p < .01, BFR-Walk versus CON-Walk.

(Table 1). After the training program, lower leg girth wasincreased (p < .01) in the BFR-Walk group, and there weresignificant (p < .01) time effects in body mass and BMI(Table 1).
During training sessions, mean HR and estimated exercise intensity for CON-Walk participants were 104 ± 5beats per minute and 44 ± 2% of HRR, respectively. In the
BFR-Walk participants, they were 122 ± 7 beats per minuteand 62 ± 9% of HRR, respectively. The ratings of perceived
exertion were slightly higher (p < .05) in the BFR-Walkgroup than in the CON-Walk group at the 5th minute (11.5 ±0.3 and 10.4 ± 0.3, respectively), 10th minute (11.7 ± 0.2
and 10.6 ± 0.3, respectively), and 15th minute (12.0 ± 0.2
and 10.9 ± 0.3, respectively) of the walk sessions.
After training, the CSA of the thigh and quadriceps muscle (3.1% and 3.0%, respectively) and muscle volume (3.7%
and 2.7%, respectively) were increased (p < .01) in the
BFR-Walk group, but not in the CON-Walk group (Table 1).
Maximal isokinetic knee extension (up to 8%, p < .01) andflexion (up to 22%, p < .01) strength were also increased in
the BFR-Walk group but not in the CON-Walk group (Table2). There were significant (p < .05) time effect in isometricknee extension. There were no significant changes forwhole muscle–specific tension in both training groups(BFR-Walk group: 2.0%; CON-Walk group: 1.1%).
There were significant (p < .05) time effects in both absolute and relative VO2peak (Table 3). There was also significant (p < .05) time effect in O2 pulse at 75% HRmax during
the submaximal exercise test (Table 3). There was a positively correlation (p < .05) between changes in O2 pulse andabsolute VO2peak in both the BFR-Walk (r = .67) and CONWalk (r = .77) groups.
The Up & Go test improved (p < .01) in only the BFRWalk group (10.7%). On the other hand, there was significant (p < .05) time effect in the chair-stand test although
percent change tended (p = .14) to be higher in BFR-Walkgroup (BFR-Walk: 20.5%; CON-Walk; 7.8%). In the BFRWalk group, the change in the Up & Go test results tended

Table 2. Changes in Maximum Isometric and Isokinetic Knee Extension and Flexion Torque and Functional Performance After 10 Weeks of
BFR-Walk or CON-Walk Training
BFR-Walk

Knee extension torque (nm)Isometric
30° per second
180° per second
Knee flexion torque (Nm)
30° per second
180° per second
Functional performance
Up & Go test, s
Chair stand test, times

CON-Walk

Pre

Post

%

Pre

Post

%

Time Effect120 (5)103 (5)66 (3)

127 (6)112 (5)*68 (3)

5.9
8.4§
2.9‡

120 (8)98 (6)
65 (3)

122 (10)98 (6)
64 (4)

1.6
0–1.9

p < .05
p < .05—48 (2)
31 (2)

56 (2)*,§
38 (2)*,§

16.1§
22.3§

44 (4)
30 (2)

42 (4)
29 (2)–3.2–4.2

p < .05
p < .01

5.0 (0.2)
23 (1)

4.5 (0.1)*
27 (1)−10.7‡
20.5

4.9 (0.2)
24 (2)

4.9 (0.2)
26 (2)–0.1
7.8

p < .05
p < .05

Notes: Data are given as mean (±SE). BFR-Walk = BFR walk training; CON-Walk = control walk training.
*p < .01, Pre versus Post; ‡ p < .05, §p < .01, BFR-Walk versus CON-Walk.

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Anthropometric variables
Age, yStanding height, mBody mass, kg
BMI, kg/m2
Midthigh girth, cm
Lower leg girth, cm
Muscle CSA, cm2
Midthigh
Midquadriceps
Muscle volume, cm3
ThighQuadriceps

CON-Walk

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BFR WALK TRAINING UPS VO2PEAK, THIGH VOLUME

Table 3. Changes in Estimated VO2peak After 10 Weeks of BFR-Walk or CON-Walk Training
BFR-Walk
Pre

Post

%

Pre

Post

%

Time Effect1.34 (0.08)
25.0 (1.3)

1.46 (0.10)
27.5 (1.6)

9.0
9.7

1.40 (0.10)
26.3 (1.1)

1.55 (0.11)
29.1 (1.4)

10.2
10.9

p < .05
p < .05

6.7 (0.5)

7.5 (0.7)

11.7

7.1 (0.4)

8.0 (0.5)

12.4

p < .01

Notes: Data are given as mean (±SE). BFR-Walk = BFR walk training; CON-Walk = control walk training.

to correlate with the change in knee flexion strength (r =.59, p = .09), and the change in the chair-stand test results
also tended to correlate with the change in knee extension
strength (r = .61, p = .08).
Discussion
This study indicated that BFR-Walk training, a single
mode of exercise training, performed at relatively low exercise intensity can elicit improvements in muscle volume
and strength in older women. Additionally, aerobic capacity
improved in both groups although its value was estimated.
Previously, concurrent improvements in muscular strengthand VO2max by single exercise training have been achieved
after high-intensity, long-duration, aerobic-type, single exercise training (23,24); yet, none of the studies demonstrated muscular hypertrophy. This suggests that theincreased muscular strength was due mainly to neural adaptations. Thus, high-intensity, long-duration, single-mode,
aerobic-type exercise training rarely produces significant
muscle hypertrophy. It has been reported in earlier studies
that maximal knee extension strength was reduced and thethigh muscle CSA was unchanged after 4 weeks of cycle
training under conditions of local leg ischemia, althoughVO2max increased (25,26). Unlike previous studies, our findings show that BFR walk training is an innovative method
for improving both muscle volume and aerobic capacity inolder women. Furthermore, the reported rate of perceived
exertion (on a scale of 6 to 20) during walk training sessions
was low in both training groups although there was a significant difference between the BFR-Walk (11.5–12.0) andthe CON-Walk (10.4–10.9) groups.
In the present study, thigh muscle CSA/volume and isokinetic knee joint strength increased by 3%–4% and 3%–
22%, respectively, after 10 weeks of BFR walk training inolder women. Takarada and colleagues (9) reported that 16
weeks of BFR resistance training at a relatively low intensity (30%–50% 1-RM) increased upper arm muscle CSA(17%–20%) and isokinetic elbow joint strength (18%) in
older women. Additionally, some studies have demonstrated
that 8–12 weeks of HI-RT leads to increases in thigh muscle
CSA (7%–11%) and isometric and isokinetic knee joint
strength (10%–19%) in the elderly participants (27,28). The
magnitude of increases in muscle size and strength in thepresent study are lower than those reported in some HI-RT
studies (27,28) and in a BFR resistance training study (9).
The differences in exercise intensity and volume or BFR
stimulus might have caused the variability in the traininginduced muscle hypertrophy and strength gain.
Our previous human studies have demonstrated that 20%
1-RM intensity knee extension exercise with BFR increased
vastus lateralis (VL) muscle protein synthesis (40%–50% at
3 hours postexercise) through the mammalian target of rapamycin (mTOR) signaling pathway in young (29) and old(30) men, although the rate of muscle protein breakdown
was not measured. These anabolic responses may contributesignificantly to BFR walk training–induced muscle hypertrophy and strength gain. On the other hand, the same laboratory using the same technique reported that 70% 1-RM
intensity knee extension exercise without BFR increased VL
muscle protein synthesis (48% at 2 hours postexercise) andthrough the mTOR pathway in young men (31). Those results indicated that increases in postexercise muscle protein
synthesis are probably similar between high-intensity resistance exercise and low-intensity BFR resistance exercise.
Our results showed that aerobic capacity improved inboth groups although its value was estimated. Several studies have reported that HI-RT (32,33) resulted in essentiallylittle or no effect on aerobic capacity in aging adult populations. Conversely, aerobic exercise training is thought tostimulate improvements in aerobic capacity (VO2max increased by 10%–20% after 8–12 weeks of training) in theelderly participants (34,35). Previously, we reported no significant improvement in estimated VO2peak after 6 weeks ofslow (67 m/min) BFR walk training in the elderly participants (12). In that study, the average exercise intensity during training sessions was about 45% of HRR (average HR =104 beats per minute). In general, the minimal stimulus
necessary to evoke change is as high as 50% of VO2max (7).
In the present study, exercise intensity and duration were set
at 45% of HRR and 20 minutes in the BFR-Walk group.
During the training sessions, however, the exercise intensity
was 62% HRR on average because HR increased due to decrease in SV by leg BFR without changes in cardiac output(36). Therefore, the exercise intensity in the BFR-Walkgroup may be within the effective exercise intensity for improvements in VO2peak.

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Estimated VO2peak
L/min
mL/kg/minO2 pulse
mL

CON-Walk

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The BFR walk training–induced increase in VO2peak may
be due to improvements in central cardiovascular and/or peripheral metabolic adaptations. The VO2max is the product ofcardiac output and arterial and mixed venous blood oxygen(a-v O2) difference at maximal exercise intensity. However,until now, there are few studies investigating the cardiovascular hemodynamic and muscle metabolic responses to
BFR exercise training. In the present study, change inVO2peak estimated was correlated with change in O2 pulse inboth the BFR-Walk and CON-Walk groups. Also, Sundberg(25) found an increase in VO2max by utilizing supine onelegged cycle training with 50 mm Hg chamber pressure (reduced leg blood flow by 16%) for 4 weeks (four sessions perweek). In that study, oxidative muscle enzyme and capillarydensity were increased in the ischemically trained leg, but
cardiovascular adaptations to the ischemic exercise training
were not found. A recent study reported that increases inVO2max and submaximal exercise SV were observed after 2
weeks of twice-daily, 6-days per week BFR walk training,whereas resting SV remain unchanged (37). Therefore, it
seems that the increase in VO2peak from BFR walk training
may be due to adaptations in muscle oxidative capacity (a-v
O2 difference) as well as in SV. Spina (38) suggested that for
older women, the increase in VO2peak is solely the result of
an improved a-v O2 difference at maximal exercise, as there
was no evidence of SV adaptation. In addition, the increasein lower body muscle mass may be associated with improvements in VO2max in the BFR training group.
Previous cross-sectional studies (39,40) showed that Up& Go and chair-stand test results are correlated with knee
extension strength in the elderly population. Our results
conform to the cross-sectional studies showing that Up &Go and chair-stand performance was improved by BFRWalk training and tended to correlate with knee joint
strength. The improvements of functional fitness in thepresent study may be mainly due to increases in strength asmeasured by significant increases in maximal isometric andisokinetic knee joint torques.
In summary, low-intensity walk training with leg BFR
concurrently improved thigh muscle size and knee joint
strength in older women. Also, functional fitness was improved by this training, which may be mainly due to increases in strength. Further research is needed to determine
the mechanism of concurrent improvement in muscular andcardiovascular adaptations by BFR walk training.

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Journals of Gerontology: Biological Sciences
cite as: J Gerontolog A Biol Sci Med Sci, 2015, 950–958
doi:10.1093/gerona/glu084
Advance Access publication June 10, 2014

Original Article

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Effects of Low-Load, Elastic Band ResistanceTraining Combined With Blood Flow Restriction
on Muscle Size and Arterial Stiffness inOlder Adults
Tomohiro Yasuda,1 Kazuya Fukumura,1 Yusuke Uchida,1 Hitomi Koshi,1Haruko Iida,1 Ken Masamune,2 Tatsuya Yamasoba,3 Yoshiaki Sato,4 andToshiaki Nakajima1
Department of Ischemic Circulatory Physiology, Graduate School of Medicine, 2Department of MechanoInformatics, Grad School of Information Science and Technology, and 3Department of Otolaryngology and Head andNeck Surgery, Graduate School of Medicine, University of Tokyo, Japan. 4Department of Basic Sciences in Medicine,
Kaatsu International University, Battaramulla, Sri Lanka.
1

Address correspondence to Tomohiro Yasuda, PhD, Department of Ischemic Circulatory Physiology, Graduate School of
Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: yasuda-tomohiro@umin.ac.jp
Received September 27 2013; Accepted May 7 2014.

Decision Editor: Rafael de Cabo, PhD

Abstract
We examined the effect of low-load, elastic band resistance training with blood flow restriction (BFR) on
muscle size and arterial stiffness in older adults. Healthy older adults (aged 61–85 years) were divided
into BFR training (BFR-T, n = 9) or non-BFR training (CON-T, n = 8) groups. Both groups performed
low-load arm curl and triceps down exercises (four sets, total 75 repetitions for each) using an elastic
band, 2 d/wk for 12 weeks. The BFR-T group wore inflated pneumatic elastic cuffs (120–270 mm Hg) on
both arms during training. Magnetic resonance imaging-measured muscle cross-sectional area of theupper arm, maximum voluntary isometric contraction of the elbow flexors and extensors, cardio-ankle
vascular index testing, and ankle-brachial pressure index were measured before and 3–5 days after the
final training session. Muscle cross-sectional area of the elbow flexors (17.6%) and extensors (17.4%)
increased, as did elbow flexion and elbow extension maximum voluntary isometric contraction (7.8%
and 16.1%, respectively) improved (p < .05) in the BFR-T group, but not in the CON-T group. In cardioankle vascular index and ankle-brachial pressure index testing, there were no changes between preand post-results in either group. In conclusion, elastic band BFR-T improves muscle cross-sectional
area as well as maximal muscle strength but does not negatively affect arterial stiffness in older adults.
Key Words: Electromyography—Muscle hypertrophy—Sarcopenia—Strength—Vascular occlusion

Age-related skeletal muscle loss (sarcopenia) inhibits mobility andincreases the risk of falls, fractures, disability, and heart disease(1,2). High-load resistance training (HL-T) can induce muscle

hypertrophy and improve insulin resistance and type-2 diabetes inthe elderly (3,4), suggesting that HL-T prevents and even improves
sarcopenia in the elderly (5). However, the use of heavy weights with© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com.

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Materials and Methods
Participants
Seventeen men and women (aged 61–85 years) volunteered toparticipate in the study and were selected according to the exclusion criteria (blood pressure >160/100 mm Hg, body mass index>30 kg/m2, history of anemia, cerebrovascular disease, myocardial
infarction, and arthroscopic joint surgery) used to define “medically stable” older participants for exercise studies proposed by
Greig and colleagues (24). In addition, volunteers who sufferedfrom a chronic disease such as severe hypertension (>180/110 mmHg), orthopedic disorders, deep venous thrombosis, peripheral
vascular disease, or cognitive dysfunction were excluded from thestudy. None of the participants had participated in resistance-type
training for a minimum of 6 months prior to the study. All participants were free of overt chronic disease as assessed by medical history, physical examination, and complete chemistry andhematologic evaluation. Participants were divided into either the
BFR training (BFR-T) group (2 men and 7 women: n = 9; age[mean ± SD]: 71.8 ± 6.2 years) or the non-BFR training (CON-T)
group (1 man and 7 women: n = 8; age: 68.0 ± 5.1 years). All participants were informed of the risks associated with involvementin the study and signed an informed consent document before
participation. The principles of the World Medical Association
Declaration of Helsinki and the American College of Sports
Medicine Guidelines for Use of Human Subjects were adopted inthis study. The study was approved by the Ethics Committee ofthe University of Tokyo.

Training Protocol
BFR-T and CON-T groups performed bilateral arm curl and triceps press down exercise training 2 d/wk for 12 weeks. Both exercise groups used the “Heavy (Green)” band for men and “Thin(Yellow)” band for women (Hygenic Corporation, Akron, OH).
This training was performed under the close supervision of thosewith technical knowledge in BFR training. One week before thestart of the training study, both groups performed practice sessions for the maximum isometric strength (maximum voluntaryisometric contraction [MVC]) test. In addition, BFR-T participants
were familiarized with the BFR stimulus. Three or four days before
training, MVC was determined. Training volume was 75 repetitions(30, 15, 15, and 15 repetitions, with 30-second rests between sets)
for both exercises (90-second rests between exercises). This protocol is typical of submaximal BFR studies (12,16,22,23,25,26).
Once the pneumatic cuffs were inflated, they remained so for thetwo exercises, including rest periods between sets and exercises.
During arm curl exercise, subjects were comfortably seated on achair (16). Elbow joint range of motion during the exercise wasapproximately 20–145° (0° being full extension). During triceps
press down exercise, subjects were comfortably seated on a rowing
chair with the body supported in the vertical position (16). Elbow
joint range of motion during the exercise was approximately 140–
5° (0° being full extension). Subjects were instructed not to let theband snap them back to the start position but to consciously control the return movement such that it would take twice as long as
the stretching movement. The repetition duration was 2.4 seconds(1.2-second concentric and 1.2-second eccentric exercise cycle) for
both exercises. The total length of the two exercises per day was
9.5 minutes for both groups.

Blood Flow Restriction
During the training sessions, BFR-T subjects wore a speciallydesigned pneumatic cuffs (30-mm width, KAATSU Master, Sato
Sports Plaza, Tokyo, Japan) around the most proximal portion of theboth arms. On the first day of training, the cuffs were set at 30 mm
Hg and air pressure gradually inflated to 120 mm Hg (Day 1). The
air pressure was increased by 10–20 mm Hg at each subsequent
training session until a pressure of approximately 270 mm Hg wasreached if each subject could perform at high levels of pressure intensity. The restriction pressure was selected in accordance with previous study (16). The mean pressure intensity throughout the periodof training was 196 ± 18 mm Hg (180–270 mm Hg at 24th training
session). Immediately after the two exercises, the pressure cuff was

Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/70/8/950/2947617 by guest on 16 December 2018weight machines/free weights required for muscle adaptation withtraditional resistance exercise may not be practical and may even be
dangerous when carried out without proper supervision. Thus, theeffectiveness of alternative exercise methods should be investigated.
Elastic bands/tubing have been used widely in rehabilitative medicine and in health enhancement for resistance training (6,7). A previous study reported that a home-based resistance training programfor older adults using elastic bands could serve as a practical andeffective means of improving muscle strength (8). Elastic bands arealso portable and are less expensive and easier to use than weightmachines and/or free weights. Elastic band resistance training has
thus been shown to be a feasible alternative to conventional training
with free weights or machines (9,10). However, as elastic resistancetraining is commonly performed using low-to-moderate resistancelevel, this training typically has little or no effect on muscle hypertrophy (8,9).
In the past decade, several studies have reported that muscle
hypertrophy can be produced with low-load resistance training(20%–30% one-repetition maximum [1RM]) combined with bloodflow restriction (BFR-T), termed “kaatsu training,” regardless ofage (11,12). The mechanism by which BFR potentiates the training
effect of low-load resistance training remains obscure but appears to
be related, in part, to an increase in muscle activation (11,13–15).
Recently, Yasuda and colleagues (16) revealed that muscle activation increased progressively during BFR-T when exercises were performed at low-resistance levels using an elastic band as well as whenusing free weights. BFR-T using elastic bands for resistance may thus
be an effective home-based resistance training program for promoting both muscle hypertrophy as well as strength.
In general, reductions in arterial compliance or increases in arterial stiffness reduce the arterial buffering function of the pulsation ofblood pressure and blood flow, which contribute to elevations in systolic blood pressure, left ventricular hypertrophy, coronary ischemic
disease, and reductions in arterial baroreflex sensitivity (17,18). Thismeans that prevention and treatment for decreased arterial compliance or stiffness is also important. However, HL-T has been reported
to induce a 20%–30% reduction in arterial compliance in young
and older adults (19,20), indicating that the use of heavy loads during resistance training has a potentially deleterious effect regarding arterial stiffness in older adults. On the other hand, previous
studies have reported that BFR-T using low loads could improve or
maintain arterial compliance or stiffness in young and older adults(21–23). We hypothesized that BFR-T using elastic bands may be auseful method for promoting muscle hypertrophy with a low risk ofincreased arterial stiffness in older adults. Thus, the purpose of thisstudy was to examine the effect of low-load elastic band training
with BFR on muscle size and arterial stiffness in older adults.

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quickly removed. The amount of time under BFR was approximately
11 minutes.

Maximum Isometric Strength Measurement

MRI-Measured Muscle Cross-Sectional Area

Arterial Function Tests

Muscle cross-sectional area (CSA) was obtained using a MRI scanner(0.2-T Open MRI, Hitachi, Tokyo, Japan). A T-1 weighted, spin-echo,
axial plane sequence was performed with a 500-millisecond repetition time and a 23-millisecond echo time. Subjects rested quietly inthe magnet bore in a supine position, with their arms extended along
their trunk. After transverse angle was set at perpendicular to thehumerus in the sagittal plane, continuous transverse images (from thelateral epicondyle of the humerus to the acromial process of the scapula) with 10-mm slice thickness were obtained from the both upperarms of the body along the humerus. Although the difference in 5°of transverse angle is equal to the difference in approximately 0.4%
in muscle CSA (cylindrical model), the differences between pre andpost for all subjects were within 5°. All MRI data were transferred
to a personal computer for analysis using specially designed image
analysis software (sliceOmatic, Tomovision Inc., Quebec, Canada).
Skeletal muscle tissue CSA was measured for elbow flexors (biceps
brachii and brachialis) at 6 cm above the elbow joint and for elbow
extensors (triceps brachii) at 16 cm above the elbow joint. The coefficient variation of this measurement was less than 1.0% (16).

FMD, CAVI, and ABI (arterial function) measurements were conducted in the supine position. The participants were instructed to
fast 6–7 hours before testing and refrain from ingesting alcohol orcaffeine for at least 12 hours prior to testing. After the participants
were asked to rest in the lying position in a quiet, dark, air-conditioned room (25–26°C) for 5 minutes, a standard cuff (UNEXCUFF,
no. 5) was positioned around the right arm, 2–3 cm distal the antecubital fossa and their systolic and diastolic blood pressures wereassessed using oscillometric methods (UA-767PC, A&D Co., Ltd.,Tokyo, Japan). Then, after the participants had rested again for atleast 15 minutes in a supine position in the same room, endothelium-dependent FMD of the brachial artery was measured using
an established noninvasive method (27). After basal measurements
were obtained, arterial occlusion was created by inflating a cuff
placed around the forearm with suprasystolic compression (50 mm
Hg above systolic blood pressure) of the right forearm for 5 minutes. After 5 minutes of inflation, the cuff was deflated producing
a brief high-flow state resulting in arterial dilation due to increased
shear stress. The diastolic diameter of the brachial artery was

Measurements Schedule

Figure 1. Experimental timeline. CSA = cross-sectional area; MTH = muscle thickness; MVC = maximum voluntary isometric contraction; RPE = ratings ofperceived exertion.

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Subject testing took place before the start of the study (pre) and
3–7 days after (post) the 12-week training period. The order ofmeasurements were magnetic resonance imaging (MRI), venous
blood samples, arterial function (flow-mediated dilatation [FMD],
cardio-ankle vascular index [CAVI] testing, and ankle-brachial pressure index [ABI]) tests, and MVC measurements. Figure 1 shows
the testing schedule for each of the measurements taken during the
12-week experimental period. All subjects were right handed except
for two women (one for BFR-T and one for CON-T). All data wereobtained from the right side of the body. Considering the schedule of examiners, all subjects and variable technologists, the MRI(10:00 and 15:00 hours), venous blood samples and arterial function tests (after 6–7 hours’ fast, 10:00 and 15:00 hours), and MVC(10:00 and 15:00 hours) measurements were obtained in 2 days (fewdays interval). The subjects were instructed to refrain from ingesting alcohol and caffeine for 24-hour prior to pre- and post-training
measurements.

MVC of the elbow flexors and elbow extensors was measured twice
by a dynamometer (Taiyo Kogyo Co., Tokyo, Japan). Each subject
was comfortably seated on an adjustable chair, with the arm positioned on a stable table at chest level with the elbow bent at an angleof 90° (0° at full extension). The upper arm was maintained in thehorizontal plane (at 90°), while the wrist was fixed at the end of
the dynamometer lever arm in a position of supination for elbow
flexion and in a position halfway between supination and pronationfor elbow extension. Both forces were measured with a transducer
while the subject performed two trials separated by a 60-second rest
interval (90-second rests between elbow flexion and elbow extension). If MVC torque for the first two MVCs varied by more than
5%, up to two additional MVCs were performed with 60-second
rest between trials (14,15). Subjects were instructed to perform an
MVC as quickly as possible during a period of about 2 seconds. The
recorded value for the MVC was taken as the highest and most stable approximately 1 second of the 2-second contraction. The highest
MVC value was used for data analysis. The coefficient variation forthis measurement from test to retest was 1.3%. The intraclass correlation coefficient of the measurements was 0.97.

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Blood Sampling and Biochemical Analyses
Venous blood samples were obtained from the antecubital vein andmeasured for fibrin/fibrinogen degradation products (FDP), d-dimer,and creatine kinase (CK). The plasma concentrations of these samples
were measured at a commercial laboratory (SRL Inc., Tokyo, Japan)
by following latex immunoassay for FDP and d-dimer and spectrophotometry for NADPH formed by a hexokinase and D-glucose-6phosphate-dehydrogenase-coupled enzymic system for CK.

Measurements of Acute Responses to Training
SessionElectromyography
The skin was shaved, abraded with a skin preparation gel (Skinpure,
Nihon Kohden, Japan), and cleaned with alcohol wipes. During theexperiment, skin impedance was less than 2 kΩ. The ground electrode was positioned on the lateral epicondyle. Bipolar (2-cm centerto-center) surface electromyography (EMG) electrodes (Ag/AgCl;
Vitrode F; Nihon Kohden, Tokyo, Japan) were placed over the muscle
belly (mid-portion) along the longitudinal axis of the biceps brachii
and triceps brachii of the right upper arm (14,15). EMG signals wererecorded and collected on a personal computer (MacBook Pro 10,1;
Apple, Japan) for subsequent analysis. All EMG signals were digitizedat a sampling rate of 1,024 Hz with a bandwidth of 0 Hz to 500 kHz(AB 6216; Nihon Kohden). To determine integrated EMG (iEMG),
signals were fully rectified and integrated (Lab Chart 7 software, AD
Instruments, Japan). During the experimental session, surface EMG
was recorded continuously and each iEMG value was divided into
groups of five successive repetitions. The average for each group of five
repetitions was represented as a single data point for statistical analysis(14,16,25). To determine the iEMG ratio of agonist muscles, iEMGsduring each exercise was normalized to Pre, which was iEMG without
BFR before the first set of training session. EMG measurement was
performed during the 23rd training session (see Figure 1). The coefficient variation for this measurement from test to retest was 5.7%.
Relative exercise loading
To determine the relative exercise loading of performing the arm
curl and triceps press down exercises, the iEMGs for the elastic band
exercises (three to five repetitions) were compared to the iEMGs during MVC of the elbow flexors and elbow extensors. This measurement was completed on the same day before 23rd training session.

MTH of the elbow flexors and elbow extensors was measured at
10 cm above the elbow joint and at mid-upper arm of the rightupper arm, respectively. Briefly, the measurements were carried out
while the subjects stood with their elbows extended and relaxed.
The upper arm length (from the lateral epicondyle of the humerus
to the acromial process of the scapula) was measured, and the 10
cm above the elbow joint for elbow flexors and 50% distance fromelbow joint for elbow extensors were marked on the subject’s skinwith a pen. A 10.0 MHz scanning head (5.5 cm length probe) was
placed on the skin perpendicular to the tissue interface. The scanning head was coated with a water-soluble transmission gel to provide acoustic contact without depressing the dermal surface. The
subcutaneous adipose tissue-muscle interface and the muscle-boneinterface were identified from the ultrasonic image. The perpendicular distance from the adipose tissue-muscle interface to the musclebone interface was taken as MTH. Ink markers on the elbow flexors
were used to ensure similar positioning over repeated MTH measurement. The coefficient variation of this measurement from test to
retest was 1.4%. The intraclass correlation coefficients of the measurements were 0.94 and 0.96, respectively (25). The same investigator (T.Y.) made all the ultrasound measurements. The MTH of theelbow flexors and elbow extensors was recorded before and immediately after the exercise bout. This measurement was completed atevery 3 weeks (1st, 4th, 7th, and 10th week) of training period, andthe average of 4 times for “before” or “immediately after” was represented as a single data point for statistical analysis, respectively.
Heart rate
During all training sessions, heart rate was recorded at baseline (pre)and immediately after the last set of each exercise (post) (Model
9560, Onyx II; Nonin Medical Inc.).
Ratings of perceived exertion
During all training sessions, ratings of perceived exertion based on anumerical scale of 6–20 were collected to assess subjective feelings ofphysical effort (ie, exertion). Ratings of perceived exertion data wererecorded immediately after the last set of each exercise (31).
Statistical analyses
Results are mean ± SD. The data were tested for normality using
Shapiro–Wilk test. Because all variables were normally distributed,
parametric statistical analyses were performed. Statistical analysis
was performed by a two-way analysis of variance with repeatedmeasures group by time. When significant main effects and/or interaction were observed, post hoc testing was performed using the
Tukey technique. Percent changes from pre were also compared
between groups using Tukey’s test. Statistical significance was set at
p <.05. The sample size was estimated from a priori power analysis(32) to detect differences (power of 0.80, an α of 0.05, two-tailed,and an effect size of 1.7) in elbow flexors muscle CSA for the interventions planned by reference to the result of previous BFR study(25). Consequently, it was determined that a minimum of seven BFR
training and seven control subjects were required to test both themain and interaction effects.

Results
Ultrasound-measured muscle thickness
Since muscle thickness (MTH) using B-mode ultrasound (Acuson
Sequoia 512; Siemens, Tokyo, Japan) has the advantage of evaluating acute change in muscle cell swelling following exercises (25),

Before training, there were no significant differences between thetwo groups for age (p = .193) and anthropometric variables (standing height, p = .315; body weight, p = .821; body mass index,
p = .157) (Table 1). A significant group by time interaction was not

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determined semiautomatically using an instrument equipped with
software for monitoring the brachial artery diameter (UNEX EF,
Unex Co. Ltd., Nagoya, Japan). Percentage of FMD was calculated
as reported previously (28,29). Then, after 20- to 30-minute rest,
CAVI and ABI were measured noninvasively using a VS-1500 system (Fukuda Denshi Co., Ltd, Tokyo, Japan). Subjects were placedsupine. Electrocardiogram and heart sound were monitored. CAVI
is automatically calculated using the formula; a {2ρ/ΔP × In(Ps/Pd)
PWV2} + b (a and b, constants; ρ, blood density; P, difference insystolic and diastolic pressure; Ps, systolic pressure wave velocity; Pd,
diastolic pressure; PWV, heart-ankle pulse wave velocity). ABI is theratio of the systolic blood pressure in the ankle to the systolic bloodpressure in the right arm (30).

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observed for body weight (p = .520) and body mass index (p = .469)
in either group following the training.

Acute Effect of BFR-T and CON-T

Chronic Effect of BFR-T and CON-T
A significant group by time interaction was observed for CSA (p <.0001 for elbow flexors and p = .013 for elbow extensors muscles,
respectively) and MVC (p = .008 for elbow flexion and p = .013
for elbow extension). Elbow flexors and elbow extensors muscle
CSA (17.6% and 17.4%, respectively) were increased (p < .0001

Table 1. Changes in Anthropometric Variables After 12 Week of Training Period
BFR-T
Pre
Anthropometric variables
Age (y)Standing height, mBody mass, kg
BMI, kg/m2
Upper arm girth, cm

72(6)1.60 (0.11)
51.7 (11.4)
20.1 (2.2)
26.6 (2.0)

CONT-T
Post

51.6 (11.4)
20.1 (2.4)
27.1 (1.8)*

%

Pre

Post

%

−0.3
−0.3
2.1†

68 (5)
1.55 (0.07)
52.8 (8.0)
22.0 (3.0)
27.7 (2.6)

52.3 (8.3)
21.7 (2.8)
27.5 (2.4)

−0.9
−0.9
−0.7

Notes: Data are given as mean (±SD). BFR-T = BFR resistance training; BMI = body mass index; CON-T = non-BFR resistance training; upper arm girth, at
50% distal between the lateral epicondyle of the humerus and the acromial process of the scapula.
*p = .08, pre vs post.
†
p < .05, BFR-T vs CON-T.

Figure 2. iEMG ratio of biceps brachii and triceps brachii muscles during arm curl (a) and triceps press down (b) for each set performed. Average for each five
repetitions was represented as a single data point. Values are means and SD. **Different from first five repetitions, p < .01. *Different from first five repetitions,p < .05. ¶¶Different from CON-T, p < .01.

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A significant group by time interaction was observed for iEMG (p <.001 for both muscles) and MTH (p = .013 for elbow flexors and p =.016 for elbow extensors muscles). During the exercise session, iEMG
ratio for agonist muscle increased progressively in the BFR-T groupfor arm curl exercise from first to last set (from p = .023 to p < .001)
and for press down exercise from the third to last set (from p = .041
to p < .001) and BFR-T was greater than CON-T at last set (p = .001)
for arm curl exercise (Figure 2). Immediately after the exercise session,mean MTH was greater with the BFR-T compared to the CON-T atanterior (p = .021, 14.2% vs 7.0%, respectively) and posterior (p =.024, 8.5% vs 3.3%, respectively) 50% of upper arm (Figure 3).
There were no differences in elastic band elongation between
BFR-T and CON-T groups for arm curl (p = 1.000, flexed position:

11.3 ± 4.1 cm vs 11.4 ± 1.5 cm and p = .113, extended position:
68.5 ± 4.2 cm vs 63.4 ± 6.1 cm) and press down (p = .998, flexed position: 16.0 ± 4.8 cm vs 16.4 ± 4.3 cm and p = .151, extended position:
74.8 ± 6.0 cm vs 69.5 ± 3.2 cm) exercises. There were no differencesin relative exercise load (p = .649 for arm curl and p = .935 for press
down exercises, respectively), range of motion (p = .412 for arm curland p = .082 for press down, respectively) between both groups.
However, ratings of perceived exertion were higher in the BFR-RT
group than in the CON group (p = .004 for arm curl and p = .001
for press down exercises, respectively) (Table 2).

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Table 2. Relative Exercise Intensity, Range of Motion, Heart Rate, and Ratings Perceived Exertion During Two Exercises
BFR-T

Relative exercise intensity, %MVC
Arm curl
Press down
Range of motion, degree
Arm curl
Press downHeart rate, bpm
Arm curl (total)  120–150 mm Hg  160–190 mm Hg  200–230 mm Hg  240–270 mm Hg
Press down (total)  120–150 mm Hg  160–190 mm Hg  200–230 mm Hg  240–270 mm Hg
Ratings of perceived exertion
Arm curl (total)  120–150 mm Hg  160–190 mm Hg  200–230 mm Hg  240–270 mm Hg
Press down (total)  120–150 mm Hg  160–190 mm Hg  200–230 mm Hg  240–270 mm Hg

CON-T

Mean (±SD)

Range

Mean (±SD)

Range

26.7 (11.1)
30.8 (12.3)

13.8–44.9
17.2–53.3

28.8 (6.7)
30.3 (7.9)

17.8–40.4
21.7–45.1

124 (14)130 (5)

93–140
123–139

118 (14)136 (9)95–137
122–146

88 (15)84 (13)85 (13)88 (17)99 (18)89 (15)83 (11)86 (14)89 (17)98 (17)

61–140
63–118
66–12561–140
69–13264–141
68–113
67–13264–141
73–13275 (7)————
77 (9)————

56–100————
51–102————

14.1 (2.1)*
15.5 (2.1)
14.0 (2.5)
13.8 (1.9)
13.7 (2.0)
14.0 (1.8)*
14.9 (2.4)
14.2 (2.4)
13.7 (1.9)
13.7 (2.1)

9–19
12–19
9–19
9–17
10–17
11–17
11–19
9–19
9–19
11–17

11.5 (0.7)————
11.2 (0.5)
—
—
—
—

9–15
—
—
—
—
8–14
—
—
—
—

Notes: BFR-T = BFR resistance training; CON-T = non-BFR resistance training; MVC = maximum voluntary contraction.
*p < .01, BFR-T vs CON-T.

and p = .0131, respectively) in BFR-T group, but not in the CON
group (Figure 4). Elbow flexion and elbow extension MVC (7.8%
and 16.1%, respectively) were increased (p = .0082 and p = .0131,
respectively) in the BFR-RT group, but not in the CON group(Figure 5).
A significant group by time interaction was not observed forheart rate (p = .671), systolic and diastolic blood pressures (p = .126
and p = .104, respectively), CAVI (p = .150), ABI (p = .485), FMD(p = .116), FDP (p = .128), d-dimer (p = .506) and CK (p = .390)(Table 3).

Discussion
It has previously been observed that BFR-T using weight machines
or free weight leads to increased muscle size and maintenance ofarterial stiffness in older adults as well as in young adults (22,23).
However, to date, no studies have discussed the muscle size and arterial stiffness following BFR-T using elastic bands. Our findings showthat low-load, elastic band resistance training (arm curl and press
down) with BFR can lead to a significant increase in muscle CSA(elbow flexors and elbow extensors) as well as maximal contractile

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Figure 3. Muscle thickness (MTH) of the elbow flexors (a) and the elbow extensors (b) before and immediately after exercise session. Values are means and SD.
**Different from before, p < .01. *Different from before, p < .05.

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956

Figure 5. Maximum isometric strength (MVC) of the elbow flexors (a) and the elbow extensors (b) pre- and post- training period. Values are means and SD.
**Different from pretraining, p < .01.

Table 3. Changes in Arterial Function, Coagulation System, andMuscle Damage After 12 Week of Training Period
BFR-T
Pre

CON-T
Post

Pre

Post

Heart rate, bpm
68 (19)67 (10)63 (11)60 (6)
Systolic BP, mm Hg
135 (16)134 (20)127 (17)120 (9)
Diastolic BP, mm Hg
81 (9)
82 (9)
80 (11)77 (8)CAVI, m/s
8.9 (1.2)
9.2 (1.1)
8.5 (0.7)
8.2 (0.8)
ABI, unit
1.17 (0.07) 1.14 (0.09) 1.10 (0.10) 1.10 (0.09)
FMD, %
3.6 (2.1)
4.3 (3.1)
4.3 (1.6)
3.5 (2.0)
FDP, µg/dL
2.9 (0.9)
3.7 (1.1)
2.9 (0.4)
3.0 (0.8)
d-Dimer, µg/dL
0.2 (0.1)
0.3 (0.1)
0.2 (0.1)
0.3 (0.2)
CK, IU/L
186 (247) 112 (44)91 (52)88 (38)Notes: Data are given as mean (±SD). BFR-T = BFR resistance training;
CON-T = non-BFR resistance training; BP = blood pressure; CAVI, cardioankle vascular index; ABI, ankle-brachial pressure index; FMD, flow-mediateddilation; FDP, fibrin/fibrinogen degradation products; CK, creatine kinase.

strength in older adults. In addition, we observed no changes in
hemodynamic parameters (heart rate and blood pressure), arterial
stiffness (CAVI), vascular endothelial function (FMD), coagulation
factors (FDP and d-dimer), and muscle damage (CK). Thus, elastic
band BFR-T can be considered as a useful method for preventing andeven improving sarcopenia in old healthy adults.

In this study, muscle size did not change in the CON-T group,suggesting that low-load elastic band training without BFR is noteffective at causing significant muscle hypertrophy. On the other
hand, BFR-T (<30% MVC) produced a hypertrophic potential of
0.73% per session (17.6% increase in elbow flexor muscle CSA over
24 training sessions), which is greater than that observed following traditional high-load resistance training at 80% 1RM or BFR-T
using free weights at 30%–50% 1RM (0.47% or 0.59% per session,respectively) in elderly adults (11). Additionally, the observed gains
in elbow flexion MVC strength (0.33% per session) was equallyeffective as high-load resistance training or low-load BFR training
using free weights (0.39% or 0.32% per session, respectively) (11)for improving arm muscle strength in older adults. Therefore, ourdata suggest that low-load elastic band training combined with BFR
can provide an effective hypertrophic stimulus for muscles in older
adults.
There are some trigger mechanisms underlying the BFR-T induced
muscle hypertrophy. In high-load training, myogenic stem cells most
likely play an important role to enhance the activity of muscle protein synthesis (33). Recently, Nielsen and coworkers (34) revealed
that BFR-T (23 training sessions, 20% 1RM using machine) leads tomarked proliferation of myogenic stem cells, resulting in an increase
in myonuclei in skeletal muscle, which is accompanied by marked
myofiber hypertrophy. Therefore, there is a high possibility thatmyogenic stem cell-derived myonuclei provide an improved capacity
for myofibrillar gene transcription, which is likely to contribute to an

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Figure 4. Muscle cross-sectional area (CSA) in the elbow flexors (a) and the elbow extensors (b) pre- and post-training period. Values are means and SD.
**Different from before, p < .01.

Journals of Gerontology: BIOLOGICAL SCIENCES, 2015, Vol. 70, No. 8

exercise intensity, because it is difficult to standardize the resistanceoffered by the resistance bands between individuals. Fourth, wemeasured CAVI, which reflects changes in both central and peripheral muscle arterial compliance, although previous studies measured
central and/or peripheral arterial compliance (19–22). Hence, morework is needed to understand the relationship between elastic band
BFR-T and muscle size and/or arterial function in older adults.
In conclusion, low-load arm curl and triceps press down training combined with BFR using elastic bands for resistance elicited
marked gains in upper arm muscle CSA and strength and did not
negatively affect arterial stiffness in older healthy adults. Thus, ourresults demonstrate that low-load, elastic band resistance training
with BFR would be beneficial in the development of safe and effective methods of promoting muscle hypertrophy in older adults.

Funding
This work was supported by JSPS KAKENHI Grant Number
24300189 (to T.N.) and 25750288 (to T.Y.) and Physical fitness
research institute Meiji Yasuda Life Foundation of Health andWelfare.

Acknowledgments
The authors thank the participants who participated in this study. We also
thank Dr. Kansei Uno, Mr. Junxiao Nie, and Mr. Hiroyuki Imuta (Universityof Tokyo) for helpful discussion and technical support and Dr. Takuhiro
Yamaguchi and Mr. Tempei Miyaji (University of Tokyo) for statistical support. Dr. Yoshiaki Sato is an inventor of low-load resistance training withblood flow restriction, so-called Kaatsu training, and the owner of KAATSU
Japan Co. Ltd.

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Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/70/8/950/2947617 by guest on 16 December 2018enhanced activity of muscle protein synthesis for BFR-T using elastic
bands as well as weight machines and/or free weights.
Previous studies reported that BFR-T–induced muscle cell swelling may contribute significantly to the anabolic benefits of BFR(25,35). With respect to acute MTH responses, BFR-T exercise
resulted in greater acute MTH compared with CON-T exercise.
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BFR-T exercise. It is known that acute cell swelling, due to osmotic
water moving into the cell, simulates anabolic processes, throughboth an increase in protein synthesis and a decrease in proteolysis(37,38). Thus, the BFR-T exercise-induced enhancement of muscle
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Previous studies have demonstrated that elastic band resistance training is well tolerated, as indicated by non-exacerbationof chronic disease conditions and lack of training-induced injury(7,8). Home-based resistance training using elastic bands has therefore been used widely for older adults and for patients with a lower
level of activity (7–9). Compared with most previous BFR-T studies(11,25,26), in the present study, the pressure cuff intensity for upperarms (180–270 mm Hg) was higher when BFR-T was combined withthe use of free weights. However, ratings of perceived exertion were
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(14 ± 2 for both exercises) when compared to ratings in a previous
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is a relatively safe training method. However, it should be noted thatthe possibility of side effects cannot be denied when subjects perform such training until near exhaustion or particularly to complete
exhaustion (39,40).
The present study has some limitations. First, it should be notedthat our sample size was small. In this study, the sample size wasestimated by reference to the result of one BFR study (25), which hada large effect size for elbow muscle CSA in BFR studies. However,some conditions (sex, age, type of exercise, duration etc.) were different in between two BFR studies, and consequently the effect sizefor muscle CSA in this study was lower than that in the previous
study (0.7 vs 1.7, respectively). Thus, future studies using morerobust experimental design with a large sample size should be taken
to verify the finding in this study. Second, since cuff pressure intensity for arms was higher than that reported in the previous studies(14,15,25,26,36), BFR-T required paying great attention to the side
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DOI 10.1007/s00421-007-0430-y

ORIGINAL ARTICLE

Hemodynamic and neurohumoral responses to the restrictionof femoral blood flow by KAATSU in healthy subjects
Haruko Iida Æ Miwa Kurano Æ Haruhito Takano Æ Nami Kubota Æ Toshihiro Morita Æ
Kentaro Meguro Æ Yoshiaki Sato Æ Takashi Abe Æ Yoshihisa Yamazaki Æ Kansei Uno Æ
Katsu Takenaka Æ Ken Hirose Æ Toshiaki Nakajima

Accepted: 14 February 2007 / Published online: 7 March 2007
 Springer-Verlag 2007

Abstract The application of an orthostatic stress such as
lower body negative pressure (LBNP) has been proposed tominimize the effects of weightlessness on the cardiovascular system and subsequently to reduce the cardiovasculardeconditioning. The KAATSU training is a novel method
to induce muscle strength and hypertrophy with blood
pooling in capacitance vessels by restricting venous return.
Here, we studied the hemodynamic, autonomic nervous
and hormonal responses to the restriction of femoral bloodflow by KAATSU in healthy male subjects, using theultrasonography and impedance cardiography. The presH. Iida  M. Kurano  H. Takano  N. Kubota 
Y. Sato  T. Nakajima (&)
Department of Ischemic Circulatory Physiology,
KAATSU Training, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japane-mail: masamasa@pb4.so-net.ne.jp
T. Morita  K. Meguro  K. Takenaka
Department of Cardiovascular Medicine,
The University of Tokyo, Tokyo, Japan
T. AbeDepartment of Human and Engineered Environmental Studies,
Graduate School of Frontier Science,
The University of Tokyo, Chiba, JapanY. Yamazaki
Japan Manned Space Systems Corporation,
Ibaraki, Japan
K. UnoDepartment of Computational Diagnostic Radiology
and Preventive Medicine, The University of Tokyo,
Tokyo, Japan
K. Hirose
Department of Rehabilitation Medicine,
The University of Tokyo, Tokyo, Japansurization on both thighs induced pooling of blood into thelegs with pressure-dependent reduction of femoral arterial
blood flow. The application of 200 mmHg KAATSU significantly decreased left ventricular diastolic dimension(LVDd), cardiac output (CO) and diameter of inferior vena
cava (IVC). Similarly, 200 mmHg KAATSU also decreased stroke volume (SV), which was almost equal to thevalue in standing. Heart rate (HR) and total peripheral
resistance (TPR) increased in a similar manner to standing
with slight change of mean blood pressure (mBP). Highfrequency power (HFRR) decreased during both 200 mmHg
KAATSU and standing, while low-frequency/high-frequency power (LFRR/HFRR) increased significantly. During
KAATSU and standing, the concentration of noradrenaline(NA) and vasopressin (ADH) and plasma renin activity(PRA) increased. These results indicate that KAATSU insupine subjects reproduces the effects of standing on HR,
SV, TPR, etc., thus stimulating an orthostatic stimulus.
And, KAATSU training appears to be a useful method forpotential countermeasure like LBNP against orthostatic
intolerance after spaceflight.
Keywords KAATSU training  Hemodynamics Autonomic function  Spaceflight  Cardiovasculardeconditioning

Introduction
During spaceflights, several serious adaptive changes in
cardiovascular function occur and consequently crew’s
health and safety are endangered. When gravitationalhydrostatic gradients are abolished, there is a shift of
intravascular fluid from the capacitance vessels of the legs
and lower body centrally toward the head. Then, elevation

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of capillary blood pressure and increased capillary perfusion pressure in tissues of the head cause facial, intracranial
edema and headache, which probably distresses astronauts
or space travelers. After short- and long-duration spaceflights, very nearly all crewmembers experience orthostatic
hypotension and reduced upright exercise capacity, which
may be attributed in part to microgravity-induced hypovolemia, decreased baroreflex responsiveness, decreased
skeletal muscle tone and increased venous compliance. On
return to Earth, orthostatic intolerance is the most serious
symptom of cardiovascular deconditioning; in addition,
significantly reduced exercise capacities and increased
resting heart rate are also observed (Blomqvist et al. 1994;
Buckley et al. 1996). Accordingly, effective countermeasures during spaceflight are critical in order to maintain the
cardiovascular system, as well as the musculoskeletal
structure and function and ensure the well-being and safetyof crewmembers during and after return to Earth. A passive
countermeasure called ‘‘bracelets’’, which are speciallydesigned elastic thigh cuffs developed in Moscow, hasbeen reported to reduce cephalic edema and make theadaptation to zero gravity (0 G) more comfortable (Arbeille et al. 1995, 1998; Lindgren et al. 1998, Millet et al.
2000). This equipment contributes to reduce the edema andthe venous stasis in the cephalic region by pooling blood
into the vascular and extravascular compartment of thelegs. Consequently, it can compensate partially for the
cardiovascular changes induced by exposure to 0 G, thus
reducing the cardiovascular deconditioning induced by
microgravity (Herault et al. 2000). Thus, it would seem thatthe most effective countermeasure regimen to prevent
cardiovascular deconditioning would be a gravitation-likestress combined with exercise.
Lower body negative pressure (LBNP) induces theretention of blood flow in lower extremities, and causes
subsequent hemodynamic changes including autonomic
nervous activities (Stevens and Lamb 1965; Bonde-Petersen et al. 1984; Tomaselli et al. 1987; Lathers and Charles
1993). Until now, when combined with intensive exercise,it has been known to be a useful method to prevent suchorthostatic intolerance after spaceflight, probably throughits effect as orthostatic stimulus (Güell et al. 1990, 1992;
Lee et al. 1997; Watenpaugh et al. 2000; Lucini et al.
2004). KAATSU training is a novel method for muscle
training combined with exercise. Under the conditions ofrestricted muscle blood flow, even short-term, low-intensity exercise such as resistance training and walking can
induce muscle strength and increase muscle mass (Takarada et al. 2000a, b, c; Abe et al. 2004). Since KAATSU
induces the venous pooling of blood into legs and inhibition of venous return (Takano et al. 2005), it appears to bean effective method to promote a state of blood pooling in
the capillaries within the limb musculature and apply an

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Eur J Appl Physiol (2007) 100:275–285

orthostatic stress like LBNP. However, the detailed hemodynamic and neurohumoral responses to KAATSU by
itself have not been investigated in details.
The purpose of the present study was to investigate thehemodynamic and neurohumonal responses to the restriction of femoral blood flow by KAATSU in supine subjects,
and compare with those induced by standing. Here, we
provide some evidence that KAATSU can be an effective
method for applying an orthostatic stress like LBNP.

Methods
Subjects
Two protocols were used to investigate the effects of
KAATSU (see below) on the femoral blood flow, and hemodynamic, autonomic nervous and hormonal parametersin healthy subjects. Both protocols were approved by the
ethics committee of the University of Tokyo, and summarized in Fig. 1. All subjects were non-trained volunteers, andinformed consent was obtained prior to the study. None of
the subjects had any diseases and took any medications. In
the first study (protocol 1), nine normal healthy adult males,
aged 31.6 ± 1.1 (26–36; mean height 1.73 ± 0.02 m; mean
body mass 67.8 ± 3.0 kg), participated to investigate theeffects of KAATSU on the femoral arterial blood flow, andechocardiographic parameters including the diameter ofinferior vena cava (IVC). In the second study, the hemodynamic, autonomic and hormonal responses induced by
KAATSU were investigated on seven males, aged 29.4 ±
2.0 (26–41), using impedance cardiography. Mean ofsubject’s stature was 1.74 ± 0.02 m, and mean body mass
was 73.6 ± 1.6 kg.

Fig. 1 Experimental design

Eur J Appl Physiol (2007) 100:275–285

Reduction of femoral muscle blood flow by KAATSU
The method for inducing the reduction of muscle blood flow
as shown in Fig. 2 is similar to that previously reported by
Takarada et al. (2000a, b, c). Specially designed KAATSU
belts (60 mm in width and 605 mm in length, Fig. 2A) or
KAATSU mini belts (33 mm in width and 880 mm inlength, Fig. 2B) were applied to the proximal ends of thesubject’s thighs to restrict venous blood flow and cause
pooling of blood in capacitance vessels distal to the cuff, andto restrict arterial blood flow. The cuff pressure was automatically controlled by KAATSU apparatus (Fig. 2A, B).
Experimental protocol number 1
Measurement of femoral arterial blood flow
The blood flow of superficial femoral artery was calculated
from the cross-sectional area (CSA) of the artery andvelocity time integral (VTI) using Aplio80 (Toshiba, Tokyo, Japan). The site recorded was ~5 cm distal to the
KAATSU belt (Fig. 2A). First, superficial femoral artery
was identified in the two-dimensional mode, and CSA wasmeasured at the end-systolic period. Then, in the pulseDoppler method, VTI, calculated as the integral under thevelocity curve, was measured. Adjustment of the angle forthe measurement was within 60. Blood flow per minute
was obtained by multiplying CSA by VTI and heart rate.
The blood flow was acquired in supine position before(pre) and during the application of KAATSU (approximately 5 min after the application of KAATSU), and10 min after releasing the pressure. The KAATSU belts277

were used in this study, and KAATSU pressure was set at
0, 100, 150, 200 and 250 mmHg.
Measurement of cardiac size, CO and diameter of IVC
Transthoracic echocardiography was performed using
Aplio80. The left ventricular end-systolic dimension (LVDd;mm) and left ventricular end-systolic dimension (LVDs;mm) were measured on the M-mode recording in theparasternal long-axis view with the pulsed wave Doppler
sample volume positioned just below the aortic valve, andthe aortic velocity time integral (VTIAo; cm) was calculated.
The diameter of left ventricular outflow tract (D; cm) was
measeured with two-dimensional echocardiography. Crosssectional area (CSAAo; cm2) of flow was calculated as p(D/2)2
based on a two-dimensional echo diameter (D) measurement. Then, CO is calculated as CSAAo multiplied by the
VTIAo and HR. The maximal diameter of IVC was measured
from the subcostal approach. The effects of KAATSU on theechocardiographic parameters including the diameter of IVC(mm) were evaluated. The parameters were measured before(pre), during the pressurization of both thighs by KAATSU
belts (approximately 5 min after the application of KAATSU), and 10 min after the release of the pressure. The
KAATSU pressure was set at 50 and 200 mmHg.
Experimental protocol number 2Experimental studies
This experimental design is shown in Fig. 1. An indwelling
heparin-lock catheter was inserted into the superficial

Fig. 2 A KAATSU Masterapparatus and KAATSU belt.
B KAATSU Mini apparatus andmini belt. C Supine, skin color
became dark-red as cutaneous
blood volume in the legs isincreased by pressurization insupine subjects (a before
pressurization, b during
pressurization)

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antebrachial vein of left arm. After a 30-min rest in a supine position, control blood samples were collected. Then,after taking rest measurements of hemodynamic parameters in this position for 3 min by using an impedance
method (see below), the pressure was applied to both thighsby means of another specially designed belt, named‘‘KAATSU mini’’ in Japanese (Fig. 2B, C). During
KAATSU, the hemodynamic parameters were continuously monitored. Then, after 15 min of KAATSU(50 mmHg), the pressure was released and the hemodynamic parameters were measured again during a 5–10-min
recovery period. Blood samples were obtained before, 1
and 10 min recovery period. All blood samples were processed to serum or plasma before storage at –20C until
analysis. After more than an hour of recovery time, asimilar study was done at a KAATSU pressure of 100–
250 mmHg. Finally, after a 30-min rest time, the hemodynamic parameters were taken at rest and during standing(5 min). The blood samples were also taken at rest and5 min after standing.

Measurement of hemodynamic parameters
To evaluate hemodynamic parameters, the Task ForceMonitor (CNSystmes Medizintechnik, Graz, Austria)(Gratze et al. 1998; Fortin et al. 1998), which includes
surface electrocardigrams (ECG), impedance cardiography(ICG), beat-to-beat blood pressure by the vascularunloading technique (Penaz 1973) and oscillometric bloodpressure were sampled at 1,000 Hz each. The data wereobtained on a beat by beat basis and were then used to
calculate online all hemodynamic parameters, which included heart rate (HR; bpm), mean blood pressure (mBP;
mmHg), stroke volume (SV; ml), cardiac output (CO;l/min) and total peripheral resistance (TPR; dyne s cm–5).
TPR was calculated in relative units as mBP/CO, and thecalculation of CO and TPR was as follows.
CO ¼ SV  HR
TPR ¼ mBP  80=CO.
Histograms of RR intervals were computed and pseudodigitized at ten samples per second. Auto-regressivemodeling (Burg method) was used to construct frequency
domain spectrograms of the heart rate variability (HRV)(Bailey et al. 1994; Burklow et al. 1999). Parameters extracted from the variability spectra were low-frequency
power (LFRR, 0.03–0.15 Hz) and high-frequency power(HFRR, 0.16–0.50 Hz), normalized to total power over therange from 0.01 to 0.50 Hz. LFRR/HFRR has been demonstrated to measure changes in sympathetic activity(Malliani et al. 1991).

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Measurement of hemoglobin, noradrenaline,
plasma renin activity and vasopressin
Blood samples for measurement of blood hemoglobin(2 ml) and hormone determination (7 ml) were collected in
pre-heparinized syringes. For hemoglobin, blood was
drawn into test tubes containing EDTA-2Na. For hormone
determination, blood was drawn into test tubes containing
10.5 mg of EDTA-2Na. All samples were kept in ice-coldwater and centrifuged (3,000 rpm) for 10 min and theplasma stored at –20C until the assays were performed.
Blood hemoglobin (Hb, g/100 ml) estimation was madeby the cyanomethemoglobin method (Coulter hemogrobinometer). The hematocrit (Hct, %) was measured by microhematocrit using ultra centrifugation. Plasma concentrationsof noradrenaline (NA) were measured using high performance liquid chromatography (HPLC) method. The lower
limit of detection of the assay was 6 pg/ml. Plasma renin
activity (PRA) was measured by the radioimmunoassay(RIA) method with a lower detection limit of 0.1 ng/ml per
h. Vasopressin (ADH) was also determined by the RIA
method. The lower limit of detection of the assay was
0.2 pg/ml. These variables were measured at commerciallyavailable laboratories (SRL Inc., Tokyo, Japan).
The change of blood volume (BV) (%) and plasma
volume (PV) (%) was derived from the following equation;
BVB =BVA ¼ HbA =HbB
%DPV ¼ 100  ðHbB =HbA Þ ðð1  HctA  102 ÞðHctB  102 ÞÞ  100
where A is the value at rest (pre), and B is the value at 1 and10 min recovery period after KAATSU.
Data analysis
All values are expressed as means ± SEM. Comparison oftime courses of parameters was analyzed by one-way
ANOVA for repeated measures. When differences wereindicated, a Bonferroni/Dunnett’s comparison was used todetermine significance. Differences were considered significant if P value was less than 0.05.

Results
Reduction of femoral arterial blood flow by KAATSU
Figures 3 and 4a show the effects of KAATSU on bloodflow of the superficial femoral artery. Figure 3 shows a
representative data recording of femoral arterial blood flow
without (pre) and with KAATSU in supine subjects. Under

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the conditions with KAATSU (100 mmHg), the diameter ofthe femoral vein (described by blue arrow) was remarkably
increased [Figs. 3Aa (pre) and Ba (100 mmHg)] andfemoral arterial blood flow (described by red arrow) was
decreased by 56.5% (Fig. 3Ab, Bb). The changes in femoral
arterial blood flow against the cuff pressure are depicted inFig. 4a. Application of 100 mmHg KAATSU decreased
femoral arterial blood flow from 298.3 ± 41.8 ml/min (pre)to 129.8 ± 25.6 ml/min (100 mmHg, n = 9, P < 0.01).
Arterial blood flow decreased with increasing levels of theapplied-pressure. The arterial blood flow decreased to63.8 ± 21.7 ml/min (200 mmHg, n = 9, P < 0.01), and34.8 ± 16.2 ml/min (250 mmHg, n = 9, P < 0.01). Immediately after releasing the pressure, femoral arterial bloodflow recovered (data not shown). These results indicate thatthe application of KAATSU to both thighs in supine subjects
restricts venous blood flow and causes venous pooling in thethighs distal to the cuff with the pressure-dependent reduction of arterial blood flow.

Hemodynamic responses to the restriction of femoral
blood flow by KAATSU
Figure 4 shows the effects of KAATSU on the diameter of
IVC, cardiac size and CO measured by echocardiography,
when the subjects were supine. We measured the diameterof IVC as a quantitative marker of venous return. Application of 200 mmHg KAATSU reduced the diameter of
IVC from 16.2 ± 1.0 to 14.0 ± 1.0 mm (Fig. 4b, n = 9,
P < 0.01). Simultaneously, left ventricular end-diastolicdimension (LVDd) was reduced from 48.1 ± 0.9 to
44.4 ± 0.9 mm (n = 9, P < 0.01, Fig. 4c). Left ventricular
end-systolic dimension (LVDs) was also decreased, but notsignificantly (Fig. 4c). In addition, cardiac output (CO) wasFig. 4 Effects of KAATSU on blood flow of superficial femoral
artery, diameter of inferior vena cava, cardiac size and cardiac output.
a Changes of blood flow of superficial femoral artery. The blood flowof right superficial femoral artery was obtained before (0 mmHg) andduring the application of various degrees of KAATSU (100–250 mmHg), when the subjects were supine. b, c and d The
parameters (b diameter of IVC, c LVDd, LVDs, d CO) are shownin control (pre) and during a set pressure of 50 mmHg, and a cuff
pressure of 200 mmHg, and after the release of KAATSU (post),
when the subjects were supine. All values are means ± SEM.
obtained from nine subjects. *P < 0.05, **P < 0.01 vs. control (pre)decreased from 5.64 ± 0.50 to 4.73 ± 0.41 l/min (n = 9,
P < 0.01, Fig. 4d). Thus, KAATSU in supine subjects
appears to induce the pooling of blood in the thighs,

Fig. 3 The ultrasonographic
findings of femoral blood flow.
The typical data are indicatedbefore (pre) and during theapplication of KAATSU(100 mmHg), when the subjects
were supine. Figure 2 Aa andBa indicate the data recordingof longitudinal section ofsuperficial femoral artery (redarrow) and femoral vein (bluearrow). Figure 1Ab and Bb
show the data recording ofblood flow velocity ofsuperficial femoral artery. Notethat KAATSU in supine
subjects markedly induces
pooling of venous blood withrestriction of arterial blood flow

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resulting in inhibiting venous return, and reducing cardiac
preload and CO.
Figures 5 and 6 show a typical time course response of
SV and HR determined by ICG during standing, and during
the application of pressure on both thighs in supine subjects. Table 1 shows the hemodynamic changes including
SV and HR following standing and 2 KAATSU conditions(50 and 200 mmHg). As shown in Fig. 5a, immediately
after beginning of standing, SV rapidly decreased (from109.4 ± 0.2 ml to 69.0 ± 0.3). Also pressurization of
200 mmHg gradually decreased SV (62.1 ± 0.3 ml at
200 mmHg). SV at 200 mmHg KAATSU (Fig. 5c, Table 1) was much lower than that at 50 mmHg (Fig. 5b,
Table 1) and at standing position. The decrease in SV
continued during the application of KAATSU, when thesubjects were supine. After the release of pressure, SV
rapidly returned to the pre test level within several minutes.
After an orthostatic stress (standing), HR promptly increased with decreasing SV (Fig. 6a). Pressurization ofFig. 5 Effects of orthostatic stress (standing) and KAATSU in strokevolume (SV). The time courses of SV before and during standing (a)or the pressurization of both legs by KAATSU [50 (b) and
200 mmHg (c)] and after the release of KAATSU, when the subjects
were supine. Note that during pressurization of both thighs by
KAATSU, SV gradually decreased. After the release of KAATSU,
SV returned to a control level immediately

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50 mmHg (Fig. 6b) in supine subjects did not affect HR.
On the other hand, 200 mmHg KAATSU increased HR
gradually from 68.1 ± 0.6 bpm to 77.2 ± 0.2. After the
release of pressure, HR returned to the pre test level(64.7 ± 0.6 bpm) within several minutes. MBP increased
significantly during standing (from 90.60 ± 3.69 mmHg to102.41 ± 6.55, n = 7, P < 0.05), and 200 mmHg increased
MBP only slightly and non-significantly (from 87.70 ±4.81 mmHg to 90.93 ± 3.52 at 50 mmHg, n = 7, n.s., andfrom 89.93 ± 2.75 to 91.22 ± 3.97 at 200 mmHg, n = 7,
P=n.s.).
Cardiac output tended to decrease during standing (from5.27 ± 0.32 l/min at supine rest to 4.83 ± 0.14). The
pressurization of KAATSU (50 and 200 mmHg) in supine
subjects decreased CO significantly as shown in Table 1(from 5.46 ± 0.35 l/min to 4.58 ± 0.26 at 50 mmHg,

Fig. 6 Effects of orthostatic stress (standing) and KAATSU on heart
rate (HR). The time courses of HR before and during standing (a) or
the pressurization on both legs by KAATSU [50 mmHg (b) and
200 mmHg (c)] and after the release of KAATSU, when the subjects
were supine. Note that HR increased during orthostatic stress(standing). When this volunteer changed position from supine rest
to standing (shown by moving), HR rapidly increased, and thendecreased, and reached to a steady-state level. HR also increased
during the pressurization of both thighs at 200 mmHg in supine
subjects, but not 50 mmHg. Immediately after the release of
KAATSU, the increased HR returned to a control level

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n = 7, P < 0.01, from 5.35 ± 0.33 to 4.05 ± 0.09 at
200 mmHg, n = 7, P < 0.01). TPR increased during
both standing and pressurization. Standing increased TPR
from 1,351.91 ± 63.48 dyne s cm–5 to 1,665.93 ± 119.95(n = 7, P < 0.05). The pressurization of 50 and 200 mmHg
in supine subjects also increased TPR from 1,272.77 ±97.42 dyne s cm–5 to 1,567.16 ± 105.54 at 50 mmHg (n = 7,
P < 0.01) and from 1,329.37 ± 68.96 to 1,758.25 ± 83.76
at 200 mmHg (n = 7, P < 0.01).
Autonomic nervous responses to the restrictionof femoral blood flow by KAATSU
Figure 7a depicts the changes in the power spectra of heart
rate variability (HRV) in control (pre), during 200 mmHg
KAATSU, after the release of KAATSU, when the subjects
were supine, and subsequently during standing. As shownin Fig. 7b and c, the HFRR-component, which is a marker
of parasympathetic activity, was reduced by both 50 and
200 mmHg KAATSU in supine subjects (Fig. 7b). On theother hand, LFRR/HFRR component was increased by both
50 and 200 mmHg as shown in Fig. 6c. HFRR markedly
decreased from 33.75 ± 5.38% to 23.94 ± 3.34 (n = 7,
P < 0.01) and LFRR/HFRR increased from 2.81 ± 0.89 before KAATSU to 4.12 ± 0.79 (n = 7, n.s.) at 200 mmHg
KAATSU.

Hormonal responses to the restriction of femoral bloodflow by KAATSU
Figure 8 depicts hormonal changes induced by KAATSU
and standing. NA, a well-known neurotransmitter released
from sympathetic nerve, increased under the pressurization.
About 50 mmHg of KAATSU in supine subjects did notchange significantly (from 197.00 ± 23.30 to 198.71 ±12.36 pg/ml, n = 7, n.s.), but 200 mmHg increased significantly (from 224.57 ± 29.98 to 333.14 ± 23.51 pg/ml,
n = 7, P < 0.01). The standing also raised NA from
207.29 ± 31.90 to 401.14 ± 63.35 pg/ml (n = 7, P < 0.01).
PRA was raised by both 200 mmHg of KAATSU in supine
subjects and standing. 50 mmHg of pressurization slightly
increased PRA from 1.04 ± 0.25 to 1.19 ± 0.28 ng/ml per h(n = 7, n.s.), and 200 mmHg of KAATSU had more effecton PRA (from 1.09 ± 0.23 to 1.66 ± 0.38 ng/ml per h, n = 7,
P < 0.01). In addition, ADH was also increased during
5-min standing and during the application of KAATSU at
200 mmHg in supine subjects (from 1.07 ± 0.06 to
1.31 ± 0.08 pg/ml, n = 7, P < 0.05).
Figure 8d and Table 2 show the percent changes ofblood volume (BV) and plasma volume (PV) induced by
KAATSU, when the subjects were supine. These values
tended be decreased by KAATSU, but these changes were
not significant except for 50 mmHg (n = 7).

Table 1 Hemodynamic parameters during standing, and KAATSU in supine position
HR (bpm)sBP (mmHg)

mBP (mmHg)

dBP (mmHg)

SV (ml)CO (l/min)

TPR (dyne s cm–5)

Pre

58.14 ± 2.01

119.55 ± 5.19

90.60 ± 3.69

74.48 ± 3.12

90.92 ± 4.62

5.27 ± 0.32

1,351.91 ± 63.48

Standing

74.12 ± 3.65**

130.38 ± 8.52*

102.41 ± 6.55*

87.79 ± 6.22**

65.81 ± 2.01**

4.83 ± 0.14

1,665.93 ± 119.95*

Pre60.60 ± 3.93

116.68 ± 5.89

87.70 ± 4.81

73.81 ± 4.01

91.51 ± 6.26

5.46 ± 0.35

1,272.77 ± 97.42

50 mmHg

58.73 ± 2.55

117.93 ± 4.82

90.93 ± 3.52

76.83 ± 3.21

78.85 ± 5.16**

4.58 ± 0.26**

1,567.16 ± 105.54**

Post

57.75 ± 2.20

117.39 ± 4.63

89.86 ± 3.46

74.91 ± 3.21

90.07 ± 4.72

5.19 ± 0.35

1,370.49 ± 91.00

Pre

58.15 ± 1.59

116.66 ± 3.95

87.82 ± 2.69

74.47 ± 2.25

91.97 ± 4.35

5.33 ± 0.27

1,298.06 ± 75.14

100 mmHg

59.73 ± 2.81

118.42 ± 5.20

89.56 ± 3.65

75.41 ± 2.06

75.83 ± 5.21*

4.45 ± 0.19*

1,568.65 ± 65.74*

Post

58.91 ± 2.27

121.14 ± 5.42

92.02 ± 4.16

76.74 ± 3.16

87.80 ± 3.65

5.14 ± 0.25

1,418.74 ± 91.31

Pre

60.19 ± 5.07

113.17 ± 5.01

84.37 ± 3.59

70.57 ± 3.09

83.40 ± 6.68

4.83 ± 0.22

1,362.48 ± 66.47

150 mmHg

64.24 ± 6.00*

119.01 ± 5.95

90.62 ± 4.31

77.11 ± 3.81*

65.61 ± 4.94**

4.05 ± 0.10*

1,746.12 ± 87.36**

Post

60.37 ± 4.62

115.40 ± 4.19

88.11 ± 3.56

73.27 ± 3.44

80.76 ± 6.20

4.71 ± 0.19

1,461.73 ± 76.28

Pre

59.16 ± 2.32

118.33 ± 4.33

89.93 ± 2.75

77.30 ± 2.47

90.97 ± 4.79

5.35 ± 0.33

1,329.37 ± 68.96

200 mmHg

65.67 ± 2.87**

119.00 ± 4.60

91.22 ± 3.97

80.13 ± 3.18

62.71 ± 3.04**

4.05 ± 0.09*

1,758.25 ± 83.76**

Post

59.44 ± 2.85

118.57 ± 5.65

90.18 ± 4.76

77.00 ± 3.46

84.09 ± 4.99

4.93 ± 0.30

1,457.82 ± 87.87

Pre
250 mmHg

60.49 ± 4.99
71.39 ± 5.37**

114.06 ± 3.52
119.79 ± 4.49*

86.14 ± 2.53
93.03 ± 3.00*

72.76 ± 2.37
79.02 ± 2.45*

85.30 ± 6.56
55.82 ± 3.91**

4.97 ± 0.23
3.87 ± 0.14*

1,352.33 ± 42.75
1,881.21 ± 96.38**

Post

60.37 ± 5.11

121.13 ± 4.35*

91.72 ± 2.50*

75.87 ± 2.04*

83.04 ± 6.80

4.79 ± 0.20

1,495.34 ± 45.55*P < 0.05, **P < 0.01 versus Pre

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Fig. 7 a The time courses of heart rate variability (HRV) during
KAATSU in a supine subject. Note that during KAATSU(200 mmHg), LFRR increased, compared with the control, while
HFRR decreased, when the subject was supine. b, c Effects oforthostatic stress (standing) and KAATSU, when the subjects weresupine, on the heart rate variability (HRV). b Effects of orthostatic
stress (standing) and KAATSU, when the subjects were supine, on
HFRR/LFRR. c Effects of orthostatic stress (standing) and KAATSU,
when the subjects were supine, on HFRR. All values are means ±SEM. obtained from seven subjects. *P < 0.05, **P < 0.01 vs.
control (pre)Discussion
We studied the effects of KAATSU on the hemodynamic,
autonomic nervous and hormonal systems. Application of
KAATSU on both thighs in supine subjects was revealed toinduce the hemodynamic, hormonal and autonomic alterations that were similar to standing.

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During an orthostatic stress (i.e., standing), part of theblood and plasma volume can pool in the capillary bed ofthe legs. Subsequently, SV decreased to about 72.4% of thecontrol. Application of KAATSU on both thighs in supine
subjects by a specially designed KAATSU belt also decreased SV by pooling blood into the vascular and extracellular compartment of the legs, which depends on the
KAATSU pressure. The increasing cutaneous blood volume in the legs could be observed by the dark-red coloration of the skin in the lower body. At 200 mmHg, SV
decreased to 68.9% of the control. The addition of KAATSU on both thighs in supine subjects gradually decreased
SV during the application of KAATSU. As shown in
Fig. 4a, KAATSU suppressed the arterial blood flow to thethighs in a pressure-dependent manner. However, even at
250 mmHg of KAATSU, arterial blood flow was notcompletely blocked, which may partly contribute to thesafety of KAATSU training wildly used for muscle training. Immediately after the release of KAATSU, the depressed SV promptly returned to the control level.
In the hemodynamic response to orthostatic stress, initially SV is decreased, but the decrease in SV is successfully compensated for by an increased HR and TPR via
baroreceptor control of circulation. Similarly, SV was decreased, and TPR was increased in cases of KAATSU evenat a set pressure of 50 mmHg. Mean BP and HR did notchange significantly. It suggests that the primary mechanism responsible for sympatho-excitation during the lowpressure is primarily due to the cardiopulmonary baroreceptors, which are located in the atria and ventricles of theheart and in the pulmonary artery and veins and are
responsive to changes in central venous pressure (Furlan
et al. 2001; Brown et al. 2003). On the other hand, application of 200 mmHg induced a much larger decrease in
SV, with the increase in HR and TRP. Thus, during highpressure such as 200 mmHg, both arterial baroreceptors
and cardiopulmonary baroreceptors were also unloaded.
Regarding autonomic nervous response, HFRR/HFRR, amarker of sympathetic activity, and the serum concentration of NA, a well-known neurotransmitter released from
sympathetic nerve, increased, which depends on the pressure of KAATSU. On the other hand, HFRR, a marker ofparasympathetic activity, decreased. Overall, it seems
likely that at low levels of pressure, the reduced venous
return induces a cardiac-unloading, resulting in an inhibition of cardiogenic sympathetic excitatory mechanisms andin an increased arterial baroreflex gain, while at high level,
the arterial baroreceptor-unloading is the dominant phenomenon leading to sympathetic excitation. During an
orthostatic stress (standing), part of the blood and plasma
volume can pool in the legs owing to the shift to thecapacitance vessels. The subsequent decrease in the plasma
volume and renal blood flow stimulates the secretion ofEur J Appl Physiol (2007) 100:275–285

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Fig. 8 Effects of orthostatic
stress (standing) and KAATSU
on the concentration ofnoradrenaline (NA, a), plasma
rennin activity (PRA, b),vasopressin (ADH, c) and blood
volume (BV, d). The blood was
obtained before (supine rest),
after 5 min standing and 15 minafter the pressurization (50 and
200 mmHg), and 10 min after
the release of KAATSU, when
the subjects were supine. All
values are means ± SEM
obtained from seven subjects.
*P < 0.05, **P < 0.01 vs.
control (pre)Table 2 Hb, Hct, percent
changes in plasma volume (PV)and blood volume (BV) during
standing, and KAATSU insupine position*P \ 0.05, **P \ 0.01 versusPre

Hb (mg/dl)

Hct (%)

BV, %D

PV, %DPre

14.5 ± 0.2

44.8 ± 0.5––

50 mmHg

14.7 ± 0.2*

45.4 ± 0.6*

–2.49 ± 0.88*–4.29 ± 1.36*

Post

14.7 ± 0.3*

45.5 ± 0.7*

–2.35 ± 1.25*–4.13 ± 2.08*

Pre

14.4 ± 0.3

44.3 ± 0.8––

100 mmHg

14.5 ± 0.4

44.5 ± 1.0–1.92 ± 1.45

–2.78 ± 2.48

Post

14.4 ± 0.3

44.6 ± 0.8–1.31 ± 1.86

–1.91 ± 2.96

Pre

14.4 ± 0.2

43.9 ± 0.4––

150 mmHg
Post

14.5 ± 0.3
14.2 ± 0.2

44.2 ± 0.7
43.5 ± 0.5–2.44 ± 2.00
–0.97 ± 1.47

–4.02 ± 3.16
–1.53 ± 2.38

Pre

14.6 ± 0.3

44.8 ± 0.8––

200 mmHg

14.8 ± 0.2

45.5 ± 0.7–2.71 ± 1.58

–5.69 ± 2.29

Post

14.7 ± 0.3

45.2 ± 0.8–1.73 ± 1.73

–4.10 ± 2.99

Pre

14.5 ± 0.3

44.4 ± 0.7––

250 mmHg

14.6 ± 0.3

44.4 ± 0.8–1.62 ± 1.14

–2.17 ± 1.81
–3.17 ± 2.33

Post

14.6 ± 1.3

44.9 ± 0.9–1.75 ± 1.41

Pre

14.7 ± 0.3

45.7 ± 0.8––

Standing

15.3 ± 0.3

47.2 ± 0.9–2.66 ± 2.22

–5.03 ± 4.18

PRA and ADH. The secretion of PRA and ADH were also
increased during KAATSU, which also depends on the
degree of the pressure. However, the blood and plasma
volume did not change significantly, suggesting that only
early adaptation to KAATSU was studied in the present
study. Thus, it is likely that the application of KAATSU onboth thighs in supine subjects simulates systemic cardiovascular, autonomic nervous and hormonal effects oforthostatic in 1 G (standing).

In spaceflight, without regular exposure to gravity (G)forces, the cardiovascular functions are compromised.
After short- and long-duration spaceflights, very nearly all
crewmembers experience orthostatic hypotension and reduced upright exercise capacity named cardiovascular deconditioning and severe muscle atrophy (Blomqvist et al.
1994; Buckley et al. 1996; Fritsch-Yelle et al. 1996; Mecket al. 2001). The cardiovascular deconditioning may be
attributed in part to microgravity-induced hypovolemia,

123

284

decreased baroreflex responsiveness, decreases skeletal
muscle tone and increased venous compliance. In addition,muscle atrophy produces greater compliance of lower
limbs and a predisposition to orthostatic intolerance. To
maintain the structure and function of musculoskeletal andcardiovascular systems during spaceflight, and to ensure
well-being and safety of crew members during spaceflightand after return to Earth, effective countermeasures during
spaceflight are critical (Convertino and Sandler 1995;
Nicogossian et al. 1995). A passive countermeasure calleda ‘‘bracelet’’ developed in Moscow has been used to reduce this cephalic edema and make the adaptation to 0 G
more comfortable (Arbeille et al. 1995; Herault et al.
2000). The bracelets are fixed at the upper part of eachthigh and applying pressure of approximately 20–
30 mmHg (where 1 mmHg = 133.3 N/m2) on the skin.
The bracelets reduce the venous return by trapping a significant amount of fluid into the lower-limb vascular andinterstitial space, subsequently followed by the fluid shift(Lindgren et al. 1998). It has been reported that suchapparatus does not prevent the cardiovascular deconditioning induced by microgravity (Herault et al. 2000).
However, it would be interesting to know whether the
KAATSU with low pressure (20–50 mmHg) can prevent
facial edema and make the adaptation to 0 G (Arbeilleet al. 1995; Lindgren et al. 1998; Herault et al. 2000).
Currently, astronauts practice 2–3 h of intensive exercise using treadmill, ergometer and resistance machines.
These time-consuming countermeasures only cannot completely prevent them from cardiovascular deconditioning.
Therefore, alternate countermeasure strategies that are
more effective and efficient are necessary. Now, it is likelythat the most effective countermeasure regimen would be a
gravitation-like stress combined with exercise. A humancentrifuge is a possible candidate, but the centrifuge
apparatus is relatively expensive and it is technicallylaborious to accommodate the apparatus on a space-craft.
In addition, it may be difficult to minimize cetrifugationinduced Coriolis effects on the vestibular system and theconsequent motion sickness associated with onboard centrifuge. LBNP has been known to induce the retention ofblood flow in lower extremities, and induce subsequent
hemodynamic changes such as decreased SV and CO andincreased TPR (Stevens and Lamb 1965; Bonde-Petersen
et al. 1984; Güell et al. 1990, 1992; Melchior et al. 1994;
Murthy et al. 1994; Lee et al. 1997; Watenpaugh et al.
2000), and produce sympathetic activation and vagal
withdrawal (Franke et al. 2000). Therefore, at present, it islikely that exercise against the suction force produced by
LBNP may provide a low mass and low-cost alternative
procedure to stress the cardiovascular systems (Hargens
1994). However, LBNP is difficult to apply when combined with several exercises, such as resistance exercises,

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Eur J Appl Physiol (2007) 100:275–285

which need large machines. Furthermore, LBNP without
exercise by itself cannot protect crew members from cardiovascular deconditioning. The present study provides
evidence that KAATSU simulates orthostatic effects (1 G)
on cardiovascular, autonomic nervous and hormonal system like LBNP at bed rest. KAATSU was originallydeveloped as a novel method for muscle strength training
and to induce muscle hypertrophy. Under the condition
with restriction of muscle blood flow by KAATSU, even a
short-term and low-intensity exercise can induce muscle
strength and muscle hypertrophy (Takarada et al. 2000a, b,
c; 2002a, b; Abe et al. 2004, 2006). Thus, KAATSU
training can be easily applied to almost all types of exercises such as treadmill, ergometer, and resistance machines, and it may be able to be used by astronauts in orderto protect against both muscle atrophy and cardiovasculardeconditioning. Furthermore, we measured the serum
concentration of lipid peroxide as a marker of oxidant
stress in some of subjects of the present study. The lipid
peroxide did not change significantly 1 and 10 min after
15 min of pressurization (150, 200, and 250 mmHg, data
not shown). Thus, it is very likely that KAATSU training
may be a very promising and safe method to counter
symptoms of orthostatic intolerance and muscle atrophy inastronauts. But further studies are needed to clarify theseinteresting possibilities.
In conclusion, the application of KAATSU on boththighs simulates cardiovascular effects of orthostasis in
1 G. In addition, it is likely that the KAATSU training can
be a useful method for potential countermeasure like LBNP
against orthostatic intolerance in spaceflight.
Acknowledgments The author thanks Dr. H. Imuta and H. Oonuma
for their valuable assistance in data analysis and preparation of thismanuscript. Y. Sato is a co-researcher of our study.

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Clin Physiol Funct Imaging (2011) 31, pp472–476

doi: 10.1111/j.1475-097X.2011.01044.x

Effects of walking with blood ﬂow restriction on limb venous
compliance in elderly subjects
Haruko Iida1, Toshiaki Nakajima1, Miwa Kurano1, Tomohiro Yasuda1, Mikako Sakamaki2, Yoshiaki Sato3,
Tatsuya Yamasoba4 and Takashi Abe2
1

Department of Ischemic Circulatory Physiology, KAATSU Training, Graduate School of Medicine, The University of Tokyo, Tokyo, 2Department of Humanand Engineered Environmental Studies, The University of Tokyo, Chiba, Japan, 3KAATSU International University, Rajagiriya, Sri Lanka and 4Department ofOtolaryngology and Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

Summary
Correspondence
Toshiaki Nakajima, M.D., Department of Ischemic
Circulatory Physiology, KAATSU Training, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-8655, Japan
E-mail: hiida-tky@umin.ac.jp

Accepted for publication
Received 11 November 2010;
accepted 23 June 2011

Key words
blood flow restriction; elder female subjects; endurance exercise; plethysmography; venous compliance

Venous compliance declines with age and improves with chronic endurance
exercise. KAATSU, an exercise combined with blood flow restriction (BFR), is aunique training method for promoting muscle hypertrophy and strength gains byusing low-intensity resistance exercises or walking. This method also induces
pooling of venous blood in the legs. Therefore, we hypothesized that slow walking
with BFR may affect limb venous compliance and examined the influence of 6 weeks
of walking with BFR on venous compliance in older women. Sixteen women aged
59–78 years were partially randomized into either a slow walking with BFR group(n = 9, BFR walk group) or a non-exercising control group (n = 7, control group).
The BFR walk group performed 20-min treadmill slow walking (67 m min)1),
5 days per week for 6 weeks. Before (pre) and after (post) those 6 weeks, venous
properties were assessed using strain gauge venous occlusion plethysmography.
After 6 weeks, leg venous compliance increased significantly in the BFR walk group(pre: 0Æ0518 ± 0Æ0084, post: 0Æ0619 ± 0Æ0150 ml 100 ml)1 mmHg)1, P<0Æ05),
and maximal venous outflow (MVO) at 80 mmHg also increased significantly after
the BFR walk group trained for 6 weeks (pre: 55Æ3 ± 15Æ6, post: 67Æ1 ±
18Æ9 ml 100 ml)1 min)1, P<0Æ01), but no significant differences were observedin venous compliance and MVO in the control group. In addition, there was no
significant change in arm compliance in the BFR walk group. In conclusion, thisstudy provides the first evidence that 6 weeks of walking exercise with BFR may
improve limb venous compliance in untrained elder female subjects.

Introduction
The venous system of the human body can be looked at as alarge blood reservoir that contains more than 70% of the total
blood volume at rest and plays an important role in maintaining
cardiovascular homeostasis. Small changes in peripheral blood
volume can greatly affect cardiac filling pressure and, subsequently, cardiac output. Therefore, appropriate regulation ofvenous blood volume is essential, especially during various
physiological conditions such as haemorrhage and orthostaticload (Olsen et al., 2000).
Ageing is one of the most important factors that influence leg
venous compliance. According to Monahan et al. (2001), calf
venous compliance was about 40% lower in elderly subjects.
Olsen & Länne (1998), Fu et al. (2000), Tsutsui et al. (2002) and
Hernandez & Franke (2005) also demonstrated similar results.
472

The mechanisms of this decline in venous compliance throughageing are not yet obvious; however, structural alterations,
namely venous wall thickening and an increase in thecollagen ⁄ elastin ratio in venous walls, which are also observedin arterial walls, may cause an age-related decline in venous
compliance (Pareira et al., 1953). On the other hand, functional
alterations such as vasomotor tone and nitric oxide synthesis arealso thought to cause age-related decline in venous compliance.
Several studies have revealed that venous compliance isimproved by habitual endurance exercise, and leg venous
compliance is decreased in sedentary subjects compared withendurance-trained men (Louisy et al., 1997; Wecht et al., 2000;
Monahan et al., 2001; Hernandez & Franke, 2005).
KAATSU, which is an exercise combined with blood flow
restriction (BFR), is one of method of trainings that uses a
specially designed belt tightened near the joints of the upper 2011 The Authors
Clinical Physiology and Functional Imaging  2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine 31, 6, 472–476

BFR walking and venous compliance, H. Iida et al. 473

arm or leg, applying pressure to the muscle and temporally
restricting blood flow. Existing research has revealed that lowintensity KAATSU training could induce muscular hypertrophyand strength gain (Takarada et al., 2002). Abe et al. (2006)
reported that the combination of slow walking and muscle BFR
induces increases in muscle size and strength despite theminimal level of exercise intensity. Therefore, slow walking
with BFR may be a potentially useful method to promote muscle
hypertrophy, especially for the elderly. During slow walking
with BFR, arterial flow is reduced and venous blood is pooled in
the leg vein (Takano et al., 2005; Iida et al., 2007). Consequently, these changes might produce hydrostatic forces in theleg vein.
We hypothesized that this change affects leg venous compliance; therefore, in the present study, we investigated the effectof 6 weeks of walking with BFR on leg venous compliance inolder women using non-invasive methods of determining limb
venous compliance.

Methods
Subjects
Sixteen elderly women aged 59–78 years participated in thisstudy. Subjects were partially randomized into either a slow
walking with BFR group (n = 9) or a non-exercising control
group (n = 7). The subjects were recruited by word of mouth.
Volunteers were free of orthopaedic disorders. None of thesubjects had participated in strength- or resistance-type training
for at least 2 years prior to the start of the study. All subjects
were informed of the methods, procedures and risks and signed
an informed consent document before participation. The study
was conducted according to the Declaration of Helsinki and wasapproved by the Ethics Committee for Human Experiments of
the University of Tokyo, Japan.
Training protocol
The training was conducted once a day, 5 days per week for
6 weeks. The subjects walked on a motor-driven treadmill at
67 m min)1 for 20 min. The walking speed and duration
remained constant throughout the training period. Subjects inthe slow walking with BFR group wore pressure belts (KaatsuMaster, Sato Sports Plaza, Tokyo) on both legs during thetraining. A non-exercising control group was advised to perform
slow walking daily for 20 min 5 days per week during thestudy. During the study, all subjects were required not to
perform any other strength- or resistance-type training or longrunning for more than 20 min.

blood flow (Takano et al., 2005; Iida et al., 2007; Nakajima et al.,2008). Prior to slow walking with BFR, the subjects were seatedon chairs and the belt air pressure was repeatedly set (30 s) andthen released (10 s) from an initial pressure of 100 mmHg to a
final training pressure of 140 mmHg (Abe et al., 2006). The
training pressure was increased by 10 mmHg each day until a final
belt pressure of 200 mmHg was reached, although two subjects
trained at 180 mmHg for the duration of the study. A restriction
pressure of 140–200 mmHg was selected for the restriction
stimulus based on a review of the data in young men (Abe et al.,2006). Blood flow to the leg muscles was restricted for a total timeof about 23 min (20 min of walking and 3 min of preparation)
during each training session for each subject, and the belt pressure
was released immediately upon completion of the session.
Venous occlusion plethysmography
Venous occlusion plethysmography with multiple proximal
occlusion pressure was used to obtain venous compliancemeasurements before and immediately after the study. A strain
gauge (EC6 plethysmograph, Hokanson, Bellevue, WA, USA) was
stretched around the largest girth of the right calf and forearm.
Thigh and upper arm pressure cuffs were connected to a rapid cuff
inflator (E20 rapid cuff inflator, Hokanson, Bellevue, WA, USA) toensure rapid and accurate filling and deflating of the cuff. Externalpressure was applied on the thigh and upper arm through an
occlusion cuff, which was attached to an electronically controlled
air pump. Pressure levels of 20, 40, 60 and 80 mmHg weredelivered consecutively after having reached a quasi-steady state at
the previous level. We calculated the following parameters fromthe plethysmographic recordings (Bleeker et al., 2004). To be
concise, venous volume variation (VVV) (in ml 100 ml)1) was
defined as the maximal relative volume increase in the limb at a
certain cuff pressure; VVV at different occlusion pressures
represents the pressure–volume curve. Venous compliance(ml 100 ml)1 mmHg)1), the ratio of a change in volume (DV)to a concomitant change in the transmural distending pressureðDPÞ : Vc ¼ DV=DP (Rothe, 1983, 1993), was derived from theslope of the pressure–volume curve. Maximal venous outflow(MVO) (in ml 100 ml)1 min)1) was calculated as the slope of thetangent at the curve from 0Æ5 to 2Æ0 s after cuff release.
Statistical analyses
All values are presented as means ± SD. We used an unpaired
Students t-test to assess baseline differences between slow
walking with BFR group and control group. We used a paired
Students t-test to examine the effect of the 6-week intervention inboth groups. Differences were considered significant if P<0Æ05.

Blood ﬂow restriction (BFR)

Results

Femoral blood flow was impaired using the KAATSU technique,which restricts venous blood flow causing pooling of blood in
capacitance vessels distal to the cuff and partial occlusion of arterial

Table 1 summarizes the anthropometric characteristics andresting cardiovascular variables of all participants in the study.
Three subjects in each group had hypertension, and no subjects

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Clinical Physiology and Functional Imaging  2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine 31, 6, 472–476

474 BFR walking and venous compliance, H. Iida et al.

Table 1 Anthropometrical characteristics and resting cardiovascularvariables.

Age (year)
Height (cm)Mass (kg)BMI (kg m)2)
HR (bpm)
Systolic blood pressure(mmHg)
Diastolic blood pressure(mmHg)
Leg compliance(ml 100 ml)1 mmHg)1)

Control group

Blood ﬂow
restriction
walk group68Æ7 ± 2Æ8150Æ1 ± 1Æ8
52Æ7 ± 3Æ3
23Æ9 ± 1Æ0
73Æ0 ± 3Æ6
129Æ7 ± 8Æ2

67Æ4 ± 1Æ6149Æ9 ± 1Æ2
51Æ9 ± 2Æ3
23Æ1 ± 0Æ976Æ8 ± 3Æ3
148Æ2 ± 7Æ1

71Æ7 ± 2Æ6

84Æ6 ± 3Æ8**

0Æ0686 ± 0Æ0160

0Æ0518 ± 0Æ0084*

(a)

(b)

**P<0Æ01, *P<0Æ05.

had heart failure or venous disease, such as varicose vein oflower extremity. Although pre intervention data of diastolicpressure differed significantly between the BFR walk group andcontrol group, there were no significant differences between thetwo groups for age, standing height, body mass and body massindex. None performed regular moderate or vigorous physicalactivity before the study.

Figure 1 Pressure–volume curves for the leg (d: pre 6-week training
and s: post 6-week training). Venous volume variation (VVV) values
are means ± SD. (a) Control group; (b) slow walking with BFR group.
*P<0.05.

Venous compliancePreintervention compliance of the control group was higher
than that of the slow walking with BFR group (Table 1). After
6 weeks of training, leg compliance in slow walking with BFRgroup increased significantly (Fig. 1, pre: 0Æ0518 ± 0Æ0084 ml
100 ml)1 mmHg)1, post: 0Æ0619 ± 0Æ0150 ml 100ml)1 mmHg)1, P<0Æ05) with significant change of leg girth(pre: 33Æ5 ± 0Æ8 cm, post: 33Æ9 ± 0Æ8 cm, P<0Æ05). Meanwhile, no significant differences were observed in the leg
compliance of the control group (Fig. 1) and in the arm
compliance of the BFR group (n = 6, Fig. 2).
Maximal venous outﬂow
Figure 3 depicts the MVO at each cuff pressure. Maximal venous
outflow at 80 mmHg increased significantly after 6-weektraining in the slow walking with BFR group (pre:55Æ3 ± 15Æ6 ml 100 ml)1 min)1, post: 67Æ1 ± 18Æ9 ml
100 ml)1Æmin)1, P<0Æ01), but no significant difference wasobserved in the control group.

Discussion
The present study provides new findings that 6 weeks ofslow walking with BFR in elderly women induce significantly increased limb venous compliance and increased MVO.
It is likely that the decline in venous compliance throughFigure 2 Pressure–volume curves for the arm obtained before andafter slow walking with BFR for 6 weeks (d: pre 6-week training ands: post 6-week training). Venous volume variation (VVV) values aremeans ± SD for six subjects. There was no significant change in arm
venous compliance in contrast to the change of leg venous compliance.

ageing is reversible and that endurance exercise withxrestriction of leg blood flow improves the limb venous
compliance.

 2011 The Authors
Clinical Physiology and Functional Imaging  2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine 31, 6, 472–476

BFR walking and venous compliance, H. Iida et al. 475

(a)

(b)

Figure 3 Effects of walking for 6 weeks on maximum venous flow in the leg of control group (a) and slow walking with BFR group (b). Maximal
venous outflow (MVO) values are means ± SD. There was a significant change in the maximum venous flow at 80 mmHg in the slow walking with
BFR group. **P<0.01.

Ageing induces the decline in limb venous compliance(Olsen & Länne, 1998), and this decline prevents the elderly
from responding to acute deterioration of cardiovascularhomeostasis. Furthermore, reduced venous compliance may
be one of the risk factors of varicose veins and deep veinthrombosis. Therefore, we need some way to counter the
decline in venous compliance.
Until now, several authors have demonstrated that venous
compliance is improved by endurance exercise. Hernandez &Franke (2005) studied the influence of a 6-month endurancetraining programme on calf venous compliance in older men
and women and revealed that it tended to be 20–30% greater inthe exercise group after 6 months of training compared with
control group. Monahan et al. (2001) sought to determine thereciprocal influences of ageing and habitual endurance exercise
on calf venous compliance in humans, and they demonstrated
that venous compliance declined with age and that calf venous
compliance was approximately 70–120% greater in endurancetrained men compared with age-matched sedentary men andapproximately 30% greater in older endurance-trained men
compared with young sedentary. These data suggest that
endurance training is useful for improving age-related decline
in venous compliance.
In the present study, we suggested that slow walking with
BFR (Abe et al., 2006) can induce significant improvement inlimb venous compliance in elderly women over shorter periods
compared with simple endurance exercise.
Although the mechanism of this prominent improvement isunclear, we can infer that slow walking with BFR has additional
effects over simple endurance exercise. Because subjects wear abelt around their legs during walking with BFR, slow walking
with BFR not only increases physical activity more than
endurance exercise does but also changes hydrostatic force inthe leg through BFR, and these changes may affect venous
vascular function synergistically. As previously reported, venous
blood outflow and arterial inflow are restricted, and blood
pooling in the lower extremities is produced during walking

with BFR (Takano et al., 2005; Iida et al., 2007). During slow
walking with BFR, venous pooling might induce the alterationin hydrostatic force in the lower extremities, and alteredhydrostatic force affects cardiovascular reflex responses and,
consequently, venous properties more quickly and more
effectively than simple endurance exercise.
According to Bleeker et al. (2004), after 18 days of headdown-tilt bed rest, leg venous compliance is reduced and leg
venous outflow resistance is increased. In the report, they
concluded that altered gravitational gradients induce alterationin hydrostatic forces and cardiovascular reflex responses. In theirstudy, the deconditioning induced by 18 days of bed rest led tono significant differences in arm venous vascular properties. In
the present study, arm venous compliance was not affected byslow walking with BFR. This differential response between legs
and arms may support our inference that walking with BFR may
affect hydrostatic gradients only in the leg and that this change
plays an important role in improving leg venous function.
Muscle compartment, which can compress the veins and resist
the expansion of the veins, is thought to be one of the structural
factors to influence the venous compliance. Convertino et al.
(1988, 1989) found that reduced muscle compartment leads theincreased leg compliance observed after exposure to simulated
microgravity. In the present study, despite the fact that the girthincreased significantly after 6 weeks walking with BFR, thevenous compliance increased significantly. This suggests thatthe increase in limb venous compliance was not caused by theincrease in muscle mass.
Haemodynamic factors may affect the venous compliance.
Although blood pressure was not checked during exercise, somestudies revealed that elevation of blood pressure during walking
with BFR is lower compared with high-intensity resistancetraining (Sakamaki et al., 2008), and there was no significant
change in blood pressure after 6 weeks in the present study(data not shown). Furthermore, other factors than muscle sizeand blood pressure may influence the result, but no remarkablechanges in anthropometrical characteristics were observed, and 2011 The Authors
Clinical Physiology and Functional Imaging  2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine 31, 6, 472–476

476 BFR walking and venous compliance, H. Iida et al.

we could not find the special characteristics of the responder or
non-responder.
However, as a result of the small sample size in this study andthe significant difference of preintervention data in leg venous
compliance between groups, statements must be made carefully
and further investigation is required. Furthermore, as we did not
check the state of venous valves during compression of the legsin the present study, more detailed investigation in the state ofvalves, hydrostatic forces and cardiovascular reflex response isrequired to make the mechanism clear.
In conclusion, 6 weeks of slow walking with BFR in elderly
subjects significantly induced increased limb venous compli-

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Conﬂicts of interest
Dr Sato Y is the Managing Director of Best Life Co., Ltd, andPresident of Sato Sports Plaza Co., Ltd. (and a stockholder ofboth companies) and is the inventor of the KAATSU Training
method. He also received U.S. Patent No. 6,149,618 andcorresponding patents outside the United States. (all assigned toBest Life Co., Ltd.) and is the inventor of other applications andpatents (assigned to Sato Sports Plaza Co., Ltd.) related to
KAATSU Training.

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T. Blood pressure response to slow walking
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Uno K, Hirose K, Matsumoto A, Takenaka K,
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 2011 The Authors
Clinical Physiology and Functional Imaging  2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine 31, 6, 472–476

ORIGINAL ARTICLE

Hemodynamic and autonomic nervous responses to therestriction of femoral blood flow by KAATSU
H. Iida, H. Takano, K. Meguro, K. Asada, H. Oonuma, T. Morita; M. Kurano, F. Sakagami, K. Uno,
K. Hirose, T. Nagata, K. Takenaka, J. Suzuki, Y. Hirata, T. Furuichi, F. Eto, R. Nagai, Y. Sato,T. Nakajima
Int. J. KAATSU Training Res. 2005; 1: 57-64

Correspondence to:Dr. T. Nakajima, Departmentof Ischemic Circulatory
Physiology, University ofTokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113-8655, Japanmasamasa@pb4.so-net.ne.jp
See end of article forauthors’ affiliations

KAATSU training is a novel method for strength training to induce muscle strength and hypertrophy.
The purpose of the present study was to investigate the hemodynamic and autonomic nervous
responses to the restriction of femoral blood flow by KAATSU. Ultrasonography, echocardiography
and impedance cardiography were performed in ten healthy male volunteers aged 34 ± 1.5 before(pre), during and after (post) pressurization on both legs with KAATSU belts placed around proximal
portion of both legs. The parameters measured were as follows; the superficial femoral arterial blood
flow, left ventricular end-diastolic/systolic dimension (LVDd/LVDs), cardiac output (CO), strokevolume (SV), diameter of inferior vena cava (IVC), heart rate (HR), mean blood pressure (mBP), total
peripheral resistance (TPR) and heart rate variability (HRV). The pressurization on both legs withKAATSU suppressed venous blood flow, and markedly induced pooling of blood into the legs withpressure-dependent reduction of femoral arterial blood flow. The application of 200 mmHg KAATSU
decreased femoral arterial blood flow, LVDd, CO, SV and IVC significantly. HR tended to increase,
and TPR increased significantly, but mBP did not change significantly. In addition, high frequency(HF RR), a marker of parasympathetic activity, decreased during KAATSU, while LF RR/HF RR, aquantitative marker of sympathetic autonomic nervous activity, increased significantly. These results
indicate that the application of KAATSU on both legs induces venous pooling in the legs, and theninhibits venous return. The reduction of venous return causes a decrease of IVC diameter, cardiac sizeand stroke volume with an increase in TPR and LFRR/HFRR. Thus, the KAATSU training appears to
become a useful method for potential countermeasure like lower body negative pressure (LBNP)
against orthostatic intolerance for long-term bed rest or space flight as well as strength training to
induce muscle strength and hypertrophy.
Key words: KAATSU training, lower body negative pressure, hemodynamics, cardiac output,
autonomic function, power spectral analysis, bed rest, space flight

INTRODUCTIONKAATSU training is a novel method for muscle
training, originally developed by Sato (2005). Under
the conditions with the restriction of muscle blood
flow, even a short-term and low-intensity exercise
can induce muscle strength, hypertrophy andincreasing muscle mass (Takarada et al, 2000a, 2000b,
2000c; Abe et al., 2005). And, now, KAATSU training
has been used to improve muscle mass and strengthin patients with cardiovascular and orthopedic
diseases as well as healthy subjects and athletes.
Hydrostatic gradients by gravity play an essential
role in determining the distribution of pressure andvolume within the cardiovascular system. Whenthese gradients are removed, such as during exposure
to space flight and bed rest, a central fluid shift occurs,
followed by a neurohumorally mediated reduction inblood and plasma volume and normalization ofhemodynamic equilibrium in the direction observedin the upright posture. This adaptation is rapid andappears to be complete within the first 24 to 48 h of
microgravity exposure (Levine et al., 1997, 2001).
When gravitational force is restored, stroke volume(SV) is reduced, and heart rate is increased. Although
vascular resistance increases, the degree of change isvariable, and the unwanted symptoms of orthostatic
intolerance are frequently developed. Lower body
negative pressure (LBNP) induces the retention ofblood flow in lower extremities, and causes
subsequent hemodynamic changes including
autonomic nervous activities (Stevens and Lamb,
1965; Bonde-Petersen et al., 1984; Tomaselli et al.,
1987; Lathers & Charles., 1993). And, until now, it
has been known to be a useful method to prevent
such orthostatic intolerance after space flight and bed
rest, probably through its effect as orthostatic stimulus(Guell et al., 1992; Lee et al., 1997; Watenpaugh etal., 2000). Recently, we have reported that

58

“KAATSU” leg resistance exercise causes a significant
exercise-induced growth hormone (GH) responseeven in short-term low-intensity resistance exercise(Takano et al., 2005a, 2005b). KAATSU also
decreased cardiac output (CO) and stroke volume(SV), due to the pooling of blood into legs andinhibition of venous return. Thus, KAATSU appears
to be an effective method to promote a state of blood
pooling in the capillaries within the limb musculature
like LBNP. And, when exercise is combined withKAATSU, KAATSU may become a useful method forpotential countermeasure against orthostatic
intolerance for long-term bed rest or space flight aswell as strength training to induce muscle strengthand hypertrophy. However, the hemodynamic andautonomic responses to KAATSU by itself have notbeen investigated in detail.
The purpose of the present study was to investigate
the hemodynamic and autonomic nervous responses
to the restriction of femoral blood flow by KAATSU.
Ultrasonography, echocardiography and impedance
cardiography were used to assess the dependent
variables.

METHODS
Subjects

Ten normal healthy adult males, aged 34 ± 1.5 (28to 46), participated in this study. All were non-trained
volunteers, and informed consent was obtained prior
to the study. Mean height was 175 ± 4 cm, and mean
weight was 66 ± 4 kg. None of the subjects had any
diseases nor took any medications. The study protocol
was approved by the ethics committee of the
University of Tokyo.
Reduction of femoral muscle blood flow by
KAATSUA method for inducing the reduction of muscle
blood flow was similar as previously reported(Takarada et al., 2000a, 2000b; Takano et al., 2005a,
2005b). Pressure was applied at the proximal ends ofboth thighs by means of specially designed belts (33mm in width and 880 mm in length) to restrict
venous blood flow and cause pooling of blood in
capacitance vessels distal to the cuff, and restrict
arterial blood flow. The cuff pressure was first set toapproximately 40~50 mmHg (mean 45 mmHg), andthe cuff pressure used was 100~300 mmHg. To
determine the hemodynamic and autonomic
responses to KAATSU, 200 mmHg was applied.
Measurement of hemodynamic parameters

To evaluate hemodynamic parameters, we used theTask Force Monitor (CNSystems Medizintechnik,Graz, Austria) (Gratze et al., 1998; Fortin et al., 1998),
which includes surface electrocardiograms (ECG),
impedance cardiography (ICG), beat-to-beat blood

Hemodynamic responses to KAATSU

pressure by vascular unloading technique (Penaz,1973) and oscillometric blood pressure recording
performed on the upper arm. The ECG, impedance
signal and beat-to-beat blood pressure was sampledwith 1000 Hz each. These data were used to calculate
online all hemodynamic parameters. The
measurements of hemodynamic parameters wereheart rate (HR), mean blood pressure (mBP), strokevolume (SV), cardiac output (CO) and total
peripheral resistance (TPR). The calculation of CO
and TPR was as follows.
CO=SV*HR
TPR=mBP*80/CO
Histograms of RR intervals were computed andpseudo-digitized at 10 samples per second. Autoregressive modeling (Burg method) was used toconstruct frequency domain spectrograms of theheart rate variability (HRV) (Bailey et al., 1994;
Burklow et al., 1999). Parameters extracted from thevariability spectra were low-frequency power (LFRR,
0.03 to 0.15 Hz) and high-frequency power (HFRR,
0.16 to 0.50 Hz), normalized to total power over therange from 0.01 to 0.50 Hz. LF RR /HF RR havepreviously been demonstrated to measure changes in
sympathetic activity (Malliani et al., 1991)
Measurement of femoral arterial blood flow

The blood flow of superficial femoral artery wascalculated from the cross-sectional area (CSA) of theartery and velocity time integral (VTI) using Aplio80(Toshiba, Tokyo). The site recorded was ~5 cm distal
to the portion of the KAATSU belt. First, superficial
femoral artery was identified in the two-dimensionalmode, and CSA was measured at the end-systolicperiod. Then, in the pulse-Doppler method, VTI,
calculated as the integral area under the velocity
curve, was measured. Adjustment of the angle for themeasurement was within 60c. Blood flow per minute
was obtained by multiplying CSA by VTI and heartrate. The blood flow was acquired in supine position
before (pre) and during the application of KAATSU,
and just after releasing the pressure.
Measurement of cardiac size, CO and diameterof inferior vena cava (IVC)

Transthoracic echocardiography was performed
using Aplio80. The left ventricular end-diastolicdimension (LVDd) and left ventricular end-systolicdimension (LVDs) were measured on the M-mode
recording in the parasternal long-axis view. The left
ventricular outflow velocity pattern was recorded
from the apical long-axis view with the pulsed wave
Doppler sample volume positioned just below theaortic valve, and the aortic velocity time integral(VTI AO ) was calculated. The diameter of left
ventricular outflow tract (D) was measured with two-H. Iida, H. Takano, K. Meguro, et al.

59

Figure 1. The ultrasonographic findings of femoral blood flow. The
typical data are indicated before (pre) and during the application of
KAATSU (100 mmHg). Fig. 1Aa and Ba indicate the data recording of
longitudinal section of superficial femoral artery (red arrow) and femoral
vein (blue arrow). Fig.1Ab and Bb show the data recording of blood flow
velocity of superficial femoral artery. Note that KAATSU markedly
induces pooling of venous blood with restriction of arterial blood flow.

dimensional echocardiography. Cross-sectional area
(CSAAO) of flow was calculated as π × (D/2)2 based ona two-dimensional echo diameter (D) measurement.
CO then is calculated as CSAAO multiplied by the
VTIAO and HR. The maximal diameter of IVC wasmeasured from the subcostal approach.
Data analysis

All values are expressed as means ± S.E.M.
Comparison of time courses of parameters wasanalyzed by one-way ANOVA for repeated measures.
When differences were indicated, a Bonferroni/
Dunnett’s comparison was used to determine
significance. Differences were considered significant
if P value was less than 0.05.

RESULTS
Reduction of femoral arterial blood flow by
KAATSU

Figure 1 & 2 show the effects of KAATSU on bloodflow of the superficial femoral artery. Fig. 1 shows a
representative data recording of femoral arterial bloodflow without (pre) and with KAATSU. Under theconditions with KAATSU (100 mmHg), the diameterof the femoral vein (described by blue arrow) was
remarkably increased (Fig. 1Aa (pre) & Fig. 1Ba (100mmHg)) and femoral arterial blood flow (describedby red arrow) was decreased by 22 % (Fig. 1Ab & Fig.
1Bb). The changes in femoral arterial blood flow
against the cuff pressure are depicted in Fig. 2.
Application of 100 mmHg KAATSU decreased
femoral arterial blood flow from 354.1 ± 37.2 ml/min

Figure 2. Changes of blood flow of superficial femoral artery.
The blood flow of right superficial femoral artery was obtained
before (0 mmHg) and during the application of various
degrees of KAATSU (100~300 mmHg). The data show means± S.E.M. obtained from 10 subjects. *P<0.05 vs control (PreKAATSU).

(pre) to 151.0 ± 22.3 ml/min (100 mmHg, n=10,
P<0.01). And, arterial blood flow decreased withincreasing levels of the applied-pressure anddisappeared at greater than 250 mmHg in mostsubjects. The arterial blood flow decreased to 36.4 ±12.9 ml/min (200 mmHg, n=10, P<0.01), and 10.8 ±8.4 ml/min (250 mmHg, n=10, P<0.01). Immediately
after releasing the pressure, femoral arterial bloodflow recovered (data not shown). These results

60

Hemodynamic responses to KAATSU

indicate that the application of KAATSU to both legs
restricts venous blood flow and causes venous
pooling in the legs distal to the cuff with the pressuredependent reduction of arterial blood flow.
Hemodynamic responses to the restriction offemoral blood flow by KAATSU

Figure 3 shows the effects of KAATSU on venous
return, cardiac size and CO measured byechocardiography. We measured the diameter of IVC
as a quantitative marker of venous return.
Application of 200 mmHg KAATSU reduced thediameter of IVC from 17.9 ± 1.3 mm to 14.3 ± 1.0
mm (Fig. 3C, n=10, P<0.01). Simultaneously, left
ventricular end-diastolic dimension (LVDd) was
reduced from 47.5 ± 1.0 mm to 42.9 ± 1.0 mm(n=10, P<0.01, Fig. 3A). In addition, cardiac output(CO) was decreased from 5.6 ± 0.2 l/min to 4.1 ± 0.3
l/min (n=5, P<0.01, Fig. 3D). Left ventricular end-

systolic dimension (LVDs) was also decreased, but notsignificantly (Fig. 3B). Thus, KAATSU appears to
induce the pooling of blood in the legs, resulting ininhibiting venous return, and reducing cardiac
preload and CO.
Figure 4 shows the changes of hemodynamic
parameters by application of pressure on both legs
measured by impedance cardiography. During
pressurization of 200 mmHg, HR increased slightly(Fig.4A). Mean blood pressure (mBP) did not change
significantly (Fig. 4B). On the other hand, CO andstroke volume (SV) were significantly decreased from
5.8 ± 0.2 ml/min to 4.3 ± 0.2 ml/min (Fig. 4C, n=10,
P<0.01) and from 88.3 ± 3.7 ml to 64.5 ± 5.0 ml (Fig.
4D, n=10, P<0.01), respectively. These changes wereconsistent with the results obtained byechocardiography. In addition, total peripheral
resistance (TPR) increased significantly from 1122.6 ±71.1 dyne*s/cm5 to 1638.7 ± 140.7 dyne*s/cm5 at

Figure 3. Effects of KAATSU on LVDd, LVDs, the diameter of IVC and

CO measured by echocardiography. The parameters (LVDd, LVDs, IVC
and CO) are shown in control (pre) and during a set pressure of 45mmHg, and a cuff pressure of 200 mmHg, and after the release of
KAATSU (post). Values are means ± S.E.M. obtained from 5-10 subjects.
*P<0.05, **P<0.01 vs. control (pre)H. Iida, H. Takano, K. Meguro, et al.

200 mmHg KAATSU (n=10, P<0.01, Fig. 4E).
Autonomic nervous responses to the restrictionof femoral blood flow by KAATSU

Figure 5 depicts an example of the changes in the
power spectra of heart rate variability (HRV) in
control (pre), during application of KAATSU at a set
pressure of 50 mmHg and a cuff pressure of 200
mmHg, and after the release of KAATSU. Application

61of pressure on both legs produced changes in HRV,
i.e. markers of autonomic modulation (Fig. 6). The
HF RR component was reduced from 41.3 ± 4.9
normalized unit (nu) to 23.4 ± 4.2 nu (n=10, Fig.
6A). The LFRR/HFRR as a quantitative marker of
sympathetic nervous activity was increased
significantly (from 1.8 ± 0.3 ms2 to 4.9 ± 1.0 ms2,
n=10, P<0.01, Fig. 6B).

Figure 4. Effects of KAASTU on hemodynamic parameters measured by

impedance cardiography. The parameters (HR, mBP, CO, SV and TPR) are shownin control (pre) and during a set pressure of 45 mmHg, and a cuff pressure of 200
mmHg, and after the release of KAATSU (post). Values are means ± S.E.M.
obtained from 10 subjects. *P<0.05, **P<0.01 vs. control (pre)62

Hemodynamic responses to KAATSU

Figure 5. The time courses of changes of heart rate variability(HRV) during KAATSU (50 and 200 mmHg). Note thatduring KAATSU (50 and 200 mmHg), LF RR increased,compared with the control, while HFRR decreased.

DISCUSSION
The major findings of the present study were as
follows: (1) Application of KAATSU on both legs
caused the pooling of venous blood with thepressure-dependent reduction of femoral arterial
blood flow; (2) The pooling of venous blood in thelegs by KAATSU reduced venous return with asignificant decrease in cardiac size and CO, and acompensated increase of TPR; and (3) Application of
KAATSU on both legs also affects autonomic nervous
activities, where an increase in the sympathetic
nervous activity was observed. Thus, KAATSU
appears to be an effective method to induce venous
pooling in the legs like lower body negative pressure(LBNP). KAATSU training also appears to be aunique method as a potential countermeasure against
orthostatic intolerance for long-term bed rest or spaceflight as well as strength training to induce muscle
strength and hypertrophy.
KAATSU training is a novel method for muscle
training to strength muscle and induce muscle
hypertrophy and increase muscle mass. Under theconditions of restricted muscle blood flow, even a
short-term and low-intensity exercise can inducemuscle strength, hypertrophy and increasing muscle
mass (Takarada et al., 2000a, 2000b, 2000c; Takaradaet al., 2002; Abe et al., 2005). Up to now, several
mechanisms underlying the effects of KAATSU
training have been proposed. First, under theconditions with restriction of muscle blood flow by
KAATSU, a large number of fast-twitch muscle fibers
are recruited in a hypoxic condition, resulting inmuscle hypertrophy (Takarada et al., 2000b; Yasuda
et al., 2004). Secondly, a combination of anaerobic
factors such as local ischemia and/or local
accumulation of lactate in the legs induced by the

Figure 6. Effects of KAATSU on heart ratevariability. The parameters (HF RR and
LFRR/HFRR) are shown in control (pre) andduring a set pressure of 45 mmHg, and a cuff
pressure of 200 mmHg, and after the release of
KAATSU (post). Values are means ± S.E.M.
obtained from 10 subjects. *P<0.05, **P<0.01
vs. control (pre)restriction of muscle blood supply may stimulate
peripheral afferent nerves, resulting in enhancing GH
secretion (Takarada et al., 2000a; Takano et al.,2005a, 2005b). GH stimulates the liver to secrete
insulin-like growth factor-1 (IGF-1) (Abe et al., 2005)
and both GH and IGF-1 can contribute to muscle
hypertrophy. Thus, the effects of KAATSU on muscle
strength and hypertrophy may be related to theseverity of the restriction of muscle blood flow and/or
accumulation of anaerobic factors. The present study
provided the quantitative data about the relationships
between the cuff pressure and femoral arterial blood
flow. Even 100 mmHg KAATSU decreased femoral
arterial blood flow by approximately 22 %. Arterial
blood flow decreased with increasing levels of
KAATSU, and disappeared at greater than 250 mmHg
in most subjects. But, the degree of restriction ofarterial blood flow by KAATSU was different amongindividuals. Besides of the pressure-dependent
inhibition of arterial blood flow, the marked venous
dilation and pooling of blood in the legs wereH. Iida, H. Takano, K. Meguro, et al.

observed under the conditions with KAATSU.
Application of KAATSU on both legs induced venous
pooling, and reduced venous return with the
reduction of IVC diameter and cardiac size and CO.
Even in cases of a set pressure of 45 mmHg, CO, SV,
and LVDd were decreased. Application of 200 mmHg
induced much larger decrease in CO, SV, LVDd andIVC. The decrease in central venous pressure andchanges in cardiac wall stress increased thesympathetic activities measured by HR variability, andHR also tended to increase during the KAATSU.
Mean arterial blood pressure did not change
significantly under the KAATSU (45~200 mmHg),
suggesting that the primary mechanism responsible
for sympathoexcitation during the pressure levels
used in the present study involved the influence ofthe cardiac receptor afferents. Thus, KAATSU appears
to be a unique method to promote a state of blood
pooling in the capillaries within the limb
musculature.
Lower body negative pressure (LNBP) has been
known to induce the retention of blood flow in lower
extremities, and induce subsequent hemodynamicchanges (Stevens and Lamb, 1965; Bonde-Petersen etal., 1984). The cardiovascular response to LBNP isthought to involve a complex sequence of steps that
occur at different rates. The initial rapid onset andreadily reversible steps include increased transmuralpressure, reactive arterial tonus, and venous poolingthat occur in the lower body with the initiation of
LBNP. The slower mechanisms of interstitial andlymphatic sequestration follow with the continued
orthostatic stress and result in an increased calf
circumference and decreased central vascular filling(Tomaselli et al., 1987; Lathers and Charles., 1993).
Melchior et al. (1994) reported that LBNP ramp testfrom 0 to -40 mmHg reduces central venous pressure(CVP) by about -5~-6 mmHg and venous return,resulting in a decrease in SV and CO by about 37 %and 32 %, respectively. In the present study, wedemonstrated that KAATSU of 200 mmHg on bothlegs produces 26.9 % reduction of SV and 25.7 %reduction of CO, which has an equal effect to LNBP
of approximately 30 mmHg. It has been also reported
that LBNP (0 to -40 mmHg) produced clear changes
in HR variability; LBNP induces sympathetic
activation and vagal withdrawal, mediated byunloading of both cardiopulmonary and arterialbaroreceptors (Franke et al., 2000; Lucini et al.,2004). Lucini et al. (2004) reported that LF RR
progressively rose from 49 ± 7 nu to 83 ± 3 nu by
LBNP of -40 mmHg. The HF RR component was
reduced from 43 ± 6 to 13 ± 3 nu and the LFRR/HFRR
was increased from 1.6 ± 0.6 to 17.5 ± 12.1. In thepresent study, the application of 200 mmHg KAATSU
on both legs increased the LFRR component (58.7 ±4.9 to 76.6 ± 4.2 nu) and the LFRR/HFRR (1.8 ± 0.3 to63

4.9 ± 1.0), while the HFRR component was decreased
from 41.3 ± 4.9 to 23.4 ± 4.2. Compared with theeffect on autonomic nervous activities with LNBP,
pressurization of 200 mmHg on both legs also has aneffect equal to a LNBP of about -20~-30 mmHg.
LBNP is known to be a useful method to prevent
orthostatic intolerance after space flight and bed rest,
probably through its effect as an orthostatic stimulus(Güell et al., 1992; Murthy et al., 1994; Buckey et al.,
1996; Lee et al., 1997; Watenpaugh et al., 2000;
Watenpaugh et al., 2001). Lee et al. (1997) reported
that supine treadmill exercise against LBNP during 5days of 6c head-down bed rest maintained
submaximal exercise responses such as submaximal
heart rate, respiratory exchange ratio, and ventilation
after bed rest. Watenpaugh et al. (2000) also reported
that daily supine exercise in a LBNP chamber at 1.01.2 body weight (58 ± 2 mmHg LBNP) maintains
aerobic fitness and sprint speed during 15 days of 6chead-down bed rest. Such preservation ofsubmaximal responses after bed rest suggests thatexercise combined with LBNP may be effective inmaintaining upright exercise capacity during longer
bed rest periods (Perhonen et al., 2001; Schneider etal., 2002). LBNP has been also used for preventing
orthostatic intolerance and micogravity-induced
cardiac remodeling/atrophy after space flight and fortraining astronauts (Watenpauch, 2001). The present
study clearly indicated that KAATSU is a noninvasive
technique that induces venous dilation and pooling ofblood in the legs like LBNP. In addition, the KAATSU
training may also be used by astronauts to preventthe loss of muscle mass and strength as well as theloss of bone density (Yamazaki Y, 2004). Thus, it isvery likely that KAATSU training may be a useful
method to counter symptoms of orthostatic
intolerance and muscle atrophy in patients, bed rest
subjects, and astronauts, but further studies areneeded to clarify these interesting possibilities.
In conclusion, the restriction of femoral blood flow
induced by the application of KAATSU on both legs
caused the marked pooling of blood with thepressure-dependent reduction of femoral arterial
blood. KAATSU training appears to be a usefulpotential countermeasure against orthostatic
intolerance for long-term bed rest or space flight aswell as strength training to induce muscle strengthand hypertrophy.

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Yasuda T, Abe T, Sato Y, Midorikawa T, Inoue K, Ryushi T, Kearns CF,
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Authors’ affiliations
H. Iida, H. Oonuma, M. Kurano, Y. Sato, T. Nakajima,
Department of Ischemic Circulatory Physiology, University of Tokyo,
Tokyo, Japan
H. Takano, K. Meguro, K. Asada, T. Morita, K. Uno, K.
Takenaka, J. Suzuki, Y. Hirata, R. Nagai, Department of
Cardiovascular Medicine, University of Tokyo, Tokyo, Japan
F. Sakagami, K. Hirose, F. Eto, Department of Rehabilitation,
Faculty of Medicine, University of Tokyo, Tokyo, Japan
T. Nagata, Department of Respiratory Medicine, University of Tokyo,
Tokyo, Japan
K. Hirose, Department of Rehabilitation, Dokkyo University, School of
Medicine, Tochigi, Japan

ORIGINAL ARTICLE

Use and safety of KAATSU training:
Results of a national survey
T. Nakajima, M. Kurano, H. Iida, H. Takano, H. Oonuma, T. Morita, K. Meguro, Y. Sato, T. Nagata,and KATTSU Training Group
Int. J. KAATSU Training Res. 2006; 2: 5-13

Correspondence to:
T. Nakajima, MD: Departmentof Ischemic Circulatory
Physiology, KAATSU Training,
University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo,
Japan 113-8655
masamasa@pb4.so-net.ne.jp
See end of article forauthors’ affiliations

KAATSU training is a novel training, which is performed under conditions of restricted blood flow. It
can induce a variety of beneficial effects such as increased muscle strength, and it has been adopted
by a number of facilities in recent times. The purpose of the present study is to know the present stateof KAATSU training in Japan and examine the incidence of adverse events in the field. The data wereobtained from KAATSU leaders or instructors in a total of 105 out of 195 facilities where KAATSU
training has been adopted. Based on survey results, 12,642 persons have received KAATSU training(male 45.4%, female 54.6%). KAATSU training has been applied to all generations of people
including the young (<20 years old) and the elderly (>80 years old). The most popular purpose of
KAATSU training is to strengthen muscle in athletes and to promote the health of subjects, including
the elderly. It has been also applied to various kinds of physical conditions, cerebrovascular diseases,
orthopedic diseases, obesity, cardiac diseases, neuromuscular diseases, diabetes, hypertension andrespiratory diseases. In KAATSU training, various types of exercise modalities (physical exercise,walking, cycling, and weight training) are used. Most facilities have used 5-30 min KAATSU training
each time, and performed it 1-3 times a week. Approximately 80% of the facilities are satisfied withthe results of KAATSU training with only small numbers of complications reported. The incidence ofside effects was as follows; venous thrombus (0.055%), pulmonary embolism (0.008%) andrhabdomyolysis (0.008%). These results indicate that the KAATSU training is a safe and promising
method for training athletes and healthy persons, and can also be applied to persons with various
physical conditions.
Key words: KAATSU training; side effects; rehabilitation

INTRODUCTIONKAATSU training is a novel method for muscle
training, originally developed by Sato (2005). Under
the conditions of restricted muscle blood flow, evenshort-term, low-intensity exercise can induce muscle
strength, and hypertrophy (Takarada et al, 2000b;
Takarada et al., 2002; Takarada & Ishii, 2002; Yasuda
et al., 2004; Abe et al., 2005a, b). In addition,
KAATSU training increases the amount of circulating
growth hormone (GH) (Takarada et al., 2000a;
Takano et al., 2005a,b; Sato et al., 2005), which may
enhance lipolysis and bone formation, resulting in a
reduction of obesity and bone diseases as well as
improving strength and inducing hypertrophy ofmuscle (Beekley et al., 2005). Also, GH stimulates theliver to secrete insulin-like growth factor-1 (IGF-1)(Abe et al., 2005a), which may improve the functionof endothelium and insulin sensitivity. Thus, until
now, KAATSU training has been widely used inhealthy subjects and athletes, and has also been
applied to various kinds of conditions such as
orthopedic diseases, obesity and diabetes. However,the present state of KAATSU training remains

unclear.
Apart from the beneficial effects of KAATSU
training, the pressurization of blood vessels may cause
the formation of thrombus, and induce microvascularocclusion (no-flow phenomenon) even after releasing
blood flow restriction, resulting in muscle cell damage
and necrosis (Harmon et al., 1948; Strock & Majno,
1969; Kawada, 2005). Therefore, we are concerned
about the formation of thrombus, muscle damage,and the occurrence of pulmonary embolism in thesubjects, when KAATSU training is applied. In
addition, although KAATSU training restricts venous
flow, induces the pooling of venous blood, andsubsequently reduces cardiac preload during exercise,
which may be useful in rehabilitation in patients withcardiac diseases (Takano et al., 2005a, b; Iida et al.,2005), the excessive inhibition of cardiac preload may
decrease cardiac output, and thereafter blood flow tothe brain and coronary circulation. Consequently,
side effects such as dizziness, fainting, cerebral anemia
and the deterioration of ischemic heart disease may
occur. But, detailed reports about the side effects of
KAATSU training have not yet been reported.

6

Use and safety of KAATSU training

Therefore, to recognize the present state of
KAATSU training and its side effects, we mailed
questionnaires and obtained results from KAATSU
leaders or instructors in a total of 105 facilities where
KAATSU training has been adopted, and described
them in this paper.

METHODS
Subject

Facilities where KAATSU training has been adopted
participated in this study (see the appendix). We
mailed questionnaire about KAATSU training to a
total of 195 facilities in Japan, which had qualificationof KAATSU leaders or instructors. The questionnaire
asked about the distribution of age, training methods,
training periods, side effects etc as described inAppendix 1.
We obtained an answer from KAATSU leaders or
instructors in 105 out of 195 facilities (approximately53%). As shown in Fig.1A, the number ofbonesetter’s and osteopath’s offices and training gyms
is larger than that of hospitals/clinics andrehabilitation centers.
Fig. 1B shows the period since the facilities havestarted KAATSU training. Most of the facilities (84%)
have started KAATSU training within 5 years. Until
now, total 12,642 persons have been received it (maleOthers15(14%)

10.2%≤ 19 y.o.

17.8%
20s

14.0%

12.4%
30s

50s

15.5%

12.7%
40s

13.1%
Figure 2. The age distribution of persons who have received
KAATSU training in a total of 105 facilities.

Hospitals andClinics
23(22%)

Training gyms
28(27%)

Bonesetter’s
and osteopath’s
offices25(24%)

Rehabilitation centers3(3%) Acupuncturist’s andmoxa-cauterizer’s offices 11(10%)

B≥ 80 y.o. 4.4%

70s

60s

RESULTSA

45.4%, female 54.6%).
Fig. 2 shows the age distribution of persons who
have received KAATSU training in 105 facilities. The
training was distributed over a wide range of ages.
Persons aged under 20 years old accounted for
17.8%, and persons aged over 70 years old accounted
for 14.6 % of the total. Thus, the KAATSU training
appears to be widely applied to all ages.
Fig. 3 shows the number of the facilities classified
by the object of the training (Fig. 3A) and the purposeof the use of KAATSU training with regard to> 5 year

16%

0

50

100

< 1 year24%

3-5 year20%
1-3 year40%
Figure 1. A: The kinds of the facilities (n=105), whoparticipated in this study. B: The distribution of the period
since the facilities introduced KAATSU training.

Figure 3. The object of the KAATSU training in each facility(A) and the symptom aimed to be improved with the use of
KAATSU training (B). Numbers of facilities are indicated ineach figure.

T. Nakajima, M. Kurano, H. Iida, et al.

symptoms (Fig. 3B). As illustrated in Fig. 3A,
KAATSU training has been applied to various kinds ofconditions; sports, healthy persons, cerebrovasculardiseases, orthopedic diseases, obesity and countering
aging. In addition, it has been also used for training
patients with cardiac diseases, muscle diseases,
diabetes, hypertension and respiratory diseases. Thus,
KAATSU training is used for training persons withvarious kinds of physical conditions. The purpose of
the use of KAATSU training by the various facilities
was as follows (Fig. 3B); improvement of muscle
strength or countering muscle atrophy, improvementof paralysis, build-up of bone-structure, reduction ofobesity and prevention of old persons from becoming
bedridden. Other purposes include improvement of
the symptoms of Berger’s disease, ateriosclerotic
obliterans (ASO), bone atrophy, lumbago andshoulder stiffness, relief of pain including menstrual
pain, countering aging, and maintenance of health.
The total number of persons per year who havereceived KAATSU training is shown in Fig. 4A. The
annual number of visits to the facilities for KAATSU
training was about 31,754, and the mean annual

7

number of visits in one facility was 345. KAATSU
training has been applied to athletes (n=5,311),
orthopedic patients (2,776), the elderly (5,382) andhealthy people (15,284) as shown in Fig. 4B. Thus,
KAATSU training has been mainly used for

Legs

Arms

Legs and arms

Figure 5. A: The distribution of type of exercises combinedwith KAATSU training in each type of facility. B: The
distribution of part of body pressurized with KAATSU in eachtype of facility.

Figure 4. A: The annual number of visits in each type of
facility. Mean numbers per facility and total numbers areindicated. B: The improvement with KAATSU training
expected by subjects. Numbers of persons classified by
expected improvement with KAATSU training are indicated.

Figure 6. Training hours distribution of each KAATSU

training.

8

Use and safety of KAATSU training

Figure 8. The proportion of facilities that were satisfied withthe effect of KAATSU training.

13.1%

Figure 7. A: Frequency of KAATSU training in each type of

facility. B: Period distribution of KAATSU training in each typeof facility.

Figure 9. The most frequent side effects of KAATSU training.

Table 1. Side effects of KAATSU training and their occurrence in each type of facility.

Total

Subcutaneoushemorrhage
Numbness
Cerebral anemia
Coldfeeling
Venousthrombus
Pain
Itch
Deteriorationofischemicheartdisease
Feeling sickk
Increasingofbloodpressure
Physical wearinessDizziness
Pulmonaryembolism
Rhabdomyolysis
Palpitation
Nosebleed
Deteriorationofdiabetic
retinopathy
Fainting
Cerebral infarction
Hypoglycemia
Edema
Chafe

1651
164
35
16
7
5
3

Hospitals and Bonesetter's andAcuouncturist's andRehabilitation
Clinics
osteopath's offices moxa-cauterizer's officecenters

156
6
10
2
1
1

300
67
3
10
3
4

86
42
21
1
3

2
1

Training gyms Others

1105
48

2
1

3

3

2

2

2
2
2
2
1
1
1

1
1
1
2
1
1
1
1

1

1

1
1
1
1
1

1
1
1
1
1

1
1
1

T. Nakajima, M. Kurano, H. Iida, et al.

strengthening of muscle in the field of sports, andhealth promotion in elderly and healthy subjects.
KAATSU training can be combined with various
types of exercises. Fig. 5A shows types of exercises
used with KAATSU training. As shown in Fig. 5A, it
has been applied to stretch exercise, walking, cycling,
and weight training. Many facilities have used bothlegs and arms as the sites of KAATSU (Fig. 5B). Figs. 6
and 7 show the percentage of the facilities classified
by the training hours, frequency and duration of
KAATSU training. Most of the facilities have been
applying 5-30 min KAATSU training each time (Fig.
6), and have been doing it 1-3 times a week (Fig. 7A).
In many cases, KAATSU training has been continued
for at least 3-12 months as shown in Fig. 7B.
The reasons why subjects ended KAATSU training
were as follows: improvement of their diseases or
symptoms, achievement of goals, end of previously
planned period, and shift to training at home. In 30
facilities, subjects have been continuing KAATSU
training without stopping it. Fig. 8 shows the
proportion of the facilities that are satisfied with theeffects of KAATSU training (approximately 80%).
Fig. 9 and table 1 summarize the side effects of
KAATSU training. The occurrence ratio of side effects
was as follows: subcutaneous hemorrhage (13.1%),
numbness (1.297%), cerebral anemia (0.277%), cold
feeling (0.127%), venous thrombus (0.055%),
pulmonary embolism (0.008%), rhabdomyolysis(0.008%), deterioration of ischemic heart disease(0.016%) (Fig. 9 and table 1). In addition, fainting
has occurred in rare cases, and hypoglycemia has
been reported.

DISCUSSION
The major findings of the present study obtained
from 105 out of 195 facilities (approximately 53%)
are as follows: 1) KAATSU training has been used fora wide generation of people including the young(under 20 years old) and the elderly (over 80 years
old), and has mainly been used for strengthening ofmuscle in the field of sports and health promotion in
healthy subjects; 2) It has been also applied to various
kinds of conditions; cerebrovascular diseases,
orthopedic diseases, obesity, cardiac diseases,
neuromuscular diseases, diabetes, hypertension, andrespiratory diseases; 3) It can be combined withvarious types of exercises (e.g., walking, cycling, andweight training). In most of the facilities, subjects
have received 5-30 min KAATSU training each time,
1-3 times a week; and 4) approximately 80% of the
facilities are satisfied with the results of KAATSU
training and there have been only a small number ofside effects. Thus, KAATSU training is a safe andpromising method of training not only for athletes,
but also for ordinary people, and it can also be applied
to persons with various physical conditions.

9

KAATSU training is a novel method for muscle
training (Sato, 2005). Under conditions of restrictedmuscle blood flow, even short-term and low-intensity
exercise can induce muscle strength and hypertrophy(Takarada et al, 2000b; Takarada et al., 2002;
Takarada & Ishii, 2002; Yasuda et al., 2004; Abe et al.,2005a, b). Therefore, as shown in the present study,
many facilities have introduced KAATSU training forstrengthening muscle in the fields of sports. The fieldof sports is indeed widespread, such as hockey,
kendo, mountain climbin, jet skiing, triathlon, rugby,
gymnastics, softball, handball, rock climbing, table
tennis, badminton, marathon, skating, bicycle [cycle]
race, skiing, snowboarding, bodybuilding, aerobics,
judo, swimming, dance, basketball, tennis, volleyball,boxing, soccer, karate, golf, baseball, and combative
sports. KAATSU training is also applied for healthpromotion in healthy subjects, even in the elderly. In
addition, it has also been used to improve muscle
strength in various conditions, including
cerebrovascular diseases, respiratory diseases,
orthopedic diseases, neuromuscular diseases, cases ofbeing bedridden, and effects of old age.
Moreover, it is likely that KAATSU training is a
useful method for training patients with a variety of
diseases such as diabetes, hypertension and obesity.
KAATSU training has additional effects, such asincreasing GH secretion (Takarada et al., 2000a;
Takano et al., 2005a, b; Sato et al., 2005). GH
enhances lipolysis and bone formation, which may
contribute to the reduction of obesity and bonediseases such as osteoporosis (Beekley et al., 2005). It
also stimulates the liver to secrete insulin-like growth
factor-1 (IGF-1) (Abe et al., 2005a), resulting in
improvement of function of the endothelial cells andinsulin sensitivity. Considering such effects of
KAATSU training, some facilities have used KAATSU
training for these patients.
In KAATSU training, various types of exercises canbe used. In the present study, 30% of the facilities
have used only KAATSU training. Even only
KAATSU can prevent muscle atrophy observed inpatients at bed rest (Takarada et al., 2000c). However,in most of facilities, various types of exercises(walking, cycling, and weight training) have beencombined with KAATSU training. It is especiallyinteresting to note that 70% of the facilities have used
walking combined with KAATSU (commonly called“KAATSU walking”). Abe et al (2005b) reported thatKAATSU walking can enhance GH responses, andthen induce muscle strength and hypertrophy. In
addition, no special machine is required in case of
KAATSU walking. Therefore, KAATSU walking canbe more widely adopted. Concerning duration andfrequency, subjects have completed 5-30 min
KAATSU training each time, 1-3 times a week inmost of the facilities. However, since KAATSU

10training produces minimal muscle damage (Takaradaet al., 2000a; Abe et al., 2005a), less recovery time isnecessary, which means that the frequency of
KAATSU training can therefore be increased
according to the degree of its effect.
The most noteworthy finding is that the number ofsevere side effects due to KAATSU training is very
low based on this survey results. The most frequentside effect was subcutaneous hemorrhage. It has been
observed in 13.1% of cases, and more frequently
occurred in arms than legs. However, subcutaneous
hemorrhage is usually transient and diminished as
the time goes on, even if training is continued.
Therefore, subjects can continue the training withlittle cause for concern. Numbness has been observedin 1.297% persons who received KAATSU training,probably due to the compression of peripheral nervesof extremities. The numbness is also only temporary
and abolished immediately after the release of
KAATSU pressure. No cases of leg paralysis haveoccurred in any facility. Therefore, this symptom also
does not interfere with KAATSU training. Several
papers showed that KAATSU training combined with
low-intensity exercise does not cause severe muscle
injury, and there is no elevation of creatine
phosphokinase (CPK) (Takarada et al., 2000a; Abe etal., 2005a) or rhabdomyolysis, as compared withheavy exercises (Chiu et al., 1976; Sorichter et al.,
1999; Clarson & Hubal, 2002). In fact,
rhabdomyolysis was noted in only 1 case.
Occlusion of blood vessels sometimes causes theformation of thrombus, and induces microvascularocclusion (no-flow phenomenon) even after releasing
blood flow restriction, resulting in muscle damage
and cell necrosis (Harmon et al., 1948; Strock &Majno, 1969; Kawada, 2005). However, fortunately,
the incidence of serious side effects was low. Venous
thrombus was observed in 7 cases (0.055%).
Pulmonary embolism was noted in only 1 case(0.008%), but this subject had not been diagnosed
definitely and had not serious problems. Recently,
Tanimoto et al (2005) showed that the muscle
oxygenation level during exercise with KAATSU
training, measured with the near-infraredcontinuous-wave spectroscopy, was larger than thatobserved in completely-occluded conditions. Thus, it
is likely that the blood flow is not completely
restricted under the usual conditions with KAATSU
exercise, which may help to avoid the severe side
effects such as venous thrombus, pulmonary
embolism and rhabdomyolysis.
Dizziness, fainting and cerebral anemia wereobserved in some cases as shown in table 2. Also, thedeterioration of ischemic heart disease has been
described in rare cases (2 cases). The conceivablereason is as follows; Application of KAATSU training
on both legs caused the pooling of venous blood with

Use and safety of KAATSU training

the pressure-dependent reduction of femoral arterial
blood flow (Iida et al., 2005). The inhibition ofvenous return during the KAATSU exercise reduces
cardiac preload during the exercise, which may bebeneficial in rehabilitation of certain patients withcardiac diseases (Takano et al., 2005a, b). On theother hand, the excessive inhibition of cardiac
preload decreases cardiac output, and subsequently
blood flow to the brain and coronary circulation.
Therefore, KAATSU training should be performed
carefully in patients with cardiac diseases such as
ischemic heart diseases, severe aortic stenosis andhypertrophic obstructive cardiomyopathy. Also, theexcessive application of KAATSU pressure may cause
larger increases in both blood pressure andcatecholamine levels as compared with low-intensity
exercise without KAATSU training (Takano et al.,2005a, b). Therefore, we also need to be cautious
when treating patients with hypertension and after
cerebral hemorrhage as well as cardiac diseases. To
minimize the side effects and complications, the
KAATSU leaders and instructors should determine
the duration and degree of KAATSU training as wellas KAATSU pressure carefully. Of course, theinformed consent about the side effects including
subcutaneous hemorrhage should be given to all
persons receiving KAATSU training. However,comparing with heavy physical exercises, where
mortality rates of 0 to 2.5% per 10,000 have beenreported, especially in older persons (ACSM, 2000;
Kallinen M, 2005), any fatal complications have notbeen occurred in KAATSU training. Thus KATSU
training is a safe and promising method for training
persons including older persons.
In conclusion, KAATSU training is a safe andpromising method for training in the field of sports
and healthy persons, and can also be applied topersons with various kinds of physical condition
including cerebrovascular diseases, orthopedic
diseases, obesity, cardiac diseases, neuromusculardiseases, diabetes, hypertension, and respiratory
diseases.

ACKNOWLEDGEMENTS
The assistance of Mr. Hiroyuki Imuta withmanuscript preparation is greatly acknowledged. Mr.
Y. Sato is a contributor of the department of KAATSU
training, Ischemic Circulatory Physiology, Universityof Tokyo.

References
Abe T, Yasuda T, Midorikawa T, Sato Y, Kearns CF, Inoue K, Koizumi
K, Ishii N (2005a) Skeletal muscle size and circulating IGF-1 areincreased after two weeks of twice daily “KAATSU” resistance training.
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Williams & Wilkins, Philadelphia.
Beekley MD, Sato Y, Abe T (2005) KAATSU-walk training increases
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Hirata Y, Furuichi T, Eto F, Nagai R, Sato Y, Nakajima T (2005)
Hemodynamic and autonomic nervous responses to the restriction offemoral blood flow by KAATSU. Int J KAATSU Training Res 1: 57-64.
Kallinen M (2005) Cardiovascular benefits and potential hazards ofphysical exercise in elderly people. Journal of Sports Science andMedicine. 4 (Suppl.7): 1-51.
Kawada S (2005) What phenomena do occur in blood flow-restrictedmuscle? Int J KAATSU Training Res 1: 37-44.
Sato Y (2005) The history and future of KAATSU training. Int J KAATSU
Training Res 1: 1-5.
Sato Y, Yoshitomi A, Abe T (2005) Acute growth hormone response to
low-intensity KAATSU resistance exercise: comparison between arm andleg. Int J KAATSU Training Res 1: 45-50.
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Takano H, Morita T, Iida H, Kato M, Uno K, Hirose K, Matsumoto A,
Takenaka K, Hirata Y, Furuichi T, Eto F, Nagai R, Sato Y, Nakajima T(2005a) Effects of low-intensity “KAATSU” resistance exercise on
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Takano H, Morita T, Iida H, Asada K, Kato M, Uno K, Hirose K,
Matsumoto A, Takenaka K, Hirata Y, Eto F, Nagai R, Sato Y, Nakajima T(2005b) Hemodynamic and hormonal responses to a short-term lowintensity resistance exercise with the reduction of muscle blood flow. Eur J
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Takarada Y, Nakamura Y, Aruga S, Onda T, Miyazaki S, Ishii N(2000a) Rapid increase in plasma growth hormone after low-intensity
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Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000b) Effects of resistance exercise combined with moderate vascularocclusion on muscle function in humans. J Appl Physiol 88: 2097-2106.
Takarada Y, Takazawa H, Ishii N (2000c) Applications of vascularocclusion diminish disuse atrophy of knee extensor muscles. Med Sci
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Takarada Y, Sato Y, Ishii N (2002) Effects of resistance exercise
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Takarada Y, Ishii N (2002) Effects of low-intensity resistance exercise
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women. J Strength Cond Res 16: 123-128.
Tanimoto M, Madarame H, Ishii N (2005) Muscle oxygenation andplasma growth hormone concentration during and after resistance
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Yasuda T, Abe T, Sato Y, Midorikawa T, Kearns CF, Inoue K, Ryushi T,
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Authors’ affiliations
T. Nakajima, M. Kurano, H. Iida, H. Oonuma, Y. Sato,
Department of Ischemic Circulatory Physiology, KAATSU Training,
University of Tokyo, Tokyo, Japan
H. Takano, T. Morita, K. Meguro, Department of Cardiovascular
Medicine, University of Tokyo, Tokyo, Japan
T. Nagata, Department of Respiratory Medicine, University of Tokyo,
Tokyo, Japan
KATTSU Training Group, See the Appendix for a list of respondents.

12

Use and safety of KAATSU training

Appendix 1. Questionnaire
1 About your facility
1-1 What kind of facility is yours?
① Hospitals and Clinics② Bonesetters’ and osteopath’s offices③ Acupuncturist’s and moxa-cauterizer’s offices④ Rehabilitation⑤ Training gyms
⑥ Others
1-2 When did your facility introduce KAATSU training?
① < 1 year ago② 1〜3 years ago③ 3〜5 years ago④ > 5 years ago
1-3(1) How many KAATSU leaders does your facility have?
persons(2) How many KAATSU instructors does your facility have?
persons
2 About your cases or patients
2-1 How is the distribution of age of your subjects who have evertaken KAATSU training in your facility?
<19 years
persons
20〜30 years
persons
30〜40 years
persons
40〜50 years
persons
50〜60 years
persons
60〜70 years
persons
70〜80 years
persons>80 years
persons
2-2 How is the proportion of sex (%) in your facility?
Male%
Female%2-3 What is the object of KAATSU training in your facility?
Training or health promotion① Athletes② Astronauts③ Ordinary healthy persons
Rehabilitation or prevention① Cardiovascular disease② Cerebrovascular disease③ Neuromuscular disease④ Orthopedic disease⑤ Diabetes mellitus⑥ Obesity⑦ Renal disease (including hemodialysis)⑧ Hypertension⑨ Depression⑩ The elderly⑪ Respiratory disease⑫ Others ()
2-4 What is the symptom aimed to be improved with the use of
KAATSU training?
① Muscle atrophy② Hypertension③ Diabetes mellitus④ Paralysis⑤ Bone disease (build-up of bone-structure)⑥ Obesity⑦ Bedridden⑧ Increase of muscle strength⑨ No particular symptom⑩ Others ()
2-5 How many visits are there in your facility a year?

3 About KAATSU training
3-1 What types of exercises are combined with KAATSU training?
① Only KAATSU② Physical exercise③ Walking (including treadmill)④ Cycling⑤ Weight training⑥ Others ()
3-2 What parts of subject’s body do you apply KAATSU training?
Legs:personsArms:
persons
Both legs and arms:
persons
3-3 How often do your subjects visit your facility?
① Everyday② 2-3 times a week
③ Once a week
④ 2-3 times a month⑤ Once a month⑥ Others ()
3-4 How is the distribution of the duration to treat each subject in yourfacility?
① < 3 months%② 3-6 months%③ 6 months - 1 year%
④ 1-3 years%⑤ > 3 years%
3-5 How long is each training period in your facility?
① < 5 minutes② 5-10 minutes③ 10-20 minutes④ 20-30 minutes⑤ > 30 minutes
4 About effect of KAATSU training
4-1 How large is the proportion of your subjects who is satisfied withthe effect of KAATSU training?
%
4-2 How many subjects have suffered from the side effect of
KAATSU training?
persons
4-3 What is the side effect of KAATSU training that your subjects
suffered from?
① Cold feeling② Numbness③ Subcutaneous hemorrhage④ Venous thrombus⑤ Pulmonary embolism⑥ Rhabdomyolysis⑦ Myocardial infarction⑧ Others ()
4-4 To what point do you pay attention while you treat your subjects?
persons

T. Nakajima, M. Kurano, H. Iida, et al.

Appendix 2
List of Respondents; Denenchofu-iin (clinic), Kohno Internal medicine
clinic (clinic), Kamo hospital (hospital), Tokuyama-seikeigeka (orthopedic
clinic), Kurihara seikeigeka (orthopedic clinic), Endo Kikyo Children’s
clinic (clinic), Konfogarden clinic (clinic), Ikujinkai Medical Corporationof Odagiri hospital (hospital), Social Insurance Shiga Hospital (hospital),
Inoue hospital/clinic (hospital and clinic), Keiyu-seikeigeka (orthopedic
hospital), Fukuda-seikeigeka (orthopedic clinic), Sata-seikeigeka hospital(hospital), Medical corporation Koueikai Inoue Orthopedic Surgery Clinic(clinic), Department of Ischemic Circulatory Physiology, KAATSU
Training, University of Tokyo (hospital), Takeuchi-seikotsuin (osteopath’s
office), Synthetic Therapy & Conditioning Plaza (osteopath’s andacupuncturist’s office), Yoshimura-sekkotsuin/Kenshin-club (bonesetter’s
office), Yomeido Acupuncture & judo therapist clinic (osteopath’s office),
Kobayashi-seikotsuin (osteopath’s office), WAKABA SEKKOTUIN(bonesetter’s office), Nishiodo seikotuin (osteopath’s office), Itosekkotsuin (bonesetter’s office), Kusaka bonesetting office (bonesetter’s
office), Kuga bonesetter’s office (bonesetter’s office), Nemoto-sekkotsuin(bonesetter’s office), Tanaka-seikotsuin (osteopath’s office), EkakuMizuno-seikotsuin (osteopath’s office), Koga JUDO Therapy Office(osteopath’s office), ARISAWA BONESETTER (bonesetter’s office),
Hayashi-sekkotsuin (bonesetter’s office), GOKISO SEKKOTSUIN(bonesetter’s office), Kanai-sekkotsuin (bonesetter’s office), KOMATA
BONESETTER’S OFFICE (bonesetter’s office), Mizuno-sekkotsuin(bonesetter’s office), Shonan-sekkotsuin (bonesetter’s office),
Magaribuchi Judo Therapy Centre, Yuri-seikotsuin (osteopath’s office),
KINOSITA SEIKOTUIN (osteopath’s office), Mori-Shuichi-seikotsuin(osteopath’s office), A spin treatment House (acupuncturist’s and moxacauterizer’s office), Athlete support/KAATSU training Toshima-branch(acupuncturist’s and moxa-cauterizer’s office), YUWA-acupuncture(acupuncturist’s and moxa-cauterizer’s office), Taiyo-shinkyuin/KAATSU
training Fukui school (acupuncturist’s and moxa-cauterizer’s office),
FURUYA ACUPUNCTURE (acupuncturist’s and moxa-cauterizer’s office),
First step (acupuncturist’s and moxa-cauterizer’s office), TOKOROZAWA

13

SPORTS CARE CENTER (acupuncturist’s and moxa-cauterizer’s office),
RITTAI CHIROPRACTIC (acupuncturist’s and moxa-cauterizer’s office),
MAEDA CHINESE MEDICAL/KAATSU training Osaka-Daito-shi-branch(acupuncturist’s and moxa-cauterizer’s office), Roppongi conditioning(acupuncturist’s and moxa-cauterizer’s office), Osaka-sakai-chiropractic(acupuncturist’s and moxa-cauterizer’s office), Inoue-conditioning(rehabilitation center), Armring Physical Plaza (rehabilitation center),Training center SUNPLAY (training gym), Maruyu-training-center(training gym), KAATSU-sports-seitai-seikotsusho (training gym), ATLAS(training gym), DO SPORTS. PLAZA (training gym), Training-collegeKubira (training gym), BODYCRAFT Sports Conditioning HIRATSUKA(training gym), KAATSU training Yotsukaichi-branch (training gym),
Fitness-care-Hokuetsu (training gym), Asahi KAATSU Training Studio(training gym), Hoasen Sports Plaza (training gym), Able-fitness-clubOkayama (training gym), Asurie-sekkotsuin/Asurie-sports-club (traininggym), GOLF & FITNESS CLUB S.I.H (training gym), Maruya-gym(training gym), TOTAL conditioning (training gym), KAATSU training
Kiryu-branch (training gym), K Medical Training Center (training gym),
KENKO PLAZA SKIP (training gym), Shinkyuin-Gen/TRAINING GYMGenkijuku (training gym), TAIL TOP (training gym), Conditioning & Curesupport (training gym), B-sports (training gym), SPORTS CLUB NAS,
ROX (training gym), Conditioning Club P.C.P (training gym), TIPNESS,TOKYU SPORTS OASIS (training gym), SPORTS GYM COSMOSÅitraining gym), Arugo Sports Service CO. Ltd. (training gym), Sato
sports plaza, Taro Ikezaki, Niigata university, KAATSU training KobeNishi-ku-branch, KAATSU training Tomakomai-branch, KAATSU
training Okinawa-branch (Ryukyu university), KAATSU training
Muroran-branch /Kyokushin-kaikan Hokkaido-Kimohuri-branch, Genkisports, Satoshi Tanabe, KAATSU training Oita-branch, KAATSU training
Kashiwa-branch, Orange garden, SAGINUMA SWIMMING CLUB,AVISPA FUKUOKA, Noriko Konuma, SPORTS SHOP XEBIO DOMESAPPORO, KAATSU training Takasaki-branch (Miho Harada), andothers.

CASE REPORTCan KAATSU be used for an orthostatic stress inastronauts?: A case study
H. Iida, M. Kurano, H. Takano, H. Oonuma, H. Imuta, N. Kubota, T. Morita, K. Meguro, Y. Sato,
T. Abe, T Yamazaki, T. Nakajima
Int. J. KAATSU Training Res. 2006; 2: 45-52

Correspondence to:Dr. T. Nakajima, MD,
Department of Ischemic
Circulatory Physiology,
KAATSU Training, Universityof Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8655,
Japan
masamasa@pb4.so-net.ne.jp
See end of article forauthors’ affiliations

The application of an orthostatic stress such as lower body negative pressure (LBNP) during exercise
has been proposed to minimize the effects of weightlessness on the cardiovascular system andsubsequently to reduce the cardiovascular deconditioning. The KAATSU training is a novel method forstrength training to induce muscle strength and hypertrophy. KAATSU induces venous pooling ofblood in capacitance vessels by restricting venous blood flow. Therefore, to investigate whether
KAATSU can be used as an orthostatic stress, we examined the effects of KAATSU on the
hemodynamic, autonomic nervous and hormonal parameters in one subject. The several parameters
were measured by impedance cardiography; heart rate (HR), mean blood pressure (mBP), strokevolume (SV), cardiac output (CO), total peripheral resistance (TPR), and heart rate variability (HRV).
These data were obtained before (pre), during and after (post) pressurization (50 and 200 mmHg) on
both thighs with KAATSU mini belts, and compared with those in standing. The serum concentrationof noradrenaline (NA) and vasopressin (ADH), and plasma rennin activity (PRA) were also measured.
The application of 200 mmHg KAATSU decreased SV, which was almost equal to the value instanding. HR and TPR increased in a similar manner as standing with slight change of mBP. Highfrequency (HFRR), a marker of parasympathetic nervous activity, decreased during both 200 mmHg
KAATSU and standing, while LFRR/HFRR, a quantitative marker of sympathetic nervous activity,
increased significantly. During KAATSU and standing, NA, PRA and ADH increased. These results
indicate that the application of KAATSU on both thighs simulates systemic cardiovascular effects oforthostasis in one gravity (1G), and that KAATSU training appears to be a useful method for potential
countermeasure like lower body negative pressure (LBNP) against orthostatic intolerance in spaceflight as well as strength training to induce muscle strength and hypertrophy.
Key words: KAATSU training; lower body negative pressure; hemodynamics; cardiac output;
autonomic function; power spectral analysis; space flight; deconditioning

INTRODUCTION
During space flights, several serious adaptivechanges in cardiovascular function occur andconsequently crew’s health and safety are
endangered. When gravitational hydrostatic gradientsare abolished, there is a shift of intravascular fluid
from the capacitance vessels of the legs and lower
body centrally toward the head. Then, elevation ofcapillary blood pressure and increased capillary
perfusion pressure in tissues of the head cause facial,
intracranial edema and headache, which probably
distresses astronauts or space travelers. After shortand long- duration spaceflights, some crew members
experience orthostatic hypotension and reduced
upright exercise capacity, which may be attributed inpart to microgravity-induced hypovolemia, decreased
baroreflex responsiveness, decreased skeletal muscle
tone and increased venous compliance. On return toEarth, orthostatic intolerance is the most serious
symptom of cardiovascular deconditioning, inaddition, significantly reduced exercise capacities andincreased resting heart rate are also observed(Blomqvist et al., 1994; Buckley et al. 1996).
Accordingly, effective countermeasures during
spaceflight are critical in order to maintain the
cardiovascular system, as well as the musculoskeletal
structure and function and ensure the well-being andsafety of crew members during and after return toEarth. A passive countermeasure called “bracelets”,
which are specially designed elastic thigh cuffs
developed in Moscow, has been reported to reduce
cephalic edema and make the adaptation to zerogravity (0 G) more comfortable (Arbeille et al., 1995;
Lindgren et al., 1998). This equipment contributes toreducing the edema and the venous stasis in the
cephalic region by pooling blood into the vascularand extravascular compartment of the legs.
Consequently, it can compensate partially for the
cardiovascular changes induced by exposure to 0 G,
but does affect the cardiovascular deconditioning

46

Gravity-like stress by KAATSU

induced by microgravity (Herault et al., 2000). It
would seem that the most effective countermeasure
regimen to prevent cardiovascular deconditioning
would be a gravitation-like stress combined with
exercise.
Lower body negative pressure (LBNP) can induce
the retention of blood flow in lower extremities, andcauses subsequent hemodynamic changes including
autonomic nervous activities (Stevens and Lamb,
1965; Bonde-Petersen et al., 1984; Tomaselli et al.,
1987; Lathers and Charles, 1993, Lucini et al., 2004).
Until now, when combined with intensive exercise, it
has been known to be a useful method to prevent
such orthostatic intolerance after space flight,
probably through its effect as orthostatic stimulus(Güell et al., 1992; Lee et al., 1997; Watenpaugh etal., 2000).
KAATSU training is a novel method for muscle
training, originally developed by Sato (2005). Under
the conditions of restricted muscle blood flow, evenshort-term, low-intensity exercises such as resistancetraining and walking can induce increased muscle
strength, hypertrophy and increased muscle mass
(Takarada et al, 2000a; b, c; Abe et al., 2004).
Recently, KAATSU training has been used to improvemuscle mass and strength in patients withcardiovascular and orthopedic diseases as well as
healthy subjects and athletes in Japan (Nakajima etal., 2006). Since KAATSU can decreases cardiac
output (CO) and stroke volume (SV), due to thepooling of blood into legs and inhibition of venous
return (Iida et al., 2005), it may be an effective andunique method for applying an orthostatic stressduring spaceflight.
In the present study, to investigate whether

Figure 1. KAATSU Mini apparatus and mini belt (60 mm
in width and 605 mm in length) developed in September
2005.

KAATSU can be used as an orthostatic stress, we
examined the effects of KAATSU on the
hemodynamic, autonomic nervous and hormonal
parameters in one subject.

METHODS
Subject

The subject was a normal healthy adult male, aged
34 years. His height was 172.5 cm and his weight was
59.4 kg. He had no disease. This study was approvedby the ethics committee of the University of Tokyo.
Experimental studies

All studies were performed in the afternoon at least
4 h after lunch. An indwelling heparin-lock catheter
was inserted into the superficial antecubital vein ofleft arm. After a 30 minutes rest in a supine position,
control blood samples were collected. Then, after
taking rest measurements of hemodynamic
parameters in this position for 3 minutes by using animpedance method (see below), both legs werepressure-applied with a specially-designed belt,
named ‘KAATSU mini’ in Japanese (Fig. 1, see
below). During KAATSU, the hemodynamic
parameters were continuously monitored (Fig. 2).
Then, after 15 minutes of KAATSU (50 mmHg), thebanding pressure was released and the hemodynamic
parameters were taken again during a 5-10 minutes
recovery period. Blood samples were obtained at 0 to
1 minute and 10 minutes after the KAATSU. All
blood samples were processed to serum or plasma
before storage at -20 ºC until analysis. After morethan an hour recovery time, a similar study was done
at a KAATSU pressure of 100-200 mmHg. Finally,
after a 30 minutes rest time, the hemodynamic

Figure 2. A healthy person wearing the apparatus of KAATSU
mini and impedance cardiography. Both thighs were pressureapplied by a special-designed belt, named KAATSU mini.

H. Iida, M. Kurano, H. Takano, et al.

parameters were taken at rest and during standing (5minutes). The blood samples were also taken at rest
and 5 minutes after standing.
Reduction of femoral muscle blood flow by
KAATSUA method for inducing the reduction of muscle
blood flow as shown in Fig. 2 is somewhat similar as
previously reported (Takarada et al., 2000a, b, c;
Takano et al., 2005a, b). Both sides of subject’s thighs
were pressure-applied at the proximal ends by meansof specially designed belts named KAATSU belts(Fig.1) to restrict venous blood flow and cause
pooling of blood in capacitance vessels distal to thecuff, and restrict arterial blood flow. In this study, a
KAATASU mini belt, recently developed, was used.
The subject did not complain of any side effects.
Measurement of hemodynamic parameters

To evaluate hemodynamic parameters, the Task
Force Monitor (CNSystmes Medizintechnik, Graz,
Austria) (Gratze et al., 1998; Fortin et al., 1998),
which includes surface electrocardigrams (ECG),
impedance cardiography (ICG), beat-to-beat bloodpressure by vascular unloading technique (Penaz,1973) and oscillometric blood pressure were sampled
at 1,000 Hz. These data were then used to calculate
online all hemodynamic parameters, which induced
heart rate (HR), mean blood pressure (mBP), SV, CO
and total peripheral resistance (TPR). The calculationof CO and TPR was as follows;
CO=SV*HR
TPR=mBP*80/CO
Histograms of RR intervals were computed andpseudo-digitized at 10 samples per second. Autoregressive modeling (Burg method) was used toconstruct frequency domain spectrograms of theheart rate variability (HRV) (Bailey et al., 1994;
Burklow et al., 1999). Parameters extracted from thevariability spectra were low-frequency power (LFRR,
0.03 to 0.15 Hz) and high-frequency power (HFRR,
0.16 to 0.50 Hz), normalized to total power over therange from 0.01 to 0.50 Hz. LF RR /HF RR havepreviously been demonstrated to measure changes in
sympathetic activity (Malliani et al., 1991). These data
were obtained every one beat, and data are expressed
as mean ± S.E.M.
Measurement of noradrenaline, plasma renin
activity and vsasopressin

Blood samples for hormone determination (7ml)were collected in pre-heparinised syringes. Blood was
drawn into test tubes containing 10.5 mg of EDTA2Na. Samples were kept in ice-cold water andcentrifuged (3000 rpm) for 10 minutes and theplasma stored at -20 ºC until the assays were47

performed. Plasma concentrations of noradrenaline(NA) were measured using high performance liquid
chromatography (HPLC) method. The lower limit ofdetection of the assay was 6 pg/ml. Plasma renin
activity (PRA) was measured by theRadioimmunoassay (RIA) method with a lower
detection limit of 0.1 ng/ml/hr. Vasopressin (ADH)
was also determined by RIA method. The lower limit
of detection of the assay was 0.2 pg/ml.

RESULTS
Hemodynamic responses to the restriction offemoral blood flow by KAATSU

Figures 3 and 4 show the time course of SV and HR
from standing as well as from the applicaton ofpressure on both legs as determined by impedance
cardiography. Table 1 shows the hemodynamicchanges following standing and the 2 KAATSU
conditions (50 and 200 mmHg). As shown in Fig. 3A,
immediately after begininng of standing SV rapidly
decreased and reached a steady-level within several
minutes (from 71.71 ± 0.14 ml to 56.87 ± 0.17). Alsopressurization of 50 and 200 mmHg gradually
decreased SV (62.30 ± 0.07 ml at 50 mmHg and57.50 ± 0.10 at 200 mmHg) within several minutes,
and the decreased SV reached a quasi-steady statelevel. SV at 200 mmHg KAATSU (Fig. 3C, Table 1)
was much lower than that at 50 mmHg and at
standing position. The decrease in SV continued
during the application of KAATSU. After the releaseof pressure, SV rapidly returned to the pre test levelwithin several minutes.
After an orthostatic stress (standing), HR promptly
increased with decreasing SV (Fig. 4A). Pressurizationof 50 mmHg (Fig. 4B) did not affect HR. On the other
hand, 200 mmHg KAATSU increased HR graduallyfrom 64.89 ± 0.25 bpm at supine rest to 75.34 ± 0.24.
After the release of pressure, HR returned to the pretest level (69.16 ± 0.27 bpm) within several minutes.
MBP decreased slightly during standing (from 94.18 ±0.29 mmHg to 88.60 ± 0.82). But the pressurizationof both 50 and 200 mmHg increased mBP (from81.69 ± 0.34 mmHg to 88.10 ± 0.55 at 50 mmHg, andfrom 90.04 ± 0.20 to 94.98 ± 0.40 at 200 mmHg).
CO decreased during standing (from 4.83 ± 0.02
l/min at supine rest to 4.19 ± 0.02). The
pressurization of KAATSU (50 and 200 mmHg) also
decreased CO as shown in Table 1, but the degree ofchange in CO did not differ much between 50 and
200 mmHg because of the compensatory increase in
HR for the decrease in venous return followed by thedecrease SV. TPR increased during standing andpressurization. Standing increased TPR from 1515.74± 8.53 dyne*sec/cm-5 to 1638.30 ± 18.37. The
pressurization of 50 and 200 mmHg also increased
TPR from 1378.78 ± 5.12 to 1811.69 ± 9.36 at 50

48

Gravity-like stress by KAATSU

Figure 3. Effects of orthostatic stress (standing) and KAATSU

Figure 4. Effects of orthostatic stress (standing) and KAATSU

on stroke volume (SV). The time courses of SV before andduring standing (A) or the pressurization of both legs by
KAATSU (50 (B) and 200 mmHg (C)) and after the release of
KAATSU. Note that pressurization of both legs by KAATSU
gradually decreased and reached a quasi-steady state levelwithin several minutes, and the decrease in SV continued
during application of KAATSU. After the release of KAATSU,
SV returned to a control level immediately.

on heart rate (HR). The time courses of HR before and during
standing (A) or the pressurization on both legs by KAATSU(50 (B) and 200 mmHg (C)) and after the release of KAATSU.
Note that HR increased during orthostatic stress (standing).
HR also increased during the pressurization of both thighs at
200 mmHg, but not 50 mmHg. Immediately after the releaseof KAATSU, the increased HR returned to a control level.

Table 1. Hemodynamic parameters during standing, and KAATSU (50 and 200 mmHg).

HR
(bpm)

mBP
(mmHg)

SV(ml)

CO(l/min)TPR(dyne*sec*cm-5)

prestanding

67.48±0.4573.80±0.28

94.18±0.29
88.60±0.82

71.71±0.1456.87±0.17

4.83±0.02
4.19±0.02

1515.74±8.530
1638.30±18.37

pre
50 mmHg
post

66.53±0.23
65.22±0.1267.48±0.25

81.69±0.34
88.10±0.55
83.75±0.43

76.37±0.1762.30±0.07
71.71±0.14

5.07±0.02
4.06±0.01
4.83±0.02

1378.78±5.120
1811.69±9.360
1515.74±8.530

pre
200 mmHg
post

64.89±0.25
75.34±0.24
69.16±0.27

90.04±0.20
94.98±0.40
94.18±0.29

75.69±0.16
57.50±0.10
69.63±0.17

4.90±0.02
4.33±0.01
4.80±0.02

1293.78±10.04
1585.17±11.67
1349.11±10.07

mmHg and from 1293.78 ± 10.04 to 1585.17 ± 11.67
at 200 mmHg.
Autonomic nervous responses to the restrictionof femoral blood flow by KAATSU

Figure 5 depicts the changes in the power spectra ofheart rate variability (HRV) in control (pre), during
200 mmHg KAATSU, after the release of KAATSU
and subsequently during standing. The HF RR

component, which is a marker of parasympathetic
activity, was reduced by both 50 and 200 mmHg
KAATSU (Fig. 6A). On the other hand, LFRR/HFRR
component was increased by both 50 and 200 mmHg
as shown in Fig. 6B. HFRR markedly decreased from55.30 ± 0.38 % to 34.64 ± 0.25 and LF RR/HF RR
increased from 1.18 ± 0.02 before KAATSU to 4.55 ±0.12 at 200 mmHg KAATSU.

H. Iida, M. Kurano, H. Takano, et al.

49

Figure 5. The time courses of heart rate variability (HRV)

during KAATSU (200 mmHg and standing). Note that during
KAATSU (200 mmHg), LFRR increased, compared with thecontrol (shown by blue arrow), while HFRR decreased (shownby red arrow) as standing.

Figure 7. Effects of orthoststic stress (standing) and KAATSU
on the concentration of noradrenaline (NA, A), plasma
rennin activity (PRA, B) and the concentration of vasopressin(ADH, C). The blood was obtained before (supine rest), after 5
minutes standing and 15 minutes after the pressurization (50and 200 mmHg), and 10 minutes after the release of
KAATSU.

and standing. 50 mmHg of pressurization increased
PRA from 1.4 ng/ml/hr to 1.9 ng/ml/hr, and 200
mmHg of KAATSU had more effect on PRA (from 1.3
ng/ml/hr to 2.2 ng/ml/hr). In addition, ADH was also
increased during 5 minutes standing and during theapplication of KAATSU at 200 mmHg.

DISCUSSION

Figure 6. Effects of orthostatic stress (standing) and KAATSU

on the heart rate variability (HRV). A: Effects of orthostatic
stress (standing) and KAATSU on HFRR/LFRR. B: Effects oforthostatic stress (standing) and KAATSU on HFRR.

Hormonal responses to the restriction of femoral
blood flow by KAATSU

Figure 7 depicts hormonal changes induced bypressurization and standing. NA, a well-known
neurotransmitter released from sympathetic nerve,
increased under the pressurization. 50 mmHg of
KAATSU increased from 183 ng/ml to 229 ng/ml,
and 200 mmHg increased from 239 ng/ml to 350
ng/ml. The standing also raised NA from 175 ng/ml
to 321 ng/ml. PRA also was raised by both KAATSU

We studied the effects of KAATSU on the
hemodynamic, autonomic nervous and hormonal
system in one subject. Application of KAATSU onboth legs induced the hemodynamic, hormonal andautonomic alterations that were similar to standing.
During an orthostatic stress (i.e. standing), part ofthe blood and plasma volume can pool in thecapillary bed of the legs. Subsequently, SV decreased
to about 79.3 % of the control in this case.
Application of KAATSU on both thighs by a speciallydesigned KAATSU mini belt also decreased SV bypooling blood into the vascular and extracellularcompartment of the legs, which depends on the
KAATSU pressure. The increasing cutaneous blood
volume in the legs could be observed by the dark-red
coloration of the skin in the lower body. At 200
mmHg, the decrease in SV (76.0 %)was almost equal
to that observed in standing. The addition of KAATSU
on both thighs gradually decreased SV, and reached
to a quasi-steady level within several minutes. The
decrease in SV remains stable during the applicationof KAATSU. This suggests that venous return isalmost consistent during KAATSU. In other words, it

50

is likely that the amount of arterial blood flow into
the legs and the amount of venous flow out of thelegs are almost equal under the pressurization. As
previously reported, KAATSU suppresses the arterial
blood flow to the legs in pressure-dependent manner(Iida et al., 2005), so in this case, at 200 mmHg of
KAATSU, venous blood flow and therefore also
arterial blood flow may not be completely blocked.
Immediately after the release of KAATSU, thedepressed SV promptly returned to the control level.
In the hemodynamic response to orthostatic stress,
initially SV is decreased, but the decrease in SV is
successfully compensated for by an increased
standing HR and TPR via baroreceptor control of
circulation. Since BP varies with both TPR and CO,
no remarkable change of mean BP was found in
standing. Even in cases of a set pressure of 50 mmHg,
SV was decreased, and TPR was elevated. Mean BP
and HR did not change significantly. It suggests thatthe primary mechanism responsible forsympathoexcitation during the low pressure is
primarily due to the cardiopulmonary baroreceptors,
which are located in the atria and ventricles of theheart and in the pulmonary artery and veins and are
responsive to changes in central venous pressure(Furlan et al., 2001; Brown et al., 2003). On the other
hand, application of 200 mmHg induced a muchlarger decrease in SV, with the increase in HR and
TRP. Thus, during high pressure such as 200 mmHg,
both arterial baroreceptors and cardiopulmonary
baroreceptors were also unloaded. Regarding
autonomic nervous response, HFRR/HFRR, a marker of
sympathetic activity, and the serum concentration ofNA, a well-known neurotransmitter released from
sympathetic nerve, increased, which depends on thepressure of KAATSU. On the other hand, HFRR, amarker of parasympathetic activity, decreased.
Overall, it seems likely that at low level of pressure
the reduced venous return induces a cardiac
unloading, resulting in an inhibition of cardiogenic
sympathetic excitatory mechanisms and in an
increased arterial baroreflex gain, while at high level
the arterial baroreceptor unloading is the dominantphenomenon leading to sympathetic excitation.
During an orthostatic stress (standing), part of theblood and plasma volume can pool in the legs owing
to the shift to the capacitance vessels. The subsequent
decrease in the plasma volume and renal blood flow
stimulates the secretion of PRA and ADH. The
secretion of PRA and ADH were also increased during
KAATSU, which also depends on the degree of thepressure. Thus, it is likely that the application of 200
mmHg KAATSU on both thighs simulates systemic
cardiovascular, autonomic nervous and hormonal
effects of orthostatic in 1G (standing).
In spaceflight, without regular exposure to gravity(G) forces, the cardiovascular functions are

Gravity-like stress by KAATSU

compromised. After short- and long- duration spaceflights, some crew members experience orthostatic
hypotension and reduced upright exercise capacity
named cardiovascular deconditioning and severe
muscle atrophy (Blomqvist et al., 1994; Buckley etal., 1996; Fritsch-Yelle et al., 1996; Meck et al., 2001).
The cardiovascular deconditioning may be attributedin part to microgravity-induced hypovolemia,
decreased baroreflex responsiveness, decreased
skeletal muscle tone and increased venous
compliance. In addition, muscle atrophy produced
greater compliance of lower limbs and a
predisposition to orthostatic intolerance. To maintainthe structure and function of musculoskeletal andcardiovascular systems during space flight, and toeusure well-being and safety of crew members during
space flight and after return to Earth, effective
countermeasures during space flight are critical(Convertino and Sandler., 1995; Nicogossian et al.,1995). A passive countermeasure called a “bracelet”
developed in Moscow has been used to reduce thiscephalic edema and make the adaptation to 0 G more
comfortable (Arbeille et al., 1995; Herault et al.,2000). The bracelets are fixed at the upper part ofeach thigh and applying pressure of approximately
20-30 mmHg (where 1 mmHg =133.3 N/m2) on theskin. The bracelets were considered to reduce thevenous return by trapping a significant amount of
fluid into the lower-limb vascular and interstitialspace, subsequently followed by the fluid shift(Lindgren et al., 1998). The KAATSU apparatus canapply the previously planned pressure to the cuff
accurately. Thus, it is interesting to know whether the
KAATSU with low pressure (20-50 mmHg) can
prevent facial edema and make the adaptation to 0 G
more comfortable than the Russian bracelets (Arbeilleet al., 1995; Lindgren et al., 1998; Herault et al.,2000). Currently, astronauts practice 2-3 h ofintensive exercise using treadmill, ergometer andresistance machines. These time-consuming
countermeasures cannot completely prevent themfrom cardiovascular deconditioning. Therefore,
alternate countermeasure strategies that are more
effective and efficient are necessary. Now, it is likelythat the most effective countermeasure regimen
would be a gravitation-like stress combined with
exercise. The present study indicates that KAATSU
can provide this gravitation-like stress in 1G.
A human centrifuge is another possible candidate,but the centrifuge apparatus is relatively expensive
and it is technically laborious to accommodate theapparatus on a space craft. In addition, it may bedifficult to minimize cetrifugation-induced Coriolis
effects on the vestibular system and the consequentmotion sickness associated with onboard centrifuge.
Therefore, at present, it is likely that exercise against
the suction force produced by LBNP may provide a

H. Iida, M. Kurano, H. Takano, et al.

low mass and low-cost alternative procedure to stressthe cardiovascular systems (Hargens, 1994).
However, LBNP is difficult to apply when combinedwith several exercise, such as resistance exercises
which needs large machines. Furthermore, LBNP
without exercise by itself can not protect crew
members from cardiovascular deconditioning.
LBNP has been known to induce the retention ofblood flow in lower extremities (Wolthuis et al.,1974), and induce subsequent hemodynamic changes
such as decreased SV and CO and increased TPR(Stevens and Lamb, 1965; Bonde-Peterson et al.,
1984; Güell et al., 1990; Güell et al., 1992; Melchior
et al., 1994; Murthy et al., 1994; Lee et al., 1997;
Watenpaugh et al., 2000), and produce sympathetic
activation and vagal withdrawal (Franke et al., 2000).
As previously reported, 200 mmHg of KAATSU has
almost equal effect on cardiovascular and autonomic
nervous system to -40 - -50 mmHg LBNP (Iida et al.,2005). In addition, the present study clearly indicatedthat KAATSU simulates orthostatic effects (1G) on
cardiovascular, autonomic nervous and hormonal
system like LBNP at bed rest. KAATSU training was
originally developed as a novel method for muscle
training to strength muscle and induce muscle
hypertrophy and increase muscle mass. Under thecondition with restriction of muscle blood flow by
KAATSU, even a short-term and low-intensity
exercise can induce muscle strength, hypertrophy
and increasing muscle mass (Takarada et al., 2000a; b;c; Takarada et al., 2002a, b; Abe et al., 2005; Yasuda etal., 2005; Abe et al., 2006). Up to now, several
mechanisms underlying the effects of KAATSU
training are proposed. First, under the ischemic
condition with restriction of muscle blood flow by
KAATSU, a larger number of fast-twitch muscle fibers
are recruited, resulting in muscle hypertrophy.
Second, a combination of anaerobic factors such as
local ischemia and/or local accumulation of lactate in
the legs induced by the restriction of muscle blood
supply may stimulate peripheral afferent nerves,
resulting in enhanced GH secretion (Takarada et al.,2000a; Takano et al., 2005 a, b). GH stimulates liver
to secrete insulin-like growth factor-1 (IGF-1) (Abe etal., 2005). Both GH and IGF-1 can contribute tomuscle hypertrophy. Thus, KAATSU training may beable to be used by astronauts in order to protect
against both musle atropny and strength andcardiovascular deconditioning. Furthermore,
KAATSU training can be easily applied to almost all
types of exercises such as treadmill, ergometer, andresistance machines without any major complications(Nakajima et al., 2006). Thus, it is very likely thatKAATSU training, if used under the suitable exercise
protocol, may be a very promising method to counter
symptoms of orthostatic intolerance and muscle
atrophy in astronauts. But further studies are needed51

to clarify these interesting possibilities.
In conclusion, the application of KAATSU on boththighs simulates cardiovascular effects of orthostasis
in 1G. The KAATSU training appears to be a useful
method for potential countermeasure like LBNP
against orthostatic intolerance in space flight as well
as strength training to induce muscle strength andhypertrophy when combined with exercise.

ACKNOWLEDGEMENT
We appreciate assistance by Daisuke Enomoto incarrying out our study. Y. Sato is a co-researcher ofour study and this work is financially supported by Y.
Sato.

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Authors’ affiliations
H. Iida, M. Kurano, H. Takano, H. Oonuma, H. Imuta, N.
Kubota, Y. Sato, T. Nakajima, Department of Ischemic Circulatory
Physiology, KAATSU Training, The University of Tokyo, Tokyo, Japan
T. Morita, K. Meguro, Department of Cardiovascular Medicine, The
University of Tokyo, Tokyo, Japan
T. Abe, Department of Human and Engineered Environmental Studies,
Graduate School of Frontier Science, The University of Tokyo, Chiba,
Japan
Y. Yamazaki, Japan Manned Space Systems Corporation, Tsukuba,
JAPANORIGINAL ARTICLE

Resistance exercise combined with KAATSU
during simulated weightlessness
N. Kubota, H. Takano, T. Tsutsumi, M. Kurano, H. Iida, T. Yasuda, K. Meguro, T. Morita, Y. Sato,
S. Kawashima, Y. Yamazaki, H. Ohshima, S. Tachibana, N. Ishii, T. Abe, T. Nakajima
Int. J. KAATSU Training Res. 2008; 4: 9-15

Correspondence to:
Toshiaki Nakajima, MD,
Department of Ischemic
Circulatory Physiology,
KAATSU Training, Universityof Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo, Japan 1138655
masamasa@pb4.so-net.ne.jp
See end of article forauthors’ affiliations

The application of a gravity-specific stress (e.g. LBNP), in combination with exercise, prevents
cardiovascular deconditioning in space flight. KAATSU training is a method to induce blood poolingin capacitance vessels by restricting venous return (as with LBNP) and which when combined with lowintensity resistance (RE) exercise produces remarkable muscle mass and muscle strength gains. The
purpose of this study was to investigate the hemodynamic and neurohumonal responses induced by
KAATSU in combination with leg RE (30 % 1 RM), during simulated weightlessness (6˚ head-down tilt
for 24 h, n=7). Following 24 h bed rest 6˚ head-down tilt, body mass was decreased from 75.3 ± 3.9
to 73.3 ± 3.8 Kg (P<0.01). Blood volume (BV) and plasma volume (PV) were reduced by -4.4 ± 1.4%
and -7.9 ± 2.5%, respectively. During RE, BV and PV were significantly decreased; the changes withKAATSU induced a lower-body venous pooling, resulting in a sustained decrease in stroke volume(SV; from 77.0 ± 4.4 ml to 55.9 ± 5.1 ml; P<0.01) that was comparable to resting SV while standing.
Consequently, RE heart rate (HR) was greater with KAATSU. The serum concentrations of plasma
renin activity (PRA), vasopressin (ADH), noradrenaline (NOR), and lactate were also significantly
elevated during RE with KAATSU as compared to control RE. These hemodynamic and neurohumoral
responses following head-down tilt and during RE closely approximate the gravity-specific stressobserved with LBNP. Thus, when used in combination with RE, KAATSU may be a usefulcountermeasure in microgravity.
Key words: KAATSU training, leg press, bed rest, plasma renin activity, noradrenaline

INTRODUCTION
Astronauts practice 2-3 h intensive exercise inspace. This time-consuming exercise training does
not prevent astronauts from cardiovasculardeconditioning, and alternative countermeasurestrategies are recommended. The most effective
regimen is a gravity-simulating stress such as lower
body negative pressure (LBNP) or artificial gravity(Güell et al., 1992; Murthy et al., 1994; Watenpaugh
et al., 2000; Iwase., 2005) combined with exercise
modalities, e.g. treadmill or ergometer. However,these methods are difficult to use in conjunction withresistance exercise.
KAATSU training is a unique technique of lowintensity resistance exercise (RE) training performedin combination with restricted muscle blood flow that
results in muscle hypertrophy and muscle strength
gains comparable to those observed with highintensity resistance exercise training (Takarada et al.
2000a; b; c; Takarada et al., 2002a,b; Abe et al. 2006;
Fujita et al., 2007). The utility of KAATSU training isthat it can be applied to most types of exercise.
Additionally, KAATSU femoral blood flow restriction
induces lower-body venous pooling and reduces
venous return (Iida et al., 2007; Nakajima et al.,2008). Thus, the addition of KAATSU to exercise

appears to induce an orthostatic stress on the
cardiovascular system as observed with LBNP plus
exercises, which may be useful in preventing
orthostatic intolerance. However, the hemodynamic
and neurohumoral responses to exercises combinedwith KAATSU have not been investigated in a zerogravity environment. The aim of the present study
was to investigate hemodynamic and neurohumoral
responses to RE with and without KAATSU during
the simulated weightlessness using head-down tilt
bed rest (Sandler, 1986; Nicogossian, 1994).

MATERIALS AND METHODS
Subjects

Seven healthy males (age, 31.6±1.1; height, 1.76 ±1.6 m; weight, 75.3 ± 3.9 kg) participated in thisstudy. This study was approved by the institutional
review board (IRB) of human research of Japan
Aerospace Exploration Agency (JAXA) and the ethics
committee of the University of Tokyo. All volunteers
had no prior experience with RE and informed
consent was obtained prior to the study. The subjects
were paid by the grant from JAXA for participating inthis study. None of the subjects had any diseases nor
took any medications.

10

KAATSU and cardiovascular function

ProtocolKAATSU Blood Flow Restriction

Subjects maintained a 24-hour period of bed restin -6 ˚ head-down tilt position (-6 ˚ bed rest).
Transportation and toilet procedures were restricted
to the head-down recumbent position. Subjects wereallowed to rest on their elbows during meals andcould move volitionally but remained horizontal tothe bed. Subject's diet, fluid intake, and urine volume
were monitored.
After 24 h -6˚ bed rest, control blood samples weretaken. Following bed rest subjects were randomly
assigned to one of two groups: one group performed
leg press RE without KAATSU, followed by a 2-h rest
interval and then repeated the leg press RE withKAATSU (〜150-160 mmHg cuff pressure; Fig.1).
The other group performed leg press RE withKAATSU followed by a 2-h rest interval and thenrepeated the leg press RE without KAATSU.
Hemodynamic parameters and venous blood samples
were collected prior to, during, and following RE. All
exercise was performed in the head-down tilt
position. Immediately following RE, the KAATSU wasreleased and hemodynamic parameters and blood
samples were again collected during a 5-10 min
recovery period. After 60 min recovery, the subjects
stood up and hemodynamic response was recorded
continuously for 5 min in standing position.

Femoral blood flow was impaired using the
KAATSU technique which also restricts venous bloodflow causing pooling of blood in capacitance vessels
distal to the cuff and partial occlusion of arterial bloodflow (Takano et al., 2005; Iida et al., 2007; Nakajima
et al., 2008). KAATSU belts, specifically designed forspace flight (65 mm in width and 650 mm in length),were applied to the proximal ends of both thighs asnear to the hip joint as possible. The cuff pressure was
150〜160 mmHg, which was controlled by the
KAATSU apparatus.

Resistance Exercise Protocol

Subjects performed leg press RE on a speciallydesigned leg press machine with -6˚ head down tilt.
Knee and hip range of joint motion during exercise
was 0 to 90˚ (0˚ being full extension). RE consisted of
4 sets of leg press. The sets consisted of the following
repetition pattern; 30 repetitions (1/3 s), 15
repetitions, 15 repetitions, 15 repetitions. There was a
1 min rest interval between sets. Contraction
intensity was 30% of predetermined one-repetition
maximum (1-RM). Individual contraction duration
was 3.0 sec with a 1.5:1.5 sec shortening-lengthening
contraction duty cycle as controlled by a metronome(40 beats per min).

Figure 1.

Experimental design. Subjects maintained 6˚head-down tilt position during the bed rest period. After
24 h at -6˚ bed rest, subjects performed leg press exerciseswith and without KAATSU (see methods).

Cardiovascular Hemodynamics

Hemodynamic parameters were determined using
the Task Force Monitor (CNSystmes Medizintechnik,Graz, Austria; Fortin et al., 1998; Gratze et al., 1998).
Analysis included electrocardiogram (ECG),
impedance cardiography, beat-to-beat blood pressure
by vascular unloading technique (Penaz, 1973) andoscillometric blood pressure. Data were obtained
every beat with a 1,000 Hz sampling rate and used to
calculate all hemodynamic parameters in real time.
Data included heart rate (HR; bpm), mean arterial
blood pressure (MAP; mmHg), systolic blood pressure(sBP), diastolic blood pressure (dBP), stroke volume(SV; ml), cardiac output (CO; l·min-1) and total
peripheral resistance (TPR; dyn·s·cm-5). TPR was
calculated in relative units as MAP·CO-1, and thecalculation of CO and TPR was as follows:
CO=SV·HR
TPR=MAP·80·CO-1
Hormone Metabolite Levels

An indwelling catheter was inserted into thesuperficial antebrachial vein of left arm and wasmaintained patent with a heparin-loc solution. Blood
samples were obtained before, 0-1 min and 10 min
recovery period. Venous blood samples were collected
and analyzed for hematocrit, hemoglobin, lactate,noradrenaline, plasma renin activity and vasopressin.
For measurement of hemoglobin and hematocrit, 2
ml of blood was placed into test tubes containing
EDTA-2Na. Blood hemoglobin (Hb; g·dl -1) was
determined by the cyanomethemoglobin method(Coulter hemoglobinometer) and hematocrit (Hct;%) by the micro-hematocrit ultra centrifugation
technique. Plasma level of lactate was measured at
S.R.L. Inc (Tokyo, Japan) by the use of an enzyme
system employing lactate oxidase combined with Nethyl-N-(3-methylphenyl)-N'-acetyl ethylenediamine
and an auto-analyzer, HITACHI Type 7170. For
hormone determination, blood (7 ml) was placed in
test tubes containing 10.5 mg of EDTA-2Na. All
samples were kept in ice-cold water and centrifuged

N. Kubota, H. Takano, T. Tsutsumi, et al.

11(3000 rpm) for 10 min and the plasma stored at -20˚Cuntil the assays were performed.
Plasma concentrations of noradrenaline (NOR;
lower limit of detection 6 pg·ml-1) were measured
using high performance liquid chromatography.
Plasma renin activity (PRA; lower limit of detection
0.1 ng·ml-1·h-1) and vasopressin (ADH; lower limit ofdetection 0.2 pg·ml -1 ) were determined byradioimmunoassay. These assays were completed atcommercially available laboratories (SRL Inc., Tokyo,
Japan).
Changes in blood and plasma volume (%) were
derived from the following equation (Iida et al.,2007):
BVB·BVA-1= HbA·HbB-1%∆PV=100·((HbB·HbA-1)·((1-HctA·10-2)/(1-HctB·10-2))-100
where A is the initial value and B is the value at thecorresponding time.
Data Analysis

urine volume, resulting in the loss of plasma volume
and an increase in Hct. The serum concentration of
PRA and ADH tended to decrease during -6˚ bed restfor 24 h. NOR and dopamine tended to decrease
following -6 ˚ bed rest, but was not statisticallysignificant. HR and sBP did not significantly change.
Fig 2 summarizes the effects of leg press RE withand without KAATSU on hemodynamic parameters.
The increase in HR with RE was significantly greaterwith KAATSU than without KAATSU (Fig. 2A). The
peak HR during exercise reached to 107.1 ± 9.4 bpm(Fig. 2B). sBP (Fig. 2C), dBP, and mBP increased(P<0.01) during KAATSU exercise, and reached peakvalues of 154.2 ± 8.2 mmHg, 99.2 ± 6.0 mmHg, and116.1 ± 6.5 mmHg, respectively (Table 2). In leg press
RE with KAATSU, SV significantly decreased from77.0 ± 4.4 ml to 55.9 ± 5.1 ml (P<0.01) comparedwith the exercises without KAATSU (Fig. 2D). The
level of SV during KAATSU was approximately equal
to that in standing. During leg press RE withKAATSU, CO increased from 4.8 ± 0.6 l·min-1 to 5.8 ±0.6 l·min-1 (P<0.01; Fig. 2E). During RE without
KAATSU, CO increased from 4.6 ± 0.4 l·min-1 to 6.0 ±All values are expressed as means±S.E.M. Student's
paired t-test and one-way ANOVA for repeatedmeasures were used, and differences were consideredsignificant if P < 0.05.

RESULTS
Table 1 shows the changes of various parameters
following bed rest. Body mass significantly decreased
from 75.3 ± 3.9 Kg (Pre, 0 h bed rest) to 73.3 ± 3.8
Kg (n=7, P<0.01) 24 h after -6 ˚ bed rest. Hctsignificantly increased from 46.4 ± 1.2% to 48.5 ±
0.8% (n=7, P<0.01). Blood volume and plasma
volume decreased by -4.4 ± 1.4% and -7.9 ± 2.5%(n=7), respectively. The urine volume (2052 ± 249
ml·d-1) markedly exceeded the volume of water
intake (1320 ± 67 ml·d-1), suggesting that the central
fluid shift of blood induced by -6˚ bed rest enhanced

Table 1. Changes of various parameters during 24 h bed rest
Parameters
Body weight (Kg)
Water balance intake (ml)Urine volume (ml)Hct (%)Hb (mg/dl)
Blood volume (%)
Plasma volume (%)
PR A (ng/ml/h)
ADH (pg/ml)
NOR (pg/ml)
Dopamin (p g/ml)
HR (/min)sBP (mmHg)*P<0.05 vs. 0 h bed rest

0 h bed rest75.3 ± 3.9------------------------------------46.4 ± 1.2
15.0 ± 0.3------------------------------------1.51 ± 0.48
1.81 ± 0.26
201 ± 457.1 ± 1.5
59.2 ± 4.0
121.9 ± 5.1**P<0.01 vs. 0 h bed rest

24 h bed rest
73.3 ± 3.8**1320 ± 67
2052 ± 249
48.5 ± 0.8*
15.7 ± 0.3*
-4.4 ± 1.4-7.9 ± 2.5
0.86 ± 0.18
1.50 ± 0.12
157 ± 245.4 ± 0.4
58.9 ± 3.7
126.0 ± 5.6

Figure 2. Effects of leg press exercises with and without
KAATSU on the hemodynamic parameters (HR (B), sBP (C),SV (D), CO (E), TPR (F)). The changes of HR during exercises
are indicated in A. Hemodynamic parameter in control (Pre,24 h bed rest), at peak exercise (EX) and 10 min after the
exercises (Post) with and without KAATSU. Effects ofstanding on these parameters are also indicated before andafter standing.*p<0.05, **p<0.01 vs. control (pre). Significant
differences between exercises with and without KAATSU are
also shown.

12

KAATSU and cardiovascular function

Table 2. Hemodynamic responses to acute leg-press exercise in healthy volunteers after 24 h-bed rest

HR (bpm)

Pre

Peak exercise

(−)
(＋)

61.3 ± 4.9
61.9 ± 4.9

85.6 ± 5.7**
107.1 ± 9.4**

Post
**

69.4 ± 6.1**
81.7 ± 8.1**(−)

76.4 ± 5.7

70.9 ± 6.6(＋)

77.0 ± 4.4

55.9 ± 5.1**

CO (l/min)

(−)
(＋)

4.6 ± 0.4
4.8 ± 0.6

6.0 ± 0.5**
5.8 ± 0.6**

4.9 ± 0.4
5.3 ± 0.4

sBP (mmHg)

(−)
(＋)

124.8 ± 6.0

139.6 ± 8.6**

126.6 ± 9.2

127.5 ± 4.9

154.2 ± 8.2**

130.3 ± 5.9(−)

79.8 ± 4.8

90.8 ± 5.4**

79.3 ± 5.8(＋)

96.4 ± 4.3

99.2 ± 6.0**

93.5 ± 4.6

mBP (mmHg) (−)

92.9 ± 5.1

105.7 ± 6.4**

92.4 ± 7.1(＋)

77.0 ± 4.4

116.1 ± 6.5**

78.5 ± 4.3(−)

1672 ± 238

1488 ± 221**

1586 ± 263(dyne*s/cm-5 ) (＋)

1666 ± 179

1655 ± 192

1431 ± 131

SV (ml)dBP (mmHg)

TPR*P<0.05 vs.Pre **P<0.01 vs. Pre**

71.7 ± 4.9
67.7 ± 5.8*P<0.05, **P<0.01 KAATSU (-) vs.

KAATSU (+)

0.5 l·min-1 (P<0.01). The increase in CO was notstatistically different between both exercises. TPR did
not change significantly at the peak exercises withand without KAATSU (Fig. 2F).
Fig 3 summarizes the effects of leg press RE withand without KAATSU on neurohumoral parameters.
Following RE, there was a significant increase in Hct(Fig.3A) and Hb which was greater during KAATSU.
These changes reflected a significant decrease in BV
and PV that was greater during KAATSU (Fig.3B).
The increase in lactate concentration after exercise
with KAATSU was much higher than that without
KAATSU (Fig. 3C). In leg press exercises withKAATSU, NOR increased from 140 ± 20 pg·ml-1 atrest to 514 ± 110 pg·ml-1 (P<0.01) immediately after
the exercise, and gradually decreased after the
exercise (Fig. 3D). On the other hand, it increased
from 131 ± 16 pg·ml-1 to 239 ± 47 pg·ml-1 (P<0.01) inthe control exercise. Thus, the increase in NOR
concentration attained in the leg press RE withKAATSU was significantly higher than that without
KAATSU.
Figs. 3E and 3F show the effects of KAATSU on
serum concentration of PRA and ADH. PRA
significantly increased from 0.7 ± 0.1 ng·ml-1·h-1 to
1.3 ± 0.3 ng·ml-1·h-1 at 10 min after the RE without
KAATSU (P<0.05), and ADH also tended to increase
from 1.5 ± 0.1 pg·ml -1 to 1.8 ± 0.2 pg·ml -1
immediately after the exercises. PRA and ADH weremore markedly raised by the application of KAATSU.
The leg press exercises combined with KAATSU
increased PRA from 1.0 ± 0.2 ng·ml-1·h-1 to 2.2 ± 0.8
ng·ml-1·h-1 (n=7, P<0.01). In addition, ADH was also
increased during the application of KAATSU (from1.7 ± 0.2 pg·ml-1 to 9.2 ± 3.0 pg·ml-1, n=7, p<0.01). In

these exercises, CPK did not change significantly(Table 3). In addition, under the simulated
weightlessness, all subjects complained no symptoms,
and completed the experiments.

Figure 3. Effects of leg press exercise with and without

KAATSU on Hct (A), plasma volume (B), lactate (C), NOR(D), PRA (E), and ADH (F). The changes of plasma
volume are shown as compared with the pre level.

N. Kubota, H. Takano, T. Tsutsumi, et al.

13

Table 3. Hemostatic responses to acute leg-press exercise in healthy volunteers after 24 h-bed rest

Hct (%)Hb (mg/dl)

BV (%△)

Pre

0-1 min10 min30 min(−)

48.8 ± 0.3

50.2 ± 0.6**

48.8. ± 0.5

48.1 ± 0.6(＋)

48.5 ± 0.6

51.6 ± 0.5**(−)

15.9 ± 0.1

16.3 ± 0.2**(＋)

15.7 ± 0.2

16.7 ± 0.2**(−)--2.9 ± 0.3**-5.9 ± 0.4**(＋)
PV (%△)(−)-5.6 ± 1.0**--11.6 ± 0.8**

(＋)

**

*

**

**

49.6. ± 0.5**
15.9 ± 0.1
16.1 ± 0.1****

48.1 ± 0.5
15.7 ± 0.1
15.7 ± 0.1-0.4 ± 0.4

1.3 ± 0.3*

-2.3 ± 0.7**

0.2 ± 0.9

-0.5 ± 0.8

2.7 ± 0.8*

-4.4 ± 1.1**

0.8 ± 1.7

NOR

(−)

131 ± 16239 ± 47**

(pg/ml)(＋)

140 ± 20514 ± 110**

Lactate(−)

8.9 ± 0.7

20.9 ± 2.6**(mg/dl)(＋)

9.7 ± 0.7

27.4 ± 3.8**

PRA

(−)

0.7 ± 0.1

0.9 ± 0.2

(ng/ml/h)(＋)

1.0 ± 0.2

1.6 ± 0.3

ADH

(−)

1.5 ± 0.1

1.8 ± 0.2

(pg/ml)(＋)

1.7 ± 0.2

9.2 ± 3.0**

CPK

(−)

103 ± 13108 ± 14103 ±13102 ±13(IU/l)(＋)

105 ± 14115 ± 16107 ±14*103 ± 14

*P<0.05 vs. Pre **P<0.01 vs. Pre

**

**

**

*

161 ± 23***224 ± 4215.0 ± 1.9*
27.1 ± 4.1**

126 ± 17144 ± 23**9.2 ± 0.6
15.6 ± 2.4

1.3 ± 0.3*

1.0 ± 0.2

2.2 ± 0.8*

1.0 ± 0.2

1.5 ± 0.2
2.4 ± 0.3*

1.6 ± 0.2*

1.7 ± 0.1

*P<0.05, **P<0.01 KAATSU (-) vs.

KAATSU (+)

DISCUSSION
The present study shows that following 24 h of bed
rest with -6˚ head-down tilt, a model simulating
microgravity effects on the cardiovascular system,
resistance exercise (RE) combined with KAATSU
mimic the exercise hemodynamic response to
exercise during standing at 1 G. Thus, KAATSU
combined with resistance exercise appears tostimulate the cardiovascular system during simulated
weightlessness and may provide an appropriate
countermeasure stimulus for the cardiovascularsystem associated with weightlessness.
6 ˚ head-down tilt bed rest (a model used tosimulate zero G) eliminates the normal downwardhydrostatic pressure gradients and causes animmediate central fluid shift from lower extremities
toward the thoracic-cephalic region (Norsk et al.,1993). The central hypervolemia affects hormonal
regulation of fluid excretion and stimulates central
cardiac volume receptors, resulting in a loss of plasma
volume (Norsk et al., 1993; Duranteau et al., 1995).
Some papers have reported that plasma volume (PV)decreases during bed rest within 1-2 d and this lower
level was maintained during subsequent bed rest
(Volicer et al., 1976; Nixon et al., 1979; Fortney et al.,
1991; Norsk et al., 1993; Johansen et al., 1997). In
the present study, 24 h 6˚ head-down tilt bed rest
resulted in a total urine volume (2052 ± 249 ml·d-1)

that was in excess of fluid intake (1320 ± 67 ml·d-1).
Blood and plasma volume was decreased by a meanvalue of 4.4% and 7.9%, respectively. This fluid
volume loss was reflected in the significant decreasein body mass, which was comparable with previous
results (Nixon et al., 1979; Gaffney et al., 1985). They
reported a significant reduction in PV of up to 500 ml
in 24 h. Furthermore, head-down bed rest induces aninitial cephalad fluid shift with an inhibition of therenin-angiotensin system and ADH. Hughson et al.
(1995) showed a 40% decrease in PRA after 10 hhead-down tilt. In the present study, concentration of
PRA (1.51 ± 0.48 to 0.86 ± 0.18 ng·ml-1·h-1, p=0.08)
and ADH (1.81 ± 0.26 to 1.50 ± 0.12 pg·ml-1, p=0.08)
tended to decrease following 24 h 6˚ head-down tilt
bed rest, but were not statistically different. NOR (201
± 45 to 157 ± 24 pg·ml-1, p=0.09) also tended todecrease following 24 h 6˚ bed rest, which has beenreported throughout spaceflight missions and bed rest
(Leach et al., 1983; 1985). Thus, it is likely thatphysiological alterations caused by 6˚ head-down tilt
bed rest condition observed here effectively mimicked
the weightless condition of space flight.
During the simulated weightlessness, weinvestigated the effects of KAATSU on hemodynamic
and neurohumoral responses to leg press RE. The
addition of KAATSU to RE induced lower-bodyvenous pooling and reduced venous return, which

14

resulted in a sustained decrease of SV comparable tothe value observed in standing at rest. Additionally, agreater increase in HR, blood lactate, NOR, PRA, andADH concentration was observed when RE wasconducted with KAATSU. Thus, the present study
shows that the combination of RE and KAATSU
during simulated microgravity, elicits hemodynamic
and neurohumoral responses that approximate agravity-specific stress on the cardiovascular system.
Thus it appears that RE and KAATSU may provide a
unique countermeasure regimen to prevent
cardiovascular deconditioning.
Currently, astronauts practice 2-3 h of intensive
exercise using treadmill, ergometer and resistancemachines. These time-consuming countermeasures
cannot completely prevent astronauts fromcardiovascular deconditioning. Therefore, alternate
countermeasure strategies are necessary. A humancentrifuge is a possible candidate, but the centrifuge
apparatus is relatively expensive and it is technicallylaborious to accommodate the apparatus on a space
craft. Now, the most effective countermeasure
regimen appears to be a gravity-like stress combinedwith exercise. LBNP has been shown to be a useful
method to prevent orthostatic intolerance after spaceflight, probably through its effect as orthostatic
stimulus (Buckey et al., 1996; Güell et al., 1992; Leeet al., 1997; Murthy et al., 1994; Watenpaugh et al.,2000). Supine treadmill exercise combined with
LBNP has been reported to maintain submaximal
exercise responses such as maximal heart rate,
respiratory exchange ratio, and ventilation after bed
rest (Lee et al., 1997). In addition, supine exercise in a
LBNP chamber (58 ± 2 mmHg LBNP) has beenreported to maintain aerobic fitness and sprint speed
during 15 d of 6˚ head-down bed rest (Watenpaugh
et al., 2000). Thus, exercise combined with LBNP
appears to provide an effective procedure to stress the
cardiovascular system (Hargens, 1994), and may be
useful in maintaining upright exercise capacity andprevent orthostatic intolerance during longer bed rest
periods or space-flight (Watenpaugh et al., 2000;
Perhonen et al., 2001; Schneider et al., 2002). LBNP
has been combined with many exercise modalities,
e.g. treadmill (Hargens et al., 1991; Murthy et al.,1994), but not resistance-type exercise. This may be
important as resistance training specifically promotes
muscle enlargement and muscular strength, which
are negatively impacted by weightlessness (Akima etal., 2003).
KAATSU training is widely used in Japan(Nakajima et al., 2006) and was originally developed
as a novel method for muscle training to increase
muscle mass and strength. Under the condition of
restricted muscle blood flow with KAATSU, even a
short-term and low-intensity exercise bout (treadmill
walking, RE, etc) can induce increased muscle mass

KAATSU and cardiovascular function

and muscular strength (Takarada et al. 2000a; b; c;Takarada et al., 2002a,b; Abe et al. 2006). KAATSU
training can be applied to most types of exercises suchas treadmills, ergometer, and resistance machines.
This low-load KAATSU training technique could be
easily applied to space flight and utilized byastronauts. Given the previous findings (increased
muscle hypertrophy and muscular strength andthe present findings), RE with KAATSU appears toprovide an interesting combination of effects
which may serve as a countermeasure to bothcardiovascular and musculoskeletal deconditioning
associated with weightlessness. However, the latter
needs to be specifically addressed.

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Authors' affiliations
N. Kubota, H. Takano, M. Kurano, H. Iida, T. Yasuda, K. Meguro, Y.
Sato, T. Nakajima, Department of Ischemic Circulatory Physiology,
KAATSU Training, University of Tokyo, Tokyo, Japan
T. Morita, Department of Cardiovascular Medicine, University of Tokyo,
Tokyo, JapanS. Kawashima, H. Ohshima, S. Tachibana, Japan Aerospace
Exploration Agency, Tsukuba, JapanY. Yamazaki, Japan Manned Space Systems Corporation, Tokyo, Japan
T. Abe, Department of Human and Engineered Environmental Studies,
Graduate School of Frontier Science, The University of Tokyo, Chiba,
Japan
N. Ishii, Department of Life Sciences, Graduate School of Arts andSciences, University of Tokyo, Tokyo, Japan
N. Kubota, T. Tsutsumi, Division of Cardiology, Showa University
Fujigaoka Hospital, Japan

ORIGINAL ARTICLE

Effects of low-intensity KAATSU resistance training
on skeletal muscle size/strength and endurance
capacity in patients with ischemic heart disease
T. Nakajima, M. Kurano, F. Sakagami, H. Iida, K. Fukumura, T. Fukuda, H. Takano, H. Madarame,
T. Yasuda, T. Nagata, Y. Sato, T. Yamasoba, T. Morita
Int. J. KAATSU Training Res. 2010; 6: 1-7

Correspondence to:
T. Nakajima, MD: Departmentof Ischemic Circulatory
Physiology, KAATSU Training,
University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo,
Japan 113-8655
masamasa@pb4.so-net.ne.jp
See end of article forauthors’ affiliations

KAATSU training induces muscle hypertrophy and strengthens muscle in athletes and healthy subjects
through short-term and low-intensity exercise. However, it remains uninvestigated whether lowintensity KAATSU resistance training (LIKRT) induces muscle strength and hypertrophy in patients withcardiovascular diseases. We examined the effects of LIKRT on skeletal muscle size/strength andendurance capacity in patients with ischemic heart disease (IHD). Seven male patients with stable IHD
performed three kinds of resistance exercises (leg press, leg curl and leg extension) with their femoral
muscle blood flow restricted by KAATSU belt two times/week for three months. We measured one RM(1-RM) in each resistance exercises, and evaluated muscle cross-sectional areas (CSA) by MRI before
training and after the training. We used cardiopulmonary examinations to measure endurance
capacity (Peak VO2 (VO2peak), VO2 at anaerobic threshold (VO2AT)). We performed blood sampling
to measure resting plasma level of insulin growth factor-1 (IGF-1) and serum high-sensitive C-reactive
protein (hsCRP). LIKRT significantly increased leg press (15%), leg curl (18%) and leg extension (17%)
1-RM strength. Increases of muscle CSA in quadriceps femoris at the proximal lower leg (30%), themid-thigh (50%), and the proximal lower leg (70%) were 5.1%, 4.6% and 10.4%, respectively.
Similarly, hamstring and adductor CSA were also increased by LIKRT. LIKRT significantly increased
VO2peak and VO2AT by 10.7% and 10.9%, respectively. IGF-1 and hsCRP were not altered before orafter the training. These results suggest that LIKRT increases muscle strength/mass and endurance
capacity in patients with IHD. LIKRT appears to be a promising and effective resistance method in
cardiac rehabilitation.
Key words: KAATSU training, ischemic heart disease, muscle hypertrophy, aerobic capacity, blood
restriction

INTRODUCTION
Cardiac rehabilitation is a well-established method
for improving quality of life and cardiopulmonary
function in patients with cardiovascular diseases.
Traditionally, aerobic exercise has been generally used
for cardiac rehabilitation in patients withcardiovascular diseases. This kinds of exercise
improve exercise endurance capacity assessed byusing parameters measured during a cardiopulmonary
exercise test like peak oxygen consumption (VO2)(VO2peak), but has a rather minor effect on skeletal
muscle weakness or mass. However, especially inpatients with muscle atrophy and elderly patients, it isdifficult to improve muscle endurance capacity byusing only aerobic exercises. Therefore, resistance
exercises combined with aerobic exercises have been
recommended (Pollock et al., 2000; Leon et al.,2005). According to the American College of Sports
Medicine (ACSM) guidelines, the conditions for
inducing muscle hypertrophy and increasing muscle
mass are as follows:(1) More than 65〜70% work load of one
repetition maximum (1-RM) is needed.
(2) Three to four sets until exhaustion.
(3) Frequency is two〜three times per week.
However, the adequate high-intensity loads can not
be applied to patients with diseases, especially inpatients with cardiovascular diseases and elderly
patients.
The KAATSU training is a novel exercise that
restricts muscle blood flow, by binding the proximal
portion of lower or upper extremities with a speciallydesigned belt. It has been reported to induce muscle
hypertrophy and strengthen muscle in athletes andhealthy subjects through short-term low-intensity
exercises (Takarada et al. 2000a; b; c; Takarada et al.,2002a,b; Abe et al. 2006; Fujita et al., 2007;
Karabulut et al., 2007, Wernbom et al., 2008;
Karabulut et al., 2010). Thus, KAATSU training
appears to be a useful muscle training method for
promotion of healthy subjects and muscle strength infields of sport. To date, 200,000 people have2

performed KAATSU training, and serious side effects
have not been reported (Nakajima et al., 2006),
suggesting that it is safe under the supervision of the
instructors. However, it remains uninvestigatedwhether low-intensity KAATSU resistance training
strengthens muscle and induces muscle hypertrophy
in patients with cardiovascular diseases.
Therefore, we investigated the effects of lowintensity KAATSU resistance exercise on skeletal
muscle size/strength and endurance capacity and its
safety in patients with stable ischemic heart disease.

MATERIALS AND METHODS
Subjects

Seven stable male patients with ischemic heartdisease (post-coronary artery bypass grafting (pCABG) 2, post-percutaneous coronary intervention(p-PCI) 5, 52 ± 4 years old) participated in this study.
These patients had no organic stenosis after CABG or
PCI, and had no symptoms at the start of this study.
This study was approved by the Ethics Committee ofthe University of Tokyo. All subjects were informed ofthe methods, procedures and risks, and signed an
informed consent document before participation.
None of the subjects had participated instrength/resistance-type training before the start ofthe study. During the study, they did not receive any
strength/resistance-type training other than KAATSU
training.
Training Protocol

Patients performed three kinds of leg resistance
exercises (leg press, leg extension, and leg curl) for
three months. The sets consisted of the following
repetition pattern: 30 repetitions, 15 repetitions, 15
repetitions, 15 repetitions. There was a one-minuterest interval between sets. Contraction intensity was
20-30% of predetermined 1-RM (leg press 30% 1RM, leg extension 20% 1-RM, and leg curl 20% 1RM). Individual contraction duration was 3.0 seconds
with a 1.5:1.5 sec shortening-lengthening contraction
duty cycle as controlled by a metronome (40 beats
per minute). Training was conducted two times per
week by the KAATSU method, which restricts muscle
blood flow. We monitored the symptom score (Borg
scale), blood pressure, and heart rate during thetraining.
Reduction of Femoral Muscle Blood Flow by
KAATSUThis method for inducing the reduction of muscle
blood flow is similar to those described in previous
papers (Takarada et al. 2000a; b; c; Takarada et al.,2002a,b; Takano et al., 2005; Abe et al. 2006; Fujita etal., 2007; Iida et al., 2007; Nakajima et al., 2008). A
specially-designed KAATSU belt applies pressure atthe proximal ends of both sides of the thighs, to

KAATSU training in patients with IHD

restrict venous blood flow. The cuff pressure was first
set at a low-pressure of 100 mmHg, and gradually
increased to 160-250 mmHg within two to three
weeks, depending on the subjects and Borg scale
during the training. The training was performed
within Borg scale of 16. The cuff pressure can becontrolled by a KAATSU apparatus.
Estimation of Muscle Cross-Sectional Area

Muscle cross-sectional area (CSA) was estimatedusing magnetic resonance imaging, (MRI)
technology before KAATSU training and threemonths after KAATSU training (“Pre” and “Pst” inthe Figures, respectively). They were evaluated at
the proximal lower leg (30%), the mid-thigh (50%),
and the proximal lower leg (70%). The % change in
CSA was calculated at the quadriceps femoris,
hamstring and adductor, separately. The total CSA(cm2) was also measured at the proximal lower leg(30%), the mid-thigh (50%), and the proximal lowerleg (70%).
Measurement of 1-RM and VO2

We measured 1-RM voluntary force, before thetraining and three months after the training. We
measured per-breath gas exchange and determined
VO2, using a standard increment cycle ergometer
protocol, with a ramp pulse (20 watt increase/min)with AE 300S (Minato Medical Science CO., LTD.,Tokyo, Japan). We measured VO2 at the anaerobic
threshold (AT) and VO2peak as well as the work loadat the AT level and the peak exercise. The VO2peakvalue in this study was 1463 ± 93 ml/min (n=7).
One RM evaluated by 8-10 RM was measured atthree different stations of a resistance exercise circuit(leg press, leg curl, and leg extension).
Blood Sampling and Hormonal Analyses

We collected venous blood samples before thetraining and three months after the training. We
obtained blood samples by venipuncture from theantecubital vein. High-sensitive C-reactive protein(hsCRP) was measured at SRL, Inc. (Tokyo, Japan) in
500 µl serum samples, using a method of latex
turbidimetric immuno assay (LTIA). The limit ofdetection of hsCRP was 50 ng/ml. Plasma level ofinsulin-like growth factor-1 (IGF-1) was determinedusing immunoradiometric assays (IRMA) specific forthe human peptides at SRL, Inc..
Data Analysis

All values are expressed as means ± S.E.M.
Student’s paired t-test and one-way ANOVA for
repeated measures were used, and differences wereconsidered significant if P<0.05.

T. Nakajima, M. Kurano, F. Sakagami, et al.

RESULTS
All participating patients had no side effects andcompleted the study. None of them had any
complaints, chest pain. There were no hospitalizations,or no exacerbations of ischemic heart disease during
the study period.
Fig. 1 shows the effects of KAATSU training on
resting plasma IGF-1 (Fig. 1A), and serum hsCRP, an
inflammatory marker (Fig. 1B). There were no
significant changes (P>0.05) in resting IGF-1 and
hsCRP between control (Pre) and three months after
the training (Post).
During the KAATSU training, muscle CSA
increased significantly for quadriceps femoris (QF, Fig.
2). Increases of muscle CSA in quadriceps femoris at
the proximal lower leg (30%), the mid-thigh (50%),
and the proximal lower leg (70%) were 5.1%, 4.6%3

and 10.4%, respectively. Similarly, CSA of hamstring(HAM) and adductor (ADD) CSA were increased by
the KAATSU training. A representative MRI finding isshown in Fig. 3.
Fig. 4 shows the effects of KAATSU training on
total muscle CSA for the proximal lower leg (30%),
the mid-thigh (50%), and the proximal lower leg(70%). After KAATSU training, muscle CSA at 30%,
50% and 70% position of femur length increased
significantly to 4.2%, 3.0% and 7.5%, respectively.
The KAATSU training significantly increased 1-RM
strength for leg press (15%), leg curl (18%) and leg
extension (17%) (Fig. 5).
Fig. 6 shows the effects of KAATSU training on
aerobic capacity in cardiopulmonary examination.
KAATSU resistance training significantly increased
the work load of the peak and AT exercise (Fig. 6A),
and significantly increased VO2 peak and VO2 AT by
10.7% and 10.9% significantly (Fig. 6A). However,resting HR and systolic blood pressure (sBP) were notsignificantly changed (Fig. 6B).

Figure 1. Changes in serum IGF-1 (A) and high-sensitive

CRP (hsCRP) (B) concentration following 3 months KAATSU
resistance training. Mean ± S.E.M. value is shown. Pre: Pretraining Post: Post-training

Figure 2. Changes in skeletal muscle size following threemonths KAATSU training. Muscle cross sectional area (CSA)
was evaluated at the proximal lower leg (30%), the mid-thigh(50%), and the proximal lower leg (70%). The % change incross sectional areas (CSA) was calculated at the quadriceps
femoris (QF), hamstring (HAM), and adductor (ADD),
separately. Mean ± S.E.M. value is shown. ＊P<0.05, ＊＊P<0.01
vs. pre (before)-KAATSU training

Figure 3. A typical MRI finding. The MRI finding is illustrated

at the proximal lower leg (30%), the mid-thigh (50%), andthe proximal lower leg (70%) before (left part) and threemonths after the training (right part).

4

KAATSU training in patients with IHD

128±7
117±7
81±3
65±4

1605±1071463±93

Figure 4. Effects of KAATSU resistance training on CSA of

1044±41

30%, 50% and 70% position of femur length. Mean ± S.E.M.
value is shown. ＊p<0.05 vs. pre (before)-KAATSU training

904±46

80±2
78±2

107±4
105±4

(bpm)

(mmHg)(ml/min) (ml/min)Figure 6. Effects of KAATSU training on the parameters

Figure 5. Effects of KAATSU resistance training on 1-RM of leg

press, leg curl, and leg extension. The % change in 1-RM isshown in each exercise. Mean ± S.E.M. value is illustrated.
＊p<0.05 vs. pre (before)-KAATSU training

DISCUSSION
These results suggest that low-intensity KAATSU
resistance exercises safely increase muscle
strength/mass and endurance capacity in patientswith ischemic heart diseases. Low-intensity KAATSU
resistance training using low-intensity resistance
exercise appears to be a promising and usefulresistance method in cardiac rehabilitation.
Several studies investigate the effects of heavy
resistance exercise on muscle strength in healthy
subjects or patients. Hakkinen et al. (2000) showedthat the increase in maximal isometric resistancestrength of the knee extensor was 28% in middle
healthy aged men (42 years), and 21% in elderlymen (72 years) 6 months after 50-80% 1-RM
resistance exercise. Brochu et al (2002) also reported
that the resistance training of 50-80% (three times
per week for six months) in older women withcoronary heart disease improved upper body strength(18%) and lower body strength (23%). In thepresent study, we investigated the effects of low-

determined by cardiopulmonary examinations. A: Change
in work load (watt) at anaerobic threshold (AT) and peak
exercise (peak). B: Change in resting HR, systolic bloodpressure (sBP), and VO2AT and VO2 Peak. The resting HR(bpm), systolic blood pressure (sBP, mmHg), and VO2AT(ml/min) and VO2 peak (ml/min) are shown before andthree months after the training. Mean ± S.E.M. value isillustrated. ＊P<0.05 vs. pre (before)-KAATSU training

intensity KAATSU resistance exercise on muscle
strength in male patients with ischemic heartdiseases, by using only 20-30% 1-RM. They had noorganic stenosis after the therapy (CABG and PCI).
The KAATSU resistance training twice a week forthree months, even by using 20-30% load of 1-RM,
significantly increased leg press (15%), leg curl (18%)
and leg extension (17%) 1-RM strength. The
magnitude of the increase in the strength was 0.17%
per day (leg press), 0.2% per day (leg curl), and
0.19% per day (leg extension). These values werelarger than those reported by Hakinnen et al. (2000)(0.15% per day) and Brochu et al. (2002) (0.13% perday), and similar to the previous papers using healthy
subjects and athletes under the restricting muscle
blood flow (see review, Karabulut et al., 2007;
Wernbom et al., 2008). Thus, low-intensity KAATSU
training appears to effectively increase muscle
strength comparable to the high-intensity exercise,even in patients with ischemic heart disease.
In the present study, significant increase of muscle
CSA in quadriceps femoris was observed. Similarly,
KAATSU training also increased hamstring andT. Nakajima, M. Kurano, F. Sakagami, et al.

adductor CSA. The estimated thigh CSA in thepresent study increased by approximately 4-10%(P<0.05) following three months of the KAATSU
training (2 days per week, 32 total training sessions).
Increases of muscle CSA in quadriceps femoris at30%, 50% and 70% position of femur length were5.1%, 4.6% and 10.4%, respectively. Therefore, themagnitude of the hypertrophic potential (percent
increase in muscle CSA divided by total training
sessions) in the thigh was about 0.17-0.31% pertraining session. Recently, Wernbom et al. (2008)
reviewed the effects of high-intensity resistance
exercise and low-intensity KAATSU resistance
exercise (leg extension) on muscle hypertrophy ofquadriceps femoris in healthy subjects. High-intensity
extension exercise two to three times per week, using
80% 1-RM (three to four sets, 6-10 repetitions,interval 60-120 s), increased muscle mass by 0.030.26% per day and 1-7% per month (3-21% per
three months). On the other hand, low-intensity
KAATSU training using 20-50% 1RM (3-4 sets, 1530 repetition, interval 30-60 s) increased it by 0.040.22% per day and 1.2-6.6% per month (3.6-18%
per three months). Thus, low-intensity KAATSU
resistance training appears to increase muscle mass ina similar way to heavy resistance exercise in healthy
subjects. In the present study, increases of muscle
CSA in quadriceps femoris at mid-thigh were 4.6%
per three months, suggesting that even low-intensity
KAATSU resistance training may be a useful method
for inducing muscle hypertrophy as well as
improvement of muscle strength in patients withischemic heart diseases.
The mechanisms of the hypertrophic response andstrength gain from KAATSU training are still poorly
understood. It has been well known that acute boutof KAATSU training sessions significantly increase
growth hormone secretion (Takarada et al., 2000a;
Takano et al., 2005; Abe et al., 2006), leading to theincreased secretion of IGF-1. The enhanced IGF-1/GH
secretion may be involved in the hypertrophic effectsof KAATSU training. However, in the presents study,
IGF-1 did not increase significantly during the threemonth low-intensity KAATSU resistance training.
Therefore, it is unlikely that IGF-1 was mainly
involved in the muscle hypertrophy induced by
KAATSU training. In fact, the involvement of
GH/IGF-1 on the hypertrophy induced by resistance
exercise has recently been denied (West et al., 2009).
The further studies are needed to clarify the basic
mechanisms of the hypertrophic response andstrength gain from KAATSU training.
It is generally known that aerobic exercises improve
exercise endurance capacity assessed by usingparameters measured during a cardiopulmonary
exercise test like VO2peak. However, especially inpatients with muscle atrophy and elderly patients, it is5difficult to improve muscle endurance capacity byusing only aerobic exercises. Therefore, resistance
exercises combined with aerobic exercises have been
recommended (Pollock et al., 2000; Leon et al.,2005). In the present study, KAATSU resistancetraining also significantly increased VO2peak andVO 2AT by 10.7% and 10.9% significantly. The
present study showed that the KAATSU resistance
exercises significantly increased skeletal muscle mass.
An increase of 1 kg skeletal muscle mass in the lowerbody skeletal muscle mass would predict an increasein maximal oxygen consumption (VO2max) of about
200 ml per minute (Frontera et al., 1990). In thepresent study, KAATSU resistance training alsosignificantly increased the work load of the peak and
AT exercise. Thus, the increase of muscle mass andthen improvement of muscle strength might play arole in the improvement of aerobic endurance
capacity induced by KAATSU resistance training inpatients with ischemic heart disease.
KAATSU training consists of exercises performed
with restricted venous blood flow. Therefore,
occlusion of blood vessels may affect the haemostasis,and cause the formation of thrombus, though serious
side effects of KAATSU training such as pulmonary
embolism have not been reported (Nakajima et al.
2006). During our study using patients with ischemic
heart disease, no venous thrombosis had developed.
This might be compatible with the previous papers
showing that vascular occlusion alone stimulates the
fibrinolytic activity without the coagulation activity
and clot formation (Nakajima et al., 2007; Madarame
et al., 2010; Clark et al., 2010). The most commonside effects in KAATSU training are petechia andtemporary numbness as described previously(Nakajima et al., 2006). The petechia is frequently
developed during the KAATSU training of upper
extremities (Nakajima et al., 2006). In the present
study, all of the patients had received acetylsalicylic
acid or ticlopidine hydrochloride, an antiplatelet drug.
But, no petechia had occurred during the training oflower extremities. Umbel et al. (2009) reported thatdelayed-onset muscle soreness was induced by lowload blood flow restricted exercise in healthy subjects.
But, in the present study, no serious delayed onset
muscle soreness was occurred. In addition, highsensitive CRP, an inflammatory marker (Nakajima etal., 2010), did not change during the KAATSU
training. Thus, low-intensity KAATSU resistancetraining using low-intensity exercise appears to be asafe method for increase in muscle strength andmuscle mass in patients with ischemic heart disease.
However, the addition of KAATSU to resistance
exercise induces a greater increase in blood pressureand noradrenaline, compared to the exercise without
KAATSU (Takano et al., 2005; Abe et al., 2006;
Kubota et al., 2009). Therefore, we must take this6

into account when the KAATSU method is applied totraining in patients with cardiovascular disease.
In summary, three months of KAATSU resistancetraining (leg press. leg curl and leg extension, 20%30% 1-RM) safely induces muscle hypertrophy/
strength and increases aerobic capacity in patientswith stable ischemic heart disease. Low-intensity
KAATSU resistance training appears to be a promisingand useful resistance method in cardiac rehabilitation.

ACKNOWLEDGEMENTS
The authors thank Mr. K. Otsuka and Mr. Y. Chujo
for contributions to this study.

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Authors’ affiliations
T. Nakajima, M. Kurano, F. Sakagami, H. Iida, K. Fukumura,
T. Fukuda, Takano, H. Madarame, T. Yasuda, T. Morita,
Department of Ischemic Circulatory Physiology, KAATSU Training,
University of Tokyo, Tokyo, Japan
T. Nagata, Sannou Hospital, Respiratory Center, Tokyo, Japan

T. Nakajima, M. Kurano, F. Sakagami, et al.

Y. Sato, Kaatsu International University, Sri Lanka
T. Yamasoba, Department of Otolaryngology and Head and Neck
Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan

7

REVIEW ARTICLE

Key considerations when conducting KAATSU training
T. Nakajima, T. Morita, Y. SatoInt. J. KAATSU Training Res. 2011; 7: 1-6

Correspondence to:
T. Nakajima, MD: Departmentof Ischemic Circulatory
Physiology, KAATSU Training,
University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo,
Japan 113-8655
masamasa@pb4.so-net.ne.jp
See end of article forauthors’ affiliations

KAATSU training is a novel training method conducted under special conditions of restricted muscle
blood flow of the limbs with a specially-designed KAATSU belt. In 2006, we conducted aquestionnaire survey across the whole of Japan to investigate the status of KAATSU training. After
that, we have performed KAATSU training mainly for patients with cardiovascular diseases at a totalof approximately 700 people per year, and no serious side effects of note have been found. However,it has also been applied for various purposes such as to increase the muscle strength and prevent themuscular atrophy of all kinds of patients including older people. And, in near future, it may be used totrain more seriously affected patients with cachexia or sarcopenia. Therefore, in this review, we
introduce the main matters reported over the five years since the questionnaire survey was conducted.
In addition, we outline key considerations concerning the implementation of KAATSU training
centered mainly on our previous experience and reports reached to us.
Key words: KAATSU training, side effects, petechial hemorrhage, contraindication, restricted muscle
blood flow

INTRODUCTIONKAATSU training refers to training conductedwhen pressure is applied in moderation to the base of
the limbs with a specially-made belt and the muscle
blood flow is restricted (Sato et al., 2007). Differing tohemostasis with a tourniquet, which completely stops
the flow of blood in arteries and veins, KAATSU
training is undertaken while accumulating blood(pooling) in the upper or lower limbs. A wide varietyof loading methods include stretching, self-weight,
walking, cycling, strength-training machine, andthera-band. It is said that over 200,000 people are
currently conducting KAATSU training to improvethe muscle strength of able-bodied people, sportsmen
and older people, and for health maintenancepurposes. There are also now hopes that it can beapplied to the rehabilitation of patients with a variety
of diseases (Sato et al., 2007; Nakajima et al. 2010).
However, because it is a training method conductedunder special circumstances, such as restricting blood
flow, abundant experience and caution is believed
necessary for implementation and indication. Newlydeveloped KAATSU devices may be launched in thenear future, and to conduct safely, spread anddevelop KAATSU training, we will outline key
considerations concerning the implementation of
KAATSU training centered mainly on our previous
experience and reports reached to us. However, there
is a possibility that key considerations will be added orchanged in the future due to the increased number ofcases.

I) Key considerations concerning KAATSU
training

The characteristics of KAATSU training are as
follows. :Point 1) Short-term and low-intensity loads
KAATSU training with high-intensity loads has
little effect, but it may be rather dangerous. Needlessto say, restricting blood flow for a long time should be
avoided.
Point 2) Hemostasis with a tourniquet should be
avoidedPoint 3) KAATSU training should, in principle, be
conducted by KAATSU trainers and instructors
This is believed to be one of the reasons why
serious complications have been seldom occurred
until now.
We conducted a questionnaire survey in 2006
across the whole of Japan to investigate the status of
KAATSU training (Nakajima et al., 2006). According
to responses gained from 106 facilities across Japan,
KAATSU training was widely provided for people intheir teens to their eighties. Main side effects include
petechial hemorrhage beneath the skin, chills,
numbness, and dizziness. Petechial hemorrhage
beneath the skin was discovered when applying
pressure, particularly to the upper limbs, at the
beginning of KAATSU training. However, thisdisappeared as the training progressed and was not a
problematic side effect. Paralysis caused by nerve
compression was also not discovered.
We have conducted KAATSU training mainly forpatients with cardiovascular disease at a total of
approximately 700 people per year since 2007, andno serious side effects of note have been found.

2

However, it has been applied for various purposessuch as to increase the muscle strength and preventthe muscular atrophy of all kinds of patients
including older people, and it is speculated that it will
be used to train more seriously affected patients withcachexia or sarcopenia in near future.
We will therefore introduce the main mattersreported over the five years since the questionnaire
survey was conducted.
1) Brain hemorrhage: there was one reported case ofbrain hemorrhage during KAATSU training. It is
known that sudden deaths very rarely occur while
playing sports. Sudden deaths have even beenreported in golf, running, and gateball. While there
have been no reported sudden deaths during
KAATSU training to date, sufficient caution isrequired. As underlying diseases of sports-related
sudden deaths, it is said that hypertrophic
cardiomyopathy, cardiomegaly (cause unknown),
coronary artery malformation, coronary arterysclerosis, aortic rupture, and brain hemorrhage arecommon among people aged 35 years and below,
while 80% of people aged over 35 years are affectedby coronary artery sclerosis and brain hemorrhage.
Accordingly, the discovery of cardiocirculatory
diseases is vital when giving medical checkups tosportsmen and, needless to say, blood pressure
management is particularly important. Considerationmust also be given to breathing methods during
muscle training (exhale when applying effort).
KAATSU training uses low-intensity loads whichraise blood pressure less than high-intensity loads(rise to 250-300mmHg or more with high-intensity
loads). In addition, hormones (catecholamine) whichcause increased heartbeat and blood pressure during
exercise increase slightly during KAATSU training,
compared to exercises when muscle blood flow is not
restricted (Takano et al., 2005; Iida et al., 2007).
Therefore, caution is required when dealing withpatients with high blood pressure, heart disease, andother diseases.

Key considerations in KAATSU training

caused by interference with platelet function and as aclotting factor defect, so careful examination by adermatologist is recommended.
Point 4: Explain prior to KAATSU training that
petechial hemorrhage beneath the skin may occur
after KAATSU training, particularly of the upper
limbs.
This normally disappears after a few days and does
not really obstruct continuation of KAATSU training,but it is vital to explain that there are very rare casesof it becoming serious. This can be particularly
problematic if not explained to young women.
Specifically, cases of people visiting for beauty are a
problem. Even patients taking anti-coagulant therapy
are not really a problem, but if their condition isserious then training should be stopped. Patients thatare administered vibration machines concurrently
with medicine have not been a problem so far, butthere has been one case of worsening petechialhemorrhage beneath the skin after KAATSU training.
3) Rhabdomyolysis: One case with a serum CPK level >10,000 IU/L has been reported both in Japan andabroad. When feeling unwell in a hot and humid
environment, repeated hard training may lead torhabdomyolysis. In addition to the hardness of the
training, patients are more susceptible when
dehydrated. KAATSU training uses low-intensity
loads so rhabdomyolysis is considered less likely tooccur than when using high-intensity loads.
Nevertheless, it is necessary to be cautious such as
cancel training when the patient is sick and provide
frequent fluid replacement during training. In
addition, heat stroke can occur more easily as it
becomes hotter, so ensure that patients are
replenished with sufficient fluids and electrolytes.
4) Cases of numbness lasting for days: While there havebeen no reports of paralysis, be sure to adhere to the
KAATSU training time and not take too long, andattach the KAATSU belt to the correct area.

2) Petechial hemorrhage beneath the skin: This refers to5) Venous thrombosis : One case has been reported.

red or purple bodily spots caused by microbleeding(collapsed capillary vessels). Petechial hemorrhage
beneath the skin is normally harmless and disappears
within a few days. But, there were a few cases ofpetechial hemorrhage beneath the skin notdisappearing and continuing for a while, however,they disappeared in the course. Although it may beunconnected, there were some cases of purpura, suchas purpura pigmentosa chronica, when conducting
KAATSU. This continued for a few months and thendisappeared. They sometimes emerge as symptoms ofthrombocytopenia (caused by side effects fromtreatment for certain types of infectious diseases),

However, appropriate application of pressure in
KAATSU training does not lead to a worsening
coagulation system. Rather, it induces a fibrinolytic
state, which helps to restrict thrombus formation(Nakajima et al., 2007; Madarame et al., 2010). In
addition, because KAATSU training is 15 to 20
minutes long, it is believed to contribute to the safetyof this treatment by not restricting blood flow for along time. But, out of 10,000 people, 1 to 3 ordinary
people, 3 to 11 women in a normal pregnancy, 30 to
40 women after normal childbirth, and 100 womenthat give birth by Caesarean section have venous
thrombosis. Therefore, while KAATSU training is

T. Nakajima, T. Morita, Y. Sato

not thrombogenic unless reckless things are done,some of the subjects receiving KAATSU training
have venous thrombosis from the beginning.
Echocardiography is recommended for suspectedcases before starting KAATSU training.

3〇 The blood vessels of people who take no
exercise will not be accustomed to this training, so
take care when applying high pressure〇 Adhere to the KAATSU training time.

6) Venous injury and induration: This has continued forII) Key considerations when conducting KAATSU
training

one to two months in women in their thirties andforties, and is sometimes accompanied by pain. After
cancelling the KAATSU training and taking a waitand-see approach, it disappeared after one to twomonths. When KAATSU pressure becomes strong or
the appropriate pressure is not applied especially tothe upper limbs, this may eventually lead to venous
damage.
Pay attention to the following.
〇 Repeat pressurization and depressurization, getblood vessels accustomed to this training, and apply
the appropriate pressure

We will now provide information on basic
treatment information required for general exercise
therapy as it will serve as a useful reference for safety
purposes when conducting KAATSU training. Basictreatment information required for general exercise
therapy is shown in Table 1. Basic treatment
information includes: 1) subjective symptoms; 2)previous medical history; 3) existence of lifestylerelated diseases; 4) family medical history; 5) lifestyle
habits. It also includes resting electrocardiograms if
possible and careful examination based on exercise
tolerance tests will also be required as appropriate.

Table 1. Basic treatment information required for exercise therapy

Basic treatment information

Necessity of an exercise tolerance test

Other action

Subjective symptoms
Chest pain / chest discomfort / palpitation / shortness of breath

Yes

Dizziness / fainting / intermittent claudication

Yes
Orthopedic examination and guidanceSpondylosis symptoms / joint symptoms
History of disorder
Cardiovascular disease

Yes
Orthopedic examination and guidance

Orthopedic disorder
Existence of lifestyle-related diseases
High blood pressure

Assessed severity

Diabetes

Assessed severity

Hyperlipidemia

Assessed severity

Obesity

Assessed severity

Family medical history*
Myocardial infarction and sudden deaths in first degree relatives

Yes

Lifestyle habits
Lifestyle guidance

Exercise / diet / smoking / alcohol
Resting electrocardiogram
Myocardial infarction

Yes

ST-T segment abnormality

Yes

Ventricular arrhythmia

Yes

Other important observations

Yes＊ A family medical history of relatively young sufferers such as father or first degree male relative aged under 55 or mother or first degree
female relative aged under 65 who have undergone myocardial infarction and coronary revascularization or died suddenly.
Table 1 and 2 are cited from the following papers, and changed: (1) Edited by Japanese Circulation Society et al. Guidelines for diagnosing
and treating cardiovascular disease. 2000-2001 Joint Research Group Report. Guidelines for exercise therapy for cardiovascular disease(JCS 2002) (Group head: Saito) (2) Manual for prescribing exercise therapy. Journal of the Japan Medical Association, 116 (3), 1996.

4

Key considerations in KAATSU training

Table 2. Indications and contraindications for exercise therapy for lifestyle-related diseases

Disease

Indication

Conditional indication

Contraindication

High blood pressure140-159/90-94 mmHg

160-179/95-99 mmHg

180/100 mmHg or more

Men aged over 40 or women aged over

CTR of 55% or more visible on a chest

50 that are in treatment and don't have aroentgenogram

contraindication value should undergo

Life-threatening arrhythmia or ischemic

an exercise tolerance test if possible.

change shown by an electrocardiogram(excluding times when safety wasconfirmed by an exercise tolerance test)
Uric protein of 100 mg/dl or hypertensivechange in the fundus oculi (more than IIb)

Diabetes

Fasting blood glucose -Fasting blood glucose - 140 - 249 mg/dl

Fasting blood glucose –110 - 139 mg/dl

Men aged over 40 or women aged over

250 mg/dl or more

50 that are in treatment and don't have a

Urinary ketone body (+)

contraindication value should undergo

Diabetic retinopathy (+)

an exercise tolerance test if possible.
Hyperlipidemia

TC：220 - 249 mg/dl

TC: 250 mg/dl minimum oror

TG: 300mg/dl or more

TG：150 - 299 mg/dl

Men aged over 40 or women aged over
50 that are in treatment should undergo
an exercise tolerance test if possible.

Obesity

BMI：24.0 - 29.9

BMI：30 or more

BMI：24.0 - 29.9 and lower limb joint
damageOrthopedic examination and exercise
restriction
2

TC: Total cholesterol; TG: Triglycerides; BMI: Body Mass Index (body weight (kg) / height (m) )Recently, KAATSU training is often used to train
metabolic syndrome and obese patients. Table 2
shows indications and contraindications of normal
exercise therapy for lifestyle-related diseases. At a
blood pressure of 180/100 mmHg or more, exercise
therapy is generally contraindication, so it would bebetter to give treatment at 160-179/95-99 mmHg. For
cases of poorly-controlled diabetic retinopathy andextreme obesity with a BMI of 30 or greater, careful
examination for the coexistence of ischemic heartdisease is recommended. It is believed that such
indications will serve as a useful reference when
conducting KAATSU training.
Key considerations when administering KAATSU
training to older people and a variety of patients arelisted as follows.
1) Pay attention to restricted blood flow
● Adhere to the basics of KAATSU to prevent
hemostasis with a tourniquet● Take care not to allow overload

Neurally-mediated syncope; refer to thepaper (Sato et al., 2007) for details● Search for complications (heart diseases, etc.)2) During training, pay attention to the following:
Sufficient stretching and fluid replacement
Patients falling3) Get an expert opinion for high-risk matters anddon’t provide training for unknown cases.
●

III) Clinical conditions and diseases to watch out
for when conducting KAATSU training

Vascular endothelial damage, stagnation of blood,and hypercoagulability are origins of pulmonary
infarction and deep-vein thrombosis. KAATSU
training is not a tourniquet, which completely stops
the flow of blood in arteries and veins, and according
to our past examinations of able-bodied people, itdoes not lead to an impairment of the coagulation
system. Rather, it induces a fibrinolytic state, which
has an antithrombotic effect (Nakajima et al., 2007;

T. Nakajima, T. Morita, Y. Sato5

Madarame et al., 2010). In addition, there have been
no reports of pulmonary infarction. However, due tothe stagnation of blood occurring during KAATSU
training, pulmonary infarction and deep-vein
thrombosis risk scores used by surgeons to conduct
safer KAATSU training will be introduced.

liaising with doctors for such cases. In addition, it isnecessary to stop loading if overload is suspected,
depending on the patient’s symptoms. In any case, it
can only be carried out under close supervision, andeven more careful examination is required in the
future.

Point 5: Using risk factors in determining KAATSU
training indication
5 points History of deep-vein thrombosis (DVT);
hereditary thrombotic tendency;
antiphospholipid antibody syndrome
4 points Pregnant women
3 points 1) Varicose veins of legs; 2) prolonged
immobility (incapable of 8 hours
thromboprophylaxis rehabilitation);
3) atrial fibrillation or heart failure
2 points 1) People aged over 60 years old; 2) BMI> 30; 3) hyperlipidemia; 4) malignancy;
5) using lower limb tourniquet; 6) using
oral contraceptives or adrenocorticalsteroids; 7) quadriplegia; 8) highhemoglobin level
1 point 1) People aged 40 to 58 years old;2) women; 3) 25 < BMI < 30

Point 6: In principle, KAATSU training should not
be provided or expert advice should be obtained
when dealing with hemodynamically unstablepatients, especially patients suffering fromcardiovascular diseases etc.

The higher the number of points the greater therisk, and the higher the combined number of points
for several risks the greater the risk. KAATSU training
for people corresponding to 5 points (history of deepvein thrombosis; hereditary thrombotic tendency;
and antiphospholipid antibody syndrome) should be
avoided. Caution is required when dealing withpregnant women, who have impairment of thecoagulation system in the latter stages of pregnancy.
We do not conduct training for these pregnant
women in principle. While there have been noreports of KAATSU affecting varicose veins of legs, areview of this is needed in the future. Older people
and bedridden patients are considered to be suitable
for KAATSU training, but it is necessary to exercise
care when providing KAATSU training for people
that originally had thrombosis. In addition, somepatients get thrombosis in the early postoperative
period and extreme caution needs to be exercised forsuch patients.
Since KAATSU training predominately involves the
restriction of blood flow, reduced stroke volume andcardiac output may be discovered depending on theextent of applied pressure (Takano et al., 2005; Iida etal., 2007). Even though KAATSU training reduces thepreload and places little stress on the heart, it canencourage a lower cardiac output for patients with asignificantly reduced heart pumping ability, so
extreme caution is required. It is therefore necessary
to carefully consider reducing KAATSU pressure or
only applying it to upper limbs or one-side, as well as

CONCLUSION
As we move increasingly towards an aged society, it
is estimated that rehabilitation for patients with low
exercise capacity and various complications such as
cardiovascular diseases will increase more and more.
KAATSU training is expected to attract increasing
attention. Accordingly, we hope that you fully
understand and pay heed to the characteristics of
KAATSU training, and conduct sensible and effective
training.
Point 7: To conduct safe as well as effective KAATSU
training
1. Confirm there are no contraindications that are
identical to ordinary exercise therapy
2. KAATSU training should either not be provided
or expert advice should be obtained when
dealing with hemodynamically unstable patients
3. KAATSU training is a contraindication or
caution should be exercised when dealing withthrombotic disease patients
4. Explain about petechial hemorrhage beneath theskin and numbness etc. when starting training
5. Training tailored to individuals’ physical capacity
and condition
Apply appropriate as well as safe and effective
pressure
Never be too eager to gain results
Avoid hemostasis with a tourniquet.
6. Build a relationship of trust with patients
7. There is a possibility that presyncope and fainting
will occur, but pay attention to prodromal
symptoms and take preventive measures such as
fluid intake.
8. Older people, bedridden patients and postoperative
patients often have venous thrombosis prior to
the training so exercise caution.
9. Ensure blood pressure is (< 160 /> 95 mm Hg)
10. Implement safety measures such as AED
11. Avoid conducting KAATSU training over a longtime. Upper limbs: 10-15 minutes; Lower limbs:
15-20 minutes
12. In principle, never conduct training when thepatient is sick. Never continue performing

6

KAATSU training, when a guest or patient feels
bad during the training.
13. When unsure about a patient’s medical condition,
consult a specialist or go straight to a medical
institution if you need to seek other medical help

References
Iida H, Kurano M, Takano H, Kubota N, Morita T, Meguro K, Sato Y,
Abe T, Yamazaki Y, Uno K, Takenaka K, Hirose K, Nakajima T (2007)
Hemodynamic and neurohumoral responses to the restriction of femoral
blood flow by KAATSU in healthy subjects. Eur J Appl Physiol 100: 275285.
Nakajima T (2010) KAATSU training and thickening of the muscle. In:
Kozuki M et al. (Eds.) Latest Rehabilitation Medicine for Rehabilitation
Physicians and Healthcare Professionals (in Japanese), Advanced
Medical Series 40, Advanced Medical Technology Institute, Japan, pp
292-297.
Nakajima T, Kurano M, Iida H, Takano H, Oonuma H, Morita T,
Meguro K, Sato Y, Nagata T, Kaatsu Training Group (2006) Use andsafety of KAATSU training: Results of a national survey. Int J KAATSU

Key considerations in KAATSU training

Training Res 2: 5-14.
Nakajima T, Takano H, Kurano M, Iida H, Kubota N, Yasuda T, Kato
M, Meguro K, Sato Y, Yamazaki Y, Kawashima S, Ohshima H,
Tachibana S, Nagata T, Ishii N, Morita T (2007) Effects of KAATSU
training on haemostasis in healthy subjects. Int J KAATSU Training Res 3:
11-21.
Madarame H, Kurano M, Takano H, Iida H, Sato Y, Ohshima H, Abe
T, Ishii N, Morita T, Nakajima T (2010) Effects of low-intensity resistance
exercise with blood flow restriction on coagulation system in healthy
subjects. Clinical Physiology and Functional Imaging 30: 210-213.
Takano H, Morita T, Iida H, Asada KI, Kato M, Uno K, Hirose K,
Matsumoto A, Takenaka K, Hirata Y, Eto F, Nagai R, Sato Y, Nakajima T(2005) Hemodynamic and hormonal responses to a short-term lowintensity resistance exercise with the reduction of muscle blood flow. Eur J
Appl Physiol. 95: 65-73.
Sato Y, Ishii, N, Nakajima, T, Abe T (2007) The theory and practice of
KAATSU training, Kodansha.

Authors’ affiliations
T. Nakajima, T. Morita, Department of Ischemic Circulatory
Physiology, KAATSU Training, University of Tokyo, Tokyo, Japan
Y. Sato, KAATSU International University, Sri Lanka

CASE REPORT

A case of dementia presenting remarkable improvementin activities of daily living through KAATSU training
T. Fukuda, K. Fukumura, Y. Uchida, T. Ootsuka, T. Yasuda, H. Iida, T. Morita, T. Nagata, Y. Sato,T. Nakajima
Int. J. KAATSU Training Res. 2011; 7: 13-17

Correspondence to:
Taira Fukuda, MD,
Department of Ischemic
Circulatory Physiology,
University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo,
Japan 113-8655●
See end of article forauthors’ affiliations

The number of patients with dementia is increasing markedly, and effective treatment and methods forprevention are needed. Moderate exercise decreases the progression of dementia. We report a caseof dementia presenting remarkable improvement in activities of daily living (ADL) through KAATSU
training. The patient was a 78-year-old woman with brain atrophy detected by magnetic resonanceimaging (MRI) at the age of 73. She had a remarkable decrease in ADL and vitality at the age of 76
and was diagnosed with frontotemporal dementia (FTD) at the age of 77. In initial presentation, she
had a humpback and Parkinsonian gait. Her muscle strength in the abdomen, lower back, and thighs
was remarkably decreased, and her trunk rotation and sense of equilibrium were also reduced. At
first, the training protocol was low-intensity resistance exercises using self-weight workouts and
KAATSU-walk training. For upper extremities exercises, dynamic movement using the truncal muscle
group was performed, and for lower extremities exercises, the sense of equilibrium was stimulatedusing standing exercises. The load and degree of difficulty were increased gradually. The average 10meter walk time, the number of steps, and the average timed up and go test time were lower after 6
months than after 2 months. The average bilateral femoral circumference increased after 6 months
compared with after 2 months. In conclusion, a patient with FTD performed KAATSU training for 6
months and had a remarkable improvement in motor function. Thus, KAATSU training may beeffective in improving ADL in patients with dementia.
Key words: elderly people, frontotemporal dementia, KAATSU training, activities of daily living

INTRODUCTION
Approximately 24.3 million people suffer fromdementia around the world, and this number is
expected to double every 20 years to 81.1 million by
2040 owing to the rapid increase in the number of
elderly people (Ferri et al., 2005). Senile dementia is
predominantly caused by neurodegenerative diseases
and cerebrovascular diseases. Alzheimer’s disease(AD) is the most common neurodegenerative disease,and various symptoms occur, including memory andorientation disturbance, depression, aggressive
behavior, hallucination, and delusion. Recently, early
diagnosis of dementia has been encouraged, owing to
the increase of older men living alone, home-nursing
insurance, and the emergence of anti-dementia drugs
such as Donepezil hydrochloride, a cholinesterase
inhibitor. Frontotemporal dementia (FTD),
characterized by progressive aphasia and curious
behavior with personality change, is also aneurodegenerative dementia, and it has been gainingsome attention as a differential diagnosis (Grossman
et al., 2002).
It has been reported that aerobic training for elderly
people without dementia may delay the onset ofdementia (Larson et al., 2006). KAATSU training is
performed under conditions using low-intensity andshort time loading (Takarada et al., 2000a, b). It can
now be applied to muscle training in healthy subjects,
elderly people, and patients with various diseases(Karabulut et al., 2010; Nakajima et al., 2010; Ozaki
et al., 2011).
In this report, we present a case of dementia
presenting remarkable improvement in activities ofdaily living through KAATSU training.

CASE REPORTThe patient was a 78-year-old Japanese womanthat had been diagnosed with depression at the age of
53. In her MRI findings, brain atrophy was detected
at the age of 73. She had a remarkable decrease in
ADL and vitality at the age of 76 and then was
diagnosed with FTD when she fell down at homeat the age of 77. Although the idea of a home nurse
had been introduced by a local doctor, she refused totake part. However, she was later introduced to
KAATSU training, and she received a check-up at this
hospital. She displayed neither an even temper nor
cooperativeness at that time. At initial presentation,
she had a humpback and Parkinsonian gait. Her
muscle strength in the abdomen, lower back, andthighs was remarkably decreased, and her trunk
rotation and sense of equilibrium were also reduced.

14

A case of dementia presenting remarkable improvement in activities of daily living through KAATSU training

Since she could hardly walk without assistance,
several evaluations were difficult to perform. This
study was approved by the ethics committee of the
University of Tokyo.

METHODS
The patient performed KAATSU training one day
per week. The training protocol began with lowintensity resistance exercises using self-weight
workouts and KAATSU-walk training. For upper
extremities exercises, dynamic movement using thetruncal muscle group was performed, and for lower
extremities exercises, the sense of equilibrium wasstimulated using standing exercises. The load anddegree of difficulty were increased gradually.
Specifically, she initially performed three sets of upper
extremities, chest presses, rowing, three sets of lower
extremities, leg extensions, knee ups, and KAATSUwalk training (Table 1). Initially, however, she could
hardly perform the training menu. In the middle ofthe training period (after 3 months), she performed
three sets of upper extremities, chest presses, rowing,side raises, three sets of lower extremities, leg
extensions, sitting leg curls, knee ups, and KAATSUwalk training. Furthermore, later on (after 5 months),
she performed three sets of upper extremities, chestpresses, rowing, side raises, three sets of lower
extremities, squats, standing leg curls, leg extensions,and KAATSU-walk training.

RESULTS
There were no side effects during this study.
Bilateral mid-upper arm circumference increased
after 6 months compared with after 4 months (Fig.
1A; right: +1.0 cm, left: +1.5 cm). Bilateral lower leg
circumference also increased after 6 months
compared with after 2 months (right: +1.0 cm, left:+1.0 cm). In particular, bilateral thigh circumference
also increased after 6 months compared with after 2
months (right: +2.0 cm, left: +3.0 cm), suggesting
enlargement of the femoral muscle group.
Shoulder range of motion increased after exercise
compared with before exercise, not only as an
immediate effect (Fig. 1B; right flexion: +5.7°, leftflexion: +2.1°, right horizontal abduction: +4.6°, lefthorizontal abduction: +2.5°), but also as a long-term
effect after 6 months compared with after 2 months(right flexion: +17.5°, left flexion: +15.0°, right
horizontal abduction: +22.5°, left horizontal
abduction: +2.5°). Posture in KATSU-walk training
also improved as shown in Fig. 2.
The 10-meter walk time was lower after 6 months
than after 2 months (Fig. 3A; before exercise: -18.5
sec, after exercise: -9.4 sec). The number of steps forthe 10-meter walk was also lower after 6 months
than after 2 months (before exercise: -24, after
exercise: -14). These findings suggest improvement inwalking speed. The timed up and go test time also
improved after 6 months compared with after 2
months (Fig. 3B; before exercise: -16.3 sec, after
exercise: -2.4 sec).

Table 1. Training menu during KAATSU training

Initial period(Before 3 Months)

Middle period(From 3 Months to 5 Months)

Late period(After 5 Months)

3 sets of upper extremities

3 sets of upper extremities

3 sets of upper extremities

chest presses

chest presses

chest presses

rowingrowingrowing3 sets of lower extremities

side raises

side raises

leg extensions

3 sets of lower extremities

3 sets of lower extremities

knee ups

leg extensions

squatsKAATSU walking

sitting leg curls

standing leg curls

knee ups

leg extensions

KAATSU walking

KAATSU walking

T. Fukuda, K. Fukumura, Y. Uchida., et al.

15

Figure 1A

Figure 1. A Changes in brachial, femoral, and lower leg
circumference through KAATSU training. B Change in rangeof shoulder motion through KAATSU training. Pre, before
exercise; post, after exercise; RF, right flexion; LF, left flexion;
RHAB, right horizontal abduction; LHAB, left horizontal
abduction.

Figure 1B

2 Mo
Figure 2. Change of posture in KAATSU-walk through KAATSU training.

6 Mo

16

A case of dementia presenting remarkable improvement in activities of daily living through KAATSU training

Figure 3A

Figure 3B

Figure 3. A Changes in 10-meter walk time and number ofsteps through KAATSU training. B Change in timed up andgo test time through KAATSU training. Pre, before exercise;post, after exercise.

DISCUSSIONKAATSU training is a novel form of strength
training which not only affects the endocrine
system, including growth hormone secretion, butalso stimulates many muscle fibers and brings
about muscle hypertrophy and muscle power
enhancement (Takarada et al., 2000a, b). It also
has pleiotropic effects including the improvementof obesity and an effect on bones. It can also be
applied to muscle training in healthy subjects,
elderly people, and patients with various diseases(Karabulut et al., 2010; Nakajima et al., 2010;
Ozaki et al., 2011). Furthermore, we have
performed KAATSU training on a total of 2,000
patients mainly with cardiovascular diseases, andserious adverse side effects have not been observed.
Thus, KAATSU training is safe under a director
familiar with appropriate methods (Nakajima et al.,2006). In this paper, we reported for the first timethat an elderly patient with dementia, who had
muscle atrophy and decreased quality of life, had aremarkable improvement in quality of life through
KAATSU training.
Regular exercise has been reported to delay theonset of dementia in a prospective cohort study(Larson et al., 2006). In this study, moderate exercise
induced an approximately 40% decrease in the riskof dementia. They conducted a follow-up survey on
1,750 subjects (aged 65 years and older) without
cognitive disturbance over a period of 6 years, andthe subjects declared their exercise patterns, including
walking, hiking, aerobics, setting-up exercises,
swimming, water aerobics, weight training, andstretching every 2 years. A total of 158 of the 1740
subjects developed dementia during 6.2±2.0 years.
Of this number, 107 subjects were diagnosed with
AD. The incidence rate of dementia was 13.0/1,000
person-year [hazard ratio 0.62 (p=0.004, 95%
confidential interval 0.44-0.86)] in subjects who
performed exercise three times or more every week,whereas it was 19.7/1,000 person-year in those thatexercised less than three times every week.
Furthermore, the decrease in risk associated with
exercise was greater in subjects with a poor
performance level than those with a maintained
performance level.
Regular exercise also improves cognitive function
in patients with dementia. The basic mechanisms
remain unclear, but brain-derived neurotrophic factor(BDNF) may be involved. BDNF, which is produced
mostly in the cerebral cortex and hippocampus, isknown to play an essential part in the life, growth,and maintenance of neurons and is strongly related
to study, memory, and cognitive function (Zigova etal., 1998; Lee and Son, 2009). In the hippocampus ofpatients with AD, a decrease in BDNF has beenreported (Pedersen et al., 2009). Recent studies
showed that BDNF plays an important role in thebeneficial effects of exercise training on dementia(Ding et al., 2006; Griesbach et al., 2004; Kim et al.,2010; Vaynman et al., 2003, 2004). It remains
unexamined whether KAATSU training can enhance
BDNF secretion. However, there is a possibility that

T. Fukuda, K. Fukumura, Y. Uchida., et al.

KAATSU training may improve cognitive function via
BDNF. In addition, we measured cerebral blood flowin healthy subjects using near-infrared spectroscopy
and compared KAATSU training to low-intensity
training without KAATSU. In this study, cerebral
blood flow increased significantly in the KAATSU
training group, suggesting favorable influence on the
cerebral center (Morita et al., 2010). From theseobservations, it is likely that KAATSU training may
improve cognitive function and delay the onset ofdementia by promoting BDNF secretion andimproving cerebral blood flow. However, further
studies are needed to clarify this possibility.
The pleiotropic effect and safety of KAATSU
training has been established. However, how
KAATSU training is provided for elderly people andpatients with dementia is important, since they often
find it difficult to continue performing training interms of understanding instructions and their ability
to concentrate. In an NIH Consensus Statement (NIHConsensus Development Panel on Physical Activity
and Cardiovascular Health, 1996), tips on continuing
exercise training included being conscious of theeffects of exercise training, performing pleasant
exercise activities, satisfying exercises, andrecognizing the safety of exercise. In these points,
KAATSU training, a man-to-man training program
involving communication with a partner, appears to
be a very suitable and effective method.
In conclusion, a patient with FTD who performed
KAATSU training one day per week over 6 months
had increased extremity circumference, increased
range of shoulder motion, improved static anddynamic position, and improved 10-meter walk andtimed up and go tests, resulting in the improvementof ADL. In addition, KAATSU training appears to be auseful method for improving ADL and cognitive
function in patients with dementia.

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Insulin-like growth factor I interfaces with brain-derived neurotrophic
factor-mediated synaptic plasticity to modulate aspects of exerciseinduced cognitive function. Neuroscience 140: 823-833.
Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, HallK, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Munezes PR,
Rimmer E, Scazufca M (2005) Global prevalence of dementia: A Delphi
consensus study. Lancet Neurol 366: 2112-2117.
Griesbach GS, Hovda DA, Molteni R, Wu A, Gomez-Pinilla F (2004)
Voluntary exercise following traumatic brain injury: Brain-derived
neurotrophic factor upregulation and recovery of function. Neuroscience
125: 129-139.
Grossman M (2002) Frontotemporal dementia: A review. J Int
Neuropsycho Soc 8: 566-583.
Karabulut M, Abe T, Sato Y, Bemben MG (2010) The effects of lowintensity resistance training with vascular restriction on leg muscle
strength in older men. Eur J Appl Physiol 108: 147-155.

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Kim SE, Ko IG, Kim BK, Shin MS, Cho S, Kim CJ, Kim SH, Baek SS, Lee
EK, Jee YS (2010) Treadmill exercise prevents aging induced failure ofmemory through an increase in neurogenesis and suppression of
apoptosis in rat hippocampus. Exp Gerontol 45: 357-365.
Larson EB, Wang L, Bowen LD, McCormick WC, Teri L, Crane P, Kukull
W (2006) Exercise is associated with reduced risk for incident dementia
among persons 65 years of age and older. Ann Intern Med 144: 73-81.
Lee E, Son H (2009) Adult hippocampal neurogenesis and related
neurotrophic factors. BMB Rep 42: 239-244.
Morita T, Fukuda T, Kikuchi H, Ikeda K, Yumoto M, Sato Y (2010)
Effects of blood flow restriction on cerebral blood flow during a single
arm-curl resistance exercise. Int J KAATSU Training Res 6: 9-12.
Nakajima T, Kurano M, Iida H, Takano H, Oonuma H, Morita T,
Meguro K, Sato Y, Nagata T, KAATSU Training Group (2006) Use andsafety of KAATSU training: Results of a national survey. Int J KAATSU
Training Res 2: 5-13.
Nakajima T, Kurano M, Sakagami F, Iida H, Fukumura K, Fukuda T,
Takano H, Madarame H, Yasuda T, Nagata T, Sato Y, Yamasoba T,
Morita T (2010) Effects of low-intensity KAATSU resistance training onskeletal muscle size/strength and endurance capacity in patients withischemic heart disease. Int J KAATSU Training Res 6: 1-7.
NIH Consensus Development Panel on Physical Activity andCardiovascular Health (1996) Physical activity and cardiovascular
health. JAMA 276: 241-246.
Ozaki H, Sakamaki M, Yasuda T, Fujita S, Ogasawara R, Sugaya M,
Nakajima T, Abe T (2011) Increases in thigh muscle volume and strength
by walk training with leg blood flow reduction in older participants. J
Gerontol A Biol Sci Med Sci 66: 257-263.
Pedersen BK, Pedersen M, Krabbe KS, Bruunsgaard H, Matthews VB,
Febbraio MA (2009) Role of exercise-induced brain-derived
neurotrophic factor production in the regulation of energy homeostasis in
mammals. Exp Physiol 94: 1153-1160.
Takarada Y, Nakamura Y, Aruga S, Onda T, Miyazaki S, Ishii N(2000a) Rapid increase in plasma growth hormone after low-intensity
resistance exercise with vascular occlusion. J Appl Physiol 88: 61-65.
Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000b) Effects of resistance exercise combined with moderate vascularocclusion on muscular function in humans. J Appl Physiol 88: 20972106.
Vaynman S, Ying Z, Gomez-Pinilla F (2003) Interplay between brainderived neurotrophic factor and signal transduction modulators in theregulation of the effects of exercise on synaptic-plasticity. Neuroscience
122: 647-657.
Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF
mediates the efficacy of exercise on synaptic plasticity and cognition. Eur
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Authors’ affiliations
T. Fukuda, K. Fukumura, Y. Uchida, T. Ootsuka, T. Yasuda, H.
Iida, T. Morita, T. Nakajima, Department of Ischemic Circulatory
Physiology, KAATSU Training, University of Tokyo, Tokyo, Japan
Y. Sato, KAATSU International University
T. Nagata, Research Center of Clinical Medicine, International
University of Health and Welfare

ORIGINAL ARTICLE

The effects of low-intensity KAATSU resistance exercise
on intracellular neutrophil PTX3 and MPO
T. Nakajima, M. Kurano, T. Hasegawa, H. Iida, H. Takano, T. Fukuda, H. Madarame, K. Fukumura,Y. Sato, T. Yasuda, T. Morita
Int. J. KAATSU Training Res. 2012; 8: 1-8

Correspondence to:
T. Nakajima, MD: Departmentof Ischemic Circulatory
Physiology, KAATSU Training,
University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo,
Japan 113-8655
See end of article forauthors’ affiliations

INTRODUCTION

Myeloperoxidase (MPO) has been suggested to have a role in atherosclerosis through its strongoxidative capacity. MPO-mediated formation of reactive oxidants is enhanced after exhaustive
exercise. Low-intensity resistance exercise (LIRE) under the conditions of restricting muscle blood flow
(KAATSU) has been reported to strengthen muscles, in a way similar to high-intensity resistance
exercise. We investigated the effects of LIRE-KAATSU on neutrophil intracellular MPO and pentraxin 3(PTX3), an inflammatory marker. Five control subjects and six patients with ischemic heart diseases(IHD) (pPCI 5, pCABG 1) have participated in this study. Each subject performed LIRE (20% 1RM leg
extension, 4 sets, 30-15-15-15) under the conditions with or without KAATSU. Neutrophils were
immunostained with a specific antibody to PTX3 and MPO and the density of these markers wasmeasured by flow cytometry analysis (FACS). FACS and immunostaining studies showed the existenceof PTX3 and MPO in neutrophils. LIRE did not particularly release PTX3 and MPO from neutrophils in
healthy subjects under the conditions with or without KAATSU. The similar results were obtained inpatients with IHD. These results suggest that the addition of KAATSU to LIRE did not enhance PTX3 andMPO release from neutrophils even in patients with IHD, which may be related to the safety of
KAATSU, compared to high-intensity resistance exercises
Key words: KAATSU training, Myeloperoxidase; Pentraxin 3; neutrophils; resistance exercise

Moderate-intensity exercise induces transientoxidative stress, stimulates redox-sensitive signals,
and then increases the antioxidant defense system,
leading to cytoprotection. However, heavy exercise
induces excessive oxidant stress, resulting in tissue
injury. The increase of myeloperoxidase (MPO), an
oxidant stress marker belonging to the heme
peroxidase superfamily, has been also reported as aresult of acute heavy exercise in healthy subjects(Suzuki et al., 1996; Nakajima et al., 2010a;
Reihmane et al., 2012). MPO is found in myeloid
cells, particularly in neutrophils (Ikitimur andKaradag, 2000; Tavora et al., 2009; Nakajima et al.,2010a), and plays an important role in the hostdefense against bacteria and viruses. On the other
hand, it has been suggested to have a role inatherosclerosis through its strong oxidative capacity.
MPO-mediated formation of highly reactive oxidants,
hypochlorous acid (HClO), causes consumption of
nitric oxide (NO) on endothelial cells and theoxidation of LDL on vascular walls in atherosclerotic
regions. Therefore, the excessive generation of MPO
leads to the formation of atheroma, then plaquerupture and acute coronary syndrome as well
(Nicholls and Hazen, 2005; Tavora et al, 2009). Thus,
MPO is a key component in the development andprogression of atherosclerosis and other forms ofcardiovascular diseases (Ikitimur and Karadag, 2010).
In addition, daily regular exercise is known to
induce anti-inflammatory effects and reduce the riskof cardiovascular diseases associated with chronic
low-grade systemic inflammations such as
atherosclerosis (Petersen and Pedersen, 2005;
Plaisance and Grandjean, 2006), resulting in adecrease of inflammatory markers such as C-reactive
protein (CRP) and pentraxin 3 (PTX3) (Kasapis andThompson, 2005; Fukuda et al., 2012). However, incontrast to the anti-inflammatory effects of exercise,acute high-intensity and prolonged exercise causes
production of stress hormones and alterations in thecirculating quantity and function of various immune
cells, including leukocyte mobilization andleukocytosis (Hoffman-Goetz and Pedersen, 1994;
Pedersen and Hoffman-Goetz, 2000; Peake et al.,
2004; 2005a; Buttner et al., 2007), and increase of
inflammatory markers, CRP and PTX3 (Nakajima etal., 2010a). The low-intensity resistance exercise
under the conditions with the restriction of muscle
blood flow named as KAATSU has been reported tostrengthen muscles in athletes and healthy subjects,
results similar to high-intensity resistance exercise(Takarada et al., 2000b; 2002; Karabult et al., 2007;
Wernbom et al., 2008; Karabult et al., 2010), which
is a promising method for rehabilitation in patients
including cardiovascular diseases (Nakajima et al.,2

2006; Nakajima et al;. 2010). We have previously
reported that KAATSU training using 20-30% 1RM
resistance exercises increase muscle strength andmuscle mass in patients with cardiovascular diseases(Nakajima et al., 2010) and applying blood flow
restriction does not affect exercise-induced
hemostatic and inflammatory responses of CRP(Madarame et al., 2012). However, responses to
KAATSU including neutrophils have not been
investigated.
Therefore, the purpose of this study is toinvestigate the effects of low-intensity resistance
exercise with KAATSU on neutrophil intracellular
MPO and PTX3 conducted on patients with ischemic
heart diseases (IHD) in comparison to control
subjects. Results have been derived by assessing the
PTX3 and MPO levels in neutrophils isolated fromthe peripheral blood by using flow cytometry analysis
as a result of the exercises.

MATERIALS AND METHODS
Subjects

Five male control subjects (37 ± 5 years) and six
male patients with IHD (post-coronary artery bypass
grafting (p-CABG) 1, post-percutaneous coronary
intervention (p-PCI) 5, 60 ± 3 years old) participatedin this study. These patients had no organic stenosis
after CABG or PCI and had no symptoms at the startof this study. This study was approved by the Ethics
Committee of the University of Tokyo. All subjects
were informed of the methods, procedures and risks,and signed an informed consent document before
participation.
Exercise Protocol

Each subject performed low-intensity leg extension
resistance exercise (20% 1RM, 4 sets) under theconditions either with or without blood flow
restriction the order of which was counterbalanced
across subjects. In each exercise session, one set with30 repetitions was followed by 3 sets with 15
repetitions. A rest period of 1 min was taken between
sets. We measured 1RM voluntary force before theexercise.
Femoral Muscle Blood Flow Reduction Method
by KAATSU

The method for inducing the reduction of muscle
blood flow is similar to that described in previous
papers (Takarada et al. 2000a; b; Takarada et al.,
2002; Takano et al., 2005; Abe et al. 2006; Fujita etal., 2007; Iida et al., 2007; Nakajima et al., 2008). A
specially-designed KAATSU belt applies pressure atthe proximal ends of both sides of the thighs torestrict venous blood flow. The cuff pressure is set to
200 mmHg.

KAATSU training and neutrophil PTX3/MPO

Blood SamplingBlood samples were obtained using an indwelling
heparin-lock catheter inserted into a superficial
antebrachial vein on the left arm. The subjects were
instructed to sit quietly before taking blood sample
for at least 30 min. The baseline (resting/preexercise) blood sample was taken before theapplication of KAATSU or the start of the exercises.
Post-exercise blood samples were further obtained
within 1-2 min after the exercise and the release of
the belt.
Neutrophils, Monocytes, and Lymphocytes
Isolation

Heparinized whole blood (5 ml) from peripheral
blood was layered over 5 ml of Polymorphprep(Axis-Shield, Oslo, Norway) and spun for 35 min at
500 g at 20 °C. Mononuclear cells (MNCs) were
harvested from the top band of the sample-medium
interface, and polymorphonuclear cells (PMNs) were
harvested from the second interface. One ml of
0.45% NaCl solution was added into each fraction to
restore normal osmolarity, washed with phosphatebuffered saline (PBS, Nacalai tesque Co., Kyoto,
Japan) and spun for 10 min at 270 g at room
temperature.
PMNs, mainly composed of neutrophils, were
resuspended in a 0.5 ml buffer (3% FBS and 0.05%
NaN3 in PBS), and mixed with a 5 ml ice-cold 70%
ethanol for 30 min and spun for 10 min at 270 g atroom temperature. Subsequently, PMNs were
resuspended in a 1 ml 70% ethanol, dropped on aslide glass, and was dried. MNCs, composed ofmonocytes and lymphocytes, were resuspended in a
1 ml buffer. Then, the cells were performed on a cell
sorter (EPICS ALTRA, Beckman Coulter, Fullerton,CA) to sort out monocytes and lymphocytes from thefraction of MNCs. Each sorted portion was spun for
10 min at 270 g at room temperature. Subsequently,
monocytes and lymphocytes were resuspended in a 1
ml 70% ethanol, dropped on a slide glass, and driedin a similar manner to PMNs.
Immunofluorescent Staining

The fixed cells were washed in PBS, and thenblocked for 15 min with 2% horse serum in PBS, andwere incubated with the primary antibody in ahumid chamber overnight at 4 °C. The primary
antibodies used were a rabbit polyclonal anti-human
myeloperoxidase (Novus Biological, Littleton, CO)and a rat monoclonal antibody against human PTX3
(clone MNB4, Alexis Biochemicals, San Diego, CA).
After the preparation of the antibodies, the cells were
washed in PBS and the secondary antibody was
incubated for 60 min at room temperature. An Alexa
Fluor 488-conjugated donkey anti-rabbit IgG (H+L)
antibody (Molecular Probes, Eugene, OR), and a

T. Nakajima, M. Kurano, T. Hasegawa., et al.

3Cy3-conjugated goat anti-rat IgG (Jackson
ImmunoResearch, West Grove, PA) were used tovisualize the MPO and PTX3 expression. For negative
controls, normal rabbit IgG and normal rat IgG(Vector laboratories, Burlingame, CA) were usedinstead of primary antibodies. The nuclei were
stained with Hoechist 33258 (Sigma Aldrich). A
confocal laser scanning microscope (Olympus
FluoView FV300, Olympus Co., Tokyo, Japan) wasused to examine the specimens.
Flow Cytometry Analysis

For the flow cytometry analysis (FACS) using
neutrophils as previously reported (Nakajima et al.,2010a), whole blood (300 μl) was lysed with a
Versalyse reagent (Beckman Coulter, Fullerton, CA)
and spun for 5 min at 270 g. Then, cells were
resuspended in a 100 μl of 4% paraformaldehyde
for 15 min. Subsequently, 1 ml of the buffer (seeabove) was added and spun for 5 min at 270 g. The
cells were resuspended in a 100 μl buffer containing
0.1% saponin for 5 min and incubated for 30 min atroom temperature with a mixture of primary
antibody (the rabbit polyclonal anti-human
myeloperoxidase (Novus Biological, Littleton, CO)and rat monoclonal antibody against human PTX3
(clone MNB1, Alexis Biochemicals, San Diego, CA).
Then, the cells were added with a 1 ml buffer
containing 0.1% saponin, spun at 270 g andincubated with a secondary antibody (Alexa Fluor
488-conjugated donkey anti-rabbit IgG (H+L)
antibody (Molecular Probes Inc., Eugene, OR) and a
PE-conjugated Goat anti-rat IgG (H+L) antibody(Beckman Coulter, Fullerton, CA). Finally, the cells
were again, resuspended in the buffer. Flowcytometry (FACS) was performed on a flow
cytometer (EPICS XL-MCL, Beckman Coulter,

Fullerton, CA).
Figure 1 shows a typical example of PTX3 inneutrophils by FACS. The expression of PTX3 was
identified in neutrophils. The right side shows
neutrophils counterstained with Hoechst33258
which helps visualize the nuclei. The mean
fluorescence intensity of PTX3 and MPO from bloodtaken immediately after the exercise and taken
before the exercise was compared. Assuming themean florescence density of MPO and PTX3 inneutrophils isolated from pre-exercise blood is 100%,
the relative value of the mean florescence density ofneutrophils isolated from blood immediately after the
exercises is calculated.
Data Analysis

All values are expressed as means ± S.E.M.
Studentʼs pared t test was used to compare two sets ofdata from the same subjects. Differences wereconsidered significant if p values were less than 0.05.

RESULTSFirst, we investigated the existence of MPO andPTX3 in human neutrophils. Immunostaining studies
demonstrated the presence of MPO (Fig. 2A) andPTX3 (Fig. 2B) in human neutrophils taken fromcontrol subjects. Flow cytometry analysis also
showed the existence of both PTX3 (Fig. 1) and MPO(Fig. 5) using a specific antibody. The data wereobtained from a control subject (Fig. 1) and a patientwith IHD (Fig. 5), respectively. The expression of
MPO and PTX was also separately investigated inneutrophils, monocytes, and lymphocytes. As shownin Fig. 3, the expression of MPO was particularly
observed in neutrophils (A), and no expression was
detected in negative controls without the antibody(B). It was also observed to a lesser extent in

Nucleuscell number

negative control
PTX3 Abfluorescence intensity
Figure 1. Flow cytometry analysis of PTX3 expression in human neutrophils isolated from peripheral blood (see methods).
The neutrophils were counterstained with Hoechst33258 to visualize nuclei shown on right.

4

KAATSU training and neutrophil PTX3/MPO

A

B

Figure 2. Immunostaining of MPO (A) and PTX3 (B) in neutrophils.

A

B

C

D

Figure 3. Immunostaining of MPO in neutrophil, monocytes, and lympocytes. A: neutrophil

B: negative control (without antibody) C: monocytes D: lympocytes. Note that the expression of
MPO in healthy subjects is particularly observed in neutrophils, and to a lesser extent in monocytes.

T. Nakajima, M. Kurano, T. Hasegawa., et al.

5

A

B

C

D

Figure 4 Immunostaining of PTX3 in neutrophils, monocytes, and lympocytes.

A: neutrophil B: negative control (without antibody) C: monocytes D: lympocytes.
Note that the definite expression of PTX3 in healthy subjects is observed only in neutrophils.

Precell number

Post

fluorescence intensity
Figure 5. Effects of low-intensity resistance exercise withKAATSU on neutrophil MPO by using flow cytometry. The
typical data obtained from a patient with ischemic heartdisease were shown before and after exercising. Note thatneutrophils isolated from blood immediately after the
exercise (Post) exhibit similar mean fluorescence for MPO
compared to those from pre-exercise blood (without
KAATSU).

monocytes (C). The very weak staining was observedin human lymphocytes (D). The marked expressionof PTX3 was observed in neutrophils (A) only as
shown in Fig. 4. No expression was detected innegative controls without the antibody (B). The
definite expression of PTX3 was not observed inhuman monocytes (C) and lymphocytes (D),compared with neutrophils (A).
Secondly, we investigated the effects of 20% 1RM
low-intensity resistance exercise with or without the
restriction of muscle blood flow (KAATSU) on
neutrophil MPO and PTX3, by using FACS. The
typical data under the KAATSU condition obtained
from a 67-year old patient are shown in Fig. 5. The
mean fluorescence density of MPO in neutrophils
isolated from post-exercise blood was similar to thatobtained at rest (pre-exercise blood).
Five control male subjects and 6 patients with IHD
were also examined as shown in Figs. 6 and 7.
Neutrophils isolated from blood immediately after
exercise without KAATSU exhibited no significant
differences in the mean fluorescence for MPO (Fig. 6)

6

KAATSU training and neutrophil PTX3/MPO

with IHD.

DISCUSSION

Figure 6. Effects of 20% 1RM resistance exercise with orwithout KAATSU on neutrophil MPO by using flow cytometry
in healthy subjects (left part) and patients with ischemic heartdiseases (IHD, right part). The mean fluorescence density of
MPO in neutrophils isolated from pre-exercise blood without
KAATSU is considered 100%, and the relative value of themean fluorescence density of neutrophils isolated from blood
immediately after exercises is shown. The data were obtained
from 5 control subjects (left) or six patients with IHD (rightpart).

Figure 7. Effects of 20% 1RM resistance exercise with orwithout KAATSU on neutrophil PTX3 using flow cytometry
in healthy subjects (left) and patients with ischemic heartdiseases (IHD, right). The mean fluorescence density of PTX3
in neutrophils isolated from pre-exercise blood without
KAATSU is considered 100%, and the relative value of themean fluorescence density of neutrophils isolated from blood
immediately after exercises is shown. The data were obtained
from 5 healthy subjects (left) or six patients with IHD (right).

and PTX3 (Fig. 7) compared to that isolated from preexercise blood in control subjects (Figs. 6 & 7, leftside) and patients with IHD (Figs. 6 & 7, right side).
Similar results were obtained from patients with IHD
under the conditions with KAATSU (Figs. 6 & 7).
Neutrophils isolated from blood immediately after
exercise with KAATSU also exhibited no significant
changes in the mean fluorescence for MPO (Fig. 6)
and PTX3 (Fig. 7) from control subjects and patients

The major findings of the present study are as
follows; 1) FACS and immunostaining studies haveshown the existence of PTX3 and MPO in
neutrophils. 2) 20% 1RM low-intensity resistance
exercise did not significantly release PTX3 and MPOfrom neutrophils in control subjects under theconditions with or without KAATSU. Similar results
have been observed in patients with IHD. Thus, theaddition of muscle blood flow (KAATSU) restrictions
to low-intensity resistance exercise did not enhance
PTX3 and MPO release from neutrophils in patientswith IHD, which may be related to the safety of
KAATSU, compared to high-intensity resistance
exercises.
First, the present study using FACS andimmunostaining studies has shown the existence of
MPO and PTX3 in neutrophils, which is consistent
with the previous papers (Ikitimur and Karadag,
2000; Jaillon et al., 2007; Tavora et al., 2009;
Nakajima et al., 2010a). As shown in Fig. 3, theexpression of MPO was particularly observed inneutrophils and to a lesser extent in monocytes. Also,
the expression of PTX3 has only been observed inneutrophils as shown in Fig. 4. Therefore, we haveinvestigated the effects of low-intensity resistance
exercise on intracellular MPO and PTX3 inneutrophils using flow cytometry analysis. Similarly,changes in neutrophil surface receptor expressions
including CD16 and degranulation have been
investigated immediately after a high-intensity
exercise (a treadmill for 1 h at 80% VO2max) (Peake
et al., 2004).
Acute exercise is an important stressor to the body,leading to an activation of immune responses(Hoffman-Goetz and Pedersen, 1994; Pedersen and
Hoffman-Goetz, 2000; Peake et al., 2004; 2005a;
Buttner et al., 2007) depending on the intensity. The
exercise-induced acute phase response consists oftypical changes including leukocytosis and release ofcytokines and acute phase proteins, similar to acutephase responses evoked by other stressors such as
trauma and sepsis (McCarthy et al., 1992; Ostrowski
et al., 2000; Shephard, 2001; Yamada et al., 2002;
Natale et al., 2003; Peake et al., 2005b; Mooren et al.,2006; Zaldivar et al., 2006). PTX3 and CRP have beenshown to be independent high-sensitive markers for
inflammation under the various pathophysiologicalconditions (Presta et al., 2007; Mantovani et al.,2008), and the increase of inflammatory markers
such as CRP and PTX3 have been reported in acuteheavy exercises (Castell et al., 1997; Nakajima et al.,2010a). High-intensity exercises also increase serum
MPO concentration which depends on the exercise
intensity (Peake et al., 2004; Reihmane et al., 2012).

T. Nakajima, M. Kurano, T. Hasegawa., et al.

Recently, we have shown that neutrophils isolated
from blood immediately after high-intensity
resistance exercise (70% 1RM) releases MPO andPTX3 in control subjects using flow cytometry
analysis (Nakajima et al., 2010a). However, thepresent study showed that 20% 1RM low-intensity
resistance exercise did not significantly releaseneutrophil MPO and PTX3 in control subjects. Thus,
the exercise-induced neutrophil MPO and PTX3
release appears to depend on exercise-intensity. The
present study also investigated the responses to
KAATSU in healthy subjects. The application of
KAATSU did not enhance neutrophil MPO and PTX3
significantly in healthy subjects. These results were incontrast with the results from high-intensity exercise,but somewhat consistent with the previous papers
showing that applying blood flow restriction does notaffect exercise-induced inflammatory responses of
CRP, another inflammatory marker (Madarame etal., 2012)..
MPO has a role in atherosclerosis through its
strong oxidative capacity. MPO-mediated formationof highly reactive oxidants, hypochlorous acid
(HClO), causes consumption of nitric oxide (NO) on
endothelial cells and the oxidation of LDL on
vascular wall in atherosclerotic regions. The excessive
formation of MPO leads to the formation ofatheroma, then plaque rupture, and acute coronary
syndrome as well (Tavora et al, 2009). Thus, MPO isa key component in the development andprogression of atherosclerosis and other forms ofcardiovascular diseases (Ikitimur and Karadag, 2010).
Therefore, we also investigated the effects of lowintensity resistance exercise with or without
KAATSU on neutrophil MPO and PTX3 in patents
with cardiovascular diseases as well as healthy
subjects. The present study has shown that KAATSU
training using low-intensity exercise did not
significantly release neutrophil MPO and PTX3
release in these patients. Similarly, we have recently
reported that applying blood flow restriction did notenhance exercise-induced inflammatory responses of
CRP in patients with IHD (Madarame et al., 2012).
Thus, the addition of KAATSU to low-intensity
resistance exercise did not enhance inflammatory
responses (CRP and PTX3) and neutrophil MPO
release from neutrophils even in patients with IHD,
which may be related to the safety of KAATSU
compared to high-intensity resistance exercise. In
fact, we have reported that KAATSU resistancetraining using 20-30% 1RM resistance exercises canincrease muscle strength and muscle mass in patientswith cardiovascular diseases. Furthermore, no
obvious side effects including coronary events haveoccurred (Nakajima et al., 2010b). However, since
the patients used in this study are very stable, andhave normal cardiac function and no significant

7coronary artery stenosis, who have received PCI or
CABG. Further studies using relatively high-riskpatients or cardiac dysfunction are needed to justify
this.
In conclusion, the addition of KAATSU to lowintensity resistance exercise did not enhance PTX3
and MPO release from neutrophils in patients withcardiovascular diseases, which suggests the safety of
KAATSU in cardiac rehabilitation compared to highintensity resistance exercise.

ACKNOWLEDGEMENTS

The authors thank Mr. K. Otsuka and Mr. Y. Chujo
for their contributions to this study.

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K, Nagasaki M, Monzen K, Uno K, Kato M, Shiga T, Maemura K,
Matsuda N, Yamashita Y, Hirata Y, Nagai R, Nakajima T (2012)
Cardiac rehabilitation decreases plasma pentraxin 3 in patients withcardiovascular diseases. European Journal of Cardiovascular Prevention
Rehabilitation (in press)
Fujita S, Abe T, Drummond MJ, Cadenas JG, Dreyer HC, Sato Y, Volpi
E, Rasmussen BB (2007) Blood flow restriction during low-intensity
resistance exercise increases S6K1 phosphorylation and muscle protein
synthesis. J Appl Physiol 103: 903-910.
Hoffman-Goetz L, Pedersen BK (1994) Exercise and the immune
system: a model of the stress response? Immunol Today 15: 382-387.
Ikitimur B, Karadag B (2000). Role of myeloperoxidase in cardiology.
Future Cardiol. 6: 693-702.
Jaillon S, Peri G, Delneste Y, Frémaux I, Doni A, Moalli F, et al (2007)
The humoral pattern recognition receptor PTX3 is stored in neutrophil
granules and localizes in extracellular traps. J Exp Med 204: 793-804.
Karabulut M, Abe T, Sato Y, Bemben M (2007) Overview ofneuromuscular adaptations of skeletal muscle to KAATSU training. Int J
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serum C-reactive protein and inflammatory markers: a systematic review.
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Abe T, Yamazaki Y, Uno K, Takenaka K, Hirose K, Nakajima T (2007)
Hemodynamic and neurohumoral responses to the restriction of femoral
blood flow by KAATSU in healthy subjects. Eur J Appl Physiol 100: 275285.
Madarame H, Kurano M, Fukumura K, Fukuda T, Nakajima T (2012)
Hemostatic and inflammatory responses to blood flow-restricted exercise
in patients with ischemic heart disease: a pilot study. Clinical Physiology
and Functional Imaging (in press)

8

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Morita T (2010b) Effects of low-intensity KAATSU resistance training onskeletal muscle size/strength and endurance capacity in patients withischemic heart disease. Int J KAATSU Training Res 6: 1-7.
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Yamaya K (1996) Capacity of circulatory neutrophils to produce reactive
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Appl. Physiol 95: 65-73.
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Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000b) Effects of resistance exercise combined with moderate vascularocclusion on muscle function in humans. J Appl Physiol 88: 2097-2106.
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combined with vascular occlusion on muscle function in athletes. Eur J
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Authors affiliations
T. Nakajima, M. Kurano, T. Hasegawa, H. Iida, H. Takano, T.
Fukuda, H. Madarame, K. Fukumura, T. Yasuda, T. Morita,
Department of Ischemic Circulatory Physiology, KAATSU Training,
University of Tokyo, Tokyo, Japan
Y. Sato, Kaatsu International University, Sri Lanka

The use of KAATSU Training or the term “KAATSU Training”
in the body text are registered trademarks of KAATSU JAPANCo., Ltd.
“KAATSU Training” is a method created by the inventor,
Yoshiaki Sato, through his more than 45 years of research.
© 2012 KAATSU International

CASE REPORT

Effect of KAATSU training on a patient with benign
fasciculation syndrome
Y. Uchida, T. Morita, K. Fukumura, T. Otsuka, T. Fukuda, Y. Sato, T. Nakajima
Int. J. KAATSU Training Res. 2012; 8: 9-12

Correspondence to:7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-8655
UCHIDAYU-REH@h.u-tokyo.
ac.jp
See end of article forauthors’ affiliations

INTRODUCTION[Objective]
Benign fasciculation syndrome (BFS) is a neurological disorder characterized by involuntary andrepeated contractions of synergetic muscles and commonly occurs in the eyelids, arms and legs. BFS isalso associated with pain, which may interfere with everyday activities. This report describes the caseof a BFS patient who performed KAATSU exercise, a type of exercises performed under the conditionsof restricting muscle blood flow.
[Methods]
The patient performed KAATSU exercise of the bilateral upper and lower extremities at a frequency of
twice a week for 3 months. Knee extensor strength as measured with a hand-held dynamometer(HHD), QOL scores as assessed by the SF-36v2 questionnaire form, and bilateral femoral muscle
mass as measured by MRI were compared before and after exercise.
[Results]
After a 3-month KAATSU exercise program, the right and left knee extensor strength as measured
with a HHD increased by about 26% from 30.9 to 38.8 kgf and by about 44% from 39.9 to 57.4 kgf,
respectively, and the bilateral femoral muscle mass as measured by MRI increased by about 23% from8,730 to 10,709 cc. Overall improvement in QOL was also observed, as assessed by the SF-36v2
questionnaire form.
[Conclusion]
For patients with neurological disorders with pain, such as the present patient, active introduction of
KAATSU-based exercise is likely to result in improved health-related QOL, as well as increased muscle
mass and strength.
Key words: Benign Fasciculation Syndrome, KAATSU training, exercise therapy

Fasciculation can be seen in healthy people, especiallyafter high-intensity exercise, but is also observed inpatients with severe neuromuscular diseases, such as
amyotrophic lateral sclerosis (ALS), and thus should
be considered in differential diagnosis. Benign
fasciculation syndrome (BFS) is a benign diseasecharacterized by fasciculation as a prominent
symptom, such as pain, anxiety, fatigability, andparesthesia, and often lasts for several months to years(Fettel et al., 1982). Major causes of BFS include
severe stress and anxiety. For treatment, exercise therapy
may be performed, but no effective rehabilitation
program has been established. KAATSU exercise, anovel, attention-drawing method of low-intensity
resistance exercise performed under the condition of
restricting muscle blood flow (Takarada et al., 2000b;
Abe et al., 2006; Karabulut et al., 2007; Wernbom etal., 2008), causes minimal strain on the musculoskeletaland cardiovascular systems compared to high-intensity
resistance exercise and thus is increasingly applied torehabilitation programs for patients with various
disorders. Meanwhile, its effect on BFS patients has

yet to be examined.
This report describes the case of a BFS patient inwhich KAATSU exercise exerted beneficial effects on
the muscles, pain, and quality of life (QOL) of thepatient.
Patient

Patient: a 44-year-old man
Diagnosis: benign fasciculation syndrome
Comorbidity: none
Previous medical history: none
Chief complaint: systemic fasciculation, pain
History of present illness: The patient noted
fasciculation of the right upper and lower
extremities in May 2010. The symptom worsened
thereafter and he started using a wheelchair in
mid-August. The symptom continued to worsen
gradually until a reduction in pain was notedaround March 2011 and the patient became able
to walk 500-600 m on a flat road without resting.
With the expectation for further improvement ofsymptoms, the patient experienced an introductory
session of KAATSU exercise at another hospital in10

Effect of KAATSU training on a patient with benign fasciculation syndrome

Table 1. Upper extremity exercise program

Exercise menuMonthTriple sets

6
●

7
●

Rowing●Side raises

●

●

8
●

Depressurization

●

9

●

●

●

●

●

●

●

●

●

●

●

Table 2. Lower extremity exercise program

Exercise menuMonthTriple set

6

9

●

●

●

●

●

●

●

●

Leg extensions

●

●

●

●

●

●

●

●

●

Leg curls

●

●

●

●

●

●

●

●

●

●

●

●

Step-up exercises●

Ladderearly May 2011, followed by the initiation of a
KAATSU exercise program at our hospital in June
2011.

MATERIALS AND METHODSThis study was approved by the ethics committee ofthe University of Tokyo. The patient was informed ofthe methods, procedures and risks, and signed an
informed consent document before participation.
Frequency of exercise: 2 sessions of 30 minutes of
KAATSU exercise of the upper and lower
extremities each week (for 3 months)
Upper extremity exercise program: The KAATSU
belt was set at 40-50/140-210 mmHg, exercise
menu consisting of triple sets, rowing, side raises,and depressurization (Table 1)
Lower extremity exercise program: The KAATSU
belt was set at 40-50/270-400 mmHg, Exercise
menu consisting of leg extensions, leg curls, andstep-up exercises (Table 2)

RESULTS

8●

Squats●7

Through the 3-month KAATSU exercise program,bilateral thigh muscle volume enhanced by about
23% (0.26%/day) from 8,730 to 10,709 cc (Fig. 1)
and right and left knee extensor strength enhanced byabout 26% (0.29%/day) from 30.9 to 39.9 kgf and by
about 44% (0.49%/day) from 38.8 to 57.4 kgf,
respectively (Fig. 2).

●

(cc)
12000
10000
8000
6000
4000
2000
0
pre

post

Figure 1. Change in femoral muscle volume

before and after KAATSU exercise

(kgf)
70
60
50
40
30
20
10
0

right
left

pre

post

Figure 2. Change in bilateral knee extensor

strength before and after KAATSU exercise

Y. Uchida, T. Morita, K. Fukumura., et al.

11

60
50
40
30
20
10

post

Ph
ys
ica
lf
un
cti
on
Ro
in
g
le
ph
ys
ica
Bo
l
di
l
y
Ge
pa
ne
in
ra
lh
ea
lth
So
cia Vitalf
un lity
cti
on
Ro
in
le
g
em
oti
on
M
en
al
ta
lh
ea
lth

0

pre

Figure 3. Results of SF-36v2 questionnaire before and after KAATSU exercise

The results of the questionnaire survey using SF36v2, a measure of health-related QOL, showed
improvements in all 8 domains, including physicalfunctioning, role functioning-physical, bodily pain,
general sense of well-being, vitality, social functioning,role functioning-emotional and mental health (Fig.
3).

DISCUSSION

We experienced the case of a patient with benign
fasciculation syndrome (BFS) in which low-intensity
resistance exercise (KAATSU) resulted in a significant
enhancement in muscle strength and myopachynsis,
as well as improved QOL, including reduced pain, asassessed by a questionnaire survey. These findings
suggest the usefulness of low-intensity KAATSU
exercise for BFS patients.
Several studies have evaluated the effect of highintensity resistance exercise on the muscle strength ofhealthy subjects and patients with various disorders.
Hakkinen et al.(2000) applied a 6-month highintensity knee extension resistance exercise program
to middle-aged and elderly subjects and reported 28%
and 21% enhancements in maximum muscle strength,
respectively. Brochu et al.(2000) also applied a
6-month high-intensity resistance exercise program toan elderly female patient with ischemic heart disease
and observed 18% and 23% enhancements in themuscle strength of the upper and lower extremities,
respectively. The present patient exhibited 26% and
44% enhancements in right and left knee extension
strength, respectively, after a 3-month exercise program.
These values were higher than those reported by
Hakkinen et al.(2000) or Brochu et al.(2002) andcomparable to those reported from studies that applied
KAATSU exercise to healthy subjects or athletes(Karabulut et al., 2007; Wernbom et al., 2008). Thesestudies include one reported by Wernbom et al.(2008),
which reviewed the effects of high-intensity lower

extremity resistance exercise and low-intensity lower
extremity resistance exercise with KAATSU on
quadriceps femoris myopachynsis of healthy subjects.
A high-intensity exercise program performed 2-3
times/week (3-4 sessions, each consisting of 6-10
repetitions at a 60-120-second interval) resulted in a
3-21% enhancement in muscle mass in 3 months
while a low-intensity KAATSU resistance exercise(3-4 sessions, each consisting of 15-30 repetitions at a30-60-second interval) resulted in a 3.6-19.8%
enhancement in muscle mass in the same period. This
result demonstrates that low-intensity KAATSU
resistance exercise results in a comparable degree of
myopachynsis to that achieved by high-intensity
resistance exercise. The present patient exhibited asignificant enhancement in the cross-sectional area
(CSA) of the quadriceps femoris muscle. The CSAs ofthe biceps femoris and adductor muscles also enhanced
after KAATSU exercise. These observations suggestthat low-intensity KAATSU exercise is beneficial for
BFS patients, as it can induce enhanced muscle
strength as well as myopachynsis in these patients.
BFS is a benign disease characterized by fasciculation
as a prominent symptom, but is also accompanied byother symptoms, such as pain, anxiety, fatigability,and paresthesia, and often lasts for several months toyears (Fettel et al., 1982). Major causes include strong
stress and anxiety. Exercise therapy may be performed
for treatment, but no effective rehabilitation program
has been established. Differential diagnoses include
amyotrophic lateral sclerosis (ALS), a serious
neuromuscular disorder. Decreased exercise tolerance
is also observed as a symptom. In the present case of a
BFS patient, low-intensity KAATSU resistance exercise
also resulted in improved QOL, as assessed by the SF36 questionnaire form. Conventional exercise methods
have been shown to induce minimal improvement
in SF-36-based QOL in elderly subjects (Chou et al.,2012). In contrast, KAATSU exercise is performed

12

under the conditions of low-intensity strain and stress,
which might have led to improved QOL. It is also
possible that the exercise program reduced stress, aprecipitating factor of BFS, and thereby improved
fasciculation.
Exercise is the most effective therapy for sarcopenia
and also greatly contributes to improve QOL of patients
through such effects as preventing lifestyle-relateddiseases and delaying the onset of dementia. Aginghas often been associated with hyposecretion of
growth hormone (GH), and GH hyposecretion has
been associated with muscle atrophy and depressive
symptoms, thereby affecting patientsʼ QOL (Hull andHarvey, 2003). Although it is unclear how KAATSU
exercise induces enhanced muscle strength and themechanism of myopachynsis, it has been shown thata significant increase in GH level is observed
immediately after KAATSU exercise (Takarada et al.,2000a; Takano et al., 2005; Abe et al., 2006). Thisobservation indicates the possible involvement of
increased GH level in the mechanism of myopachynsis
in BFS patients. It is also possible that increased GH
level might have led to improved depressive symptoms
and subsequent improvement in QOL, although GH
level was not measured in the present case. Futurestudies should examine whether GH has a role in the
improvement of QOL.
In conclusion, KAATSU exercise was safely
performed on a patient with BFS and improved muscle
strength, muscle volume, and health-related QOL,
including reduced pain, as assessed by the SF-36v2
questionnaire form. For patients with neurologicaldisorders with pain, such as the present patient, active
introduction of KAATSU-based exercise is likely toresult in improved health-related QOL, as well as
enhanced muscle mass and strength.

References
Abe T, Kearns CF, Sato Y (2006) Muscle size and strength are increased
following walk training with restricted venous blood flow from the leg
muscle, Kaatsu-walk training. J Appl Physiol 100: 1460-1466.
Brochu M, Savage P, Lee M, Dee J, Cress ME, Poehlman ET, Tischler M,

Effect of KAATSU training on a patient with benign fasciculation syndrome

Ades PA (2002) Effects of resistance training on physical function inolder disabled women with coronary heart disease. J Appl Physiol 92:
672-678.
Chou CH, Hwang CL, Wu YT (2012) Effect of exercise on physicalfunction, daily living activities, and quality of life in the frail older adults:
a meta-analysis. Arch Phys Med Rehabil 93: 237-244.
Fetell MR, Smallberg G, Lewis LD, Lovelace RE, Hays AP, Rowland LP(1982) A benign motor neuron disorder: delayed cramps andfasciculation after poliomyelitis or myelitis. Ann Neurol 11: 423-427.
Häkkinen K, Alen M, Kallinen M, Newton RU, Kraemer WJ (2000)
Neuromuscular adaptation during prolonged strength training,
detraining and re-strength-training in middle-aged and elderly people.
Eur J Appl Physiol 83: 51-62.
Hull KL, Harvey S (2003) Growth hormone therapy and Quality of Life:possibilities, pitfalls and mechanisms. J Endocrinol 179: 311-333.
Karabulut M, Abe T, Sato Y, Bemben M (2007) Over view ofneuromuscular adaptations of skeletal muscle to KAATSU training. Int J
KAATSU Training Res 3: 1-9.
Takano H, Morita T, Iida H, Asada K, Kato M, Uno K, Hirose K,
Matsumoto A, Takenaka K, Hirata Y, Eto F, Nagai R, Sato Y, Nakajima T(2005) Hemodynamic and hormonal responses to a short-term lowintensity resistance exercise with the reduction of muscle blood flow. Eur J
Appl Physiol 95: 65-73.
Takarada Y, Nakamura Y, Aruga S, Onda T, Miyazaki S, Ishii N(2000a) Rapid increase in plasma growth hormone after low-intensity
resistance exercise with vascular occlusion. J Appl Physiol 88: 61-65.
Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000b) Effects of resistance exercise combined with moderate vascularocclusion on muscle function in humans. J Appl Physiol 88: 2097-2106.
Wernbom M, Augustsson J, Raastad (2008) Ischemic strength training:a low-load alternative to heavy resistance exercise? Scand J Med Sci
Sports 18: 401-416.

Authors affiliations
Y. Uchida, T. Morita, K. Fukumura, T. Otsuka, T. Fukuda, T.
Nakajima, Department of Ischemic Circulatory Physiology, KAATSU
Training, 22nd Century Medical and Research Center, The University ofTokyo, Japan
Y. Sato, KAATSU International University, Sri Lanka

The use of KAATSU Training or the term “KAATSU Training”
in the body text are registered trademarks of KAATSU JAPANCo., Ltd.
“KAATSU Training” is a method created by the inventor,
Yoshiaki Sato, through his more than 45 years of research.
© 2012 KAATSU International

ORIGINAL ARTICLE

Low-intensity kaatsu resistance exercises using anelastic band enhance muscle activation in patients withcardiovascular diseases
T. Fukuda, T. Yasuda, K. Fukumura, H. Iida, T. Morita, Y. Sato, T. Nakajima
Int. J. KAATSU Training Res. 2013; 9: 1-5

Correspondence to:T. Fukuda, Health Center,
Hitotsubashi University, 2-1
Naka, Kunitachi, Tokyo,186-8601 JapanSee end of article forauthors’ affiliations

INTRODUCTION

We examined the effects of blood flow-restricted, low-intensity resistance exercise (termed kaatsu),
using an elastic band for resistance, on muscle activation in patients with cardiovascular diseases. Six
patients with cardiovascular diseases [male, 69±12 (SD) years old, five old myocardial infarction and
one dilated cardiomyopathy] performed biceps flexion exercises (four sets) using an elastic band forresistance with blood flow restriction [BFR (kaatsu training)] or CON (unrestricted blood flow). During
a BFR (kaatsu training) session, subjects wore a kaatsu belt inflated to 110–160 mmHg on theproximal region of both arms. Surface electromyography (EMG) was recorded from the biceps
brachii muscles, and mean integrated EMG (iEMG) was analyzed. Ratings of perceived exertion (RPE)
were measured using the Borg scale immediately after the last set of each exercise (Post). During
exercises, muscle activation increased progressively under BFR (kaatsu training) (approximately 40%),
but not under CON; muscle activation was higher under BFR (kaatsu training) than that under CON inall exercises (P < 0.001). RPE at Post was also higher (P < 0.05) under BFR (kaatsu training) than that
under CON in all exercises. RPE at Post was significantly correlated with increased iEMG in biceps
flexion exercises (r = 0.68, P < 0.001). We conclude that kaatsu training using elastic bands forresistance enhances muscle activation in patients with cardiovascular diseases and may be aneffective method to promote muscle hypertrophy in patients with cardiovascular diseases.
Key words: elastic band, electromyography, kaatsu training

Muscle wasting results from sarcopenia due to aging
and from cachexia caused by diseases such as chronic
heart failure (CHF), chronic obstructive pulmonary
disease (COPD), cancer, chronic kidney disease andother diseases (Thomas 2007). Above all, CHF is adisease of remarkable muscle wasting, and preventing
it by exercise training is important. Nakajima et al.
(2010) recently reported that low-intensity kaatsu
resistance exercises safely increase the muscle
strength/mass and endurance capacity in patientswith ischemic heart disease. Kaatsu training using a
low-intensity resistance exercise appears to be a
promising and useful resistance method for cardiac
rehabilitation.
According to the American College of Sports
Medicine guidelines, the conditions for inducing
muscle hypertrophy and increasing muscle mass are
as follows: (1) More than 65-70% work load of one
repetition maximum (1-RM) is needed. (2) Three tofour sets until exhaustion. (3) Frequency is two-threetimes per week. However, such high-intensity loads
cannot be applied to patients with diseases, especiallyto patients with cardiovascular diseases and to elderly

patients. In the past decade, several studies havereported that muscle hypertrophy can be producedwith low-intensity (20–30% 1-RM) kaatsu training,
regardless of age (Takarada et al. 2000; Abe et al. 2006;
Fujita et al. 2007). As this type of exercise does not
require lifting heavy weights, it might be a feasible
method for cardiac rehabilitation requiring resistance
exercise (Pollock et al. 2000; Balady et al. 2007).
As an elastic band is inexpensive, compact, and easy
to use compared with machines/free weights, elastic
band resistance training is feasible for use in homebased training programs for older subjects or forpatients with a lower level of activity (Zion et al. 2003;
Ribeiro et al. 2009; Colado et al. 2010). We examinedthe effects of low-intensity kaatsu exercise using anelastic band for resistance on muscle activation inpatients with cardiovascular diseases.

MATERIALS AND METHODS
Subjects

Six patients with cardiovascular diseases [male,69±12 years old, five old myocardial infarction and
one dilated cardiomyopathy] participated in this study.
Left ventricular ejection fraction was 55±10% by2

Low-intensity kaatsu resistance exercises using an elastic band enhance muscle activation in patients with cardiovascular diseases

ultrasonic cardiogram. All subjects received a verbal
and written description of the study and provided
written, informed consent prior to participating in the
study. This study was approved by the Ethics
Committee of the University of Tokyo.
ProtocolOne week prior to experiments, all subjects
completed an orientation session, which included
familiarization with BFR and the elastic band exercises
using the “medium” bands (i.e., Red Thera-Bands;
Hygenic Corporation; Akron, Ohio, USA) for 5 subjects
and the “thin” band (i.e., Yellow Thera-Band) for 1
subject. During the orientation session, subjects sat ina chair with the testing arm placed on a table at heartlevel. During biceps flexion exercise, subjects wereseated comfortably on a chair. Both exercises were
performed using an elastic band. The exercise duration
was 2.4 sec and included a 1.2-sec concentric and 1.2sec eccentric exercise cycle controlled by a metronome(50 beats/min). The exercise session (30 repetitions
followed by three sets of 15 repetitions, with rest
periods of 30 sec between sets and exercises) was
determined based on previous studies (Yasuda et al.
2009, 2012).

BFR

In the orientation session, all subjects received
instructions on how to wear the kaatsu belt (30-mm
width; Kaatsu-Master, Sato Sports Plaza, Tokyo,
Japan) at the most proximal region of both arms. Prior
to exercise with BFR, subjects were seated on a chair
and the kaatsu arm cuff was tightened around the arm
to a belt pressure of 40 mmHg. The cuff was theninflated to a pressure of 100 mmHg for 30 sec and thendeflated for 10 sec. This procedure was repeated, until
the final cuff restriction pressure of 110–160 mmHg
was achieved. Once the cuffs were inflated, theyremained inflated for the entire experimental session,
including rest periods between sets and exercises.

ELECTROMYOGRAPHY (EMG)

The skin was abraded with a skin preparation gel(Skinpure, Nihon Kohden, Tokyo, Japan), and cleaned
with alcohol wipes. During the experiment, skin
impedance was less than 2 kΩ. The ground electrodewas positioned on the lateral epicondyle. Bipolar (1cm center-to-center) surface EMG (sEMG) electrodes(Ag/AgCl; Vitrode F; Nihon Kohden) were placedalong the longitudinal axis of the biceps brachii of theleft upper arm. The electrode placement on the biceps
brachii was at the mid position of the upper arm limb
length. EMG signals were recorded and collected on a
personal computer for subsequent analysis. All EMG
signals were digitized at a sampling rate of 1024 Hz
with a bandwidth of 0 Hz–500 kHz (AB 6216; Nihon
Kohden). To determine integrated EMG (iEMG),

signals were fully rectified and integrated (Power Lab
Chart 7 software, ADInstruments, Nagoya, Japan).
During the experimental session, sEMG was recorded
continuously, and each repetition was analyzed
individually for iEMG. iEMG values were divided into
groups of five successive repetitions, and the averagevalue for each group of five repetitions was represented
as a single data point for statistical analysis. To
determine the iEMG ratio of agonist muscles, iEMGsduring each exercise were normalized to Pre, whichwere iEMGs without BFR before the first set of each
exercise. RPE was measured using the Borg scale
immediately after the last set of each exercise (Post)(Borg 1973).

STATISTICAL ANALYSIS

Results are expressed as means ± standard deviation(SD). A two-way analysis of variance with repeatedmeasures (condition / time) was used to evaluate thetraining effects for all dependent variables. Post-hoc
testing was performed using Tukeyʼs technique whenappropriate. All calculations were made with JMP
statistical software package v.9.0 (SAS Institute Inc.,Tokyo, Japan). Pearsonʼs product correlation was used
to determine the relationship between change iniEMG and RPE. Statistical significance was set at P <0.05.

RESULTS

During exercises, muscle activation increased
progressively under BFR (approximately 40%, Fig.1,
Fig. 2), but not under CON. Muscle activation was
significantly higher under BFR than that under CON
in all exercises (P < 0.001, Fig. 2). However, during
exercises, iEMGs were similar among the last five
repetitions of each set under BFR and CON (BFR, 1set,
1.36±0.18, 2set, 1.37±0.28, 3set, 1.44±0.16, 4set,
1.43±0.18, P = NS; CON, 1set, 0.98±0.19, 2set,
0.84±0.12, 3set, 0.86±0.17, 4set, 0.93±0.11, P = NS).
RPE at Post was also higher under BFR than under
CON in all exercises (BFR vs. CON; 1set, 12.5±0.5 vs.
11.3±0.8; 2set, 13.0±1.1 vs. 11.7±1.0; 3set, 13.2±1.0
vs. 11.7±1.0; 4set, 13.8±1.3 vs. 11.8±1.0; all P < 0.05,
Fig. 3). During exercises, RPE significantly increased
progressively under BFR (P < 0.005, 4 set vs. 1 set),
but not under CON. RPE at Post was significantly
correlated with increased iEMG in biceps flexion
exercises (r = 0.68, P < 0.001, Fig. 4).

DISCUSSION

These results suggest that low-intensity kaatsu
resistance exercises using an elastic band increase
muscle activation in patients with cardiovasculardiseases. Low-intensity kaatsu resistance training
using an elastic band appears to be a promising anduseful resistance method for cardiac rehabilitation.
In our previous study, a significant increase of

T. Fukuda, T. Yasuda, K. Fukumura., et al.

3

Fig.1

ｓEMG

iEMG

Relatiive iEMG for agonist musc
cle

1.8
1.6

***

***

CON

***

18

***

1.2
1.0
08
0.8

CON

0.6

BFR

BFR

y = 2.77x + 9.19
r = 0.68
p < 0.001

16

14
1.4

14
12
10

0.4
02
0.2

8

0.0
1

2

3

0.0

4

0.5

1.0

1.5

2.0

Relative iEMG for agonist muscle

sets

Figure 2. Relative integrated EMG data for agonist muscle in

Figure 4. Correlation between relative integrated EMG for

agonist muscle in the last five repetitions of each set and Borg
the experiments. Data represent the last five repetitions ofscale after the last set of each exercise.
each set. CON=control, BFR=blood flow***,
restriction(kaatsu*** p<0.001<0 001 vs. CON
CON; Mean±SD.
M±SD
training). ***, P<0.001 vs. CON; Mean ± SD.
16

*¶

15

13

*

*

14

Bo
org

Fig 3
Fig.

Fig.
g 4

Borg scale
B

Fig. 2

Figure 1. Representative EMG traces fromthe experiment including 30 repetitive
contractions followed by three sets of 15
repetitions. Muscle contractions werebiceps curls. CON=control, BFR=bloodflow restriction (kaatsu training).

*
CON

12

BFR

11
10
1

2

3

4

sets

Figure 3. Borg scale after the last set of each exercise.

CON=control, BFR=blood flow restriction (kaatsu training).
*, P<0.05 vs. CON; ¶, P<0.005 vs. 1 set; Mean ± SD.
*, p<0.05 vs. CON；muscle cross-sectional area (CSA) in the quadriceps
femoris was observed in patients with ischemic heartdisease (Nakajima et al. 2010). Similarly, kaatsu
training also increased hamstring and adductor CSA.
The estimated thigh CSA in that study increased byapproximately 4-10% (P<0.05) following threemonths of the kaatsu training (2 days per week, 32
total training sessions). Muscle CSA in the quadriceps
femoris at 30%, 50% and 70% position of femur
length increased 5.1%, 4.6% and 10.4%, respectively.
Therefore, the magnitude of the hypertrophic potential(percent increase in muscle CSA divided by total
training sessions) in the thigh was about 0.17-0.31%
per training session. Recently, Wernbom et al. (2008)
reviewed the effects of high-intensity resistance
exercise and low-intensity kaatsu resistance exercise¶, p<0.005 vs.1set; Mean±SD.

4

Low-intensity kaatsu resistance exercises using an elastic band enhance muscle activation in patients with cardiovascular diseases(leg extension) on muscle hypertrophy of thequadriceps femoris in healthy subjects. High-intensity
extension exercise two to three times per week, using
80% 1-RM (three to four sets, 6-10 repetitions,interval 60-120 sec), increased the muscle mass by
0.03-0.26% per day and 1-7% per month (3-21% per
three months). On the other hand, low-intensity
kaatsu training using 20-50% 1-RM (three to four
sets, 15-30 repetition, interval 30-60 sec) increased it
by 0.04-0.22% per day and 1.2-6.6% per month (3.618% per three months). Thus, low-intensity kaatsu
resistance training appears to increase muscle mass ina similar way to heavy resistance exercise in healthy
subjects. In our previous study, increases of muscle
CSA in the quadriceps femoris at mid-thigh were
4.6% per three months (Nakajima et al. 2010),
suggesting that even low-intensity kaatsu resistancetraining may be a useful method for inducing muscle
hypertrophy in patients with cardiovascular diseases.
The mechanism by which BFR potentiates thetraining effect of low-intensity resistance training
remains obscure, but it appears to be related, in part,to an increase in muscle activation (Moritani et al.
1992; Takarada et al. 2000; Yasuda et al. 2009). Yasuda
et al. (2009) examined muscle activation during lowintensity kaatsu resistance exercise in healthy subjects.
Unilateral elbow flexion muscle contractions (20%1-RM) were performed in their experiment (three tofour sets, 15-30 repetitions, interval 30 s) with amoderate restriction of blood flow, complete occlusionof blood flow or unrestricted blood flow (control). In
that experiment, the changes in iEMG were greaterwith moderate restriction of blood flow than in thecontrol but without the apparent contractile metabolic
impairment observed with complete occlusion,suggesting that low-intensity muscle contractions
with moderate restriction of blood flow leads to more
intense activation of the muscle relative to the externalload. Meanwhile, recently, the potential mechanisms
behind the blood flow restriction stimulus (5 min, 5
repetitions, interval 3 min) in the absence of exercise
were investigated (Loenneke et al. 2012). Significant
increases in muscle thickness were observed for boththe vastus lateralis (6%, P<0.05) and rectus femoris(22%, P=0.001) along with a significant decrease inplasma volume (15%, P=0.001) and the changes inmuscle thickness were maintained even after the cuffs
had been removed, suggesting that the attenuation ofboth the muscle atrophy and the decline in strengthpreviously observed with brief applications of bloodflow restriction may have been mediated through anacute fluid shift-induced increase in muscle size. Thus,
the mechanism by which BFR potentiates the training
effect of low-intensity resistance training may in partbe related to the acute muscle swelling effects as wellas an increase in muscle activation.
Elastic bands/tubing are widely used in rehabilitative

medicine and in health enhancement for resistancetraining (Zion et al. 2003; Ribeiroet al. 2009; Colado etal. 2010). Elastic bands are also portable, less expensive
and easier to use than weight machines/free weights.
Elastic resistance training has been shown to be afeasible alternative to high-intensity resistance training(Colado & Triplett 2008; Ribeiro et al. 2009; Andersen
et al. 2010). Yasuda et al. (2012) observed that lowintensity, elastic band resistance exercise combinedwith BFR enhances muscle activation in healthy
young subjects. Similar findings were observed in ourstudy using patients with cardiovascular diseases.
Hemostatic and inflammatory responses are major
concerns for patients with cardiovascular disease
when performing an exercise, because these responses
may be related to the cardiovascular events observed
during and after strenuous exercise (Womack et al.
2003). However, our previous study showed that
applying BFR during low-intensity resistance exercise
did not affect exercise-induced changes in markers ofhemostasis (D-dimer and FDP) and inflammation(hsCRP) in patients with ischemic heart disease,although the heart rate and plasma noradrenaline
concentration were increased (Madarame et al. 2013).
Thus, it was suggested that low-intensity kaatsu
resistance training using an elastic band was safe aswell as effective.
In conclusion, low-intensity kaatsu resistancetraining using elastic bands enhances muscle activationin patients with cardiovascular diseases and may be aneffective method to promote muscle hypertrophy inpatients with cardiovascular diseases. Low-intensity
kaatsu training using an elastic band may therefore bean effective method to promote muscle hypertrophy
in older adults or in patients capable of tolerating only
low-load resistance exercise.

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Limacher M, Pina IL, Stein RA, Williams M, Bazzarre T (2000) AHA
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Authors affiliations
T. Fukuda, Health Center, Hitotsubashi University, Tokyo, Japan,
T. Fukuda, T. Yasuda, K. Fukumura, H. Iida, T. Morita, T.
Nakajima, Department of Ischemic Circulatory Physiology, University ofTokyo, Tokyo, Japan,
Y. Sato, Department of Basic Sciences in Medicine, Kaatsu International
University, Battaramulla, Sri Lanka,

The use of KAATSU Training or the term “KAATSU Training”
in the body text are registered trademarks of KAATSU JAPANCo., Ltd.
“KAATSU Training” is a method created by the inventor,
Yoshiaki Sato, through his more than 47 years of research.

CASE REPORTKAATSU training® in a case of patients withperiventricular leukomalacia (PVL)
H. Iwashita, T. Morita, Y. Sato, T. Nakajima
Int. J. KAATSU Training Res. 2014; 10: 7-11

Correspondence to:
H. Iwashita,
Komone Acupuncture Clinic,
3-10-18 Mukaihara,
Itabashi-ku, Tokyo, 173-0036,
Japan
iwashita@komone.jp
See end of article forauthors’ affiliations[Objective] The effectiveness of KAATSU training has been reported in wide-ranging fields fromsports medicine to rehabilitation, and KAATSU training has been clinically applied. However, there
have been only limited reports on pediatric cases. We performed KAATSU training in a pediatricpatient with periventricular leukomalacia (PVL) and examined its effectiveness and safety for cerebral
palsy. We report here the results of this examination.
[Methods] KAATSU training was performed on a PVL patient on an outpatient basis. This training
was performed once a week for 14 weeks and involved mainly three specified motions of the upperand lower limbs. Evaluation was performed using the Gross Motor Function Measure (Gross Motor
Function Classification System: GMFM) and videos. In this report, the effectiveness of short-term
KAATSU training was compared with that of intensive physical therapy using data in the literature.
[Results] QOL improved due to short-term reduction of muscle tonus and increased acquired
movements resulting from KAATSU training.
[Conclusion] The results of this report suggest that KAATSU training can be effective in PVL patients.
Further examination is necessary with increased cases and evaluation methods.
Key words: Periventricular leukomalacia, KAATSU training, spastic paralysis, cerebral palsy

INTRODUCTION

PVL is a disorder reported by Banker et al. in 19621).
It occurs most commonly in premature infants, mainly
those born at less than 32 weeks of gestation. It is alesion with periventricular necrosis as its major
component. Since the corticospinal tracts pass throughthe periventricular white matter, spastic paraplegia
develops that is particularly severe in the lower limbs.
The severity of the disability or impairment can vary,
including severe impairment such as dragging of feetwhen walking, inability to sit, inability to walk, andinability to swallow. Intellectual impairment is also
seen in many cases. There is currently no effective
treatment. We report here a case of PVL in which
KAATSU training was effective for spastic quadriplegia.
In addition, we compared the effectiveness of shortterm KAATSU training with that of intensive physicaltherapy using data in the literature.

METHODS

1. Ethical consideration

This study was approved by the Research Ethics
Committee of the Graduate School of Medicine andFaculty of Medicine at the University of Tokyo(application number: 3088). Informed consent was
obtained from the guardian of the patient before
participation in this study.

2. Case report

Patient: A boy aged 7 years and 10 months
Diagnosed disease: PVL
Chief complaint: Spastic quadriplegia
Family history: Non-contributory
History of present illness: The patient was born bycesarean section at 28 weeks and 1 day of gestationand had a birth weight of 996g.
The patient and his twin sibling were conceived
naturally. His twin sibling was born first and had diedat birth.
One- and five-minute Apgar scores were 6 and 7,
respectively.
The patient was an extremely low-birth weight infant
with apneic events and RDS and was hospitalized in
the NICU until 91 weeks after birth.
Age 1 year and 7 months: initiation of physical therapy
Age 2 years and 9 months to 3 years and 10 months:
initiation of botulinum toxin therapy (total: 4 times)
Age 4 years and 10 months: bilateral muscle release in
the hip
The patient continued rehabilitation therapy but
began KAATSU training because muscle tonus
increased with the growth of the body and acquisitionof movements slowed.
3. Methodsa) Motion conditions
KAATSU belts were placed around the upper arms

8

KAATSU training® in a case of patients with periventricular leukomalacia (PVL)

in the axillary area and around the upper legs in
the thigh area. KAATSU MASTER was used for the
training. The upper limb training began with a cuff
tightness pressure of 40-45 mmHg and a settingpressure of 80-90 mmHg, and the lower limb training
with 55-65 mmHg and 110-120 mmHg, respectively.
Since the subject was unable to speak, appropriatepressure was estimated using the coloration of thepalms and feet, pulse rate, and facial expression.
Pressure was applied and released and this process was
repeated three times. Passive ROM training was
performed, and then KAATSU training was begun.
The training involved the following items: three
specified motions of the upper and lower limbs,
KAASTU walk, and muscle strength training using
light weights. One to two sets of the first item were
performed once a week for 14 weeks. Generally, thisitem was performed 10-20 times for the first set andin an all-out manner for the second set. Carefulobservations were made of changes in the patientʼsphysical conditions during the training. Care wastaken to control the vagal reflex by keeping thepatientʼs head below the level of his heart when thepressure was released.
b) Evaluation
1) GMFMThe GMFM evaluates the motor ability of children
with cerebral palsy and involves movements that canbe performed by children with normal motor ability
by age 5 years. These movements are classified into
five dimensions of A: lying and rolling, B: sitting, C:
crawling and kneeling, D: standing, and E: walking
and running. The GMFM contains 88 items each ofwhich is scored on a 0-3 rating scale and can assess indetails the motor ability of young children2,3). The
GMFM is effective in the evaluation of short-termchanges4). It was used to evaluate and compare ourpatientʼs motor ability before KAATSU training andafter 14 weeks of training.
2) Video
In cerebral palsy associated with PVL, there is acombination of various factors, including delayed
motor development, abnormal postural tone suchas hypertonia, and sensory, perception, andcognitive immaturity5). Therefore, its mechanism ofpathogenesis is difficult to evaluate. Thus, in thisreport, comprehensive evaluation and examination
were performed using evaluation of videos.

RESULTS

1. GMFM results

Table 1 shows the GMFM results of the patient. The
GMFM was also evaluated before and after botulinum
toxin therapy and before and after bilateral muscle
release in the hip. These results are also included in
the table. The GMFM dimensions of D: standing and
E: walking and running were omitted because thepatient was unable to perform these motor functions.
When the GMFM results were compared before
botulinum toxin therapy and at the third therapy
session, the motor functions were markedly improved
as shown in Table 1. However, when comparison wasmade for each injection, there was less improvement.
There was almost no improvement at the third therapy
session. For bilateral muscle release in the hip, Table 1
shows improvements but the scores were decreased
before KAATSU therapy began. That is, bilateralmuscle release in the hip has limited effectiveness, andit also places a burden on young children.
For KAATSU training, there was one post-training
evaluation at three months after training. Thus, longterm evaluation is necessary. In the short-term
evaluation, the scores increased to 51/51 for A: lying
and rolling and 36/60 for B: sitting. Therefore,
KAATSU training showed effectiveness that wascomparable to or better than other treatment methods.

Table 1. GMFM evaluation of KAATSU training, botulinum toxin therapy, and bilateral muscle release in the hip in our patient

KAATSU training
At thestart

After 3mo

Bilateral muscle
release in the hip

Botulinum toxin therapy
First

SecondThird

Beforeinjection

After 3mo

Beforeinjection

After 3mo

Beforeinjection

After 3mo

Beforesurgery

After 1mo

A: Lying androlling

41/51
51/51
(80.0%) (100%)43(84.3)

43(84.3)

45(88.2)

50(98.0)

50(98.0)

50(98.0)

45(88.2)

51(100)

B: Sitting

28/60(46.6)

36/60(60.0）

11(18.3)

20(33.3)

20(33.3)

26(43.3)

26(43.3)

29(48.3)

20(33.3)

29(48.3)

C: Crawling andkneeling

5/42(11.9)

8/42(19.0)

0

3
(7.1)

3
(7.1)

7
(16.6)

7(16.6)

6(14.2)

3(7.1)

9(21.4)

H. Iwashita, T. Morita, Y. Sato., et al.

9

VIDEO EVALUATION

Figure 1 shows images of the patient immediately
after beginning KAATSU training. There was severe
muscle tonus, and bands were placed at his waist andankles for immobilization when sitting in thewheelchair (Fig. 1a). Adductor muscle tonus wasparticularly severe, and three staff members wererequired to place KAATSU belts on the lower limbs at
the first training session. The patient also had difficulty
moving the upper limbs only and the lower limbs

only. When the patient performed arm curls, his trunk
would bend backward (Fig. 1b). Similarly, when thepatient kicked a ball, his trunk would bend backward
and he needed to be supported from the back (Fig. 1c).
In KAATSU walk, his feet would move forward but his
knees would not fully extend, showing equinus
deformity (Fig. 1d).
Figure 2 shows the conditions on the 14th week of
KAATSU training. The patient achieved independent
sitting and reduced adductor muscle tonus (Fig. 2a).

Figure(a)Figure(b)Figure(c)Figure(d)Figure 1. Photographs taken immediately after KAATSU training began (explanations for Figures 1a, 1b, 1c, and 1d are in themain text)

Figure(a)Figure(b)Figure 2. Conditions during KAATSU training on the 14th week (explanations for Figures 2a and 2b are in the main text)

Figure(a)Figure(c)Figure(b)Figure 3. Acquired movements after KAATSU training (on the 14th week)(explanations for Figures 3a, 3b, and 3c are in the main text)

10

KAATSU training® in a case of patients with periventricular leukomalacia (PVL)

In addition, the patient was able to move the upper
limbs only and the lower limbs only. Beginning aroundthe tenth week, he was able to sit on a chair on his
own to perform his upper limb training (Fig. 2b).
Figure 3 shows the acquired movements after 14
weeks of KAATSU training. Since paper cups are softand easily crushed, handling such cups is a difficult act
for young children with severe spasticity. Our patient
was able to use paper cups after KAATSU training (Fig.
3a). He was previously unable to crawl because histrunk area was weak and he could not maintain the
posture. However, he was able to successfully crawl
after KAATSU training (Fig. 3b). The changes in thelower limbs were not sufficiently large to be observableon images. However, the patient was able to extend
his knees to put his heels on the floor while staff
supported him in standing training (Fig. 3c). When
comparison was made between the video immediately
after training began and that after 14 weeks of training,
the results suggest that KAATSU training can help
reduce muscle tonus, improve muscle control, andincrease muscle strength.

DISCUSSION

When the effectiveness of training in young children
is examined, it is most important to determine if thepositive results are due to childrenʼs development or
the effects of training. There are several reports ondevelopment that is characteristic of young children
with cerebral palsy. In the report by Rosenbaum et al.,the motor development curve was until 15 years ofage. The children reached 90% of their motor function
based on the GMFM by approximately age 5 years,
and the motor development curve plateaued byapproximately 7 years6). In addition, the subjects were
determined to have level IV severity of cerebral palsy
based on a five-level severity scale of the Gross Motor
Function Classification System (GMFCS)7). Hanna et
al. reported that prognosis differed depending on the
GMFCS level and that the muscle strength in level IV
children decreased starting around 7 years of age8). It

is also speculated from the results of these reports thatthe subjects were in a state where acquisition of
movements was difficult due to his development. In
such a state, acquired movements gained in the shortterm of 14 weeks can be attributed to the effectivenessof KAATSU training.
The effectiveness of short-term KAATSU training
was compared with that of intensive physical therapy.
Intensive physical therapy increases the GMFM scorescompared with conventional physical therapy and isrecommended (grade B) in the second edition of the
Guidelines for Rehabilitation of Children with Cerebral
Palsy9). Comparison was made between our patientand other patients with GMFCS level IV (same as ourpatient) who were reported in the literature10),11),12) (asshown in Table 2). In the study of Asakai et al.13), themean GMFM percent score of patients at GMFCS level
IV was 28.8% at the first examination, and there wasan improvement of 2.1 percentage points after a meanof 1.9 months of intensive physical therapy. In ourpatient, the mean GMFM percent score was 27.7% at
the initial examination, and there was an improvementof 8.1 percentage points after 14 weeks of KAATSU
training. Asakai et al. used a short training period witha mean of 1.9 months. The frequency was 5 sessions
per week (40 minutes per session) for physical therapy,
5 sessions per week (20 minutes per session) for
in-ward training (standing and walking training
performed by ward personnel), and a mean of 3
sessions per week for occupational therapy. Other
services were provided as needed, including speechtherapy and psychological evaluation and counseling.
Our patient underwent less frequent and shorter
training sessions at one session per week and about 40
minutes per session (including time used to place thedevice). Asakai et al. found that the effectiveness ofintensive training was shown by approximately 7-10
years of age, mainly for gross motor functions in young
children with spastic cerebral palsy at GMFCS level IV.
The effectiveness was particularly marked by age 6.
The mean age of these children was 3 years and 8

Table 2. Effectiveness of intensive physical therapy and KAATSU training in improvement of GMFM

Study

No. ofcases

GMFM severity

Mean age

Frequency of
training

Training
periodChanges intotal score

1 yr

4.2%

2 yr

7.2%

McLaughlin et al.

1998

17

71.3%

7.2 yr171.8 h/yr

Wright et al.

1998

12

56.5%

4 yr 10 mo

116 min/wk

1 yr

4.4%

Bower E. et al.

2001

28

GMFM III or below

5.5 yr

1 h/day or more

6 mo

5.1%

Asakai et al.

2003

47

GMFM III 52.6%

5 yr 5 mo

2.1 mo

3.7%

55

GMFM IV 28.8%

3 yr 8 mo

40 min/day or
more

1.9 mo2.1%

Our patient

2013

1

GMFM IV

7 yr 10 mo

40 min/wk

14 wk

8.1%

27.7%

(partly revised from Asakai et al.13)

H. Iwashita, T. Morita, Y. Sato., et al.

months. Our patient was older at 7 years and 10
months, but there was large improvement of 8.1
percentage points. These results suggest that a certain
level of effectiveness can be expected from KAATSU
training in young children with cerebral palsy
compared with other training methods. In addition,
KAATSU training has the advantages of being
minimally invasive and easy to perform repeatedly.
However, there are many issues, including accuracy inthe comparison of our case with cases in other reports
because of the small number of cases and nonuniformity of severity, rehabilitation period, andenvironment. Thus, further studies are necessary.

CONCLUSION

The results of this study suggest that KAATSU
training can be an effective treatment method foryoung children with PVL. Further studies are necessary
with increased number of patients and evaluation
methods.

References
1) Banker BQ，Larroche JC: Periventricular leukomalacia of infancy .
Arch Neurol 7：386-410，1962
2) Rusell D, Rosenbaum P, Cadman D, et al: The gross motor function
measure: A means to evaluate the effects of physical therapy. Dev
Med Child Neurol 31 : 341-352, 1989
3) Rusell D，Rosenbaum P，Gowland C, et al：GMFM̶Gross motor
ability scale. Rating Scale for cerebral palsy (in Japanese), second
edition, translated by Kondo Izumi, Michitaka Fukuda, Igaku Shoin,
Tokyo, p9-38，2000
4) Takahashi H, Seki M, Riu M: A study of pediatric rehabilitation
treatment with Gross Motor Function Measure the (GMFM)–Literature
review (in Japanese) Rehabilitation Medicine 42: 475-488，2005
5) Kaneko T, Noguchi K, Matsumura S: Developmental characteristics
and exercise therapy of cerebral palsy and diplegia withperiventricular leukomalacia (in Japanese) Physical Therapy 30; 162-

11

165,2003
6) Rosenbaum PL, Walter SD, Hanna SE et al：Prognosis for grossmotor function in cerebral palsy : creation of motor development
curves. JAMA 288:1357-1363 , 2002
7) Wood E, Rosenbaum P: The gross motor function classification systemfor cerebral palsy: a study of reliability and stability over time. Dev
Med Child Neurol 42(5) : 292-296 , 2000
8) Hanna SE, Rosenbaum P, Bartlett D et al: Stability and decline ingross motor function among children and youth with cerebral palsy
age 2 to 21 years. Dev Med Child Neurol 51(4) : 295-302, 20099) Kondo I, Takahashi H, Saeki M, et al.: Cerebral palsy rehabilitation
guidelines, the second edition of the Japanese Association of
Rehabilitation Medicine practice guidelines committee, the Japanese
Association of Rehabilitation Medicine cerebral palsy rehabilitation
guidelines development committee editing, Kanehara-shuppan, Tokyo
123-124, 201410) McLaughlin J, Graubert C, Hays Roberts T, et al: Selective dorsal
rhizotomy : efficacy and safety in an investigator masked randomized
clinical trial. Dev Med Child Neurol 40:220-233, 1998
11) Wright FV, Sheil EMH, Drake JM, et al: Evaluation of selective
dorsal rhizotomy : meta-analysis of three randomized controlled
trials. Dev Med Child Neurol 40 :239-247,1998
12) Bower E, Michell D, Burnett M, et al : Randomized controlled trialof physiotheraphy in 56 children with cerebral palsy followed for 18
months. Dev Med Child Neurol 43:4-15,2001
13) Asakai Y, Watanabe Y: Significance of intensive training for grossmotor in infant with cerebral palsy (in Japanese). Rehabilitation
Medicine 40: 833-838, 2003

Authors affiliations
Hiroki Iwashita, Komone Acupuncture Clinic,
Toshihiro Morita, Toshiaki Nakajima, Department of Ischemic
Circulatory Physiology – KAATSU Training, University of Tokyo,
Yoshiaki Sato, KAATSU International University

The use of KAATSU Training or the term “KAATSU Training”
in the body text are registered trademarks of KAATSU JAPANCo., Ltd.
“KAATSU Training” is a method created by the inventor,
Yoshiaki Sato, through his more than 48 years of research.

CASE REPORTKAATSU training® as a new exercise therapy forfemoral head avascular necrosis: A case study
T. Nakajima, T. Yasuda, K. Fukumura, M. Kurano, T. Imanishi, T. Morita, Y. Sato, Y. Hiraizumi
Int. J. KAATSU Training Res. 2015; 11: 1-6

Correspondence to:
Toshiaki Nakajima, Heart
Center, Dokkyo Medical
University HospitalProf. Toshiaki Nakajima, M.D.
Heart Center, Dokkyo Medical
University Hospital, 880
Kitakobayashi, Mibu-machi,
Shimotsuga-gun, Tochigi, 3210293, Japan
nakat@dokkyomed.ac.jp
See end of article forauthors’ affiliations

Introduction

Femoral head avascular necrosis is a condition in which part of the femoral head undergoes necrosis
due to decreased blood flow. The femoral head gradually disintegrates causing pain and even today,
there are no effective rehabilitation methods other than symptomatic treatment such as decreasing theload on the hip joints with the use of a cane or walker. We herein describe our insights into thiscondition based on our experience with a case of femoral head avascular necrosis caused by steroid
use in which KAATSU training was found to be highly effective. The patient was a 34-year-old woman(154 cm tall and weighing 50 kg, a radiologist). Since the age of 23, this patient had been receiving
steroid treatment to control her refractory asthma. She later developed pain in her right hip andgradually suffered hip joint deformation, restricted range of motion, and difficulty in walking. MRI
revealed Association Research Circulation Osseous (ARCO) stage IV disease. She suffered marked
pain of the right hip joint every time she walked, occasionally falling and required a cane to walk. At
the patientʼ s own request, she received KAATSU training including KAATSU walking over a period of
3 months (total 28 sessions). Various assessments were carried out before and after training todetermine the effects of KAATSU training. QOL was determined by SF–36v2, and marked
improvement of role physical, body pain, general health, vitality, and social functioning were noted.
Before training, the Japanese Orthopaedic Association (JOA) hip scores for pain were 10 (right), 40(left), walking ability 16 (right), 20 (left), while 3 months after training, these scores were markedly
improved in the affected side. Furthermore, not only did muscle strength on the affected side show
marked improvement, but the MRI also revealed a tendency for improvement of the right femoral headavascular necrosis. DEXA showed signs of a clear increase in bone mineral density. Based on theabove, these results suggest that KAATSU training is extremely useful as a rehabilitation method inpatients with femoral head avascular necrosis. But, further larger scale investigations should be
carried out in the future to support our findings.
Key words: Femoral head avascuar necrosis, KAATSU training, Bone density, Pain, Rehabilitation

Femoral head avascular necrosis is a condition inwhich part of the femoral head suffers necrosis due toa decrease in blood flow. Although the cause remains
unknown, possibilities include thrombosis due toabnormalities in the blood coagulation system, andinjuries of the vascular endothelium (Chang et al.,1993). Risk factors include the administration ofsteroids (Weinstein, 2011). Steroid administration
leads to decreases in blood flow due to increases in theinternal pressure of the femoral head resulting fromhypertrophy and proliferation of adipocytes. Together
with decrease in blood flow, it has been reported that
direct inhibition of osteoblasts and osteocytes may also
be involved (Cruess, 1976; Kerachian et al., 2009;
Ding et al., 2015). Pain occurs as the femoral headdisintegrates, and other than symptomatic treatment
such as using canes and walkers to reduce weightbearing stress upon the hip joint, there are no effective
rehabilitation methods (Wang et al., 2014). Muscle

strength training is often used in the rehabilitation
exercises but there are cases where pain will make it
impossible to exercise while weight-bearing is notpossible and so this is often ineffective. Therefore,
even today, it is difficult to prevent the progressionof disease with conservative treatment alone, andprognosis is poor so that surgery is eventually required.
KAATSU training (Takarada et al., 2000; Sato et al.,2007) allows for muscle growth when blood flow isrestricted, even with low stress training, and major
increases in muscle mass can be achieved. It is indeed
a useful rehabilitation method for patients withvarious diseases and our aging society (Nakajima,
2010; Abe et al., 2010; Ozaki et al., 2011; Nakajima
et al., 2011; Yasuda et al., 2014). Exercise methods
include no load, elastic band (Yasuda et al., 2015), andin addition to free weight, walking (Abe et al., 2006),
and ergometer (Abe et al., 2010). In this way KAATSU
training is being featured as a method of rehabilitationin cases where high exercise loads are to be avoided.

2

KAATSU training® as a new exercise therapy for femoral head avascular necrosis: A case study

In addition, KAATSU training with restricted bloodflow causes decreases in the intramuscular oxygen
partial pressure during exercise and hypoxemia. With
active refilling of vasculature in response to belt
release, reactive hyperemia develops and vascularendothelial growth factor (VEGF) and nitric oxide(NO) production are enhanced (Takano et al., 2005;
Horiuchi and Okita, 2012) and this may lead to
improvements in both endothelial function andcirculation. In this way, KAATSU training appears tobe effective as a rehabilitation method in patients withfemoral head avascular necrosis, but there are few
reports regarding the effects of KAATSU training inthese patients until now.
We experienced a case of femoral head avascularnecrosis in one patient and would like to report ourfindings.

1. Case introduction

Case report: A 34-year-old woman (height 154 cm,
weight 50 kg, profession radiologist)
Diagnosis: femoral head avascular necrosis
Chief complaint: pain of the hip joint during
ambulation, gait disturbance.
Family history: no notable findings.
History of present illness: bronchial asthma with an
onset during youth. Since experiencing a severe
attack of aspirin-induced asthma at age 15, the patient
became dependent on steroids and repeatedly required
hospitalization because of poor control and had
continued to take a large dose of steroids. As of age 23,
HOT was introduced, and since age 25, as soon as her
clinical rotations started, pain in the right hip joint
began to manifest. Thereafter, deformation of the right
hip joint progressed until at age 33, and she developed
femoral head avascular necrosis (OA). Gradually, thehip joint pain worsened with the limitations in her
range of motion (ROM), and abduction externalrotation contracture appeared. The patient suffered
extreme pain in the right pelvis during walking and inorder to reduce the joint load during walking had
been using a cane. She presented at our hospital
hoping to receive exercise treatment with KAATSU
training. The patient had been taking prednisolone 3
mg/day, theophylline, montelukast sodium, andsalmeterol/fluticasone.
This research was approved by the Institutional
Review Board at the University of Tokyo andperformed after receiving patient consent.

2. KAATSU training protocol

A KAATSU belt is wrapped around the base of thethigh and a KAATSU Master device (KAATSU Japan,
Co., Ltd) was used. KAATSU training was provided
for a total of 28 sessions over 3 months. Base pressure
was 45 – 50 SKU. The optimal pressure started at 100– 140 SKU and while repeatedly pressurizing anddepressurizing, it gradually increased in 20 SKU
increments, until an optimal pressure was reached.
The training menu was as follows. 1) 3 point set: Toecurls, ankle dorsiflexion, and ankle plantar flexion. 2)
KAATSU walk: gradually increased distance toapproximately 150 to 300m during each session until
a comfortable walking speed was achieved. 3) NonKAATSU walk: belts were removed and the patient
was allowed to walk for 75m to check for symptoms.
In late stage intervention, calf-raises and squats wereadded, and the patient extended her comfortable
walking distance to approximately 300m. Calf raises
and squats were performed standing and bearing oneʼs
own weight. The KAATSU side in the early stage ofintervention was the affected leg only, starting with a
KAATSU pressure of 300-320 SKU. In the latter stages,
in addition to the affected right thigh, the healthy left
thigh (160-300 SKU) exercise therapy under KAATSU
condition was also conducted.

3. Evaluation

The following evaluations were conducted before
and after training.
1) Magnetic resonance imaging (MRI)2) Life functioning: 36-item short form health survey(SF–36v2).
The effect of training on life functioning wasinvestigated using the SF-36v2 evaluation survey.
Role physical, body pain, general health, vitality,
social functioning, role emotional, and mental
health were assessed.
3) Muscle strength evaluation using Cybex
Measurements were taken with the subject seatedin a chair with the trunk and thighs immobilized.
Exercise involved bending the knee joint 90°, froma flexed position to extension and flexion. Bilaterallower limb muscle strength (isomeric knee extension
strength: knee joint 75°, isokinetic knee extension
and flexion muscle strength: 30°/sec, 90°/sec, 180°/sec) was determined.
4) Functional analysis of the hip joint by Japanese
Orthopaedic Association (JOA) hip scores as shownin Table 1 (Takatori et al., 2010)5) Dual energy x-ray absorbed absorptiometry (DEXA)
bone mineral density measurement device.

4. Results and clinical course

MRI findings before training are shown in Fig. 1A(left). T1 and T2 weighted images of the right femoral
head weight-bearing areas revealed areas of low
intensity signals. The surrounding areas showed highsignals in the T2 weighted image, suggesting bone
necrosis and an edematous change of the surrounding
marrow. Her right hip joint showed joint space
narrowing and formation of bone spurs, while thefemoral head showed signs of flattening leading to

T. Nakajima, T. Yasuda, K. Fukumura., et al.

3

Table 1. JOA scores for the hip joint (From Takatori et al., 2010)

I. Painpoint
No complaints regarding the hip joint
40
Indefinite complaints (feeling strange, fatigue) present but no pain
35
No pain during walking (however at the start of walking or after walking for long distances there is sometimes pain) 30
No spontaneous pain. Pain during walking, but disappears with short rests
20
Spontaneous pain is sometimes present. Pain during walking but alleviates with rest
10
Continuous spontaneous pain or nocturnal pain0
II. Range of motion assessment
Flexion: Joint angle counted in 10° intervals, one point per 10°. However, all points beyond 120° are counted
as 12 points (if joint contracture is present this is subtracted and evaluations based on movable range).
Abduction: Joint angles are measured in 10° increments and each 10° is counted as 2 points.
However any angle over 30° is counted as 8 points
III. Walking ability
Absolutely no complaints regarding the joint
40
Indefinite complaint (feeling strange, fatigue), no pain
35
No pain during walks (however there may be pain at the start of the walk or after walking long distances)
30
No spontaneous pain. Pain during walks disappears after short rests.
20
Spontaneous pain is sometimes present. Pain present during walks but is relieved after rest.
10
Continuous or spontaneous pain or nocturnal pain.
0
IV. Activities of daily living (ADL)
Evaluationeasy
difficult
impossible
Knee blankets
420Standing work (includes housework) (continues for about 30 minutes).
4
2
0
If rests are required, it is considered “difficult”. In cases where exercise
can only be continued for 5 minutes, it is considered “impossible”.
Squatting and standing (those who require assistance: consider it “difficult”)
4
2
0
Climbing up and down stairs (those who require a railing: consider it “difficult”)
4
2
0
Getting on and off cars and buses
4
2
0

Figure 1. A: MRI findings before and after KAATSU training. Before training (left), after training (right) B: Dual-energy x-ray
absorptiometry (DEXA) scan bone mineral density findings before and after KAATSU training. After training, bone mineraldensity in the right leg (affected side) was clearly increased, compared with the left leg (healthy side).

4

KAATSU training® as a new exercise therapy for femoral head avascular necrosis: A case study

Figure 2. Efficacy of KAATSU training in a patient with femoral head avascular necrosis. A: Effect on JOA score. a: JOA score(total, comprehensive), b: Pain, c: Walking, d: ROM (range of motion), B: SF-36v2. Role physical, Body pain, General health,
Vitality, Social functioning, Role emotional, Mental healtha case of secondary arthrosis. Surrounding areas
included a small high-signal intensity subchondralbone cyst. The other hip joint showed no signs ofabnormally high intensity areas. Based on these MRI
findings, the patient was diagnosed with Association
Research Circulation Osseous (ARCO) stage IV rightfemoral head avascular necrosis and secondary hiparthrosis.
Before and after training, several evaluations werecarried out. Fig. 2A shows the effectiveness of KAATSU
training on JOA hip scores. JOA (pain, b) scores
were 10 (right), 40 (left); while the JOA (walk, c)scores were 16 (right), 20 (left); and JOA (score,comprehensive, a) was 55 (right), 84 (left). After
training, all scores showed marked improvement in
the right affected leg compared to the left healthy leg.
JOA (ROM (range of motion), d) revealed no signs ofimprovement on the affected side. In the latter half oftraining, pain of the hip joint during walking dissipated
so that the patient no longer required a cane to walk.
In addition, there was a clear improvement in thepatientʼs walking style.
Fig. 2B shows the effect on SF–36v2 before andafter KAATSU training. Role physical, body pain,
general health, vitality, social functioning, roleemotional, and mental health were evaluated. Physicalfunction, role physical, body pain, general health,vitality, social functioning all improved after KAATSU
training
Figure 3 shows the effects of KAATSU training onlower limb muscle strength (extension and flexion).
Muscle strength during extension and flexion wasmarkedly improved in the right leg on the affectedside, compared to the healthy left leg.
Fig. 1B shows the efficacy of using KAATSU training
on bone mineral density measured by DEXA. There
was a clear increase in right affected leg bone mineraldensity from 0.798 to 0.836. On the other hand, theleft healthy leg went from 0.857 to 0.868 with no clear
signs of improvement. Furthermore, MRI findings
after KAATSU training shown in Fig. 1A (right)
showed a tendency for the right femoral head necrosis
to improve.

T. Nakajima, T. Yasuda, K. Fukumura., et al.

5

Figure 3. Effect of KAATSU training on lower limb muscle strength (knee extension, knee flexion) measured by Cybex.

5. Discussion

We treated a patient with femoral head avascularnecrosis for 3 months with KAATSU training andnoted the following improvements. 1) After KAATSU
training, the JOA score of the hip joint and the JOA
pain score both improved markedly. 2) Together with
an apparent improvement in gait, femoral muscle
strength improvement was noted while bone mineraldensity of the lower limbs had clearly increased in
the affected side. 3) MRIs showed a tendency for
improvement of the right femoral head necrotic site.
In this patient, SF–36v2 was evaluated. Of the life
functions, physical function, role physical, general
health, vitality, social functioning, and walking ability
based on the Japan Orthopedic Association hip score(JOA hip score) (Takatori et al., 2010) had all improved.
Furthermore, muscle strength on the affected side had
increased, proving that muscle strength improvementwith KAATSU training can lead to improved walking
ability and have a major impact on enhancing QOL.
This meant that in the latter half of the training, thepatient became able to walk without a cane. In
addition, the affected limb could support weight
without use of a cane, and it is believed that there wasa clear increase in bone mineral density on the affectedside.
The mechanism for this effect of KAATSU training
includes a characteristic of KAATSU training (Takaradaet al., 2000; Sato et al., 2007) which is that exercise
under restricted muscle blood flow conditions leads toincreased muscle strength and muscle growth after
only a short period of low stress exercise. In this case,
we observed a clear increase in muscle strength with
only 3 months of KAATSU training. KAATSU training
is just the right rehabilitation method for patients withvarious diseases and our aging society (Nakajima,
2010; Abe et al., 2010; Ozaki et al., 2011; Nakajima etal., 2011; Yasuda et al., 2014). Loading included nonweight bearing, elastic band (Yasuda et al., 2015), a

dumbbell, walking (Abe et al., 2006), and ergometer(Abe et al., 2010) loads. In this way, KAATSU training
is an extremely useful rehabilitation method foruse in patients in whom excessive stress would beinappropriate. In our case, we added squats and calf
raises to the KAATSU walking schedule, carrying out
various forms of exercise in a way that the femoral
head would not have to bear any weight. As a result,patient ADLs improved markedly. However, the ROM
did not improve. Therefore, in the future we believe a
longer investigation is warranted.
Furthermore, after KAATSU training, pain scoresbased on the SF–36v2 and JOA hip scores showed
clear signs of improvement. With improvement ofher pain, the patient no longer required a cane andwe believe her quality of life has been greatly
improved because she regained the ability to walk.
The mechanism responsible for improving pain in
KAATSU training is still unknown, but increased
muscle strength, muscle growth and alleviation of theweight-bearing on the hip joints are believed to play arole. On the other hand, KAATSU training leads to adecrease in intramuscular partial O2 pressure andhypoxemia during exercise under restricted blood
flow. Reactive hyperemia develops and vascularendothelial growth factor (VEGF), and nitric oxide(NO) production is enhanced (Takano et al., 2005;
Horiuchi and Okita, 2012) in response to vascularrefilling after the belts are released, leading to
improvements in endothelial function and blood
flow. We propose these improvements in blood flow
helped to heal the necrosis in the femoral head.
Animal models of femoral head avascular necrosis
caused by steroids have actually shown that as bloodflow into the femoral head decreases, both VEGF
protein and mRNA decrease (Wang et al., 2010).
However, the improvement of MRIs in the present
study for 3 months was minor so the effects should befurther confirmed in a long-term study. In addition,

6

KAATSU training® as a new exercise therapy for femoral head avascular necrosis: A case study

investigations into elucidating the mechanism behind
pain relief with KAATSU training are warranted.
Conservative treatment for femoral head avascularnecrosis should be instituted carefully to avoid
crushing the femoral head, and there are currently
no effective rehabilitation methods other thansymptomatic treatment such as using a cane or walker
to reduce placing weight on the affected hip joint.
From the present study, KAATSU training may be auseful rehabilitation method to treat femoral headavascular necrosis.

Summary

We reported our experience with a patient who
developed femoral head avascular necrosis while onsteroid therapy who was successfully treated withKAATSU training. We believe further clinical research
will be necessary.
<Nakajima T, Yasuda T, Fukumura K, and Morita T
have participated in seminars until September 2014
donated by KAATSU Japan.>

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11) Ozaki H, Sakamaki M, Yasuda T, Fujita S, Ogasawara R, Sugaya
M, Nakajima T, Abe T (2011) Increases in Thigh Muscle Volume andStrength by Walk Training with Leg Blood Flow Reduction in Older
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12) Sato Y, Ishii N, Nakajima T, Abe T (2007) Theory and Practice of
KAATSU Training, Kodansha.
13) Takano H, Morita T, Iida H, Asada K, Kato M, Uno K, Hirose K,
Matsumoto A, Takenaka K, Hirata Y, Eto F, Nagai R, Sato Y,
Nakajima T (2005) Hemodynamic and hormonal responses to ashort-term low-intensity resistance exercise with the reduction ofmuscle blood flow. Eur J Appl Physiol. 95:65-73.
14) Takatori Y, Ito K, Sofue M, Hirota Y, Itoman M, Matsumoto T,
Hamada Y, Shindo H, Yamada H, Yasunaga Y, Ito H, Mori S, Owan I,
Fujii G, Ohashi H, Mawatari T, Iga T, Takahira N, Sugimori T,
Sugiyama H, Okano K, Karita T, Ando K, Hamaki T, Hirayama T,
Iwata K, Matsuura M, Jingushi S (2010) Investigation Group into
Coxarthrosis and Acetabular Dysplasia in Japan. Analysis ofinterobserver reliability for radiographic staging of coxarthrosis andindexes of acetabular dysplasia: a preliminary study. J Orthop Sci.
15:14-19.
15) Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000) Effects of resistance exercise combined with moderatevascular occlusion on muscular function in humans. J Appl Physiol.
88:2097-2106.
16) Wang C, Peng J, Lu S (2014) Summary of the various treatments forosteonecrosis of the femoral head by mechanism: A review. Exp Ther
Med. 8:700-706.
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osteonecrosis. J Int Med Res. 38:1060-1069.
18) Weinstein RS (2011) Glucocorticoid-induced bone disease. (2011)
N Engl J Med. 365:62-70.
19) Yasuda T, Fukumura K, Fukuda T, Uchida Y, Iida H, Meguro M,
Sato Y, Yamasoba T, Nakajima T (2014) Muscle size and arterial
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Authorʼs affiliations
T. Nakajima, Heart Center, Dokkyo Medical University Hospital,
Tochigi, JapanT. Yasuda, School of Nursing, Seirei Christopher University, Shizuoka,
Japan
K. Fukumura, Kanto Central Hospital of the Mutual Aid Association of
Public School Teachers, Tokyo, Japan
M. Kurano, Jumonji University, Research Institute of Food and Nutrition
and Health, Tokyo, Japan
T. Imanishi, Medical Affairs, Kyokushin-Kaikan, Kanagawa, Japan
T. Morita, Y. Sato, KAATSU International University, Sri Lanka
Y. Hiraizumi, Department of Orthopaedic Surgery, Showa University
School of Medicine, Tokyo, JapanThe use of KAATSU Training or the term “KAATSU Training”
in the body text are registered trademarks of KAATSU JAPANCo., Ltd.
©2015 KAATSU JAPAN Co., Ltd.

ORIGINAL ARTICLE

Effects of low-intensity “KAATSU” resistance exercise on
hemodynamic and growth hormone responses
H. Takano, T. Morita, H. Iida, M. Kato, K. Uno, K. Hirose, A. Matsumoto, K. Takenaka, Y. Hirata,
T. Furuichi, F. Eto, R. Nagai, Y. Sato, T. Nakajima
Int. J. Kaatsu Training Res. 2005; 1: 13-18

Correspondence to:Dr. T. Nakajima, Departmentof Ischemic Circulatory
Physiology, Kaatsu Training,
University of Tokyo, 7-3-1
Hongo, Bunkyo-ku,
Tokyo, Japanmasamasa@pb4.so-net.ne.jp
See end of article forauthors’ affiliations

Growth hormone (GH) is secreted in a pulsatile fashion during exercise, which promotes skeletal
muscle growth and muscle strength. We compared the effects of different types of short-term lowintensity resistance exercise (STLIRE) on the hemodynamic and GH responses of men aged 20 to 45
years. Eleven untrained men performed 30 repetitions for 2 to 4 sets (mean 61 ± 7 repetitions) until
fatigue for bilateral leg extension-flexion exercise (20% of 1 RM -Proteus Multi Exercise Machine)
under the conditions of reduced muscle blood flow by applied pressure at the proximal ends of bothlegs by a specially-designed belt (Kaatsu Training). In the controlled exercise condition, without
Kaatsu (n=9), subjects again performed the same exercise protocol as described above. Finally, agroup of 5 men performed 3 sets of 10 repetitions using the Power Rehabilitation machine.
Hemodynamic parameters were measured by using the impedance cardiography. Serum
concentrations of GH, noradrenaline (NOR), and lactate were also measured. STLIRE with Kaatsu
significantly increased GH, compared to STLIRE without Kaatsu. Maximal heart rate (HR) and bloodpressure (BP) in STLIRE with Kaatsu were higher when compared to the control condition, however,stroke volume (SV) was lower compared to the controlled condition due to a decreased venous return
induced by Kaatsu training. Total peripheral resistance (TPR) did not change significantly. The
increase in NOR and lactate in STLIRE with Kaatsu was also significantly higher than without Kaatsu.
These results suggest that “Kaatsu” leg resistance exercise caused a significant exercise-induced GH
response even in STLIRE, with a reduction of cardiac preload during exercise. The results of the study
indicate that Kaatsu training may become a unique method for rehabilitation in patients with cardiac
diseases or low physical fitness.
Key words: resistance exercise, growth hormone, hemodynamics, cardiac output, rehabilitation

INTRODUCTION
Heavy resistance training has been known to be apotent stimulus for muscle cell growth andhypertrophy (MacDougall et al., 1977; Staron et al.,1984), resulting in improvement of muscle strengthand increased exercise capacity. This is due, in part, tothe exercise-induced increase of endogenous anabolic
hormones and growth factors such as GH and IGF-1(Kraemer et al., 1990). GH has also been wellestablished as a regulator of cardiac growth, structureand function (Lombardi et al., 1997; Khan et al.,2002), and GH has been used in the treatment ofcongestive heart failure in patients with dilated
cardiomyopathy and myocardial infarction (Fazio etal., 1996; Genth-Zots et al., 1999). However, exerciseinduced GH secretion depends on specific exercise
characteristics, and only certain heavy resistance
exercise protocols are required to induce significant
elevations in serum GH (Lukaszewska et al., 1976;
VanHelder et al., 1984). Therefore, it is difficult to geta significant GH response for patients withcardiovascular diseases in rehabilitation programs andthe aged because of the heavy loads that are required.
Alternatively, a variety of other factors such asincreased metabolic demand and hypoxia may exert
an influence on the exercise-induced GH response.
Low resistance exercise with tourniquet ischemia has
been shown to be an useful method for strength
training (Shinohara et al., 1998; Takarada et al.,2000a), where the potent secretion of GH may play apart in obtaining muscle hypertrophy (Takarada et al.,2000b). High-intensity resistance exercises (~80 % of
1 repetition maximum (1-RM)) produce a 100-foldincrease in plasma concentration of GH (Kraemer etal., 1990), on the other hand, short-term lowintensity “Kaatsu” resistance exercise produces a 290fold increase (Takarada et al., 2000b), resulting inmuscle hypertrophy and strength gains even after
short-term training in healthy subjects (Abe et al.,2004). These results strongly suggest that short-term
low-intensity resistance exercise (STLIRE) with
Kaatsu may be a novel method for training cardiac
patients, but the influence of the “Kaatsu” exercise on
hemodynamic responses has not been investigated.

14

Low-intensity Kaatsu resistance exercise

Therefore, the purpose of the present study was tocompare the hemodynamic and exercise-induced GH
responses (EIGHR) during STLIRE with/without
Kaatsu in healthy non-trained males.

METHODS
Subject

Sixteen normal healthy adult males, 20-45 yr (32± 5 yr), participated in this study. All were non-trained volunteers, and informed consent was
obtained prior to the study. Mean height was 175 ±4 cm, and mean weight was 66 ± 4 kg. None of thesubjects had any diseases, nor took any medications.
The study protocol was approved by the ethics
committee of the University of Tokyo.
Exercise protocols

All the studies were performed in the afternoon atleast 4 h after the last lunch. An indwelling heparinlock catheter was inserted into the superficial vein ofleft arm. After 30 min of supine rest, control blood
samples were collected and hemodynamic
parameters were recorded for 3 min by using animpedance method (see below). Subjects were thenseated against a backrest, with both arms resting on atable throughout the protocol. Resting hemodynamic
parameters were again measured in this sitting
position for 3 min. Blood flow to both legs was thenrestricted by an applied pressure using a speciallydesigned belt (Kaatsu), as described below.
Subsequently, under the condition with Kaatsu,
eleven subjects performed bilateral leg extensionflexion exercise (Proteus Multi Exercise Machine)with the lower extremity positioned at ~90゜flexion.
The intensity of STLIRE was about 20% of 1 RM,
which was obtained at least one week prior to testing.
Subjects performed 30 repetitions, and after a 20seconds rest, they performed repeated knee
extensions and flexions until exhaustion. Following
completion of the exercise protocol, i.e., muscularfatigue was achieved, unrestricted blood flow was
returned to the lower limbs and blood samples wereobtained immediately after exercise, 10 and 30 min
after the exercise. All blood samples were stored at-20゜
C until analyzed. For the controlled exercise
condition, nine of the initial 11 subjects performed
the same exercise protocol but this time, without
Kaatsu, with both sessions being separated by at least
2 to 4 weeks.
For the exercise condition, 5 healthy males
performed the same bilateral leg extension-flexion
resistance exercise (20 % of 1-RM) utilizing a
different type of exercise equipment (POWER
Rehabilitation machine, Compass series, ProxomedCo., Germany). These subjects performed 10
repetitions, and after a 20-seconds rest, they
performed three additional sets.

Induction of the reduction of muscle blood flowby Kaatsu

The method for inducing the reduction of muscle
blood flow has been previously described (Takarada etal., 2000b). Local application of external pressure
over both legs (a banding pressure of 1.3 times higher
than resting systolic blood pressure, 160-180 mmHg)
was used to reduce exercise blood flow. Briefly, boththighs had pressure applied at the proximal ends ofthe lower limbs by means of specially designed belts(33 mm in width, 880 mm in length) just before thestart of the exercise, and the pressure was released
immediately after the exercise.
Measurement of hemodynamic parameters

To evaluate hemodynamic parameters, a Task ForceMonitor (CNSystems Medizintechnik, Graz, Austria)(Gratze et al., 1998; Fortin et al., 1998), which
includes surface electrocardiograms (ECG),
impedance cardiography (ICG), beat-to-beat bloodpressure by the vascular unloading technique (Penaz,1973) and oscillometric blood pressure recording for
the upper arm was used. The ECG, impedance signal
and beat-to-beat blood pressure were sampled with
1000 Hz. These data were then used to calculate all
hemodynamic parameters which included heart rate(HR), blood pressure (systolic (sBP), diastolic (dBP)
and mean (mBP)), left ventricular ejection time
(LVET), stroke volume (SV), stroke index (SI), cardiac
output (CO), cardiac index (CI), total peripheral
resistance (TPR) and total peripheral pressure index(TPRI). The calculation of SI, CO, CI, TPR and TPRI
was as follows.
SI=SV/BSA
CO=SV･HR
CI=CO/BSA
TPR=mBP･80/CO
TPRI=mBP･80/CI,
where BSA was body surface area.
Biochemical analyses

Plasma levels of lactate were measured by the useof an enzyme system employing lactate oxidase
combined with N-ethyl-N-(3-methylphenyl)-N’acetyl ethylenediamine and an auto-analyzer,
HITACHI Type 7170. Growth hormone (GH) was
measured with radioimmunoassay. Plasma
noradrenaline (NOR) levels were measured by highperformance liquid chromatography.
Data analyses

All values are expressed as means ± SE. Student’s
paired t-test was used to compare two sets of datafrom the same subjects. Comparisons of time coursesof parameters were analyzed by one-way ANOVA for
repeated measures. When differences were indicated,
a Bonferroni/Dunnett’s comparison was used toH. Takano, T. Morita, H. Iida, et al.

determine significance. Spearman rank correlation
coefficients (r) were used to examine therelationships between the individual exercise-inducedchanges. Differences were considered significant if P
value was less than 0.05.

RESULTS
Hemodynamic changes in short-term low-intensity
leg extension-flexion exercise with and without
KaatsuFig. 1 shows a typical recording of hemodynamics(HR, BP and SI, CI, and TPRI) before, during and after
exercise. This subject performed 4 sets of exercise
until fatigue under the conditions with Kaatsu (total
100 repetitions) with a 9 kg load. Resting, seated HR
increased from 69 bpm to 113 bpm at the peak of
exercise, sBP increased from 150 mmHg to 210
mmHg, CI increased from 2.8 L/min to 3.3 L/min,and TPRI increased from 3324 dyn*sec/cm5 to 3767
dyn*sec/cm5. Eleven men performed for 2 to 4 sets
(total 61 ± 7 repetitions) until fatigue
Fig. 2 shows the effects of STLIRE on HR and BP.
HR increased from 73 ±3 bpm at rest to 109 ±5 bpm(Fig. 2A, n=9, P<0.01) at peak exercise with Kaatsu,
which corresponds to 55 ± 4 % of target heart rate as
calculated from age and gender. SBP, dBP, and mBP
significantly increased from 127 ± 4 mmHg (Fig. 2B),
86 ± 5 mmHg (Fig. 2C), and 98 ± 6 mmHg (Fig. 2D)
to 182 ± 6 mmHg, 105 ± 6 mmHg, and 127 ± 4mmHg, respectively. On the other hand, the increasein HR and BP was lower in STLIRE without Kaatsu or

15

control STLIRE (10 repetitions x 3 sets, n=5) than in
STLIRE with Kaatsu.
Fig. 3 shows the effects of STLIRE on the
hemodynamic parameters (CO, SV, TRP and LVET).
In STLIRE with Kaatsu, CO increased from 5.1 ± 0.5l/min at rest to 6.2 ± 0.5 l/min (Fig. 3A, n=9, P<0.01)
at the peak of exercise, while STLIRE without Kaatsu,
CO increased from 5.2 ± 0.3 l/min to 6.9 ± 0.5 l/min(P<0.01). In STLIRE with Kaatsu, SV significantly
decreased from 71 ± 9 ml to 62 ± 7 ml (Fig. 3B,
P<0.05), while it did not significantly change in
STLIRE without Kaatsu. TRP did not change

Figure 2. Effects of STLIRE with/without Kaatsu on HR and
BP. HR and BP (sBP, dBP, and mBP) at rest in sitting position
and at the peak exercise are shown in STLIRE with (n=9,closed circles) and without Kaatsu (open circles), and control
STLIRE (10 repetitions x 3 sets; n=5, open squares). Values
are means ± S.E.. Significant difference between rest andexercise and between the 2 different types of exercise areshown. *P<0.05, **P<0.01

Figure 1. Hemodynamic changes in a single bout of short-

Figure 3. Effects of STLIRE with/without Kaatsu on theterm low-intensity resistance exercise with Kaatsu.
Hemodynamic parameters (heart rate (HR), continuous bloodpressure (ContBP), stroke index (SI), cardiac index (CI), andtotal peripheral resistance (TPRI) were measured at rest
(supine and sitting position), during the short-term lowintensity resistance exercise with Kaatsu and after the
exercise. The proximal portions of both thighs were banded
by a specially designed-belt (denoted as lines).

hemodynamic parameters (SV, CI, TRP and LVEF). The
hemodynamic parameters at rest in sitting position and at thepeak exercise are shown in STLIRE with (n=9, closed circles),and without Kaatsu (open circles), and control STLIRE (10repetitions x 3 sets; n=5, open squares). Values are means ±S.E.. Significant difference between rest and exercise and thatbetween 2 types of exercise are shown. *P<0.05, **P<0.0116

significantly (1650 ± 205 dyn*sec/cm5 at rest and1554 ± 214 dyn*sec/cm5 (Fig. 3C, P=N.S.) at thepeak exercise of STLIRE with Kaatsu), similar to the1473 ± 109 dyn*sec/cm5 at rest and 1471 ± 209
dyn*sec/cm5 (P=N.S.) at the peak of exercise of
STLIRE without Kaatsu. LVET was decreased in both
STLIRE with and without Kaatsu (Fig. 3D, P<0.05).
Changes in serum concentrations of NOR andlactateFig.4A and B show the time courses of the changes
in serum NOR (A) and lactate (B) concentrations
during STLIRE with and without Kaatsu. In STLIRE
with Kaatsu, NOR increased from 0.2 ± 0.06 ng/ml
at rest to 0.54 ± 0.14 ng/ml (Fig. 4A, P<0.01)
immediately after the exercise, and gradually
decreased after the exercise. Serum lactate level
increased from 11.2 ± 1.5 mg/dl at rest to 24.1 ±
2.6, 30.9 ± 4.3 and 16.8 ± 2.4 mg/dl (P<0.01)
immediately after exercise, at 10, and 30 min after
the exercise with Kaatsu, respectively (Fig. 4B). On
the other hand, the increase in NOR and lactate waslower in STLIRE without Kaatsu or control STLIRE(10 repetitions x 3 sets, n=5) than in STLIRE with
Kaatsu.
Effects of STLIRE with Kaatsu on plasma concentrations of GH

Fig. 4C shows the time course of plasma
concentrations of GH. After the exercise with Kaatsu,
GH significantly increased, first increasing gradually
after the exercise, then reaching a peak at 30 min
after the exercise (Fig. 4C) (0.11 ± 0.03 ng/ml to 8.6

Figure 4. Time course of changes in plasma concentrations of
norepinephrine (NOR), lactate, and GH in STLIRE with andwithout Kaatsu. The concentrations of NOR, lactate and GH at
rest in sitting position and after the exercise are shown in
STLIRE with (n=9, closed circles), and without (open circles),and control STLIRE (10 repetitions x 3 sets; n=5, open
squares). Significant difference between rest and exercise andthat between 2 types of exercise are shown. *P<0.05,**P<0.01

Low-intensity Kaatsu resistance exercise± 1.1 ng/ml; n=9; P<0.01). On the other hand, in

STLIRE without Kaatsu, GH only slightly increased
from 0.16 ± 0.08 ng/ml to 0.48 ± 0.26 ng/ml(P<0.05) following the exercise session, then returnedback to resting values following 30 minutes of rest.
Similarly, GH elevation in control STLIRE (10repetitions x 3 sets, n=5) was much less than that in
STLIRE with Kaatsu (P<0.01) and essentially did notchange over the entire time period.
Figures 5A and B show the relationships between
the changes of serum lactate/NOR concentrations andthose of GH. There were no statistical differences
between the changes of serum lactate (n=11, Fig. 5A)
or NOR (Fig. 5B) concentration and those of GH.

DISCUSSION
The major findings of the present study are as
follows; (1) STLIRE when combined with the
reduction of muscle blood flow to both legs (Kaatsu)
resulted in a significant exercise-induced GH response(EIGHR) which was much higher than experienced
without Kaatsu. (2) The increase in HR and BP
during STLIRE with Kaatsu was larger than without
Kaatsu. (3) During STLIRE with Kaatsu, the increase
in CO depended on the increase of HR, but not SV,
since SV declined probably due to the inhibition ofvenous return by banding both legs. (4) The increasein NOR and lactate concentrations attained in STLIRE
with Kaatsu was higher than without Kaatsu, but theincrease in GH was related to neither NOR nor
lactate. These results suggest that the short-term lowintensity “Kaatsu” leg resistance exercise significantly
induces a growth hormone response, with the
reduction of a cardiac preload during exercise. This
may suggest that Kaatus resistance exercise may
become a unique method for rehabilitation inpatients with cardiac diseases or low physical fitness.
GH is secreted in a pulsatile fashion mainly during

Figure 5. Relation between the changes of serum GH andthose of serum lactate (A) or NOR (B) induced by STRILE
with Kaatsu. Relationship between individual exerciseinduced changes (peak level of postexercise - preexercise
level) ( Δ lactate, Δ GH, ΔNOR). (A, C) Relation between Δ
GH and Δ lactate (B, D) Relation between Δ GH and Δ
NOR. *P<0.05, **P<0.01 vs. control

H. Takano, T. Morita, H. Iida, et al.

exercise and sleep. The exercise-induced pulsatile
release of GH is more effective than continuous
administration to induce a GH response at the target
organs such as muscle and bone (Isgaard et al., 1988;
Materson and Preston, 1999; Jaffe et al., 2002),
which can ultimately result in improved muscle
strength and an increased exercise capacity. GH has
also been well established as a regulator of cardiac
growth, structure, and function (Lombardi et al.,
1997; Khan et al., 2002), and the subcutaneous or
intravenous application of GH has been used for thetreatment of congestive heart failure in patients withdilated cardiomyopathy and myocardial infarction(Fazio et al., 1996; Genth-Zots et al., 1999). In
general, EIGHR is dependent on specific exercise
characteristics, those usually involving certain heavy
resistance exercise protocols (i.e. 60% of 1 RM)(Lukaszewska et al., 1976; VanHelder et al., 1984).
Therefore, it has been difficult to apply heavy exercise
protocols for aged people and patients withcardiovascular diseases in rehabilitation programs,
who cannot tolerate high mechanical stress placed on
muscle, tendon, and joints. However, other factors
may influence on the exercise-induced GH response,such as increased metabolic demand or hypoxia. In
previous studies, hypoxia has been induced bytourniquet ischemia in combination with low
resistance exercise and has been reported as a
successful method for strength training (Shinohara etal., 1998; Takarada et al., 2000a). In our study, weused STLIRE (20% of 1 RM and 30 repetitions x 2-4,
total 61 ± 7 repetitions) with Kaatsu. The maximal
heart rate attained during the exercise with Kaatsu
only reached 109 ± 5 bpm, which equals
approximately 55 ± 4 % of estimated maximal heart
rate when adjusted for gender and age. The ratepressure product, which is accepted as a non-invasive
estimate of myocardial oxygen demand duringphysical stress, achieved a final value of 198x102
mmHg.bpm. Even in spite of such mild strength
exercises, the increased plasma GH concentrations
after the exercise were approximately 100-times ashigh as that at rest. The level of the increased GH
concentration reached levels previously described forhigh-intensity exercise (~80% 1 RM, 10 repetitions x6) (Kraemer et al., 1990). Takarada et al. (2000b)
reported similar results for STLIRE (20% of 1 RM and
14 repetitions x 5 sets, total 70 repetitions) withyoung male athletes aged 20-22 yr. Their plasma GH
concentration increased ~290 times compared toresting vales. They also reported much larger
increases in the concentrations of NOR and lactatecompared to the values obtained in our study,
suggesting that the differences between the twostudies may depend on the total exercise volume.
Baically, STLIRE when combined with Kaatsu
appears to be a useful method to induce significant

17

EIGHR, while exercise at the same intensity but
without Kaatsu is ineffective for inducing a GH
response, however, it is unclear whether the pulsatile
EIGHR can improve cardiac function in a similarmanner to GH therapy (Fazio et al., 1996; Genth-Zots
et al., 1999). On the other GH has been well known
to increase serum IGF-1 stability, which may also
improve cardiac function, but further clinical trials areneeded to clarify this possibility.
The several mechanisms underlying GH releaseduring STLIRE with Kaatsu may be proposed. Under
the conditions with Kaatsu, serum lactate and NOR
concentrations increased following the exercise
protocol compared to the controlled exercise protocol
without Kaatsu, suggesting that exercise with Kaatsu
produces a greater demands on anaerobic glycolysis
which may stimulates serum GH elevation. However,since no consistent systematic relationships between
GH and lactate/NOR were observed, a combination ofanaerobic factors such as local ischemia and/or local
accumulation of lactate in the legs induced by the
restriction of muscle blood supply may then stimulate
peripheral afferent nerves, resulting in enhancing
GH-releasing hormone secretion and/or inhibition ofsomatostatin (Glustina et al., 1998). Kaatsu by itself,
in the absence of exercise, failed to induce any
significant GH secretion in healthy males (data notshown), suggesting that exercise is also required. The
greater GH secretion during Kaatsu exercise may befrom afferents originating in fast twitch skeletal
muscle fibers (Gosselink et al., 1998) since fast twitch
fibers have been reported to be recruited
preferentially during Kaatsu resistance exercise(Yasuda et al., 2004) or under dynamic ischemic
training (Nygren et al., 2000). These mechanisms arestill speculative and further studies are needed toclarify the basic mechanisms of GH release inducedby the Kaatsu exercise.
It has been known that moderate to heavy
resistance exercise markedly increases BP (Kilbom
and Brundin, 1976; Bosisio et al., 1980; Bezucha etal., 1982; Lewis et al., 1983). Even though heavy leg
extension exercise appears to be a predominately
dynamic in nature, it still has a substantial static
component (Miles et al., 1987). During static exercise,
there is a rise in BP caused by an increase in CO,
which in turn is due to an increase in HR (Helfant etal., 1971; Perez Gonzalez, 1981). In STLIRE with
Kaatsu, CO increased without significant changes in
TPR, and a decrease in SV (about 12 %) whencompared to control exercise, which was probably
due to the reduced venous return during venous
restriction. Thus, the increase in BP was largely
dependent on the increase in CO due to a significant
increase in HR, not SV. Therefore, the increase in BP
observed in our exercise was more typical of an
exercise with a static component. The inhibition of

18

venous return during STLIRE with Kaatsu can reduce
cardiac preload during exercise, which may be usefulin rehabilitating patients with cardiac diseases.
In conclusion, the short-term low-intensity“Kaatsu” leg resistance exercise significantly induced
GH responses with a reduction in cardiac preload
during exercise, which may provide to be a promising
method for rehabilitation in patients with cardiac
diseases or low physical fitness.

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CG (1983) Cardiovascular responses to exercise as functions of absoluteand relative work load. J Appl Physiol 54: 1314-1323.
Lombardi G, Colao A, Cuocolo A, Longobardi S, Di Somma C, Orio F,
Merola B, Nicolai E, Salvatore M (1997) Cardiological aspects of growth
hormone and insulin-like growth factor-I. J Pediatr Endocrinol Metab 10:553-560.
Lukaszewska J, Biczowa B, Bobiewicz D, Wilk M, ObuchowiczFidelus B (1976) Effect of physical exercise on plasma cortisol andgrowth hormone levels in young weight lifters. Endokrynol Pol 27: 149157.
MacDougall JD, Ward GR, Sale DG, Sutton JR (1977) Biochemical
adaptation of human skeletal muscle to heavy resistance training andimmobilization. J Appl Physiol 43: 700-703.
Materson BJ, Preston RA (1999) Classic therapeutic trials in
hypertension: were patients vulnerable to unsuppressed peak morning
blood pressure? Am J Hypertens 4: 449S-453S.
Miles DS, Owens JJ, Golden JC, Gotshall RW (1987) Central andperipheral hemodynamics during maximal leg extension exercise. Eur J
Appl Physiol 56: 12-17.
Nygren AT, Sundberg CJ, Goransson H, Esbjornsson-Liljedahl M,
Jansson E, Kaijser L (2000) Effects of dynamic ischaemic training on
human skeletal muscle dimensions. Eur J Appl Physiol 82: 137-141.
Penaz J (1973) Photoelectric measurement of blood pressure, volume
and flow in the finger. Digest of the 10th International Conference on
Medical and Biological Engineering, Dresden.
Perez Gonzalez JF (1981) Factors determining the blood pressure
responses to isometric exercise. Circ Res 48: 176-186.
Shinohara M, Kouzaki M, Yoshihisa T, Fukunaga T (1998) Efficacy of
tourniquet ischemia for strength training with low resistance. Eur J Appl
Physiol 77: 189-191.
Staron RS, Hikida RS, Hagerman FC, Dudley GA, Murray TF (1984)
Human skeletal muscle fiber type adaptability to various workloads. J
Histochem Cytochem 32: 146-152.
Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000a) Effects of resistance exercise combined with moderate vascular
Takarada Y, Nakamura Y, Aruga S, Onda T, Miyazaki S, Ishii N(2000b) Rapid increase in plasma growth hormone after low-intensity
resistance exercise with vascular occlusion. J Appl Physiol 88: 61-65.
VanHelder WP, Radomski MW, Goode RC (1984) Growth hormone
responses during intermittent weight lifting exercise in men. Eur J Appl
Physiol 53: 31-34.
Yasuda T, Abe T, Sato Y, Midorikawa T, Inoue K, Ryushi T, Kearns CF,
Ishii N (2004) Muscle fiber cross-sectional area increased after two
weeks of low-intensity “Kaatsu” resistance training (Abstract). 9th Annual
Congress European College of Sports Science, Book of Abstracts: 195.

Authors’ affiliations
H. Takano, T. Morita, H. Iida, M. Kato, K. Uno, A. Matsumoto,K. Takenaka, Y. Hirata, R. Nagai, T. Nakajima, Department of
Cardiovascular Medicine, University of Tokyo, Tokyo, Japan
K. Hirose, F. Eto, Department of Rehabilitation, Faculty of Medicine,
University of Tokyo, Tokyo, Japan
Y. Sato, T. Nakajima, Department of Ischemic Circulatory Physiology,
Kaatsu Training, University of Tokyo, Tokyo, JapanT. Furuichi, K. Hirose, Department of Rehabilitation, Dokkyo University
School of Medicine, Tochigi, Japan

Case ReportElectromyographic responses of arm and chest muscle
during bench press exercise with and without KAATSU
T. Yasuda, T. Fujita, Y. Miyagi, Y. Kubota, Y. Sato, T. Nakajima, M.G. Bemben, T. Abe
Int. J. KAATSU Training Res. 2006; 2: 15-18

Correspondence to:T. Yasuda, Department of
Exercise and Sport Science,
Tokyo Metropolitan University,
1-1 Minami-ohsawa, Hachioji,
Tokyo 192-0397, Japan
yasuda-tomohiro@c.metro-u.
ac.jp
See end of article forauthors’ affiliations

The purpose of this study was to compare the EMG activity of blood flow restricted (limb) and nonrestricted (trunk) muscles during multi-joint exercise with and without KAATSU. Twelve (6 women and6 men) healthy college students [means (SD) age: 24.1 (3.5) yrs] performed 4 sets (30, 15, 15, and
15 reps) of flat bench press exercise (30% of a predetermined one repetition maximum, 1-RM) during
two different conditions [with KAATSU and without KAATSU (Control)]. In the KAATSU condition, a
specially designed elastic cuff belt (30 mm wide) was placed at the most proximal position of theupper arm and inflated to a pressure of 100% of individual’s resting systolic blood pressure. Surface
EMG was recorded from the muscle belly of the triceps brachii (TB) and pectoralis major (PM)muscles, and mean integrated EMG (iEMG) was analyzed. During 4 sets of the exercise, gradualincreases in iEMG were observed in both TB and PM muscles for the KAATSU condition. The
magnitude of the increases in iEMG in the TB and PM muscles were higher (P<0.05) with KAATSU
compared to the Control condition. In the first set, the mean exercise intensity from normalized iEMG
was approximately 40% of 1-RM in both Control and KAATSU conditions. However, the mean
exercise intensity of both muscles were 60-70% of 1-RM for the KAATSU condition and only about
50% of 1-RM for the Control condition, respectively, during the fourth set. We concluded that
increases in iEMG in the trunk muscle during KAATSU might be an important factor for KAATSU
training-induced trunk muscle hypertrophy.

INTRODUCTION
A number of publications have reported that lowintensity exercise training combined with KAATSU
training (restriction of muscular venous blood flowfrom the limb muscles) can result in significant andrapid increases in muscle size and strength in the armand thigh muscles (Burgomaster et al., 2003; Kawada
and Ishii, 2005; Shinohara et al., 1998; Takarada etal., 2000; 2002). To the best of our knowledge, only
one study has focused on KAATSU training-induced
trunk muscle hypertrophy. They reported thatmuscle hypertrophy occurred not only in the limb
muscle but also in the trunk muscle following
KAATSU resistance training (Abe et al., 2005). The
results of previous studies indicate that muscle
hypertrophy can occur in blood flow restricted limb
muscle, and also in non-restricted trunk muscle
following multi-joint KAATSU resistance training,
however, the mechanism for this adaptation is not
fully understood.
Resistance exercise with restricted muscular bloodflow has been shown to result in an increase in the
integrated electromyogram (EMG) of the active limb
muscle (Moritani et al., 1992; Takarada et al., 2000;
2002), and this response is an important factor for
KAATSU training-induced limb muscle hypertrophy(Takarada et al., 2000; 2002). Under these

conditions, synergistic action between limb and trunk
muscles may occur during the multi-joint KAATSU
resistance exercise. Therefore, we hypothesized that
increases in EMG activity during KAATSU resistance
exercise could be achieved not only in the limb
muscle but also in the trunk muscle. Thus, thepurpose of this study was to compare the EMG
activity of the blood flow restricted (limb) and nonrestricted (trunk) muscles during multi-joint exercise
with and without KAATSU.

METHODS
Subjects

Twelve (6 women and 6 men) healthy college
students [age, 24.1 (3.5) yrs; height, 167.5 (8.4) cm;
weight, 61.8 (11.2) kg, means (SD)] with no previous
resistance training experience volunteered for the
study. All subjects were informed of the procedures,risks, and benefits, and signed an informed consent
document before participation. The study conformed
to all standards for the use of human subjects inresearch as outlined in the Helsinki declaration and
was approved by the Tokyo Metropolitan University
Ethics Committee for Human Experiments.
Experimental design and exercise protocols

The subjects participated in two conditions [with16

EMG responses of arm and chest muscle during KAATSU-exercise

KAATSU and without KAATSU (Control)] of flatbench press exercise in random order (about 5 hours
interval between the conditions). A supinated grip at
the standard grip position (160% of biacromial
distance) was used (Lehman 2005). The subjects
performed 30 repetitions (approximately constantvelocity in 2.4 sec, 1.2 sec for the eccentric phase and1.2 sec for the concentric phase) of bench press
exercise at 30% of a pre-determined one repetition
maximum (1-RM). Following a 30 sec rest period,
the subjects then performed three sets of 15
repetitions, with each set separated by a 30 sec rest
period (Abe et al., 2005; Sato et al., 2005).
Restriction of muscular blood flow by KAATSU

A specially designed elastic belt (30 mm wide) was
placed around the most proximal portion of each
upper arm during KAATSU testing only. The belt
contained a pneumatic bag along its inner surface
that was connected to an electronic air pressure
control system that monitored the restriction pressure(Kaatsu-Mater, Sato Sports Plaza Ltd., Tokyo, Japan).
Prior to the KAATSU testing, the subjects were seatedon a chair, the belt air pressure was set at 60 mmHg
for 30 s, and the air pressure was released. The airpressure was increased by 20 mmHg and held for 30s, then released for 10 s between occlusive
stimulations. This process was repeated until a final
restriction pressure of 100% of an individual’s resting
systolic blood pressure was reached. This pressure
was then maintained for the entire exercise session,
including the rest periods. The belt pressure wasreleased immediately upon completion of the session.
Resting systolic blood pressure of the arm (at heartlevel) was measured using an automatic
sphygmomanometer (Fit Cuff, Omron, Tokyo, Japan)

before KAATSU testing.
EMG measurement and analysis

EMG activities of the triceps brachii (TB) andpectoralis major (PM) muscles were measured withbipolar surface electrodes (Vitrode F, Ag/AgCl, 1-cm
diameter, Nihon Kohden, Tokyo, Japan) placed oneach muscle with a fixed 2-cm inter-electrodedistance (center to center). Prior to electrodeplacement, the skin area was polished with skinpreparation gel and cleaned with ethanol in order toreduce skin impedance and to ensure good adhesionof the electrodes. The EMG signals were sampled via
differential amplifiers (Nihon Kohden AB-621G,
Tokyo, Japan) at 1000 Hz for each muscle (Figure 1).
Raw EMG signals were digitized and stored on harddisk in a computer by the Chart software program,version 4.2 (AD Instruments Pty Ltd, Australia).
Digital rectification and integration of EMG (iEMG)
data were performed with the same computer.
Normalized iEMG and relative exercise intensity
determination

To determine the relative exercise intensity during
bench press exercise with and without KAATSU foreach set, a correlation between relative lifting load
(20, 30, 40, 50, 60, and 70% of 1-RM, 5 repetitions
for each load) and corresponding iEMG was
measured for each subject before testing. Using theregression line between lifting load and iEMG (Figure2), the relative intensity was calculated from iEMG
data during bench press exercise with and without
KAATSU.
Statistical analyses

All values are expressed as means (standard

TB muscle

30
Control

KAATSU

30reps15reps15reps15repsPM muscle

iEMG (μV/s)

30μV

Triceps brachii
Subj. SS20
y = 0.0035x + 0.0054

10
0

10μV
Control

KAATSU

Figure 1. Typical examples of EMG signals recorded fromtriceps brachii (TB) and pectoralis major (PM) muscles during
low-intensity flat bench press exercise with and without
KAATSU.

0

20

40

60

80

Load （%1RM）
Figure 2. Relationship between relative lifting load and meaniEMG during bench press exercise (subject SS). The relative
exercise intensity during bench press with and without
KAATSU was calculated using the regression line.

T. Yasuda, T. Fujita, Y. Miyagi, et al.

17deviations) for all variables. Statistical analyses were
performed by a two-way analysis of variance(ANOVA) with repeated measures [Condition(Kaatsu and Control) x Time (sets)]. Post-hoc testing
was performed by a student’s paired t-test. Statisticalsignificance was set at P < 0.05.

RESULTSA significant condition x time interaction wasobserved for the normalized mean iEMG in TB andPM muscles (P<0.01, Figure 3). Post hoc analyses
indicated that KAATSU bench press resulted in asignificantly greater (P<0.05 or P<0.01) increase inmean iEMG activity when compared to the Control
bench press. During the first 30 reps of bench press,
mean exercise intensity from the normalized iEMG
was approximately 40% of 1-RM in both Control and
KAATSU conditions. In the third set of 15 reps, themean exercise intensity was 60-70% of 1-RM in both
TB and PM muscles for the KAATSU condition andonly about 50% of 1-RM in both muscles for theControl condition. There was no gender difference in

KAATSU
Control
Triceps brachii
*

]

ns

40
20
0
**

]

100

*

]

Pectoralis major
(B)

60

*

]

**
80

]

Normalized iEMG (%1-RM)

]
**

80
60

]

(A)

***

]

100

40
20
0
30 reps

1st
15 reps

2nd
15 reps

3rd
15 reps

Figure 3. Changes in exercise intensity determined bynormalized iEMG during 4 sets of bench press exercise withand without KAATSU. *P<0.05, **P<0.01, KAATSU vs.
ControliEMG activity during bench press exercise with andwithout KAATSU (data not shown).

DISCUSSION
It is known that low-intensity resistance exercise
with restricted venous blood flow (KAATSU)(Takarada et al., 2000; 2002) or occluded blood flow(Moritani et al., 1992) has been shown to result in an
increase in the integrated EMG of the active limb
muscle. However, it is unknown whether theincrease in EMG activity during multi-joint exercise
with KAATSU or blood flow occlusion could beachieved, not only in the limb muscle, but also intrunk muscles. Our findings demonstrated that
increases in iEMG activity was observed in both limb
(triceps brachii) and trunk (pectoralis major) muscles
during low-intensity KAATSU bench press exercise.
The results of this study support our hypothesis that
EMG activity is increased by the synergistic action ofblood flow restriction in both limb muscles and nonrestricted trunk muscles in the shoulder joint.
KAATSU exercise-induced increases in EMG activity
in the trunk muscle may be one of the importantfactors for the muscle hypertrophy seen in the trunk
muscle following low-intensity KAATSU resistancetraining in a previous study (Abe et al. 2005).
Blood flow restriction pressure (belt air pressure) is
an important variable for determining the exercise
intensity during KAATSU exercise (Abe et al., 2006).
A previous study reported that increase in EMG
activity depends on blood flow restriction pressureduring a constant load of KAATSU exercise (Yasuda
et al. 2006). In the present study, the restriction
pressure was set at 100% of individual’s resting
systolic blood pressure (approximately 110 mmHg),
resulting in blood lactate concentrations measured
immediate after the KAATSU exercise to increase toabout 4 mmol/L (data not shown). Previous
KAATSU-training studies have used similar or evenhigher restriction pressures compared to the present
study which resulted in blood lactate concentrations
to rise to about 10 mmol/L after low-intensity
KAATSU exercise (Sato et al., 2005; Takarada et al.,2000). During exercise with highly restricted bloodflow from the working muscle, the EMG activity may
be increased to a greater extent than exercise alone,which would recruit more fast-twitch fibers and theirhigher threshold motor units in both arm and trunk
muscles during milt-joint KAATSU exercise.
Therefore, our results support the previous findings ofmuscle hypertrophy seen in the trunk muscle
following multi-joint KAATSU exercise training (Abeet al. 2005).

18

References
Abe T, Yasuda T, Midorikawa T, Sato Y, Kearns CF, Inoue K, Koizumi
K, Ishii N (2005) Skeletal muscle size and circulating IGF-1 areincreased after two weeks of twice daily “KAATSU” resistance training.
Int J Kaatsu Training Res 1: 6-12.
Abe T, Kearns CF, Sato Y (2006) Muscle size and strength are
increased following walk training with restricted venous blood flow fromthe leg muscle, Kaatsu-walk training. J Appl Physiol 100:1460-1466.
Burgomaster KA, Moore DR, Schofield LM, Phillips SM, Sale DG,
Gibala MJ (2003) Resistance training with vascular occlusion: metabolic
adaptations in human muscle. Med Sci Sports Exerc 35:1203-1208.
Kawada S, Ishii N (2005) Skeletal muscle hypertrophy after chronic
restriction of venous blood flow in rats. Med Sci Sports Exerc 37:11441150.
Lehman GJ (2005) The influence of grip width and forearm
pronation/supination on upper-body myoelectric activity during the flatbench press. J Strength Cond Res 19:587-591.
Moritani T, Michael-Sherman W, Shibata M, Matsumoto T, Shinohara
M (1992) Oxygen availability and motor unit activity in humans. Eur J
Appl Physiol 64:552-556.
Sato Y, Yoshitomi A, Abe T (2005) Acute growth hormone response to
low-intensity KAATSU resistance exercise: Comparison between arm andleg. Int J KAATSU Training Res 1:45-50.
Shinohara M, Kouzaki M, Yoshihisa T, Fukunaga T (1998) Efficacy of
tourniquet ischemia for strength training with low resistance. Eur J Appl

EMG responses of arm and chest muscle during KAATSU-exercise

Physiol 77:189-191.
Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N(2000) Effects of resistance exercise combined with moderate vascularocclusion on muscular function in humans. J Appl Physiol 88:20972106.
Takarada Y, Sato Y, Ishii N (2002) Effects of resistance exercise
combined with vascular occlusion on muscle function in athletes. Eur J
Appl Physiol 86:308-314.
Yasuda T, Shirakawa J, Fujita T, Beekley MD, Sato Y, Abe T (2006)
Comparison of EMG activity among low-intensity exercise with andwithout KAATSU and ischemic conditions. Med Sci Sports Exerc
38:S234.

Authors’ affiliations
Yasuda T, Fujita T, Abe T, Department of Exercise and Sport Science,
Tokyo Metropolitan University, 1-1 Minami-ohsawa, Hachioji, Tokyo
192-0397, Japan
Miyagi Y, Kubota Y, BodybyVital Research Laboratory, Yoyogi,
Tokyo, Japan
Sato Y, Nakajima T, Department of Ischmic Circulatory Physiology,
The University of Tokyo, Tokyo, Japan
Bemben MG, Department of Health and Exercise Sciences, Universityof Oklahoma, Norman, Oklahoma, USA
Sato Y, Abe T, Graduate School of Frontier Sciences, The University ofTokyo, 5-1-5 Kashiwa-no-ha, Kashiwa, Chiba 277-8563, Japan

ORIGINAL ARTICLE

Effects of KAATSU training on haemostasis in healthy
subjects
T. Nakajima, H. Takano, M. Kurano, H. Iida, N. Kubota, T. Yasuda, M. Kato, K. Meguro, Y. Sato,Y. Yamazaki, S. Kawashima, H. Ohshima, S. Tachibana, T. Nagata, T. Abe, N. Ishii, T. Morita
Int. J. KAATSU Training Res. 2007; 3: 11-20

Correspondence to:
T. Nakajima, MD: Departmentof Ischemic Circulatory
Physiology, KAATSU Training,
University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo
113-8655, Japanmasamasa@pb4.so-net.ne.jp
See end of article forauthors’ affiliations

Purposes: The KAATSU training is performed under the reduction of muscle blood flow by a speciallydesigned belt (KAATSU belt), which induces blood pooling in capacitance vessels by restricting
venous return. However, no prior studies have examined the effects of KAATSU training on
haemostasis. The purpose of the present study was to investigate acute effects of KAATSU training on
haemostasis including fibrinolytic responses in healthy subjects. Methods: Two protocols have been
performed. (1) 6 healthy men (mean age= 48 ± 5 yr) performed KAATSU (160 mmHg) of both thighs
for 15 minutes and then KAASTU training combined with low-intensity leg and foot aerobic exercisesfor ~10 minutes in hypobaric chamber, which mimics 8000 feet in airflight. (2) Another 7 men (meanage=30 ± 4 yr) performed leg press exercises (30 % 1 RM) with and without KAATSU of both thighs
24 h after bed rest. Blood samples were taken at rest, immediately after KAATSU, and exercises withor without KAATSU, and after exercise. For the investigation of blood fibrinolysis, determinations oftissue-type plasminogen activator (tPA) activity or antigen, plasminogen activator inhibitor (PAI)-1
activity or antigen, fibrin degradation product (FDP) and D-dimer were used. Prothrombin time (PT)and platelet counts were also measured. Results: (1) In hypobaric chamber, KAATSU by itself
significantly increased tPA activity, while PAI-1 activity was unchanged. Furthermore, immediately
after the exercise, tPA activity increased significantly. (2) During the exercises combined with KAATSU
24 h after bed rest, tPA antigen significantly increased, compared with control exercises, but PAI-1
antigen was unchanged. In both cases, KAATSU training did not induce fibrin formation as assessedby fibrin D-dimer and FDP. Conclusions: This study indicates that potentially favorable changes occur
in fibrinolytic factors after KAATSU and KAATSU training in healthy subjects.
Key words: KAATSU training; fibrinolytic activity; tissue-type plasminogen activator (tPA);
plasminogen activator inhibitor (PAI)-1; bed rest; airflight; exercise

INTRODUCTION
The KAATSU training is a novel method for muscle
training performed under the reduction of muscle
blood flow by a specially-designed belt (KAATSU
belt). Under the conditions of restricted muscle blood
flow, even short-term, low-intensity exercise such as
walk training can induce muscle strength, andincreased muscle mass (Takarada et al. 2000a; b; c;Takarada et al., 2002a,b; Abe et al. 2006). In addition,
KAATSU femoral blood flow restriction induces
lower-body venous pooling and reduces venous
return (Takano et al., 2006), resulting in stimulating
cardiovascular effects of orthostasis in 1G like lower
body negative pressure (LBNP) (Iida et al., 2007).
Since the most effective countermeasure regimen toprevent cardiovascular deconditioning in space flightwould be a gravitation-like stress combined with
exercises, the use of KAATSU in combination with
low-intensity resistance exercise would provide asignificant countermeasure like LBNP for space flightcountering both cardiovascular and musculoskeletal

decline. Thus, the KAATSU training may be a
promising training in astronauts to prevent
cardiovascular deconditioning and muscle atrophy inspace flights (Iida et al., 2006) as well as athletes andhealthy persons as described previously (Nakajima etal., 2006).
Haemostasis is achieved through a delicate
equilibrium between the coagulation and fibrinolytic
cascades (Wu and Thiagarajan, 1996). Exercises havebeen shown to affect activation of both thecoagulation and fibrinolytic cascades (Davis et al.,
1976; Andrew et al., 1986; Boman et al., 1994; Weisset al., 1998; El-Sayed et al., 2000; Ribeiro et al.,2006). Regular exercise preferentially activates
fibrinolysis, which is generally associated withfavorable alterations in risk from cardiovascularmorbidity, while strenuous exercise may increase
blood coagulation, and promote thrombus formation(Hilberg et al., 2002), resulting in exertion-related
ischemic events (Giri et al., 1999). Thus, it is likelythat effects of exercise on the haemostatis are12

Effects of KAATSU on haemostasis

dependent upon exercises intensity and duration(Rosing et al., 1970; Weiss et al., 1998; Molz et al.,
1993; Rankinen et al., 1995). The KAATSU training is
an exercise performed under the restriction of venous
blood flow. Therefore, occlusion of blood vessels may
affect the haemostasis, and cause the formation ofthrombus, though serious side effects of KAATSU
training such as pulmonary embolism have not beenreported until recently (Nakajima et al. 2006).
However, no prior studies have examined the effectsof KAATSU training on haemostasis.
The coagulation cascade may be enhanced invarious conditions such as airflight and bed rest.
Economy class syndrome is a serious problem inairflight, where the activation of the coagulationcascade and subsequently thrombus formation may
occur. Since the KAATSU training is a novel exercise
performed under the restriction of venous blood flow,
it is interesting to know the effects of the KAATSU
training on the haemostasis under the airflight and
bed rest that are known to increase the risk forcoagulation.
Therefore, we investigated acute effects of the
KAATSU training on haemostasis including
fibrinolytic responses under the conditions inhypobaric chamber and 24 hours after bed rest in
healthy subjects.

METHODS
Subjects

This study consisted of two protocols as shown in
Fig.1. Protocol 1 was approved by the ethics
committee of the University of Tokyo. Protocol 2 wasapproved by the institutional review board (IRB) of
human research of Japan Aerospace Explosion
Agency (JAXA) and the ethics committee of the

University of Tokyo. All were non-trained volunteers,and informed consent was obtained prior to thestudy. None of the subjects had any diseases and took
any medications. (1) In protocol 1, 6 healthy adultmales, aged 48 ± 5 years (mean height, 1.71 ± 0.2
metres; mean weight, 70.1 ± 4.3 kg), performed
KAATSU only and KAATSU training in hypobaric
chamber (8000 feet). (2) Another 7 men, aged 31.6 ±1.1 years (mean height, 1.76 ± 1.6 metres; mean
weight, 75.3 ± 3.9 kg), performed leg press exercises(30 % 1 RM) with and without KAATSU after 24hours bed rest.
Protocol 1

Aircraft cabins are pressurized so that the cabinpressure is maintained at the equivalent of around
5,000-8,000 feet altitude irrespective of the cruising
altitude. Therefore, subjects entered the 8,000 feethypobaric chamber in JAXA (Fig.1A). The protocol isshown in Fig. 1B. After 30 minutes of rest in theseated position, a sample of blood was taken to
represent 0 feet. The pressure of the chamber was
decreased to the pressure of 8000 feet in airflight. The
rest sample of blood at 8,000 feet was taken after 30
minutes of rest in the seated position. Subsequently,
KAATSU at the pressure of 160 mmHg was applied toboth thighs by using KAATSU master belt for 15
minutes. Immediately after the release of KAATSU,
the blood sample was again obtained. After 15
minutes rest of sitting position, the subjects
performed 5 lower extremity exercises (~10 minutes
total exercise time) while seated and under a
KAATSU pressure of 160 mmHg. The exercises
consisted of 1) toe flexion and extension (20 reps, 2sets), 2) ankle dorsi flexion (20 reps, 2 sets), 3) ankle
plantar flexion (20 reps, 2 sets), 4) unilateral knee

Figure 1. Experimental design. (A) The model of hypobaric chamber in JAXA (B) Protocol 1 (C) Protocol 2

T. Nakajima, H. Takano, M. Kurano, et al.

extension (20 reps each), and 5) unilateral leg press
motion (20 reps each) Immediately after the
exercises, the pressure was released. Blood samples
were also taken immediately after the release of
KAATSU and 15 minutes after the exercises. O2
saturation was monitored from right finger by Onyx
(Nonin Medical, Inc. M.N. U.S.A).
Heart rate (HR) and blood pressure (BP) wereobtained by the Task Force Monitor (CNSystmes
Medizintechnik, Graz, Austria) (Gratze et al. 1998;
Fortin et al. 1998; Takano et al., 2005).
Protocol 2

Subjects maintained 6° head-down tilt position
during the bed rest period, where the coagulationcascade may be enhanced. The protocol is shown in
Fig. 1C. After 24 h -6° bed rest, the control blood
samples were collected. After that, each subject was
divided into two groups randomly; One groupperformed leg press exercises without KAATSU first,
and 2 hours later, the similar resistance exercises
were performed under the application of KAATSU at
the pressure determined automatically (auto) as
described below. The other group performed leg press
exercises with KAATSU and 2 hours later, the similar
resistance exercises without KAATSU were done. In
these exercises, HR and BP were continuously
recorded for 5 minutes before exercises (Pre) andduring exercises with and without KAATSU, by using
Task-Force monitor. All exercises were performed on
the leg press exercises in the 6° head-down tilt
position. The resistance protocol involved performing
4 sets (1 set of 30 repetitions followed by 3 sets of 15
repetitions) at an intensity of 30% 1RM (repetition
maximum). The speed of the movement during each
repetition was held constant at approximately 1
repetition per 3 seconds. 1RM was determined inadvance. Blood samples were taken immediately
before and 1, 10, and 60 minutes into the recovery
period after exercise with or without KAATSU. Blood
samples were obtained using an indwelling heparinlock catheter inserted into the superficial antebrachialvein of left arm. All blood samples were processed toserum or plasma before storage at -20°C until
analysis.
Reduction of femoral muscle blood flow by
KAATSUA method for inducing the reduction of muscle
blood flow is similar as previously reported (Takaradaet al. 2000a; b; c; Takarada et al. 2002a,b; Takano etal. 2005; Abe et al., 2006). Both sides of their thighs
had pressure applied at the proximal ends by
KAATSU Master belt (protocol 1) or belts developed
for space (protocol 2). In space, it is convenient thatKAATSU can be applied automatically to astronauts.
To obtain it, the apparatus developed for space was

13

used. It can apply KAATSU at the pressure, where thepulse wave of leg becomes maximal, named as auto.
The level of auto was 172.5 ± 6.75 mmHg and 1.42 ±0.10 times larger than systolic blood pressure (sBP) at
the sitting position, and it was 158.8 ± 2.95 mmHg
and 1.36 ± 0.07 times larger than sBP at 6° head
down tilt position after 24 h bed rest.
Measurement of hemoglobin, lactate,noradrenaline, and haemostasis parameters

Blood samples for measurement of blood
hematocrit (Hct), and hemoglobin (Hb, 2 ml) andhormone determination (7 ml) were collected in preheparinised syringes. For Hb, blood was drawn into
test tubes containing EDTA-2Na. Blood Hb (g/100 ml)
was measured by the cyanomethemoglobin method(Coulter hemoglobinometer). Hct (%) was measured
by micro-hematocrit using ultra centrifugation. For
hormone determination, blood was drawn into test
tubes containing 10.5 mg of EDTA-2Na. All samples
were kept in ice-cold water and centrifuged (3000rpm) for 10 minutes and the plasma stored at -20ºC
until the assays were performed. Plasma
concentrations of noradrenaline (NOR) were
measured using high performance liquid
chromatography (HPLC) method. The lower limit ofdetection of the assay was 6 pg/ml. Ten milliliters ofblood were collected into 3.2% sodium citrate fortissue type plasminogen activator (tPA) activity or
antigen assay, plasminogen activator inhibitor (PAI)-1
activity or antigen assays, prothrombin time (PT),thrombin time (TT), D-dimer (D-D), fibrin
degradation products (FDP), fibrinogen, factor 8 andfactor 10. The following assays were performed byusing ELISA: tPA antigen (Technoclone GmbH,
Vienna, Austria); tPA activity (Molecular Innovations,Inc., M.I., U.S.A.); PAI-1 antigen (Technoclone
GmbH, Vienna, Austria); PAI-1 activity (HYPHEN
BioMed., Neuville-Sur-Oise, France). The othervariables were measured at commercially available
laboratories (SRL Inc., Tokyo, Japan).
The change of blood volume (BV) (%) and plasma
volume (PV) (%) was derived from the following
equation;
BVB/BVA= HbA/HbB%∆PV=100*((HbB/HbA)*((1-HctA*10-2)/(1-HctB*10-2))-100
where A is the value at rest (pre), and B is thevalue at the corresponding time.
Data analysis

All values are expressed as means ± S.E.M.
Student’s paired t-test was used to compare two setsof data from the same subjects. Comparison of timecourses of parameters was analyzed by one-way
ANOVA for repeated measures. When differences

14

Effects of KAATSU on haemostasis

were indicated, a Bonferroni’s comparison was used
to determine significance. Differences wereconsidered significant if P value was less than 0.05.

RESULTS
Effects of KAATSU training on haemostasis in
hypobaric chamber

In hypobaric chamber (8000 feet), oxygen
saturation by pulse oximetry (SpO 2) markedly
decreased from 99 ± 0.3 % to 91 ± 1.1 % (n=6,P<0.01), but brain natiuretic peptide (BNP) did notchange significantly as shown in table 1 and Fig.2.
The pressurization of KAATSU (160 mmHg) to boththighs by itself did not affect SpO2, but a series ofshort-term and low-intensity aerobic exercises
combined with KAATSU increased SpO 2 . HR
increased to 81.1 ± 8.0 bpm at the peak of theexercises (Table 1). KAATSU by itself significantly
increased NOR from 394 ± 67 pg/ml to 525 ± 96
pg/ml (n=6, P<0.01, table 1), and KAATSU combinedwith exercises induced a further increase in NOR(738 ± 78 pg/ml, P<0.01). The serum concentrationof lactate increased from 14.2 ± 1.5 mg/dl at rest 8000
feet to 26.3 ± 1.9 mg/dl (n=6, P<0.01) after the
exercises. PV and BV tended to decrease during
KAATSU, but statistically not significant. On the other
hand, PV and BV significantly decreased during theexercises combined with KAATSU. PV significantly
decreased during the exercises combined withKAATSU, compared with rest (0 feet).
Under these hypobaric conditions, where SpO2
markedly decreased, we investigated the effects of
KAATSU and KAATSU combined with the exerciseson haemostatis as shown in table 2 and Fig. 3. As

shown in table 2, PT, TT, fibrinogen, factor 8 and Plt
did not change significantly. Both D-D and FDP also
did not significantly change during KAATSU and
KAATSU combined with the exercises. TPA activity
resting at 8000 feet altitude was not statisticallydifferent from that resting at 0 feet altitude (0.24 ±0.01 vs. 0.26 ± 0.02). On the other hand, tPA activity
was significantly increased from 0.26 ± 0.016 U/ml
resting at 8000 feet altitude to 0.32 ± 0.04 U/ml
resting at 8000 feet with KAATSU (Fig. 3A, n=6,
P<0.05). TPA activity increased more when exercises
were combined with KAATSU (0.34 ± 0.03 U/ml,n=6). In contrast, PAI-1 activity (Fig. 3B) did not
significantly change during KAATSU and exercises
combined with KAATSU.

Figure 2 . Time courses of SpO 2 under the hypobaric
conditions (8000 feet) during KAATSU and a series of shortterm and low-intensity aerobic exercises combined withKAATSU. All values are means ± S.E.M. obtained from 6
subjects. ** p<0.01 vs. rest (0 feet)

Table 1. Effects of KAATSU and exercises combined with KAATSU on various parameters
under the conditions of 8000 feet in airflight
0 feet8000 feet

KAATSU
15 minKAATSU +Exercises

Recovery
15 minHR (bpm)

71.0 ± 8.2

70.3 ± 8.5

72.6 ± 9.1

81.1 ± 8.0**

71.7 ± 8.7

SBP (mmHg)

113.9 ± 7.1

116.5 ± 4.9

125.1 ± 6.2

128.2 ± 8.1**

115.8 ± 3.0

HT (%)

46.0 ± 1.1

45.4 ± 1.2

47.6 ± 1.1

50.8 ± 1.0**

48.0 ± 1.0

(%△)

–

1.46 ± 3.1–3 ± 1.2–8 ± 1.0**–3.1 ± 1.1

PV ((%△)–

3.09 ± 5.9–5.9 ± 2.2–16 ± 1.5**–6.7 ± 1.9

NOR (pg/ml)

336 ± 26394 ± 67525 ± 96**738 ± 78**492 ± 84**

Lactate (mg/dl)

16.9 ± 1.2

14.2 ± 1.5

14.3 ± 1.7

26.3 ± 1.9**

24.0 ± 1.0**

BNP (pg/ml)

14.5 ± 7.0

13.2 ± 6.1

19.5 ± 8.2

14.5 ± 7.8

14.6 ± 7.9* p<0.05 vs. 0 feet** p<0.01 vs. 0 feetParameter

BV

T. Nakajima, H. Takano, M. Kurano, et al.

15

Table 2. Effects of KAATSU and exercises combined with KAATSU on haemostaticparameters under the conditions of 8000 feet in airflight

0 feet8000 feet

KAATSU
15 minKAATSU +Exercises

Recovery
15 minPT (%)

30.4 ± 1.7

31 ± 1.5

31.9 ± 1.0

33.7 ± 3.1

29.9 ± 1.4

TT (sec)

100 ± 0100 ± 0100 ± 0100 ± 0100 ± 0Fibrinogen(mg/dl)260 ± 31243 ± 27

227 ± 24230 ± 47254 ± 33

Factor 8 (%)

117 ± 21121 ± 24105 ± 19138 ± 27138 ± 20

FDP (µg/ml)

2.17 ± 0.17

2.00 ± 0.00

2.00 ± 0.00

3.33 ± 0.95

2.50 ± 0.34

D-D (µg/ml)

0.47 ± 0.15

0.42 ± 0.14

0.41 ± 0.14

0.43 ± 0.14

0.39 ± 0.13

Plt (x10000/µl)

16.5 ± 2.7

16.0 ± 3.6

17.2 ± 3.1

18.3 ± 2.9

16.4 ±3.0

Parameter

Figure 3. Effects of KAATSU only and low-intensity aerobic
exercises combined with KAATSU on tPA activity (A) andPAI-1 activity (B) under the hypobaric condition (8000 feet).
All values are means ± S.E.M. obtained from 6 subjects.
* p<0.05, ** p<0.01 vs. rest (0 feet)

Effects of leg press exercises combined withKAATSU on haemostasis parameters at -6° bed
rest for 24 h

Next, we examined the effects of leg press exercises(30% 1 RM) combined with and without KAATSU at
24 h -6° bed rest. Tables 3 and 4 summarize theeffects of leg press exercises with and without
KAATSU on hemodynamic and neurohumoral
parameters. HR at the peak exercises with KAATSU
was larger than that without KAATSU. The peak
exercise HR with KAATSU increased from 61.9 ± 4.9
bpm at rest to 107.1 ± 9.4 bpm (n=7, P<0.01) during
exercise. SBP increased during KAATSU exercise, andreached to 154.2 ± 8.2 mmHg. Table 3 also shows thetime courses of the changes in serum lactate and NOR
concentration during the leg press exercises with andwithout KAATSU. The increase in lactate
concentration after exercise with KAATSU was muchhigher than that without KAATSU. In leg press
exercises with KAATSU, NOR increased from 140 ±20 pg/ml at rest to 514 ± 110 pg/ml (n=7, P<0.01)
immediately after the exercise, and gradually
decreased after the exercise. On the other hand, it
increased from 131 ± 16 pg/ml to 239 ± 47 pg/ml(n=7, P<0.01) in the control exercise. Thus, theincrease in NOR concentration attained in the leg
press exercises with KAATSU was significantly higher
than that without KAATSU. PV and BV decreased
during exercises with and without KAATSU. But, theexercises combined with KAATSU showed a larger
decrease in PV and BV, compared with the control
exercise as shown in table 3.
The effects of exercises combined with KAATSU on
haemostatis were investigated at -6° bed rest for 24 h
as shown in Fig. 4 and table 4. As shown in table 4,
PT, fibrinogen, factor 10, and Plt did not change
significantly. Both D-D and FDP also did not
significantly change during leg press exercises
combined with KAATSU. TPA antigen did not change
significantly during the leg press exercises without
KAATSU (2.2 ± 0.1 g/ml at rest and 2.3 ± 0.1 ng/ml
immediately after the exercise). On the other hand,tPA antigen increased from 2.1 ± 0.1 ng/ml to 2.7 ±0.2 ng/ml (n=7, P<0.05) immediately after the
exercises combined with KAATSU as shown in Fig.
4A. The increased tPA antigen returned to the control
level within 10-30 minutes after the exercise. In
contrast, PAI-1 antigen (Fig. 4B) did not significantly
change during KAATSU and the exercises combinedwith KAATSU.

16

Effects of KAATSU on haemostasis

Table 3. Effects of leg press exercises (EX) with (+) and without (-) KAATSU compared to resting values (Pre) on
various parameters 24 h after -6° bed rest
Parameter

Pre

EX

HR

(–)

61.3 ± 4.9

85.6 ± 5.7**

(bpm)

(+)

61.9 ± 4.9

107.1 ± 9.4**

sBP

(–)

124.8 ± 6.0

139.6 ± 8.6**(mmHg) (+)

127.5 ± 4.9

154.2 ± 8.2**

ParameterPre

0–1 min(–)

48.8 ± 0.3

50.2 ± 0.6**

Hct
(%)

(+)

48.5 ± 0.6

51.6 ± 0.5**

BV

(–)

–

–2.9. ± 0.3**

(%△)

(+)

–

–5.9 ± 0.4**

PV

(–)

–

–5.6 ± 1.0****

10 min48.8 ± 0.5
**

**

(+)

–

–11.6± 0.8**

NOR

(–)

131 ± 16239 ± 47**

(pg/ml)(+)

140 ± 20514 ± 110**lactate(–)

8.9 ± 0.7

20.9 ± 2.6**(mg/dl)9.7 ± 0.7(+)

49.6 ± 0.5**

48.1 ± 0.6*

48.1 ± 0.5–0.4 ± 0.4

1.3 ± 0.3*

–2.3 ± 0.7**

0.2 ± 0.9
2.7 ± 0.8*

–0.5± 0.8**(%△)

30 min–4.4 ± 1.1****

0.8 ± 1.7

161 ± 23**224 ± 42126 ± 17*144 ± 23

15.0 ± 1.9***

27.4 ± 3.8*** p<0.05 vs. Pre*p<0.05 KAATSU(–) vs. KAATSU(+)** p<0.01 vs. Pre**p<0.05 KAATSU(–) vs. KAATSU(+)

27.1 ± 4.1**

9.2 ± 0.6**

15.6 ± 2.4

Table 4 . Effects of leg press exercises (EX) with (+) and without (-) KAATSU
compared to resting values (Pre) on haemostatic parameters 24 h after -6° bed rest
ParameterPre

0–1 min10 min30 min(–)

83.6 ± 3.3

85.3 ± 3.0

83.6 ± 2.6

82.9 ± 3.0(+)

82.3 ± 2.7

86.4 ± 3.0

83.7 ± 3.1

83.6 ± 3.6

Fibrinogen(–)

239 ± 28251 ± 29232 ± 22238 ± 27

(mg/dl)(+)

237 ± 25

264 ± 31239 ± 28235 ± 26

FDP

(–)

2±0

2±0

2±0

2±0

(µg/ml)(+)

2±02.14 ± 0.14

2.57 ± 0.30

2.71 ± 0.57

D–D

(–)

0.21 ± 0.04

0.23 ± 0.03

0.20 ± 0.03

0.21 ± 0.05(µg/ml)(+)

0.21 ± 0.06

0.27 ± 0.08

0.25 ± 0.05

0.26 ± 0.05

Plt

(–)

25.1 ± 1.7

26.0 ± 2.1

25.5 ± 1.5

25.0 ± 1.9(x10000/µl)(+)

25.0 ± 1.8

27.2 ± 2.4

26.1 ± 2.1

24.9 ± 1.0

Factor 10(–)

105 ± 6111 ± 7107 ± 5105 ± 5(%)(+)

105 ± 5116 ± 6108 ± 5103 ± 3PT (%)*

T. Nakajima, H. Takano, M. Kurano, et al.

Figure 4. Effects of leg press exercises combined with andwithout KAATSU on tPA antigen (A) and PAI-1 antigen (B)after 24 h at -6° bed rest. The serum concentration of tPA and
PAI-1 antigen in control rest (24 h bed rest), immediately
after exercises (0-1 minute), 10 and 30 minutes after exercises
are shown in leg press exercises with KAATSU and without.
All values are means ± S.E.M. obtained from 7 subjects.
* p<0.05 vs. control (Pre).

DISCUSSION
The present study shows that the KAATSU training
did not induce fibrin formation as assessed by fibrin
D-dimer and FDP, while potentially favorable changes
occur in fibrinolytic factors after KAATSU and
KAATSU training in healthy subjects. Thus, thisenhanced fibrinolytic activity may be an importantmechanism mediating cardioprotective effect provide
by the KAATSU training.
Haemostasis is achieved through a delicate
equilibrium between the coagulation and fibrinolytic
cascades (Wu and Thiagarajan, 1996). Exercises havebeen shown to affect activation of both thecoagulation and fibrinolytic cascades (Smith, 2003).
Regular moderate aerobic exercise preferentially
activates fibrinolysis (Davis et al., 1976; Andrew et al.,
1986; Weiss et al., 1998; El-Sayed et al., 2000; Hilberg
et al., 2003a,b), subsequently generally associatedwith favorable alterations in risk from cardiovascularmorbidity. In contrast, strenuous exercise may
increase blood coagulation, and promote thrombus
formation (Hilberg et al., 2002), resulting in exertionrelated ischemic events (Giri et al., 1999). Thus, theeffects of exercise on the haemostatis may be strongly
dependent upon exercises intensity and duration(Rosing et al., 1970; Weiss et al., 1998; Molz et al.,
1993; Rankinen et al., 1995). The KAATSU training is

17

a novel training performed under the restriction ofvenous blood flow, but occlusion of blood vessels may
affect the haemostasis and then cause the formationof thrombus. Therefore, we examined the effects of
KAATSU training on haemostasis under theconditions in hypobaric chamber and 24 h after bed
rest in healthy subject, where the activation of thecoagulation cascade and subsequently thrombus
formation may be occurred. Under the training
combined with KAATSU 24 h after bed rest, plasma
volume (PV) significantly decreased, as observed inheavy resistance exercises. Similarly, a decrease in PV
was observed in aerobic exercises combined withKAATSU under a hypobaric chamber, where SpO2
markedly decreased to approximately 90%. In some
types of exercise, the shortening of PT, a measure of
the activity of extrinsic and common coagulation
pathways, and TT, a measure of common coagulation
pathway, has been reported due to the enhanced
coagulation cascade (El-Sayed et al., 1995; Smith,2003). However, under our conditions, PT and TT did
not change. Changes in individual components of thecoagulation cascade as a result of exercise have also
been reported. Factor 8 has been reported to increase,dependent on volume and intensity of exercise(Andrew et al., 1986). In the present study, factor 8
did not significantly change. Fibrinogen level also did
not change in both protocols used in the present
study, suggesting that fibrinogen is not consumed inour experimental conditions. The end products offibrinolysis, fibrin degradation products (FDP), and DD, products of the breakdown of activated factor 8(fibrin stabilizing factor) have been reported toincrease after heavy endurance exercises of different
types (Arai et al., 1990; Molz et al., 1993; Prisco et al.,1998). However, in the present study, FDP and D-D
did not significantly change. From these observations,
it is likely that the KAATSU training used in thepresent study did not activate coagulation cascade,induce fibrin formation and subsequently thrombosis
as summarized in table 5.
Generally, during physical heavy exertion, potential
for blood coagulation increases, and typicallybalanced by a corresponding increase in fibrinolytic
activity, defined as the capacity to lyse inappropriate
or excessive clot. The capacity to thrombolize fibrin
clots is influenced by many factors of the fibrinolytic
system, but particularly tPA and PAI-1. The increased
fibrinolytic potential occurs due to an increase of tPA
activity or antigen, which catalizes the conversion ofplasminogen into plasmin, and/or a decrease in PAI-1(Collen et al., 1980; Molz et al., 1993; Rankinen et al.,
1995; Weiss et al., 1998; El-Sayed et al., 2000; Huber,
2001; Ivey et al., 2003; Cooper et al., 2004; Womack
et al., 2006). Under basal conditions, tPA circulates
mainly as a complex with PAI-1 with low levels of
free tPA, and PAI-1 inhibits tPA by binding to it and18

Effects of KAATSU on haemostasis

Table 5 . Summary of effects of exercises combined withKAATSU on markers of coagulation and fibrinolysis
Parameters

Types of exercises
low-intensity aerobic exercises(8000 feet)leg press exercises(24 h bed rest)

CoagulationPT

unchanged

unchangedTTunchanged

not done

Factor 8

unchanged

unchanged

Factor 10

unchanged

unchanged

unchanged

Fibrinolysis
FibrinogenunchangedtPA

increased

increased

PAI-1

unchanged

unchanged

FDP

unchanged

unchanged

D-D

unchanged

unchanged

unchanged

unchanged

Platelet aggregation
Plt accountforming an inactive complex. Synthesis of both tPA
and PAI-1 occurs in the vascular endothelial cells (Wuand Thiagarajan, 1996). Thus, fibrinolytic responses
to acute exercises play an important role inpreventing exertion-related ischemic events (Giri etal., 1999) due to the thrombosis. The present study
showed that larger fibrinolytic responses of tPA
activity or antigen to the KAATSU training wereobserved, compared with the control exercises. The
similar findings were observed in KAATSU training
under hypobaric chamber, where SpO2 decreased toapproximately 90%. Therefore, the enhanced
fibrinolytic activity observed in the KAATSU training
may be an important mechanism mediating
cardioprotective effect provide by the KAATSU
training.
Acute hypoxemia may affect fibrinolytic activity.
Under a hypobaric chamber of 8000 feet, SpO2
markedly decreased to approximately 90%. However,tPA activity at rest (8000 feet) was not statisticallydifferent from rest (0 feet) (0.24 ± 0.01 vs. 0.26 ±0.02). PAI-1 activity also did not change significantly.
Therefore, acute hypoxia did not affect blood
fibrinolytic activity, which was compatible with theprevious paper (Stegnar et al., 1987). On the other
hand, during the conditions used in the present study,
where the coagulation cascade may be enhanced, the
KAATSU training increased tPA activity, but did not
activate coagulation cascade, induce fibrin formationand subsequently thrombosis. Several mechanisms
may be involved in enhancement of tPA activity
observed during the KAATSU training. During
KAATSU only for 15 minutes, tPA activity

significantly increased. Venous occlusion has beenreported to enhance the fibrinolytic activity(Szymanski et al., 1994; Nikfardjam et al., 1999;
Monagle et al., 2003), where tPA activity or antigen
increases. Since KAATSU training restricts venous
flow, and then pooling of blood, the similar
mechanism may be involved in the enhancement oftPA activity or antigen observed during KAATSU.
However, the further increase in tPA activity or
antigen was observed in the exercises combined withKAATSU. It has been reported that the fibrinolytic
responses to exercise are related to changes in plasma
lactate and /or NOR (Davis et al., 1976; Wheeler etal., 1986; Weltman et al., 1994; Hilberg et al., 2003b).
The underlying mechanism has not been clarified,
but it may depend on exercise intensity and duration
exercise. Some papers showed that lactate thresholdor sympathetic drive may be a critical intensity toelicit acute fibrinolytic changes in tPA (Davis et al.,
1976; Wheeler et al., 1986; Weltman et al., 1994). In
the present study, the increase in lactate and NOR
concentration after exercise with KAATSU was muchhigher than that without KAATSU. Thus, the increasein lactate and NOR may also contribute to theenhanced fibrinolytic activity during the KAATSU
training.
The KAATSU training is an exercise performed
under the restriction of venous blood flow. Therefore,
occlusion of blood vessels may affect the haemostasis,and cause the formation of thrombus, though serious
side effects of KAATSU training such as pulmonary
embolism have not been reported until recently(Nakajima et al. 2006). In this report, one patient wassuspected of pulmonary embolism. However, thispatient was not admitted the hospital, and had noserious problems. He might have had acutebronchitis, judging from the hearing of the instructor.
In addition, pulmonary embolism has not occurredamong approximately 200,000 subjects, who havereceived KAATSU training (Sato Y, personalcommunication). It may be compatible with thepresent findings that the KAATSU training, evenunder the conditions of airflight and bed rest, where
the coagulation cascade may be enhanced, did not
activate coagulation cascade, induce fibrin formationand subsequently thrombosis, but rather enhanced
fibrinolytic activity.
In conclusion, the KAATSU training did not induce
fibrin formation as assessed by fibrin D-dimer and
FDP, while potentially favorable changes occur infibrinolytic factors after the KAATSU training evenunder the conditions where the coagulation cascade
may be enhanced.

ACKNOWLEDGEMENT
The authors thank the subjects who participated inthis study. This study is partly financially supported by

T. Nakajima, H. Takano, M. Kurano, et al.

Japan Aerospace Explosion Agency and the
University of Tokyo.

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Author’s affiliations
T. Nakajima, H. Takano, M. Kurano, H. Iida, N. Kubota, T.
Yasuda, Y. Sato, Department of Ischemic Circulatory Physiology,
KAATSU Training, University of Tokyo, Tokyo, Japan

Effects of KAATSU on haemostasis

M. Kato, K. Meguro, T. Morita, Department of Cardiovascular
Medicine, University of Tokyo, Tokyo, JapanY. Yamazaki, Japan Manned Space Systems Corporation, Tokyo,
Japan
S. Kawashima, H. Ohshima, S. Tachibana, Japan Aerospace
Explosion Agency, Tsukuba, Japan
T. Nagata, Department of Respiratory Medicine, University of Tokyo,
Tokyo, Japan
T. Abe, Department of Human and Engineered Environmental Studies,
Graduate School of Frontier Science, University of Tokyo, Chiba, Japan
N. Ishii, Department of Life Sciences, Graduate School of Arts andSciences, University of Tokyo, Tokyo, JapanEur J Appl Physiol (2008) 104:727–737
DOI 10.1007/s00421-008-0834-3

ORIGINAL ARTICLE

Hemodynamic responses to simulated weightlessness of 24-h
head-down bed rest and KAATSU blood flow restriction
Toshiaki Nakajima Æ Haruko Iida Æ Miwa Kurano Æ Haruhito Takano ÆToshihiro Morita Æ Kentaro Meguro Æ Yoshiaki Sato Æ Yoshihisa Yamazaki ÆSino Kawashima Æ Hiroshi Ohshima Æ Shouichi Tachibana Æ Naokata Ishii Æ
Takashi Abe

Accepted: 10 July 2008 / Published online: 24 July 2008
Ó The Author(s) 2008

Abstract The KAATSU training is a unique method ofmuscle training with restricting venous blood flow, whichmight be applied to prevent muscle atrophy during spaceflight, but the effects of KAATSU in microgravity remain
unknown. We investigated the hemodynamic responses to
KAATSU during actually simulated weightlessness (6°head-down tilt for 24 h, n = 8), and compared those to
KAATSU in the seated position before bed rest. KAATSU
was applied to the proximal ends of both the thighs. In theseated position before bed rest, sequential incrementing of
KAATSU cuff pressure and altering the level of blood flow
restriction resulted in a decrease in stroke volume (SV)with an increase in heart rate (HR). KAATSU (150–
200 mmHg) decreased SV comparable to standing.
T. Nakajima (&)  H. Iida  M. Kurano  H. Takano  Y. Sato
Department of Ischemic Circulatory Physiology,
KAATSU Training, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8655, Japane-mail: masamasa@pb4.so-net.ne.jp
T. Morita  K. Meguro
Department of Cardiovascular Medicine, University of Tokyo,
Tokyo, JapanY. Yamazaki
Japan Manned Space Systems Corporation, Tokyo, JapanS. Kawashima  H. Ohshima  S. Tachibana
Japan Aerospace Explosion Agency, Tsukuba, Japan
N. Ishii
Department of Life Sciences, Graduate School of Arts
and Sciences, University of Tokyo, Tokyo, Japan
T. AbeDepartment of Human and Engineered Environmental Studies,
Graduate School of Frontier Science, The University of Tokyo,
Chiba, Japan

Following 24-h bed rest, body mass, blood volume (BV),
plasma volume (PV), and diameter of the inferior vena
cava (IVC) were significantly reduced. Norepinephrine(NOR), vasopressin (ADH), and plasma renin activity(PRA) tend to be reduced. A decrease in SV and CO
induced by KAATSU during the simulated weightlessness
was larger than that in the seated position before bed rest,and one of eight subjects developed presyncope due tohypotension during 100 mmHg KAATSU. High-frequency
power (HFRR) decreased during KAATSU and standing,while low-frequency/high-frequency power (LFRR/HFRR)
increased significantly. NOR, ADH and PRA also
increased during KAATSU. These results indicate thatKAATSU blood flow restriction reproduces the effects ofstanding on HR, SV, NOR, ADH, PRA, etc., thus stimulating a gravity-like stress during simulated weightlessness.
However, syncope due to lower extremity blood poolingand subsequent reduction of venous return may be induced
during KAATSU in microgravity as reported in cases oflower-body negative pressure.
Keywords KAATSU training  Autonomic function Space flight  Cardiovascular deconditioning 
6° head-down tilt bed rest  Sympathetic activity

Introduction
The weightless environment of space flight causes serious
adaptive changes in cardiovascular function as well as
muscle atrophy. A shift in blood volume from lower-body
capacitance vessels toward the head and elevation of tissue
capillary perfusion pressure in the head causes facial andintracranial edema and headache, which distresses astronauts. And, nearly all crew members develop cardiovascular

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deconditioning characterized by orthostatic intolerance andreduced upright exercise capacity, which is manifest after
space flight (Nicogossian et al. 1995; Buckey et al. 1996;
Fritsch-Yelle et al. 1996). The mechanisms involved in thisdeconditioning include hypovolemia, decreased baroreflex
responsiveness, and decreased skeletal muscle stiffness.
Therefore, effective countermeasures during spaceflight areneeded to maintain the cardiovascular system, as well as
the musculoskeletal structure–function to ensure the wellbeing and safety of crew members during space flight andupon return to Earth.
An elastic thigh cuff, called ‘‘bracelets’’, has beenreported to be an effective passive countermeasure for
reducing edema and venous stasis in the cephalic region bypooling blood in the vascular and extravascular compartments of the legs, easing the stress of zero gravity(Lindgren et al. 1998; Arbeille et al. 1999; Millet et al.
2000). However, the effectiveness of bracelets to prevent
cardiovascular deconditioning is incomplete, providing
only partial compensation for the cardiovascular changes(Herault et al. 2000). The most effective countermeasurefor preventing cardiovascular deconditioning appears to be
imposition of a gravity-like stress, such as lower-bodynegative pressure (LBNP) (Güell et al. 1990, 1992; Lathers
and Charles 1993). When combined with intensive exercise, LBNP is a potent orthostatic stimulus, which
presumably provides an effective prevention of orthostatic
intolerance following space flight (Lee et al. 1997; Watenpaugh et al. 2000). However, a large-scale apparatus
combined with exercise machine is required. In addition,
LBNP can be combined with treadmill (Murthy et al.
1994), but not resistance-type machines. The use of resistance exercises may be essential to prevent muscle atrophyduring space flight as resistance training specifically promotes muscle enlargement and muscular strength, which
are negatively impacted by weightlessness. Thus, if amethod of exercise with a potent orthostatic stimulus like
LBNP exists, it may provide an effective countermeasure
for cardiovascular deconditioning as well as muscle atrophy in weightlessness.
The key physiological features of LBNP are lower
extremity blood pooling, reduction of venous return to theheart, and subsequent hemodynamic changes including
increased autonomic nervous system activation (Stevensand Lamb 1965; Tomaselli et al. 1987; Lathers and Charles
1993). The KAATSU training is a unique technique of
performing low-load exercises such as resistance exercises
and treadmill with restricted muscle blood flow that results
in an increase in muscle mass and muscular strength comparable to high-intensity training (Takarada et al. 2000; Abeet al. 2006; Fujita et al. 2007). Since KAATSU femoral
blood flow restriction induces the retention of blood flow inlower extremities, it reduces venous return, and induces

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Eur J Appl Physiol (2008) 104:727–737

subsequent hemodynamic changes such as decreased SV
and CO and increased TPR like LBNP (Stevens and Lamb
1965; Güell et al. 1990, 1992; Melchior et al. 1994; Murthy
et al. 1994; Lee et al. 1997; Watenpaugh et al. 2000; Iida
et al. 2007). Thus, KAATSU may partly provide an orthostatic stimulus, and an effective countermeasure for
cardiovascular deconditioning in weightlessness like
LBNP. However, the potency of KAATSU for inducing
pooling of venous blood and then hemodynamic changes in
microgravity has not been investigated. In addition, theoccurrence of syncopal attack has been reported in cases of
LBNP, especially when using high pressure more than 40 mmHg (Stevens and Lamb 1965), but the safety of
KAATSU in microgravity remain unclear.
Therefore, the aim of this study is to examine thehemodynamic responses to KAATSU during actuallysimulated weightlessness (6° head-down tilt for 24 h), andto compare those to KAATSU in the seated position before
bed rest. In addition, the potency for inducing pooling ofvenous blood and then hemodynamic changes during
KAATSU is compared to those reported during LBNP.

Materials and methods
Subjects
Eight males (age 32.8 ± 1.0 years; height 176 ± 16 cm;
weight 75.3 ± 3.9 kg) participated in the following
experiments. All subjects were healthy, free of neuromuscular or cardiovascular disease, were not on any
medication, and none had a specific history of physicalexercise training. This investigation was approved by theinstitutional review board (IRB) of human research ofJapan Aerospace Explosion Agency (JAXA) and the ethics
committee of the University of Tokyo, and all subjects
gave their informed consent prior to inclusion.
Experimental protocol
This study consisted of two experiments as summarized inFig. 1. All experiments were separated by 1–2 weeks, andwere performed at the Japanese Aerospace Explosion
Agency between 25 September and 26 October in 2006.
Experiment A
As shown in Fig. 1a, to mimic KAATSU training on Earth,
the effects of sequential incrementing of KAATSU cuff
pressure (50 mmHg step) on hemodynamic parameters inthe seated position were examined in the morning. After a
30-min rest in the seated position, we took rest measurements of hemodynamic parameters at this position forEur J Appl Physiol (2008) 104:727–737

Fig. 1 Experimental design. a KAATSU in the seated position(mimic KAATSU on Earth) b simulated weightlessness and KAATSU (mimic KAATSU on space)

5 min by using an impedance cardiography. Then, both theproximal thighs were pressure-applied with the speciallydesigned belt developed for spaceflight (see below). After
recording the hemodynamic parameters for 10 min under
100 mmHg KAATSU, the banding pressure was released
and the hemodynamic parameters were continuously taken
during a 5–10 min recover time. After the additional
30 min rest in the seated position, the effects of 150 mmHg
KAATSU on hemodynamic parameters were investigated.
Similarly, we repeated the experiments of KAATSU(200 mmHg). Finally, the effects of standing on hemodynamic parameters were also investigated. During the firstexperiment, nobody complained of any symptoms including syncopal attack.
Experiment B
This experiment was designed to investigate the effects of
KAATSU on hemodynamic parameters during theweightlessness, which was simulated for 24 h using bed
rest with a 6° head-down tilt. Subjects maintained 6° headdown tilt position during the entire bed rest period.
Transportation and toilet procedures were restricted to thehead-down recumbent position. Subjects were allowed torest on their elbows during meals and could move volitionally but remained horizontal to the bed. To ensurecompliance, the volunteers were monitored at all times byvideo-camera surveillance. Subject’s diet, fluid intake, andurine volume were also monitored.

729

The control echocardiographic data, and blood samples
were collected after 10 min (0-h bed rest) after bed rest.
After 24 h after bed rest (24-h bed rest), the effects of
KAATSU on hemodynamic parameters were examinedwhile maintaining the head-down tilt and bed rest position.
Control hemodynamic parameters after 24-h bed rest weremonitored continuously for 5 min, followed by echocardiography and collection of blood samples. Then,
hemodynamic responses to KAATSU were studied at twolevels of KAATSU belt pressure (50 and 100 mmHg). The
following timing pattern was employed: apply KAATSU,
10 min continuous hemodynamic measurement, remove
KAATSU, and record an additional 10 min of continuous
hemodynamic response, then rest without KAATSU for
30 min. The KAATSU pressure was first set to 100 mmHg,
but the first subject complained of presyncopal attack andwas excluded from the following experiments and data
analysis. Therefore, the remaining subjects (n = 7) beganwith a lower KAATSU cuff pressure (50 mmHg) prior to
100 mmHg. After completing the two KAATSU pressure
trials in bed rest position, subject stood up and hemodynamic response was recorded continuously for 5 min instanding position. We had not examined 150 mmHg due tothe marked decrease in SV during 100 mmHg. With eachpressure perturbation, blood samples were collected
immediately following release of KAATSU (0–1 min), and30 min after the release. The data obtained from sevensubjects who completely finished both experiments wereshown.
Methods
KAATSU blood flow restriction
Femoral blood flow was impaired using the KAATSU
technique, which restricts venous blood flow and causes
pooling of blood in capacitance vessels distal to the cuff
(Takarada et al. 2000; Takano et al. 2005; Abe et al. 2006;
Fujita et al. 2007; Iida et al. 2007). KAATSU was applied
to the proximal end of both the thighs as near to the hip
joint as possible by using KAATSU belts (65 mm in widthand 650 mm in length). The cuff pressure was controlled
by the KAATSU apparatus as previously described (Iidaet al. 2007).
Cardiovascular hemodynamics
Hemodynamic parameters were determined using the Task
Force Monitor (CNSystmes Medizintechnik, Graz, Austria)
as previously described (Takano et al. 2005; Iida et al.
2007). Analysis included electrocardiograms (ECG),
impedance cardiography, beat-to-beat blood pressure byvascular unloading technique and oscillometric blood

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pressure. Data were obtained for every beat with a
1,000 Hz sampling rate and used to calculate all hemodynamic parameters in real time. Data included heart rate
(HR; bpm), mean arterial blood pressure (mAP; mmHg),
systolic blood pressure (sBP), diastolic blood pressure(dBP), stroke volume (SV; ml), cardiac output (CO; l/min)and total peripheral resistance (TPR; dyne s cm-5). TPR
was calculated in relative units as MAPCO-1, and thecalculation of CO and TPR was as follows.
CO ¼ SV  HR
TPR ¼ MAP  80  CO1
Histograms of RR intervals were computed and pseudodigitized at ten samples per second. Auto-regressivemodeling (Burg method) was used to construct frequency
domain spectrograms of the heart rate variability (HRV).
Parameters extracted from the variability spectra were lowfrequency power (LFRR, 0.03–0.15 Hz) and high-frequency
power (HFRR, 0.16–0.50 Hz), normalized to total powerover the range from 0.01 to 0.50 Hz.
Cardiac dimensions
Trans-thoracic echocardiography was performed using
Aplio80. Left ventricular end-systolic dimension (LVDs;mm), left ventricular end-diastolic dimension (LVDd; mm)and the diameter of inferior vena cava (IVC; cm) were
determined using the M-mode recording in the parasternal
long-axis view with the pulsed wave as described previously (Iida et al. 2007).
Hormone-metabolite levels
Venous blood samples were collected and analyzed forhematocrit, hemoglobin, noradrenaline, plasma renin activity and vasopressin. Blood sample was accomplished with anindwelling catheter inserted into the superficial antebrachialvein of left arm. For measurement of hemoglobin andhematocrit, 2 ml of blood was placed into test tubes containing EDTA-2Na. For hormone determination, blood(7 ml) was placed in test tubes containing 10.5 mg of EDTA2Na. All samples were kept in ice-cold water and centrifuged(3,000 rpm) for 10 min and the plasma was stored at -20°C
until the assays were performed. Blood hemoglobin (Hb,g dl-1) was determined by the cyanomethemoglobin method(Coulter hemoglobinometer) and hematocrit (Hct, %) by the
micro-hematocrit ultra centrifugation technique. Plasma
concentrations of noradrenaline (NOR; lower limit ofdetection 6 pg ml-1) were measured using high performance liquid chromatography. Plasma renin activity (PRA;
lower limit of detection 0.1 ng ml-1 h-1) and vasopressin(ADH; lower limit of detection 0.2 pg ml-1) were123

Eur J Appl Physiol (2008) 104:727–737

determined by radioimmunoassay. These assays were completed at commercially available laboratories (SRL Inc.,Tokyo, Japan).
Changes in blood and plasma volume (%) were derived
from the following equation;
1
BVB  BV1
A ¼ HbA  HbB

%DPV ¼ 100  HbB  Hb1A 
 1  HctA  102 = 1  HctB  102
 100
where A is the initial value and B is the value at the corresponding time.
Data analysis

All values are expressed as means ± SEM Student’s paired
t-test was used to compare two sets of data from the same
subjects. Comparison of time courses of parameters wasanalyzed by one-way ANOVA for repeated measures.
When differences were indicated, a Bonferroni’s comparison was used to determine significance. Differences wereconsidered significant if P \ 0.05.

Results
Table 1 shows the hemodynamic changes during KAATSU(100–200 mmHg) in the seated position and the standing
position before bed rest. The pressurization of 100–
200 mmHg significantly increased HR, and decreased SV,
which depended on the pressure. 200 mmHg KAATSU
increased HR from 64.8 ± 3.2 to 74.0 ± 4.0 bpm (n = 7,
P \ 0.01). After the release of pressure, HR promptly
returned to the pre test level. The pressurization of
200 mmHg decreased SV from 73.6 ± 3.5 to 60.2 ± 2.2 ml(n = 7, P \ 0.01). After an orthostatic stress (standing), HR
increased with decreasing SV. The decrease in SV observed
during 150–200 mmHg was lower than that in the standing
position (66.9 ± 2.4 ml). CO did not significantly change
during KAATSU in the seated position before bed rest. TPR,sBP, mBP, and dBP were also not significantly altered during
KAATSU.
Following 24 h of 6° head-down tilt bed rest, there was a
2.0 kg decease in body mass (75.3 ± 3.9 to 73.3 ± 3.8 kg,
n = 7, P \ 0.01) associated with a significant urine output(2052 ± 249 ml d-1) that markedly exceeded water intake(1320 ± 67 ml d-1). After 24 h of 6° head-down tilt bed
rest, blood (4.4 ± 1.4%) and plasma (7.9 ± 2.5%) volume
decreased as Hct (46.4 ± 1.2% to 48.5 ± 0.8%, P \ 0.01)
and Hb (15.0 ± 0.3 to 15.7 ± 0.3 mg/dl, P \ 0.01) significantly increased.

Eur J Appl Physiol (2008) 104:727–737

731

Table 1 Hemodynamic responses during KAATSU in the seated position
HR (bpm)sBP (mmHg)

mBP (mmHg)

dBP (mmHg)

SV (ml)CO (l min-1)

TPR (dyne s cm-5)

Pre68.8 ± 3.1

122.9 ± 6.8

93.8 ± 4.6

81.5 ± 4.0

74.8 ± 3.1

5.1 ± 0.31459 ± 103

100

70.2 ± 3.7**

118.5 ± 6.4

93.0 ± 5.2

82.5 ± 4.6

67.7 ± 2.9**

4.7 ± 0.3

1570 ± 128

Post

69.7 ± 3.7

124.4 ± 5.7

97.4 ± 4.5

85.4 ± 3.7

67.5 ± 3.6**

4.7 ± 0.3

1679 ± 135

Pre65.5 ± 3.2

122.0 ± 6.5

96.0 ± 4.9

83.3 ± 4.4

71.0 ± 3.8

4.6 ± 0.3

1689 ± 168

150

72.3 ± 3.6**

123.9 ± 4.5

95.4 ± 3.8

84.4 ± 3.5

63.5 ± 2.5**

4.6 ± 0.3

1664 ± 123
1638 ± 120

Post

67.4 ± 3.5

125.4 ± 4.5

94.6 ± 3.2

82.1 ± 3.8

69.9 ± 3.8

4.7 ± 0.3

Pre64.8 ± 3.2

124.1 ± 4.7

93.9 ± 4.1

82.6 ± 3.9

73.6 ± 3.5

4.8 ± 0.3

1576 ± 114

200

74.0 ± 4.0**

124.2 ± 5.2

97.6 ± 3.9

86.6 ± 3.5

60.2 ± 2.2**

4.4 ± 0.3

1758 ± 126

Post

67.3 ± 3.2

124.4 ± 4.5

99.3 ± 3.8

86.2 ± 3.2

68.2 ± 3.2**

4.5 ± 0.3

1758 ± 111

Pre66.7 ± 2.8

125.9 ± 6.0

98.8 ± 4.8

85.1 ± 4.1

68.2 ± 2.2

4.5 ± 0.31723 ± 109

Stand71.4 ± 3.4**

129.6 ± 5.7*

104.5 ± 4.5*

91.6 ± 4.2*

66.9 ± 2.4**

4.7 ± 0.2

1753 ± 109* P \ 0.05 versus Pre** P \ 0.01 versus Pre

There was a significant decrease in the diameter of IVC(1.71 ± 0.13 cm to 1.34 ± 0.12 cm, P \ 0.05, n = 7) following 24 h of head-down tilt bed rest (P \ 0.05) that was
associated with the reduced plasma volume and thenvenous return. The diameter of LVDd (51.6 ± 1.3 to51.2 ± 1.1 mm) was not significantly altered by 24 h ofhead-down tilt bed rest. HR (59.2 ± 4.0 to 58.9 ± 3.7 bpm),
and sBP (121.9 ± 5.1 to 126.0 ± 5.6 mmHg) were also notaltered by 24 h of head-down bed rest.
The serum concentration of PRA (1.51 ± 0.48 to
0.86 ± 0.18 ng ml-1 h-1, n = 7, P = 0.08), ADH(1.81 ± 0.26 to 1.50 ± 0.12 pg ml-1, P = 0.08), NOR(201 ± 45 to 157 ± 24 pg ml-1, P = 0.09), and DOP(7.1 ± 1.5 to 5.4 ± 0.4 pg ml-1, P = 0.09) tended todecrease following 24 h of 6° head-down tilt bed rest.
During experiment B, one subject complained of dizziness and developed neurocirculatory presyncope becauseof hypotension, *5 min after 100 mmHg KAATSU. No
other symptoms were articulated or observed in theremaining seven subjects for the duration of theexperiment.

IVC was significantly reduced by KAATSU at
50 mmHg (1.34 ± 0.12 to 1.09 ± 0.09 cm, n = 7,
P \ 0.05), and 100 mmHg (to 1.05 ± 0.15 cm, n = 7,
P \ 0.05). LVDd was reduced with both 50 mmHg
KAATSU (51.2 ± 1.1 to 46.4 ± 1.3 mm, P \ 0.01) and
100 mmHg KAATSU (to 45.44 ± 1.63 mm, P \ 0.01).
SV (Table 2) was significantly reduced by KAATSU at
50 mmHg (88.0 ± 5.3 to 68.5 ± 3.9 ml, P \ 0.01) and
100 mmHg (84.8 ± 4.5 to 58.3 ± 3.3 ml, P \ 0.01).
Although there was a significant increase in HR, CO wassignificantly reduced at each level of KAATSU. SV, HR,
and CO returned to pre-KAATSU levels immediately after
the release of KAATSU (data not shown). There were nochanges in Hct, Hb, BV, or PV associated with KAATSU
blood flow restriction (50, 100 mmHg; Table 3). Uponstanding, SV decreased (82.7 ± 4.7 to 54.4 ± 2.1 ml,
P \ 0.01); a decrement comparable to 100 mmHg KAATSU. The significant increase in HR upon standing was
greater than that observed during KAATSU, and thus, CO
was maintained during standing (Table 2). TPR increased
at each level of KAATSU, but was significantly less than

Table 2 Hemodynamic responses during KAATSU following 24-h bed rest
HR (bpm)sBP (mmHg)

mBP (mmHg)

dBP (mmHg)

SV (ml)CO (l min-1)

TPR (dyne s cm-5)

Pre58.9 ± 3.7

126.0 ± 5.6

93.3 ± 3.2

79.4 ± 2.5

88.0 ± 5.3

5.2 ± 0.61480 ± 145

5062.8 ± 4.0**

122.8 ± 5.2

89.0 ± 3.6

75.7 ± 3.1

68.5 ± 3.9**

4.3 ± 0.5**1732 ± 157**

Post

58.0 ± 4.0

122.8 ± 5.9

91.1 ± 3.8

76.0 ± 3.0

87.2 ± 5.4

5.1 ± 0.61485 ± 143

Pre
100

56.3 ± 4.2
67.3 ± 3.3**

123.7 ± 4.3
119.7 ± 3.3

91.6 ± 3.5
89.2 ± 2.1

79.0 ± 3.0
76.7 ± 1.9

84.8 ± 4.5
58.3 ± 3.3**

4.8 ± 0.6
3.9 ± 0.4**1605 ± 211
1878 ± 166*
1668 ± 211

Post

58.6 ± 3.0

124.2 ± 6.8

92.4 ± 5.2

77.6 ± 4.0

79.3 ± 5.8

4.7 ± 0.6

Pre58.5 ± 3.1

124.7 ± 5.3

95.6 ± 3.7

82.8 ± 3.9

82.7 ± 4.7

4.8 ± 0.61657 ± 186

Stand77.9 ± 3.9**129.0 ± 7.3

104.5 ± 6.5*

91.4 ± 7.0

54.4 ± 2.1**

4.3 ± 0.3

1996 ± 189*

* P \ 0.05 versus Pre** P \ 0.01 versus Pre

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Eur J Appl Physiol (2008) 104:727–737

Table 3 Hemostatic responses during KAATSU following 24-h bed rest
Hb (mg dl-1)

Hct (%)

BV (%D)

PV (%D)

NOR (pg ml-1)

PRA (ng ml h-1)

ADH (pg ml-1)

Pre

15.7 ± 0.25

48.5 ± 0.75

-4.4 ± 1.4-7.9 ± 2.5

157 ± 240.86 ± 0.18

1.5 ± 0.12

50

15.7 ± 0.25

48.2 ± 0.77

-3.9 ± 1.5-6.4 ± 2.5

211 ± 35**

0.94 ± 0.14

1.9 ± 0.18

Pre

15.6 ± 0.26

47.9 ± 0.81

-3.6 ± 1.3-5.5 ± 2.4

148 ± 200.77 ± 0.13

1.39 ± 0.17100

15.8 ± 0.21

48.4 ± 0.63

-4.7 ± 1.7-7.5 ± 2.9

235 ± 41**1.09 ± 0.20**

2.2 ± 0.62*

Post

15.6 ± 0.25

48.0 ± 0.74

-3.6 ± 1.4-5.8 ± 2.5

174 ± 23

0.69 ± 0.12

1.7 ± 0.20

* P \ 0.05 versus Pre** P \ 0.01 versus Pre
The data of BV and PV show the percentage changes (%D), compared with the volume at 0-h bed rest

the increase observed upon standing. BP did not change
significantly. Upon standing, mBP was significantly
increased (Table 2).
Figure 2 summarizes comparative effects of 100 mmHg
KAATSU on hemodynamic parameters in the seatedposition before bed rest and at 6° head-down tilt bed rest
during the simulated weightlessness. HR (Fig. 2a) and sBP
Fig. 2 Comparative effects of
KAATSU (100 mmHg) on the
hemodynamic parameters in theseated position before bed rest
and 6° head-down position 24 hafter bed rest. Effects of
KAATSU (100 mmHg) on HR(a), sBP (b), SV (c), CO (d) andTPR (e) are illustrated. All
values are means ± SEM
obtained from seven subjects.
* P \ 0.05, ** P \ 0.01

123

(Fig. 2b) during KAATSU in the simulated weightlessness
were not significantly different from those in the seatedposition before bed rest. On the other hand, KAATSU
markedly reduced SV (Fig. 2c) and CO (Fig. 2d) withan increase in TPR (Fig. 2e) during the simulated
weightlessness, compared to the seated position before bed
rest.

Eur J Appl Physiol (2008) 104:727–737

NOR, PRA, and ADH were all significantly increased
during 100-mmHg KAATSU, but NOR only significantly
increased with 50 mmHg KAATSU (Table 3). All values
returned to pre-KAATSU levels during the recovery
period.
HFRR (Fig. 3b), determined from the power spectra of
HR variability (HRV; Fig. 3a), was reduced with
100 mmHg KAATSU (P \ 0.05) and tended to decrease
with 50 mmHg KAATSU (P = 0.17). In contrast, the
LFRRHFRR-1 component was increased during each
KAATSU trial (Fig. 3c). All changes returned to preKAATSU levels during the recovery period. Upon standing, HFRR decreased significantly and equivalently to thechanges with KAATSU (Fig. 3b), however, the increase in
LFRR/HFRR was greater than that observed during KAATSU (Fig. 3c).

Discussion
The present study shows that following 6° head-down tilt
bed rest for 24 h, a model simulating microgravity effects
on the cardiovascular system, KAATSU blood flow
restriction reproduces the effects of standing on HR, SV,
NOR, ADH, PRA, etc., thus stimulating a gravity-likestress during simulated weightlessness. However, syncope
due to lower extremity blood pooling and subsequent
reduction of venous return may be induced during KAATSU in microgravity as reported in cases of LBNP.
During 6° head-down tilt bed rest, a model to simulate
zero G eliminates the normal downward hydrostatic pressure gradients and causes an immediate central fluid shift
from lower extremities toward the thoracic–cephalic region(Norsk et al. 1993). The central hypervolemia affects733

hormonal regulation of fluid excretion and stimulates
central cardiac volume receptors, resulting in a loss ofplasma volume (Norsk et al. 1993; Duranteau et al. 1995).
In the present study, 24 h 6° head-down tilt bed rest
resulted in a total urine volume (2,052 ± 249 ml d-1) thatwas in excess of fluid intake (1,320 ± 67 ml d-1). Then,
blood and plasma volume was decreased by a mean valueof 4.4 and 7.9%, respectively. This fluid volume loss wasreflected in the significant decrease in body mass and IVC
diameter, which was compatible with the previous papers(Nixon et al. 1979; Gaffney et al. 1985). Furthermore,head-down bed rest induces an initial cephalad-fluid shift
with an inhibition of the renin-angiotensin system and
ADH. Hughson et al. (1995) showed a 40% decrease in
PRA after 10-h head-down tilt. In the present study, concentration of PRA and ADH tended to decrease following
24 h of 6° head-down tilt bed rest, but not statisticallydifferent. NOR (201 ± 45 to 157 ± 24 pg ml-1,
P = 0.09) also tended to decrease as reported throughout
space flight missions and bed rest (Leach et al. 1983). Thus,
it is likely that physiological alterations caused by 6° headdown tilt bed rest condition observed here mimicked theweightless condition of space flight.
During an orthostatic stress, part of the blood andplasma volume can pool in the capillary bed of the legs,
and subsequently, SV decreases because of reduced venous
return. KAATSU applied to both the legs also decreased
venous return by pooling blood into the vascular andextracellular compartment of the legs and ultimately
induced the hemodynamic alterations comparable tostanding as previously reported (Iida et al. 2007). A
decrease in SV induced by KAATSU (150–200 mmHg) in
the seated position was larger than that induced by standing. Similarly, during the simulated weightlessness, theFig. 3 Effects of KAATSU onheart rate variability (HRV)
after 24-h 6° bed rest. a The
time courses of HRV during
KAATSU. Note that during
KAATSU (100 mmHg), LFRR
increased, compared with thecontrol, while HFRR decreased.
b Effects of orthostatic stress(standing) and KAATSU on
HFRR. c Effects of orthostatic
stress (standing) and KAATSU
on HFRRLFRR-1. All values aremeans ± SEM obtained fromseven subjects. * P \ 0.05,** P \ 0.01 versus control
(pre)

123

734

decrease in SV induced by 100 mmHg KAATSU wasapproximately equivalent to that induced by standing. The
effects of 50 mmHg KAATSU on SV were less than
100 mmHg KAATSU. Thus, the magnitude of venous
pooling, reduced venous return, and the decrement of SV isgreatly dependent upon the level of the KAATSU (Iidaet al. 2007). While orthostatic stress decreases SV, andinduces hypotensive stimuli, CO and BP are maintained byan increased HR and TRP via arterial and cardiopulmonary
baroreceptor control of circulation. Under the hypovolemic
condition of 24-h bed rest, KAATSU (50 and 100 mmHg)
induced a larger decrease in SV with an increase in HR and
TRP. Thus, during KAATSU, arterial baroreceptors as wellas cardiopulmonary baroreceptors were unloaded (Furlan
et al. 2001; Brown et al. 2003), which mimicked orthostatic
stress. During actual space flight, the Russian physicians
have already used a unique method for a countermeasure,called ‘‘bracelets’’ to reduce edema and venous stasis in the
cephalic region by pooling blood in the vascular andextravascular compartments of the legs (Lindgren et al.
1998; Arbeille et al. 1999; Millet et al. 2000). This method
applies a pressure of *30 mmHg, proposing that thedegree of venous pooling induced by the bracelets is much
lower than that observed in KAATSU, where the cuff
pressure of 100–250 mmHg is used to restrict muscle bloodflow and increase muscle mass. Regarding autonomic
nervous responses to KAATSU, HFRRLFRR-1, a marker of
sympathetic activity, and the serum concentration of NOR,
a well-known neurotransmitter released from sympathetic
nerve, increased, which depended on the pressure of
KAATSU. On the other hand, HFRR, a marker of parasympathetic activity, decreased with KAATSU. Overall, italso indicates that during KAATSU, the arterial baroreceptor unloading is the dominant phenomenon leading tosympathetic excitation during the simulated weightlessness. The renin-angiotensin system is activated by anorthostatic stress (Duranteau et al. 1995). And, orthostatic
intolerance after bed rest or spaceflight may partly result
from impaired vasoconstriction, possibly due to adecreased secretion of renin-angiotensin (Fortney et al.
1991). During 6° head-down bed rest, the secretion of PRA
and ADH was increased during KAATSU, depending on
the degree of the pressure. From these observations, it islikely that the application of KAATSU, when using aproper pressure, on both the thighs partly simulates
hemodynamic, systemic cardiovascular, autonomic nervous and hormonal effects of orthostasis during thesimulated weightlessness.
Both LBNP and KAATSU induce the retention of bloodflow in lower extremities, and induce subsequent hemodynamic changes such as decreased SV and CO andincreased TPR (Stevens and Lamb 1965; Güell et al. 1990,
1992; Melchior et al. 1994; Murthy et al. 1994; Lee et al.

123

Eur J Appl Physiol (2008) 104:727–737

1997; Watenpaugh et al. 2000; Iida et al. 2007). The
mechanism triggered by these methods (negative pressure
vs. KAATSU) is quite different. However, the key physiological features of both the methods are lower extremity
blood pooling, reduction of venous return to the heart, andsubsequent hemodynamic changes including increased
autonomic nervous system activation (Stevens and Lamb
1965; Tomaselli et al. 1987; Lathers and Charles 1993).
Therefore, the effects of KAATSU and LBNP on hemodynamic parameters previously reported (Frey et al. 1986;
Sandler et al. 1988; Tomaselli et al. 1990; Lathers andCharles 1993; Melchior et al. 1994; Iida et al. 2007) arecompared and summarized in Table 4. Application of
LBNP (-30, -40 and -50 mmHg) decreases SV in apressure-dependent manner. 50 mmHg LBNP simulates
systemic cardiovascular effects of orthostasis in 1 G(Wolthuis et al. 1974). On the other hand, KAATSU (150–
200 mmHg) in the supine position (Iida et al. 2007)
decreases SV, which is comparable to standing and LBNP
of -30 to -40 mmHg as shown in Table 4. The present
study showed that during actually simulated weightlessness(6° head-down tilt for 24 h), KAATSU 100 mmHg on boththe thighs produced 32% reduction of SV, which was equal
to that observed in LBNP (-40 mmHg). Thus, KAATSU
appears to effectively induce pressure-dependent retentionof blood flow, and induce subsequent hemodynamicchanges like LBNP.
Syncopal attack has been reported to occur in LBNP,
especially when using high pressure more than -40 mmHg
(Stevens and Lamb 1965). The mechanisms in the occurrence of syncope remain unsettled, but several factors suchas blood pooling in the extremities and splanchnic territory,
and the deterioration of distal leg arterial and venous
compliance have been proposed. The present study also
showed that during actually simulated weightlessness, one
subject had presyncope due to a drop of blood pressureduring 100 mmHg KAATSU. This subject had no signs orverbal complaints associated with KAATSU (100–200 mmHg) in the seated position before bed rest. And,KAATSU markedly reduced SV and CO with an increasein TPR during the simulated weightlessness, comparedwith the seated position before bed rest, proposing thatblood pooling in the extremities under hypovolemia
developed during bed rest may be partly involved in the
induction of presyncope. Thus, the occurrence of syncope
should be taken into account during the actual space flight,
when the KAATSU training is used during space flight.
But, the KAATSU training is usually combined with
exercises, and during exercise, the skeletal muscle pumping mechanism partially counteracts accumulation of bloodin hyperemic lower extremities like LBNP (Eiken et al.
1986; Watenpaugh et al. 1994), where dynamic leg exercise combined with LBNP has been reported to doubleHR heart rate, bpm; SV stroke volume, ml; SVI stroke volume index, ml m-2; CO cardiac output, l min-1; CI cardiac index, l min m-2 (% change)

The data are shown as mean value reported in the references

63 (+22)59

Control

58

Control

90

88

5.3

5.2

KAATSU 50 mmHg

69 (-21)

4.3 (-17)

67 (37)KAATSU 100 mmHg

4.0 (-25)
62 (-31)
66 (+14)66 (-27)
64 (+10)KAATSU 150 mmHg

4.0 (-25)

KAATSU 200 mmHg

(-20)
(-20)
(+4)

(-30)
(-36)
(+10)
(-23)
(-24)
(+5.7)

58 (-32)

3.9 (-19)

71 (+22)56 (-37)

3.9 (-26)

Present study (bed rest)

Iida et al. (2007)

735

(+8)

KAATSU 250 mmHg

(-27)
(-39)

45 (-48)
74 (+30)
3.5 (-30)
59 (-31)
66 (+16)
3.8 (-24)
63 (-27)
62 (+9)5.0
8657

Lathers and Charles (1993)

Melchior et al. (1994)

Sandler et al. (1988)

Tomaselli et al. (1990)
3.2 (-36)

3.3 (-34)
38 (-51)
89 (+39)
3.7 (-26)

2.1 (-20)
32 (-31)51 (-35)

2.1 (-20)

67 (+7.9)

4.0 (-20)

61 (+3)35 (-25)

69 (+8)

47
59

2.7

79
64

5.0

61 (-21)78 (+21)

SV(I)
HR
CO(I)
SV(I)
HR
CO(I)
SV(I)
HR
CO(I)
SV(I)
HR

LBNP 40 mmHg
LBNP 30 mmHg
Control

Table 4 Comparative effects of LBNP and KAATSU on hemodynamic parameters reported in the references

LBNP 50 mmHg

CO(I)References

Frey et al. (1986)

Eur J Appl Physiol (2008) 104:727–737

LBNP tolerance (Watenpaugh et al. 1994). In a similarway, leg exercise combined with KAATSU may increase
the tolerance for developing syncope and then prevent its
occurrence.
Currently, astronauts practice 2–3 h of intensive exercise using treadmill, ergometer and resistance machines.
These time-consuming countermeasures decrease plasma
volume loss, and partly prevent muscle atrophy and boneloss. But, they cannot prevent astronauts from cardiovascular deconditioning. Therefore, alternate countermeasurestrategies are necessary. Now, the most effective countermeasure regimen appears to be a gravitation-like stresscombined with exercises. LBNP combined with treadmill
has been shown to be a useful method to prevent orthostatic
intolerance after space flight or during bed rest periods,
probably through its effect as orthostatic stimulus (Güell
et al. 1992; Murthy et al. 1994; Buckey et al. 1996; Leeet al. 1997, 2007; Watenpaugh et al. 2000; Schneider et al.
2002). It has been reported to maintain sub-maximal
exercise responses such as maximal heart rate, respiratoryexchange ratio, and ventilation, aerobic fitness and sprint
speed, then preventing orthostatic intolerance during bed
rest (Lee et al. 1997; Watenpaugh et al. 2000). In thepresent study, KAATSU appears to effectively inducepressure-dependent retention of blood flow, and induce
subsequent hemodynamic changes like LBNP. The KAATSU training has been reported to result in an increase inmuscle mass and muscular strength without any complications (Takarada et al. 2000; Abe et al. 2006; Fujita et al.
2007). And, it can be applied to all types of exercises
including treadmill, ergometer, and resistance machines,
which can be easily used by astronauts. Thus, the KAATSU training may provide an appropriate countermeasure
for cardiovascular deconditioning as well as musculoskeletal decline associated with weightlessness. However,further studies are needed to clarify this interesting possibility as well as the safety during the long-term
weightlessness.
Acknowledgments This study is partly financially supported by
Japan Aerospace Explosion Agency and the University of Tokyo.
Open Access This article is distributed under the terms of theCreative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.

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Eur J Appl Physiol (2010) 110:905–913
DOI 10.1007/s00421-010-1572-x

ORIGINAL ARTICLE

Pentraxin3 and high-sensitive C-reactive protein are independent
inflammatory markers released during high-intensity exercise
Toshiaki Nakajima • Miwa Kurano • Takaaki Hasegawa • Haruhito Takano • Haruko Iida •Tomohiro Yasuda • Taira Fukuda • Haruhiko Madarame • Kansei Uno • Kentaro Meguro •Taro Shiga • Mina Sagara • Taiji Nagata • Koji Maemura • Yasunobu Hirata •Tatsuya Yamasoba • Ryozo Nagai

Accepted: 5 July 2010 / Published online: 17 July 2010
Ó Springer-Verlag 2010

Abstract High-intensity exercise shares similarities withacute phase responses of inflammatory diseases. We
investigated the influences of acute exercise on inflammatory markers, plasma pentraxin3 (PTX3) and serum highsensitive C-reactive protein (CRP) (hsCRP). Nine healthy
male subjects (41 ± 3 years old) participated. Each subject
performed three types of exercise; ergometer exercise at
70% workload of anaerobic threshold (AT) for 30 min(70% AT exercise), peak ergometer exercise (peak EX, 20
watt increase/min until fatigue) and resistance exercises of
70% 1 RM (70% RE) until exhaustion. We measured
plasma PTX3, serum hsCRP, lactate, noradrenaline (NOR),
white blood cells (WBC), interleukin-6 (IL-6) andCommunicated by Susan Ward.
T. Nakajima (&)  M. Kurano  T. Hasegawa  H. Takano 
H. Iida  T. Yasuda  H. Madarame  K. Meguro
Department of Ischemic Circulatory Physiology,
KAATSU Training, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8655, Japane-mail: masamasa@pb4.so-net.ne.jp
T. Fukuda  K. Uno  T. Shiga  K. Maemura  Y. Hirata 
R. Nagai
Department of Cardiovascular Medicine,
The University of Tokyo, Tokyo, Japan
M. Sagara
The Perseus Proteomics Inc, Tokyo, Japan
T. Nagata
Department of Respiratory Medicine,
The University of Tokyo, Tokyo, JapanT. Yamasoba
Department of Otolaryngology and Head and Neck Surgery,
Faculty of Medicine, The University of Tokyo, Tokyo, Japan

myeloperoxidase (MPO), a marker of neutrophil degranulation. The effects of exercise on intracellular PTX3 andMPO in neutrophils were also investigated, by using flow
cytometry analysis. Circulating PTX3 and hsCRP significantly increased immediately after 70% RE and peak EX,
while they did not increase after 70% AT exercise. The
exercise-induced fold increase in PTX3 and hsCRP relative
to the resting level was positively correlated with thechanges in WBC, NOR, lactate and MPO. The exerciseinduced fold increase in IL-6 was positively correlated withthat in NOR, but not with that in PTX3 and hsCRP. Neutrophils isolated immediately after 70% RE, but not 70%
AT exercise, exhibited lower mean fluorescence for PTX3
and MPO than those from pre-exercise blood. These results
provide the evidence that high-intensity exercises significantly increase circulatory PTX3 as well as hsCRP. The
release from peripheral neutrophils is suggested to be
involved in the exercise-induced plasma PTX3 increase.
Keywords Pentraxin3  High-sensitive CRP 
Inflammation  Neutrophil  Interleukin-6 Resistance exercise  High-intensity exercise 
Myeloperoxidase  Flow cytometry

Introduction
Pentraxins, a family of multimeric pattern-recognition
proteins highly conserved in evolution (Mantovani et al.
2008), are divided into two groups (short pentraxins andlong pentraxins), based on the primary structure of thesubunit. C-reactive protein (CRP), a classic short pentraxin,
is mainly produced in the liver and operates as a major
acute phase reactant with a pronounced rise in plasma
concentration in response to a variety of inflammatory

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diseases or tissue injury (Volanakis 2001; Pepys andHirschfield 2003). On the other hand, PTX3 is a newly
identified long pentraxin and produced by various cell
types including skeletal muscle, monocytes/macrophages,
endothelial cells, and vascular smooth muscle cells at thesite of inflammation in response to primary inflammation
or tissue injury (see review, Presta et al. 2007; Mantovani
et al. 2008). PTX3 has also been reported to exist in neutrophils, suggesting that neutrophils are one of the sourcesof PTX3 (Jaillon et al. 2007). Thus, PTX3 is thought to bea useful serological marker reflecting tissue inflammationand damage under diverse clinical conditions, but it iscompletely distinct from CRP (Presta et al. 2007; Mantovani et al. 2008). Elevated plasma PTX3 levels have also
been described in acute myocardial infarction, chronic
renal failure, cardiac surgery, immediately after coronary
stenting (Latini et al. 2004; Boehme et al. 2007; Kunes
et al. 2007; Malaponte et al. 2007; Presta et al. 2007;
Kotooka et al. 2008) and in systemic or localized inflammation such as sepsis (Muller et al. 2001). A generalcharacteristic emerging from these studies about PTX3
blood levels in human pathology is considered to be therapid rate of increase compared with CRP, together with alack of correlation between CRP and PTX3 levels.
Daily regular exercise is known to induce anti-inflammatory effects and protect against the risk of cardiovasculardiseases associated with chronic low-grade systemic
inflammation such as atherosclerosis (Petersen and Pedersen
2005; Plaisance and Grandjean 2006), resulting in a decrease
in serum CRP (Kasapis and Thompson 2005). Recently, we
have reported that cardiac rehabilitation using aerobic
exercise in patients with cardiovascular diseases decreases
plasma PTX3 level as well as hsCRP (Nakajima et al. 2009).
However, in contrast with anti-inflammatory effect of
exercise, acute high-intensity and prolonged exercise by
itself causes production of stress hormones and alterations in the circulating quantity and function of various
immune cells, including leukocyte mobilization and leukocytosis (Hoffman-Goetz and Pedersen 1994; Pedersen and
Hoffman-Goetz 2000; Peake et al. 2004; 2005a; Büttner
et al. 2007). As such, strenuous exercise activates acutephase inflammatory response, the release of inflammatory
mediators and cytokines such as interleukin (IL)-1, IL-6 andgranulocyte colony-stimulating factor (G-CSF) (McCarthy
et al. 1992; Ostrowski et al. 2000; Yamada et al. 2002;
Natale et al. 2003; Peake et al. 2005a, b; Mooren et al. 2006;
Zaldivar et al. 2006), alterations in gene expression profilesof neutrophils (Fehrenbach et al. 2003; Büttner et al. 2007)
and causes substantial tissue injury (Shephard 2001). Thus,
high-intensity exercise elicits inflammatory responses similar to many clinical physical stressors including surgery,trauma and sepsis, indicating that exercise may be a goodmodel for the inflammatory response (Hoffman-Goetz and123

Eur J Appl Physiol (2010) 110:905–913

Pedersen 1994; Shephard 2001). Until now, there have been
several studies on the effects of acute exercise on serum
CRP. Long-lasting strenuous exercise such as a marathon
run has been reported to increase serum CRP, measured 16 h
after activity (Castell et al. 1997). Risøy et al. (2003)
reported a rapid increase in CRP with 1 h running, and anincrease of CRP level has been also reported after eccentric
exercise (Phillips et al. 2003). Thus, high-intensity exercise
elicits inflammatory response and then increases serum
CRP. On the other hand, there is no information regarding
the changes in plasma PTX3 levels in exercise-induced
inflammatory responses.
Therefore, the purpose of the present study is to investigate the influences of various types of acute exercise on
inflammatory markers, plasma pentraxin3 (PTX3) andserum CRP, and the characteristics of these markers inacute exercise-induced inflammation. Serum levels of highsensitive CRP (hsCRP), a sensitive marker of CRP, andplasma levels of PTX3 were measured concurrently inthree types of exercise. We also measured serum myeloperoxidase (MPO), a marker of neutrophil degranulation,and compared these with the increase in hsCRP and PTX3.
In addition, neutrophils isolated from the peripheral blood
were assessed for the effects of exercise on intracellular
PTX3 and MPO in neutrophils by using flow cytometry
analysis. Here, we provide the evidence that high-intensity
exercises significantly increase circulatory PTX3 as well as
hsCRP. The release from peripheral neutrophils is suggested to be involved in the exercise-induced plasma PTX3
increase.

Methods
Subjects and experimental designs
Nine healthy males [age, 41 ± 3 years old; height,
169 ± 8 cm; weight, 70 ± 7 kg, body mass index (weight/
height2, 24 ± 2 kg/m2)] participated in this study. This
study was approved by the Ethics Committee of the
University of Tokyo. All subjects were informed of themethods, procedures and risks, and signed an informed
consent document before participation. None of the subjects had any diseases or took any medications such as antiinflammatory drugs and steroids. They were non-smokers,
and sedentary, and none of the subjects had participated instrength/resistance-type training for a minimum of 2 years
prior to the start of the study.
Each subject visited the laboratory on a total of fiveoccasions within this study of 4 weeks. On visits 1 and 2,
the peak oxygen uptake (VO2 peak) and one-repetition
maximal (1 RM) voluntary force were measured. Perbreath gas exchange was measured, and VO2 peak wasEur J Appl Physiol (2010) 110:905–913

determined using a standard increment cycle ergometer
protocol, using a ramp pulse (20 watt increase/min) withAE 300S (Minato Medical Science CO., LTD., Tokyo,
Japan). The peak VO2 value in this study was 30 ± 5 ml/
min/kg (n = 9). One RM was measured at three different
stations of a resistance exercise circuit: leg press, leg curl
and leg extension. Subsequently, on visits 3–5, subjects
were assigned to a sequence of three experimental conditions, using a randomized block design described as follows: (1) prolonged ergometer exercise at 70% workload ofanaerobic threshold (AT) for 30 min (70% AT exercise);(2) Peak ergometer exercise (Peak EX; 20 watt 4 min andthen 20 watt ramp; 20 watt increase/min exercise) until
fatigue; (3) resistance exercises (RE) using 70% 1RM (legpress, leg extension and leg curl) (70% RE). Subjects
performed four sets of each exercise with 1-min interval
until exhaustion. The total mean repetitions were 52 ± 4(leg press), 52 ± 3 (leg curl) and 53 ± 2 (leg extension).
Each of the three experimental exercise trials was separated
at least by 5 days.
In flow cytometry analysis using peripheral neutrophils,
three subjects performed two types of exercise (70% RE
and 70% AT exercise) within 2 weeks again.
Blood sampling and analysis
On each exercise visit (visits 3–5), blood samples wereobtained at 9:00–10:00 a.m. using an indwelling heparinlock catheter, which was inserted into the superficial antebrachial vein of the left arm. The subjects were instructed tosit quietly before taking blood sample. The baseline (resting/pre-exercise) blood sample was taken before the start ofexercise. Further blood samples were obtained immediately
after each exercise and after a 1-h recovery period. The
subjects were instructed to sit quietly during the recovery
phase. All samples were kept in ice-cold water and centrifuged (1,500g) for 10 min and the plasma was stored at-20°C until the assays were performed. Blood samples formeasurement of blood hemoglobin (Hb), hematocrit (Htc)
and white blood cell count (WBC) (2 ml) were drawn into
test tubes containing EDTA-2 K. Blood hemoglobin (Hb,g dl-1) was measured by the cyanomethemoglobin method(Coulter hemoglobinometer). Htc was measured by amicro-hematocrit using ultracentrifugation. For hormone
determinations, blood (7 ml) was drawn into test tubes
containing 10.5 mg EDTA-2Na. The plasma noradrenaline(NOR) concentration was measured using a high-performance liquid chromatography (HPLC) method. The lower
limit of detection of the assay was 6 pg/ml. The plasma
lactate level was measured using an enzyme system basedon lactate oxidase combined with N-ethyl-N-(3-methylphenyl)-N-acetyl ethylenediamine and an auto-analyzer,
HITACHI Type 7170.

907

For immunostaining, blood samples (5 ml) were collected in pre-heparinized syringes from three subjects at
rest. For flow cytometry analysis, whole blood (300 ll)
from pre-exercise and immediately after each exercise wasdrawn into test tubes containing EDTA-2K.
Serum IL-6 and G-CSF levels were measured using the
Cytometric Bead Array (CBA) from BD Biosciences (CA,USA). Serum myeloperoxidase (MPO) level was measured
by an ELISA with Immundiagnostik AG (Benshein, Germany). The limit of detection for the human IL-6, G-CSF
and MPO assays was 0.09 pg/ml, 0.1 pg/ml and 1.9 ng/ml,
respectively.
High-sensitive CRP was measured at SRL Co. (Tokyo,
Japan) in 500 ll serum samples, using a method of latex
turbidimetric immunoassay (LTIA). The limit of detectionof hsCRP was 50 ng/ml. Plasma PTX3 levels were measured at Perseus Proteomics Inc. (Tokyo, Japan), using asandwich ELISA technique as previously reported (Inoueet al. 2007; Kotooka et al. 2008). The limit of detection of
the PTX3 assay was 0.1 ng/ml.
Neutrophils isolation and immunostaining
Whole blood (5 ml) from peripheral blood was layered
over 5 ml of Polymorphprep (Axis-Shield, Oslo, Norway)
and spun for 35 min at 690 g at 20°C. Neutrophils (polymorphonuclear leukocytes, PMNs) were harvested fromthe second interface, washed with phosphate-buffered saline (PBS, Wako Pure Chemical Industries, Ltd., Osaka)and spun for 10 min at 270 g at room temperature. Neutrophils were resuspended in the buffer (3% FBS and0.05% NaN3 in PBS), mixed with ice-cold 70% ethanol for
30 min and spun for 10 min at 270 g at room temperature.
Subsequently, neutrophils were resuspended in 1 ml 70%
ethanol, dropped on a slide glass and dried. For immunostaining, the fixed cells were washed in PBS, blocked for
10 min with 2% horse serum in PBS and incubated withthe primary antibody in a humid chamber overnight at 4°C.
The primary antibodies were the rabbit polyclonal antihuman myeloperoxidase (Novus Biological, Littleton, CO)and rat monoclonal antibody against human PTX3 (clone
MNB4, Alexis Biochemicals, San Diego, CA). After the
preparations were washed in PBS, the secondary antibody
was incubated for 60 min at room temperature. Alexa Fluor
488-conjugated donkey anti-rabbit IgG (H ? L) antibody(Molecular Probes, Molecular Probes, Eugene, OR), andCy3-conjugated goat anti-rat IgG (Jackson ImmunoResearch, West Grove, PA) were used to visualize MPO andPTX3 expression. For negative controls, cells were treated
without antibody. The cells were also stained with Hoechist
33258 (Sigma-Aldrich) to visualize nuclei. A confocal
laser scanning microscope (Olympus FluoView FV300,
Olympus Co., Tokyo, Japan) was used for observations.

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Flow cytometry
For flow cytometry analysis using neutrophils, whole blood(300 ll) was lysed with Versalyse reagent (Beckman
Coulter, Fullerton, CA) and spun for 5 min at 270 g. Then,cells were resuspended in 100 ll of 4% paraformaldehyde
for 15 min. Then, 1 ml of the buffer (see above) was added
and spun for 5 min at 270 g. The cells were resuspended in
100 ll buffer containing 0.1% saponin for 5 min andincubated for 30 min at room temperature with a mixtureof primary antibody (the rabbit polyclonal anti-human
myeloperoxidase (Novus Biological, Littleton, CO) and rat
monoclonal antibody against human PTX3 (clone MNB1,
Alexis Biochemicals, San Diego, CA) for 30 min. Then,the cells were added with 1 ml buffer containing 0.1%
saponin, spun at 270g and incubated with secondary antibody (Alexa Fluor 488-conjugated donkey anti-rabbit IgG(H ? L) antibody (Molecular Probes Inc., Eugene, OR)
and PE-conjugated goat anti-rat IgG (H ? L) antibody(Beckman Coulter, Fullerton, CA). Finally, the cells wereagain resuspended in the buffer. Flow cytometry was performed on a flow cytometer (EPICS XL-MCL, Beckman
Coulter, Fullerton, CA).

Eur J Appl Physiol (2010) 110:905–913

As shown in Fig. 1 and Table 1, the inter- and intra-individual CV was lower for the resting plasma PTX3 level
than for the resting serum hsCRP level, suggesting thatplasma PTX3 is relatively stable compared with serum
hsCRP. Figure 1c shows the absence of a significant correlation between resting plasma PTX3 and serum hsCRP
level.
Figure 2a–c shows the effects of three types of exercise
on WBC (Fig. 2a), lactate (Fig. 2b), and NOR (Fig. 2c).
All three types of exercise induced a significant increase in
WBC (Fig. 2a, p \ 0.01) immediately after exercise, butbaseline values were restored by 1 h after exercise. The
peak value of WBC was greater for peak EX and 70% RE
than 70% AT exercise (p \ 0.01). Both lactate and NOR
concentration were significantly increased immediately
after peak EX and 70% RE (p \ 0.01), while it did notchange significantly after 70% AT exercise (Fig. 2b, c).

Data analysis
All values are expressed as the mean ± SE. Statisticalanalyses were performed by a two-way analysis of variance(ANOVA) with repeated measures [Time (pre- and posttesting) 9 group (Peak EX, 70% AT exercise and RE)].
When differences were indicated, Bonferroni’s comparison
was used to determine significance. Student’s paired t test
was used to compare two sets of data from the same subjects. Spearman’s rank correlation coefficient (r) was used
to examine the relationship between individual exerciseinduced changes. Differences were considered significant if
p value was less than 0.05. The intra- and inter-individual
coefficients of variation (CV) were determined as the ratioof the standard deviation to the mean value.

Results
We first investigated the daily variation of plasma PTX3
and serum CRP level obtained from nine healthy malesubjects under resting conditions and the relationships
between them. Blood samples were obtained three times
under resting condition for each subject at the same time on
different days before three exercise trials were performed.
The daily variability of plasma PTX3 (A) and serum
hsCRP (B) level is shown for each subject (Fig. 1a, b). The
mean value, and inter- and intra-individual coefficient ofvariation (CV) for PTX3 and hsCRP are shown in Table 1.

123

Fig. 1 Diurnal variation of resting plasma PTX3 (a) and serum
hsCRP level (b). Blood samples were obtained three times underresting condition for each subject at 9:00–10:00 a.m. before three
exercise trials were performed. Plasma PTX3 and serum hsCRP were
measured, and the data were plotted in Rest 1, Rest 2 and Rest 3.
c Correlations between resting plasma PTX3 and serum hsCRP levelobtained from nine healthy subjects

Table 1 Mean value, intra- and inter-individual coefficients of variation for plasma PTX3 and serum hsCRP levels in nine healthy
subjects
MeanInter-individual CV

Intra-individual CV

PTX3 (ng/ml)

1.83

0.38

0.13

hsCRP (ng/ml)

368

0.98

0.37

PTX3 pentraxin3, hsCRP high-sensitive CRP, CV coefficient ofvariation

Eur J Appl Physiol (2010) 110:905–913

909

Fig. 2 White blood cell count(WBC, a), lactate (b),noradrenaline (NOR, c),hematocrit (Htc, d), CPK(e) and myeloperoxidase (MPO,f) before exercise (Pre EX),
immediately after (Post EX) and1 h after EX. Peak ergometer
exercise until fatigue (PeakEX); ergometer exercise at 70%
workload of anaerobic threshold(AT) for 30 min (70% AT
exercise); resistance exercises(leg press, leg curl and leg
extension) of 70% 1 RM until
exhaustion (70% RE). Values
are means ± S.E. for ninesubjects. **Significantly
different from Pre EX,
p \ 0.01. *Significantly
different from Pre EX, p \ 0.05

Fig. 3 Correlations between the fold increase in serum MPO level
and that in lactate (a), WBC (b) and noradrenaline (NOR, c)

Figure 2d, e shows the effects of three types of exercise
on Htc and CPK. The significant rise in Htc was observed
immediately after both peak EX and 70% RE (p \ 0.01).
But, Htc did not significantly increase in 70% AT exercise.
CPK (Fig. 2e) increased from pre-exercise to post-exercise(time effect, p \ 0.01); however, no significant group differences were observed (p [ 0.05).
Figure 2f shows the effects of three types of exercise on
serum MPO concentration, a marker of neutrophil
degranulation. A rise in serum MPO was observed immediately after both peak EX and 70% RE (p \ 0.01), but not
after 70% AT exercise. Figure 3 shows the correlation
between the fold increase in serum MPO and that in lactate,
WBC and NOR. The fold increase in MPO was positively
correlated with WBC, NOR and lactate.
Figure 4 shows the effects of three types of exercise on
serum hsCRP (Fig. 4a) and plasma PTX3 (Fig. 4b). As
shown in Fig. 4, both peak EX and 70% RE significantly
increased hsCRP and PTX3 (p \ 0.01) immediately after
exercise. The increased hsCRP and PTX3 level returned tobaseline levels within 1 h. Figure 4c shows the correlation
between the fold increase in hsCRP and that in PTX3
during the exercise. The fold increase in PTX3 was positively correlated with that in hsCRP. On the other hand,neither hsCRP nor PTX3 were significantly affected by
70% AT exercise (Fig. 4a, b).
We compared the fold increase in lactate, NOR, WBC
or MPO with that in serum hsCRP or plasma PTX3 asshown in Table 2. The fold increase in hsCRP and PTX3

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Eur J Appl Physiol (2010) 110:905–913

Fig. 4 Serum hsCRP (a) and plasma PTX3 (b) level before (Pre EX),
immediately after (Post EX), and 1 h after EX. Peak EX, 70% AT
exercise, and 70% RE. Values are means ± SE for nine subjects.
**Significantly different from Pre EX, p \ 0.01. c Correlations
between the fold increase in hsCRP and that in PTX3 during exercises

obtained from three subjects examined. The nucleus
staining is shown in Fig. 5b. Figure 6 shows the effects ofexercise (70% AT exercise and 70% RE) on PTX3 andMPO in neutrophils using flow cytometry. The typical data
are shown in Fig. 6a, b. The mean fluorescence density of
PTX3 and MPO in neutrophils isolated from pre-exercise
blood is considered as 100%, and the relative value of themean fluorescence density of neutrophils isolated fromblood immediately after exercises is shown in Fig. 6c. The
data were obtained from three subjects. Neutrophils isolated from blood immediately after 70% RE exhibited
lower mean fluorescence for PTX3 and MPO than thosefrom pre-exercise blood (Fig. 6a, c). On the other hand,neutrophils isolated from blood immediately after 70% AT
exercise exhibited no significant changes of the mean
fluorescence for PTX3 and MPO (Fig. 6b, c), comparedwith those isolated from pre-exercise blood.

Discussion
relative to the resting level was positively correlated withthat in WBC, NOR, lactate and MPO.
It is well known that the inflammatory markers hsCRP
and PTX3 are induced by cytokines such as IL-6 and IL-1
(Li and Goldman 1996; Mantovani et al. 2008). Therefore,
we investigated the effects of exercise on serum IL-6 andG-CSF level. Peak EX significantly increased IL-6 from
0.89 ± 0.48 pg/ml at rest to 1.40 ± 0.60 pg/ml immediately after exercise (p \ 0.01). The increased IL-6 level
returned to 0.99 ± 0.47 pg/ml at 1 h after exercise; 70%
RE did not significantly increase IL-6 (0.66 ± 0.28 pg/ml
at rest, 1.03 ± 0.44 pg/ml immediately after exercise and1.06 ± 0.35 pg/ml at 1 h after exercise); 70% AT exercise
also did not change IL-6. On the other hand, G-CSF was
not significantly affected by these exercises (data notshown). The fold increase in IL-6 or G-CSF was not correlated with that in PTX3 or hsCRP (Table 2).
Finally, we investigated the existence of PTX3 andMPO in human neutrophils. The flow cytometry analysis
showed the existence of both PTX3 (Figs. 5a, 6) and MPO(Fig. 6) using specific antibody. Immunostaining studies
also demonstrated the presence of MPO (Fig. 5c) andPTX3 (Fig. 5d) in human neutrophils. Similar data wereTable 2 Correlation between
inflammatory markers (foldincrease in hsCRP or PTX3) andneurohumoral responses (foldincrease in lactate, NOR, WBC,
MPO, G-CSF or IL-6)

The major findings of the present study are as follows.
(1) The short-term acute high-intensity exercise (peak EX
and 70% RE) until exhaustion increased plasma PTX3
and serum MPO as well as serum hsCRP in untrained
healthy male subjects. (2) The increase in PTX3 andhsCRP was positively correlated with that in NOR, lactate, WBC and MPO, but not with IL-6 or G-CSF. (3)Neutrophils isolated from blood immediately after 70%
RE, but not after 70% AT exercise, exhibited lower mean
fluorescence for PTX3 and MPO than those from restingblood. These results provide the evidence that highintensity exercises significantly increase circulatory PTX3
as well as hsCRP. The release from peripheral neutrophils is suggested to be involved in the exercise-induced
plasma PTX3 increase.
Acute exercise is an important stressor to the body,leading to an activation of immune responses (HoffmanGoetz and Pedersen 1994; Pedersen and Hoffman-Goetz
2000; Peake et al. 2004; 2005a; Büttner et al. 2007). Suchan exercise-induced acute phase response consists of typical changes including leukocytosis and release of cytokines and acute phase proteins, similar to acute phase

Lactate

NOR

WBC

MPO

G-CSF

IL-6

r value

0.75

0.71

0.55

0.47

0.14

0.32

(p value)(6 9 10-6)(5 9 10-5)(2 9 10-4)(7 9 10-3)(0.2)(0.06)

0.56

0.5

0.67

0.48

0.22

0.1

(0.12)(0.28)

hsCRP

PTX3
r value(p value)123-3(1 9 10 )-3(6 9 10 )-5(8 9 10 )-3(6 9 10 )Eur J Appl Physiol (2010) 110:905–913

911

Fig. 5 Expression of MPO and PTX3 in human neutrophils isolated
from peripheral blood. a Flow cytometry analysis of PTX3 expression
in human neutrophils isolated from peripheral blood. The neutrophils
were counterstained with Hoechst33258 to visualize nuclei in b. c,d Immunostaining of MPO (c) and PTX3 (d) in neutrophils

responses evoked by other stressors such as trauma andsepsis (McCarthy et al. 1992; Ostrowski et al. 2000;
Yamada et al. 2002; Natale et al. 2003; Peake et al. 2005b;
Mooren et al. 2006; Zaldivar et al. 2006). In the present
study, peak EX and 70% RE markedly increased NOR,
lactate and WBC, compared with 70% AT exercise. These
high-intensity exercises also increased serum MPO concentration, a marker of neutrophil degranulation, which isconsistent with previous papers showing that changes inserum MPO concentration depends on exercise intensity(Peake et al. 2004). In addition, flow cytometry analysis
showed that neutrophils isolated from blood immediately
after RE, but not after 70% AT exercise, exhibited lower
mean fluorescence for MPO than those from resting blood,suggesting that high-intensity exercise released MPO fromperipheral neutrophils. Serum CPK level increased frompre-exercise to post-exercise independently of exercise
programs. The mean fold increase in serum CPK value at
70% RE was 1.15. These values are almost equal to the risein Htc, indicating that the increase in serum CPK might
be partly explained by the hemoconcentration with therelatively high-intensity exercise compared with the lowintensity exercise of 70% AT exercise. However, we cannot exclude the possibility that some muscle damage might
have occurred during exercise.
Cytokines are produced by a wide variety of cell types,
including skeletal muscle, when exposed to various inflammatory stimuli such as acute high-intensity exercise.

Fig. 6 Effects of 70% RE and 70% AT exercise on MPO and PTX3
in neutrophils using flow cytometry. The typical data are shown at
70% RE (a) and 70% AT exercise (b). Note that neutrophils isolated
from blood immediately after 70% RE, but not 70% AT exercise,
exhibit lower mean fluorescence for PTX3 and MPO than those frompre-exercise blood. The mean fluorescence density of MPO and PTX3
in neutrophils isolated from pre-exercise blood is considered as 100%,and the relative value of the mean fluorescence density of neutrophils
isolated from blood immediately after exercises is shown in c. Data
were obtained from three subjects. Note that the mean fluorescencedensity of MPO and PTX3 in neutrophils isolated from blood
immediately after 70% RE, but not 70% AT exercise, significantly
decreased, compared with the pre-exercise level (100%). *p \ 0.05
versus pre-exercise level

Production of IL-6 in contracting human skeletal muscles
can account for the exercise-induced increase in plasma IL-6
(Steensberg et al. 2000). The present study also showed that
IL-6 significantly increased in peak EX. On the other hand,
G-CSF plays essential roles in bone marrow release of cells
from a neutrophil lineage and activates neutrophils. Intensive exercise has been reported to increase serum
G-CSF level (Smith et al. 2000; Suzuki et al. 2000; Yamada
et al. 2002). In our study, however, G-CSF was not significantly increased after peak EX and 70% RE, which might be

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912

due to differences in exercise protocols (intensity andduration) and the ages of subjects studied.
Long-lasting strenuous exercise, such as a marathon run,has been reported to increase serum CRP, measured 16 h
after the activity (Castell et al. 1997). Risøy et al. (2003)
also reported a rapid blood increase in CRP in healthy
untrained subjects after a single 1–1.5 h run (from 2.6 to
5.1 ng/ml) on measuring hsCRP. However, until now, theeffects of various types of acute exercise on CRP have notbeen fully investigated. The present study using hsCRP
showed that the short-term acute high-intensity exercise(70% RE and peak EX) increased serum hsCRP in healthy
male subjects. CRP is produced mainly in the liver under
the regulatory control of IL-6 (Li and Goldman 1996).
However, it is unlikely that IL-6 may be involved in the
rapid increase of serum CRP in our exercise protocol, since
we used short-term exercise within 30 min, and theincrease in serum CRP was not correlated with that inserum IL-6. Alternatively, the rapid increase in serum CRP
may be caused by release of the preformed protein from theliver. Actually, it has been shown that the rate of CRP
secretion is greatly accelerated during the acute phase
response (Macintyre et al. 1985). However, the additionalsites of CRP production such as kidney and vascular wall
could not be excluded (Volanakis 2001; Sun et al. 2005).
As compared with hsCRP, PTX3 has been shown to be astable and high-sensitive marker for inflammation underthe various pathophysiological conditions (Presta et al.
2007; Mantovani et al. 2008). In the present study, nocorrelations were found between the resting plasma PTX3
and serum hsCRP levels, proposing that CRP and PTX3 are
independent markers of inflammation, as previously
described (Presta et al. 2007; Mantovani et al. 2008). We
also showed that the inter- and intra-individual CVs for the
resting plasma PTX3 level were less than that for the
resting serum hsCRP levels, suggesting that plasma PTX3
may be a relatively stable marker compared with hsCRP. In
addition, we provided the evidence that plasma PTX3
increased with high-intensity exercise (peak EX and 70%
RE), but not with 70% AT exercise.
The exercise-induced increase in hsCRP was strongly
correlated with that in NOR and lactate, WBC and MPO,
while the exercise-induced increase in PTX3 was strongly
correlated with that in WBC and MPO. Thus, it is likelythat the trigger mechanisms underlying the acute exerciseinduced CRP and PTX3 may be different. PTX3 as well as
CRP are known to be induced by cytokines such as IL-1 (Liand Goldman 1996; Mantovani et al. 2008). However, in asimilar fashion to CRP, the increase in PTX3 was notcorrelated with that in serum IL-6 or G-CSF investigated in
the present study. Thus, a rapid increase in PTX3 may be
due to the release of the preformed protein. Jaillon et al.
(2007) reported that PTX3 exists in neutrophils and is123

Eur J Appl Physiol (2010) 110:905–913

stored in granules, suggesting that neutrophils could be oneof the sources of PTX3 released into the blood stream. The
present study also showed the presence of PTX3 as well as
MPO in neutrophils. Recently, Kotooka et al. (2008)
reported that rapid changes in plasma PTX3 occurred
across the stented vascular bed within 15 min, and therelationship between the response of plasma PTX3 andactivated macrophage antigen-1 suggests that local leukocytes recruited on the stented lesion in response to stentinduced vascular injury may be the major cellular source
responsible for the increased PTX3. The present study
showed that 70% RE increased serum MPO as well as
plasma PTX3, and neutrophils isolated from blood immediately after 70% RE exhibited lower mean fluorescencefor PTX3 and MPO than those from resting blood. These
results suggest that high-intensity exercise releases both
PTX3 and MPO from peripheral neutrophils, which may be
involved in the exercise-induced PTX3 and MPO increase.
Similarly, changes in neutrophil surface receptor expression including CD16 and degranulation have also beenreported immediately after high-intensity exercise (atreadmill for 1 h at 80% VO2max) (Peake et al. 2004).
Thus, under high-intensity exercise, the rapid release ofstored PTX3 by activated neutrophils appears to play a rolein the early phase of its elevation preceding gene expression-dependent production, as described for acute exerciseinduced gene alterations (Büttner et al. 2007).
In conclusion, high-intensity exercises significantly
increase circulatory PTX3 as well as hsCRP. The releasefrom peripheral neutrophils is suggested to be involved in
the exercise-induced plasma PTX3 increase.
Acknowledgments This study was supported by the Program of
Fundamental Studies in Health Sciences of the National Institute of
Biomedical Innovation (NIBIO). The authors thank Drs. Morita T,
Kato M and Monzen K for their contributions to this study.

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DOI 10.1007/s00380-016-0801-6

ORIGINAL ARTICLE

Repetitive restriction of muscle blood flow enhances mTOR
signaling pathways in a rat model
Toshiaki Nakajima1 · Tomohiro Yasuda3 · Seiichiro Koide4 · Tatsuya Yamasoba5 ·Syotaro Obi2 · Shigeru Toyoda1 · Yoshiaki Sato6 · Teruo Inoue1 · Yutaka Kano4

Received: 20 October 2015 / Accepted: 15 January 2016
© Springer Japan 2016

Abstract Skeletal muscle is a plastic organ that adapts its
mass to various stresses by affecting pathways that regulate
protein synthesis and degradation. This study investigatedthe effects of repetitive restriction of muscle blood flow
(RRMBF) on microvascular oxygen pressure (PmvO2), mammalian target of rapamycin (mTOR) signaling pathways,
and transcripts associated with proteolysis in rat skeletal
muscle. Eleven-week-old male Wistar rats under anesthesia
underwent six RRMBF consisting of an external compressive force of 100 mmHg for 5 min applied to the proximal
portion of the right thigh, each followed by 3 min rest. During RRMBF, PmvO2 was measured by phosphorescencequenching techniques. The total RNA and protein of thetibialis anterior muscle were obtained from control rats, andrats treated with RRMBF 0–6 h after the stimuli. The protein
expression and phosphorylation of various signaling proteins
were determined by western blotting. The mRNA expression
level was measured by real-time RT-PCR analysis. The total* Toshiaki Nakajima
nakat@dokkyomed.ac.jp
1

Department of Cardiovascular Medicine, Dokkyo Medical
University and Heart Center, Dokkyo Medical University
Hospital, 880 Kitakobayashi, Mibu, Tochigi 321‑0293, Japan2

Department of Cardiovascular Medicine and Research
Support Center, Dokkyo Medical Univerasity, Tochigi, Japan

3

Seirei Christopher University, Shizuoka, Japan

4

Department of Engineering Science, Bioscienceand Technology Program, University of ElectroCommunications, Tokyo, Japan

5

Department of Otolaryngology, University of Tokyo, Tokyo,
Japan

6

Department of Basic Sciences in Medicine, Kaatsu
International University, Battaramulla, Sri Lanka

muscle weight increased in rats 0 h after RRMBF, but not inrats 1–6 h. During RRMBF, PmvO2 significantly decreased(36.1 ± 5.7 to 5.9 ± 1.7 torr), and recovered at rest period.
RRMBF significantly increased phosphorylation of p70
S6-kinase (p70S6k), a downstream target of mTOR, and ribosomal protein S6 1 h after the stimuli. The protein level of
REDD1 and phosphorylation of AMPK and MAPKs did notchange. The mRNA expression levels of FOXO3a, MuRF-1,
and myostatin were not significantly altered. These results
suggested that RRMBF significantly decreased PmvO2, andenhanced mTOR signaling pathways in skeletal muscle usinga rat model, which may play a role in diminishing muscle
atrophy under various conditions in human studies.
Keywords Blood flow restriction · Mammalian target of
rapamycin (mTOR) · Microvascular pO2 · Muscle atrophy ·Myostatin · p70 S6-kinase · Rat skeletal muscle · Hypoxia
Abbreviations
RMBF	Restriction of muscle blood flow
RRMBF	Repetitive restriction of muscle blood flow
PmvO2	Microvascular oxygen pressure
HIF-1α	Hypoxia-inducible factor-1αmTOR	Mammalian target of rapamycin
p70S6k	p70 S6-kinase
ERK1/2	Extracellular signal-regulated kinase 1/2
FOXO3a	Forkhead box O3A
MuRF-1	Muscle ring finger-1
VEGF	Vascular endothelial growth factor

Introduction
It has been well known that muscle size is mainly determined by the balance between muscle protein synthesis and13

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degradation [1, 2]. Muscle hypertrophy occurs when the protein synthesis exceeds the protein degradation, while muscle
atrophy occurs when the protein degradation overcomes theprotein synthesis. After muscle disuse, for example duringlong-term bed rest, spaceflight, and simulated models of nobearing activity, skeletal muscle atrophy develops due to thealtered protein metabolism, leading to decreased muscle contractile protein content. To prevent it and increase muscle protein synthesis, resistance exercise, an established potent stimulus for enhancing muscle protein synthesis and subsequentmuscle hypertrophy, is usually used. The increased muscle
protein synthesis is associated with enhanced phosphorylation events on numerous kinases to regulate mRNA translation, including mammalian target of rapamycin (mTOR1)/
p70 S6-kinase (p70S6k) signaling pathways [3, 4].
The conventional strength training pursued at intensity
lower than 60–70 % 1RM usually does not increase muscle
size, compared with high-intensity exercise. However, highintensity loading entails a risk of injury to the moving organs
or circulatory system in elderly individuals and patients withvarious diseases. On the other hand, several human studies
have shown that low-intensity (20–30 % 1RM) resistance
exercise under restriction of muscle blood flow (RMBF),
also known as KAATSU training [5, 6], is a new strength
training method which can stimulate numerous muscle fibers
and produce increased muscle size and strength even with
low-intensity loading [6, 7]. Fujita et al. [8] reported that theprotein synthesis increased in healthy young adults 3 h aftera brief session of RMBF knee extension exercise. Additionally, they showed that phosphorylation of p70 S6-kinase,a key regulator of the mTOR pathway, was enhanced after
RMBF exercise, compared with control exercise. Moreover,reduced expression of the proteolysis-related genes such as
forkhead box O3A (FOXO3a), atrogin-1 and muscle ring
finger-1 (MuRF-1) as well as myostatin, a negative regulatorof muscle mass, has been reported after acute RMBF exercise [9, 10]. These mechanisms may play a role on hypertrophic effects of RMBF exercise, even by using low-intensity resistance exercise. On the other hand, skeletal muscle
is a plastic organ that adapts its mass to various stresses byaffecting pathways that regulate protein and cellular turnover. Takarada et al. [11] reported that repetitive restriction of muscle blood flow (RRMBF) even without exercise
effectively diminished postoperative disuse atrophy of knee
extensors in patients who underwent reconstructive surgeryof the anterior cruciate ligament. They used RRMBF stimulus, each consisting of five repetitions of RMBF (meanmaximal pressure, 238 mmHg) for 5 min, and release ofpressure for 3 min. Kubota et al. [12] also reported that theapplication of RRMBF to the lower extremity prevented
disuse muscular weakness induced by immobilization without weight bearing. They used RRMBF at an external compressive force of 200 mmHg for 5 min, followed by 3 min

13rest, a regimen repeated five times in a single session. Thus,
RRMBF appears to be a novel stimulus of skeletal muscle
to induce a net positive protein balance and prevent atrophy.
However, the underlying mechanisms of RRMBF have notbeen investigated.
Therefore, we investigated the effects of RRMBF onmTOR signaling pathways involved in initiating skeletal
muscle translation, and transcripts associated with proteolysis as well as microvascular pO2 (PmvO2) in skeletal
muscle using a rat model. Here we documented for the
first time that RRMBF significantly decreased PmvO2, andenhanced mTOR signaling pathways in skeletal muscle
using a rat model.

Materials and methods
Animals
Male Wistar rats (n = 34, age 11 weeks) were used in ourstudy (Japan SLC, Inc., Shizuoka Lab. Animal Center).
All rats were housed in a temperature-controlled roomat 22 ± 2 °C with a light–dark cycle of 12 h, and weremaintained on rat feed and water ad libitum as previously
described [13]. All procedures for microvascular PO2(PmvO2) measurement and blood flow restriction experiments were performed under isoflurane anesthesia (50 mg/
kg body wt). All experiments were conducted under theguidelines established by the Physiological Society ofJapan and were approved by University of Electro-Communications Institutional Animal Care and Use Committee.
Repetitive restriction of muscle blood flow (RRMBF)
Under isoflurane anesthesia, rats were secured in a supine
position, and the hip and knee joint of the right leg werebent in 90° flexion. The right leg was fixed mechanicallyand positioned on a firm and stable pedal as shown in
Fig. 1a. Blood flow restriction to the right lower extremity
was induced by compressing the proximal end of the rightthigh with a Durable Digit Cuff (latex cuff; overall cuff size
16 mm width, 90 mm length; D.E. Hokanson, Inc.). The
RRMBF stimulus, which consisted of an external compressive force of 100 mmHg for 5 min, followed by 3 min of rest,
was repeated six times during a 48-min interval (Fig. 1b) as
described in the previous clinical studies [11, 12].
Experimental protocol
Microvascular PO2 (PmvO2) measurement
Phosphorescence quenching as described previously [14]was utilized to determine PmvO2 during a blood flow

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phosphorometer (Oxygen Enterprises, Philadelphia,
PA) was used to determine PmvO2. The common endof the bifurcated light guide was placed approximately
2–3 mm above the medial region of the tibialis anterior muscle. The theoretical basis for phosphorescence quenching has been reported previously [15,16]. Briefly, the Stern–Volmer relationship describes
the quantitative O2 dependence of the phosphorescentprobe. R2 is a nontoxic dendrimer that binds to albumin at 38 °C and pH 7.4, with a quenching constant of
409 mmHg−1 s−1 and a 601 μs lifetime of decay of in
the absence of O2, under the physiological conditions
extant herein [17]. The net negative charge of R2 also
facilitates restriction of the compound to the vascularspace. Thus, PmvO2 reflects the pO2 within capillary
blood, which constitutes the principal intramuscularvascular space [15, 18].
Isolation of muscle tissue
Fig. 1  Experimental protocols. a Blood flow restriction (BFR) using
a durable digit cuff. Under isoflurane anesthesia, rats were kept at
supine position and the right leg was fixed on a firm and stable pedal
at 2–3 cm above the chest level with both hip and ankle joint of 90°(0° at full extension). b Protocols of repetitive restriction of muscle
blood flow (RRMBF). The RRMBF stimuli, consisting of external
compressive force of 100 mmHg for 5 min followed by 3 min ofrest, were repeated six times for 48 min. c Experimental protocol for
microvascular PO2 (PmvO2) measurement during RRMBF (Experi‑
ment 1 EX1) and muscle tissue isolation (Experiment 2 EX2). Phosphorescence quenching method was utilized for the determination of
PmvO2 during RRMBF protocol within the medial region of the tibialis anterior muscle. In EX2, rats in each group (n = 6) were sacrificed
in control (pre), immediately after (0 h), 1, 3, and 6 h after RRMBF,
and the total tibialis anterior muscles were dissected from both rightleg (BFR side) and left leg (control side)

restriction protocol applied to the medial region of the tibialis anterior muscle. Rats were anesthetized with isofurane
anesthesia. To monitor arterial blood pressure and heartrate, the left carotid artery was cannulated (PE50). This
catheter was also used to infuse a phosphorescent probe[palladium meso-tetra (4-carboxyphenyl) porphyrin dendrimer (R2)] at 15 mg/kg body wt. A lateral incision of theskin and overlying fascia was made to expose the tibialis
anterior muscle of the right leg (Fig. 1a). The muscle surface was superfused with Krebs-Henseleit solution, equilibrated with 5 % CO2–95 % N2 at 38 °C, and adjusted to pH
7.4. The phosphor R2 was applied via the arterial cannula
15 min before the beginning of experiments, which were
performed in a darkened room to prevent contamination byambient light. The total duration of the experiments did notexceed 1 h.
PmvO2 was determined at 1-s intervals before andduring RRMBF, and for 5 min during recovery [Fig. 1c,Experiment (EX) 1]. A PMOD 2000 frequency domain

Male Wistar rats (n = 30) underwent RRMBF under isoflurane anesthesia (50 mg/kg body wt) in 100 % O2.
Rats in each group (n = 6) were sacrificed immediately(~approximately 5 min after RRMBF) (0 h), 1 h, 3 h, and6 h after RRMBF, and the entire tibialis anterior muscle
was collected from both the right leg (blood flow restriction side) and left leg (control side). The harvested tissue
was immediately flash frozen in liquid nitrogen and storedat −80 °C until use in experiments [Fig. 1c, Experiment(EX) 2].
RNA extraction and real‑time quantitative reverse
transcriptase/polymerase chain reaction (RT‑PCR)
All cellular RNA was extracted from each tibialis anterior
muscle using an RNeasy mini kit (Qiagen, Cambridge,MA). For RT-PCR, complementary DNA (cDNA) was
synthesized from 1 µg of total RNA using a reverse transcriptase with random primers (Toyobo, Osaka). Realtime quantitative RT-PCR was performed using realtime Taq-Man technology and a sequence detector (ABI
PRISM®7000, Applied Biosystems, Foster City, CA).
Gene-specific primers and Taq-Man probes were used toanalyze transcript quantity. The 18S ribosomal RNA level
was analyzed as an internal control and used to normalize
the values for transcript quantity of mRNA. The probes
used in this study were purchased as part of the Assay-onDemand service from Applied Biosystems (Foster City,CA): Assay ID Rn01441087_m1 for forkhead box O3A(FOXO3a), Rn00590197_m1 for muscle ring finger-1(MuRF-1), Rn00569683_m1 for myostatin, Rn00577560_
m1 for hypoxia-inducible factor-1α (HIF-1α), and4310893E for 18S rRNA endogenous control.

13

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Western blotting analysis
Proteins were separated on 10 % polyacrylamide gelsfor 60 min at 200 V and then transferred to Amersham
Hypond-P membranes (GE Healthcare UK Ltd., Buckinghamshire, England) for 60 min at 72 mA using the semidry method. After the transfer, the membrane was blockedwith 2–3 % skim milk in PBS (0.01 M phosphate buffer,
0.138 M NaCl, 0.027 M KCl, pH 7.4) with 0.1 % Tween 30(PBS-T) at room temperature for 1 h. The membrane wasthen exposed to antibodies at the appropriate dilutions inblocking buffer overnight at 4 °C. The probed membrane
was then washed three times in PBS-T for 15 min eachtime and was subsequently incubated with peroxidaselinked anti-rabbit IgG (Santa Cruz Biotechnology, Inc.,
CA; diluted 1:5000 with blocking buffer) for 1 h at room
temperature. After three additional washes, bound antibodies were detected with a Chemi-Lumi One Super kit(Nacalai Tesque, Kyoto, Japan) and analyzed with an LAS3000 mini-image analyzer (Fuji-Film, Tokyo, Japan).
Phosphorylation of Akt (Protein kinase B, PKB) on
Ser473 was assessed using anti-phospho-Akt antibody(#4060, Cell Signaling Technology, Beverly, MA, USA)and anti-total Akt antibody (#4691, Cell Signaling Technology). Phosphorylation of mTOR on Ser2448 was measured
using anti-phospho-mTOR antibody (#2971, Cell Signaling Technology) and anti-total mTOR antibody (#2972,
Cell Signaling Technology). Phosphorylation of p70 S6
kinase (p70S6 k) on Thr389 was determined using antiphospho-p70 S6 kinase antibody (#9234, Cell Signaling
Technology) and anti-total p70 S6 kinase antibody (#2708,
Cell Signaling Technology). Ribosomal protein S6 phosphorylation (rpS6) on Ser240/244 was evaluated using
anti-phospho-S6 antibody (#5364, Cell Signaling Technology) and anti-total S6 antibody (#2317, Cell Signaling
Technology). Antibody dilutions were 1:1000 in each case.
Phosphorylation of eEF2 on Thr56 was determined using
anti-phospho-eEF2 antibody (#2331, Cell Signaling Technology) and anti-total eEF2 antibody (#2332, Cell Signaling Technology). 4E-BP1 phosphorylation on Thr37/46
was assessed using anti-phospho-4E-BP1 antibody at adilution of 1:4000 (#2855, Cell Signaling Technology) andanti-total 4E-BP1 antibody (#9644, Cell Signaling Technology). AMPK phosphorylation on Thr172 was assessedusing anti-phospho-AMPKα antibody (#2535, Cell Signaling Technology) and anti-total AMPKα antibody (#2532,
Cell Signaling Technology). Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) at Thr202/
Tyr204, p38 mitogen-activated protein kinase (p38MAPK)at Thr180/Tyr182, and c-Jun N-terminal kinase 1 (JNK1) at
Thr183/Tyr185 was measured using anti-phospho-ERK1/2
antibody (#4370, Cell Signaling Technology) and anti-total
ERK1/2 antibody (#4695, Cell Signaling Technology),

13

anti-phospho-p38MAPK antibody (#4511, Cell Signaling
Technology) and anti-total p38MAPK antibody (#2307,
Cell Signaling Technology), and anti-phospho-JNK1/2
antibody (# 9255, Cell Signaling Technology) and antitotal JNK1/2 antibody (#3708, Cell Signaling Technology), respectively. No change in total protein content wasobserved for any of the variables during these experiments.
Anti-REDD1 (regulated in development and DNA damage responses) rabbit polyclonal antibodies (NOVUS,
NBP1-95,188) were obtained from Novus Biological.
Anti-HIF-1α antibody and anti-vascular endothelial growth
factor (VEGF) rabbit polyclonal antibody were purchasedfrom Abcam. Blots were loaded according to protein concentration (approx. 100–150 µg).
Data analysis
All values are expressed as mean ± SEM. Differences
between groups were compared by one-way ANOVA and
Bonferroni’s post hoc test. The level of significance was set
at P < 0.05.

Results
PmvO2 response during RRMBF
Figures 2a, b show dynamic PmvO2 profiles in response to
RRMBF. The typical data obtained from a rat are illustrated
in Fig. 2a. During the application of RRMBF, dynamic
PmvO2 decreased rapidly and reached a level of approximately 5–8 torr. After release of the cuff pressure, dynamic
P PmvO2 returned to a control level. During RRMBF,
similar dynamic PmvO2 profiles were observed. Figure 2b
shows mean PmvO2 profiles during RRMBF obtained
from four different rats. Baseline values of PmvO2 were36.1 ± 5.7 torr (n = 4). The minimum PmvO2 level during RRMBF changed in the range of 4.8–9.0 torr (n = 4).
The mean value was 5.9 ± 1.7 torr (n = 4), and gradually
recovered during a rest period.
Animal data
Figures 2c, d show the effects of RRMBF on total weightof the tibialis anterior muscle and total muscle weight/
body weight. Total weight of the tibialis anterior muscle(Fig. 2c) and total muscle weight/body weight (Fig. 2d)increased significantly in rats sacrificed immediately after
RRMBF, compared with control rats. It is therefore likelythat the application of RRMBF using 100 mmHg in thepresent model induced venous pooling of blood in thelower leg and swelled the tibialis anterior muscle, a known
phenomenon of KAATSU training [5, 19]. The increase inHeart Vessels

Fig. 2  a, b Effects of RRMBF on microvascular pO2 (PmvO2) measurement. a Typical data recording of the dynamic PmvO2 profiles in
response to RRMBF. Note that during the application of RRMBF, thedynamic PmvO2 rapidly decreased, and reached to a level of approximately 4.8–9.0 torr. After the release of BFR, the dynamic PmvO2
returned almost to a control level. b The mean PmvO2 profiles during RRMBF obtained from four different rats. The values of PmvO2
at rest were 36.1 ± 5.7 torr (n = 4), and significantly decreased to
5.9 ± 1.7 torr significantly (n = 4) during RRMBF. c, d Effects of

RRMBF on total muscle weight (c) and total muscle weight/bodyweight of the tibialis anterior muscle (d). The total muscle weight
and total muscle weight/body weight of the tibialis anterior muscle
were measured in control rats, and rats immediately (0 h), 1, 3, and6 h after RRMBF. Each data were obtained from both sides of themuscles (n = 6). Note that the total muscle weight and total muscle
weight/body weight of the tibialis anterior muscle increased significantly in rats sacrificed immediately after RRMBF. *P < 0.05 vs.
control (pre)total weight of the tibialis anterior muscle and total muscle weight/body weight had returned to control levels at 1 h
after RRMBF.

4E-BP1 at Thr37/46 (Fig. 4b) and phosphorylation of eEF2
at Thr56 (Fig. 4c) did not change significantly at any time
point in response to RRMBF, compared with control rats.
As shown in Fig. 5a, Akt phosphorylation at Ser473,
a marker for Akt activation (Alessi et al. 1996), did notchange significantly at any time point in response to
RRMBF. Phosphorylation of mTOR on Ser2448, a site
directly phosphorylated by Akt [21], tended to increase at
1 h after RRMBF (P = 0.06, Fig. 5b), but not statisticallysignificantly.

Effects of RRMBF on mTOR signaling pathways
Figure 3 shows the effects of RRMBF on phosphorylationof p70S6k, a downstream target of mTOR and a factor insynthesis regulation of some ribosomal proteins. As shownin Fig. 3a, p70S6 k phosphorylation at Thr389, a phosphorylation site associated with maximal activation of thekinase [20], in the right tibialis anterior muscle (BFR leg)
was increased significantly 1 h after RRMBF, comparedwith control rats (p < 0.05). However, p70S6k phosphorylation in the left tibialis anterior muscle (non-BFR leg) was
not changed significantly at any time point in response
to RRMBF (Fig. 3b). The enhanced phosphorylation of
p70S6k had returned to control levels 3 h after the stimuli(Fig. 3c). S6 phosphorylation at Ser240/244, a downstream
target of p70S6k, was also increased significantly 1 h after
RRMBF (P < 0.05, Fig. 4a), which returned to the control
level 3 h after the stimuli.
Figures 4b, c illustrate the effects of RRMBF on phosphorylation of 4E-BP1 and eEF2. Phosphorylation of

Effects of RRMBF on AMPK phosphorylation
and REDD1AMPK phosphorylation at Thr172 did not change significantly at any time point in response to RRMBF (Fig. 5c).
There was no difference in REDD1 total protein content incontrols and after RRMBR (Fig. 5d).
Effects of RRMBF on myostatin, MuRF‑1,
and FOXO3a mRNA expression
We also investigated the effects of RRMBF on MuRF-1
and FOXO3a mRNA expression, factors associated with13

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Fig. 3  Phosphorylation of p70 S6-kinase (p70S6k) on Thr389 in rat
tibialis anterior skeletal muscle before (control, c), immediately after(0 h), 1, 3 and 6 h after RRMBF. In a, b the representative immunoblots (phospho- p70S6k and total p70S6k) are shown above eachgroup. The data in a were obtained from the right tibialis skeletal
muscle (BFR side). The data in b were obtained from the right (BFRside) and left tibialis anterior muscle (non-BFR side). In this and following figures, proteins with a phosphorylation site are shown as aphospho to total ratio. Proteins without a regulatory phosphorylationsite are indicated as total protein content. The ratio of p- p70S6k/total
p70S6k is shown in c. The data for each time were obtained from six
different rats. Note that RRMBF enhanced the phosphorylation of
p70S6k in right tibialis anterior muscle (BFR leg), but not left muscle(non-BFR leg) 1 h after the stimuli. *P < 0.05 vs. control (pre)the regulation of muscle protein breakdown. As shown in
Fig. 6, there were no significant differences in MuRF-1(Fig. 6a, p > 0.05) and FOXO3a mRNA (Fig. 6b, P > 0.05)
levels in controls and after RRMBF. Figure 6c shows theeffects of RRMBF on myostatin mRNA level. There were
no difference in myostatin mRNA in controls and after
RRMBF.
Effects of RRMBF on muscle HIF‑1α mRNA, HIF‑1α
and VEGF protein
To determine whether hypoxia induced by RRMBF stimulates hypoxia-related genes and proteins, we investigatedthe effects of RRMBF on HIF-1α protein and gene expression. As shown in Fig. 6d, HIF-1α mRNA expression was
not significantly changed after RRMBF (P > 0.05, Fig. 6d).
HIF-1α protein expression was increased 1 h after RRMBF(P < 0.05), compared with controls (Figs. 6e, f), while it
was not significantly changed at 0 h (~ approximately
5 min) after RRMBF. VEGF protein expression was notaltered at any time point in response to RRMBF (Fig. 6g).

13

Fig. 4  Phosphorylation of S6 at Ser240/244 (a), 4E-BP1 at Thr37/46(b), eEF2 at Thr56 (c) in rat tibialis anterior skeletal muscle before(control), immediately after (0 h), 1, 3, and 6 h after RRMBF. Two
different representative immunoblots (phosphorylation and total) attimes indicated are shown. The data were obtained from the right tibialis anterior muscle (BFR side) of six different rats. The phospho tototal ratio is shown on the right. *P < 0.05 vs. control (pre)Effects of RRMBF on MAP kinase phosphorylation
Figure 7 shows the effects of RRMBF on phosphorylationof ERK1/2, p38MAPK, and JNK1/2. As shown in Fig. 7,
phosphorylation of ERK1/2 (Fig. 7a) at Thr202/Tyr204,
p38 MAPK (Fig. 7b) at Thr180/Tyr182, and JNK1/2(Fig. 7c) at Thr183/Tyr185 did not change significantly at
any time point in response to RRMBF.

Discussion
The major findings of our study are as follows. (1) During RRMBF, PmvO2 decreased from 36.1 ± 5.7 to
5.9 ± 1.7 torr, and recovered gradually during a rest period.
(2) RRMBF significantly increased p70S6k phosphorylation, a downstream target of mTOR, and ribosomal protein
S6 phosphorylation at 1 h after stimulation. (3) Protein levels of REDD1, AMPK and MAPKs phosphorylation did
not change significantly. (4) The mRNA expression levelof FOXO3a, MuRF-1 and myostatin was not significantly
altered during RRMBF. These results showed for the firsttime that RRMBF significantly decreased PmvO2, andenhanced mTOR signaling pathways in skeletal muscle
using a rat model, which may play a role in diminishingmuscle atrophy under various conditions in human studies.

Heart Vessels
Fig. 5  Phosphorylation of
Akt at Ser473 (a), mTOR at
Ser2448 (b), AMPK (Thr172)(c) and REDD1 protein (d)expression in rat tibialis anterior
skeletal muscle before (control),
immediately after (0 h), 1, 3,
and 6 h after RRMBF. Two different representative immunoblots (phosphorylation and total)
are shown above each group in(a–c). The data were obtained
from right tibialis anterior
muscle (BFR side) at times
indicated. The phospho to total
ratio is shown in lower part.
In d, two different representative immunoblots (REDD1)
obtained from right muscle areshown. The protein density of
REDD1 is shown in D (rightpart). Each datum was obtained
from six different rats

Our study showed the first model of RMBF using rats.
In this model, we applied an RRMBF stimulus without
exercise comprising an external compressive force of
100 mmHg, which is lower than systolic blood pressureof rats to avoid hemostasis. With this restriction, the total
weight of tibialis anterior muscle and total muscle weight/
body weight ratio increased significantly in rats sacrificed
immediately after RRMBF, suggesting that the applicationof RRMBF at 100 mmHg pressure does not completely
block blood flow, and induces venous pooling of blood in
the lower legs and swelling of the tibialis anterior muscle.
It is a characteristic phenomenon of KAATSU training [5,19, 22]. During RRMBF, PmvO2 decreased significantly
from 36.1 ± 5.7 to 5.9 ± 1.7 torr, and gradually recovered during a rest period. NMR techniques for myoglobin saturation have shown that resting intracellular PO2
in human skeletal muscle is estimated to approximately
34 mmHg, and drops to approximately 23 mmHg, whensubjects breathe ambient 10 % O2 [23]. However, duringnear-maximal exercise, intracellular PO2 drops to values
as low as 2–5 mmHg [24]. In addition, mean tissue PO2
in lower limb muscle made ischemic by complete obstruction of blood flow drops to less than 1.9 mmHg [25]. Thus,
the level of PmvO2 reached in our study is higher than thatinduced by complete obstruction of blood flow, and thatreached during the near-maximal exercise as described
previously [24, 25].
Oxygen is an essential regulator of cellular metabolism. Under hypoxic conditions, cells rapidly activate avariety of adaptive responses that limit energy expenditure
by inhibiting energy-intensive processes including proteintranslation [26, 27]. One related mechanism involves inhibition of mTOR activity, an anabolic pathway for skeletal
muscle, observed following exposure to hypoxia (1 % O2)[28]. HIF-1α activity is known to increase under continuous hypoxia due to decreased rates of oxygen-dependent
proline hydroxylation, ubiquitination, and proteasomal
degradation of the HIF-1α subunit. And, hypoxic regulation of mTOR activity occurs through a pathway involving the REDD1 gene [29], where REDD1 expression ishighly induced in response to hypoxia via HIF-1α [29,30]. In our study employing RRMBF protocols, expression
level of REDD1 protein did not change significantly. In
general, the increased HIF-1α protein elicited by hypoxia
quickly returns to control levels immediately after the reoxygenation [31]. In the present study, expression levelof HIF-1α protein did not significantly change immediately after RRMBF, while it increased 1 h after RRMBF.
Hypoxia is also known to increase the expression of VEGF
via HIF-1α [32], and VEGF protein expression did not significantly differ at any time point in response to RRMBF.
Thus, it is likely that RRMBF used in our protocol did not
activate HIF-1α activity enough to inhibit mTOR pathways
and enhance VEGF expression. Alternatively, AMPK is anenergy-sensing serine/threonine kinase activated by metabolic stressor that depletes ATP and increases AMP during
exercise, hypoxia and glucose deprivation. Once activated,
AMPK inhibits ATP consuming anabolic processes suchas protein translation largely through inhibition of mTOR
signaling [33]. However, AMPK phosphorylation also did
not change significantly at any time point in response to
RRMBF.

13

Heart Vessels

Fig. 6  a–c Skeletal muscle MuRF-1 (a), FOXO3a (b), and myostatin (c) mRNA in responses to RRMBF. The levels of MuRF-1 (a),FOXO3a (b) and myostatin (c) mRNAs were measured by the quantitative real-time RT-PCR, and normalized to those of the 18S ribosomal RNA levels. The relative abundance of mRNA is shown before(control), immediately after (0 h), 1, and 3 h after RRMBF. *P < 0.05
vs. control (pre). d–f Skeletal muscle HIF-1α mRNA (d), HIF-1α
protein (e, f) and VEGF protein (g) in responses to RRMBF. The levels of HIF-1α mRNA are normalized to those of the 18S ribosomal
RNA levels, and the relative abundance of mRNA is shown before(control), immediately after (0 h), 1, and 3 h after RRMBF. *P < 0.05
vs. control (pre). In e, two different representative immunoblots
obtained from right muscle are shown above each group. The protein
density of HIF-1α and VEGF is illustrated in f and g, respectively.
The data were obtained from six different rats. *P < 0.05 vs. control(pre)Several studies have shown that activation of mTOR andp70S6 k phosphorylation in the recovery phase after highintensity resistance exercise is associated with increased
protein synthesis [3, 34–36]. And, phosphorylation of
p70S6k leads to S6 protein phosphorylation, which isthought to promote translation of the mRNAs that encodes
ribosomal proteins and other translation factors. S6 protein
activation leads to increased cellular capacity for protein
synthesis. Recently, low-intensity resistance exercise under
RMBF in healthy subjects has been reported to increase
muscle strength and size even with low-intensity loads [6,7]. Sessions of RMBF exercise have also been reported toincrease protein synthesis through post-translation regulation in the Akt/mTOR pathway [8, 37]. They showed that
the RMBF exercise increased p70S6k phosphorylation.
Previous human studies have also reported that RRMBF

13Fig. 7  Phosphorylation of extracellular signal-regulated kinase 1/2(ERK1/2, a), p38 MAP kinase (p38MAPK, b) and c-Jun N-terminal
kinase 1/2 (JNK1/2, c) before (control), immediately after (0 h), 1, 3,
and 6 h after RRMBF. A representative immunoblot (phosphorylationand total) at time indicated is shown. The data were obtained fromright tibialis anterior muscle (n = 6, BFR side) at times indicated.
The phospho to total ratio is shown in lower parteven without a combination of exercise effectively diminishes post-operation disuse atrophy of knee extensors [11],and muscle weakness induced by immobilization without
weight-bearing [12], but the underlying mechanisms havenot been investigated. Here, we showed for the first timethat RRMBF had significantly increased p70S6k phosphorylation, a downstream target of mTOR, and ribosomal
protein S6 phosphorylation in a rat model. The degree of
p70S6k phosphorylation in the first few hours after a session of high-intensity resistance exercise has been reported
to be correlated with percentage change in muscle mass
after several weeks of exercise in both rodents and humans[35, 38]. S6 phosphorylation is also regarded as a stimulation of protein synthesis [35, 36, 38]. Thus, RRMBF
appears to increase protein synthesis due to enhanced
p70S6k and S6 phosphorylation, possibly resulting in
diminishing muscle atrophy as described previously inhuman studies [11, 12].
Several mechanisms for the effects of RRMBF on
p70S6k and S6 phosphorylation in rat skeletal muscle may
be proposed. Resistance exercise is an established andpotent stimulus for enhancing muscle protein synthesis andsubsequent muscle hypertrophy. The activation of mTOR
signaling pathways is a primary mechanism by which
resistance exercise stimulates translation initiation, elongation, and the rate of muscle protein synthesis [39]. Akt is anHeart Vessels

upstream positive regulator of mTOR. However, RRMBF
did not increase phosphorylation of Akt. Phosphorylation of mTOR on Ser2448 tended to increase at 1 h after
RMBF, but not statistically significant. Thus, our study was
unable to determine the involvement of Akt on increased
p70S6k and S6 phosphorylation after RRMBF. However, we showed for the first time that RRMBF enhanced
p70S6k phosphorylation, a downstream target of mTOR, ina rat model. RRMBF did not enhance the phosphorylationin control legs, suggesting that the local factors induced by
RRMBF, but not systemic factors, are involved in enhanced
p70S6k phosphorylation.
MAPK cascades are potential physiological mechanisms involved in the exercise-induced regulation of gene
expression and protein synthesis in skeletal muscle [40].
The MAPK family members are separated into distinct
parallel pathways, including ERK1/2, stress-activatedprotein kinase cascades (SAPK1/JNK) and SAPK2/p38[41]. Downstream cytosolic targets for ERK1/2 include
p90 ribosomal S6 kinase [42], and ERK1/2 is capable ofphosphorylating S6 on its Ser235/236 regulatory site [43].
The kinases JNK and p38 MAPK are known as stressactivated protein kinases because of their activation byenvironmental stressors including osmotic shock and heatshock [44, 45]. RMBF induces an acute fluid shift from thevascular space into the muscles, and then muscle volume
changes [5, 19, 22], which may be involved in the BFR
exercise–induced anabolic response of skeletal muscle asproposed recently [22]. In our study, the total weight of
the tibialis anterior muscle increased significantly in rats
immediately after RRMBF, suggesting that application of
RRMBF in the present model induced venous pooling ofblood into the lower legs, and swelling the muscle. However, RRMBF did not increase phosphorylation of MAPK
including ERK1/2. Thus, it is most likely that RRMBF
enhances mTOR signaling pathways in rat skeletal muscle
independently of MAPK signaling pathways. The formation of reactive oxygen species (ROS) in skeletal muscle
has been also described in response to muscle stimulation,
heat stress, and ischemia–reperfusion injury [46]. ROS
have been proposed to play physiological roles on cellsignaling in skeletal muscle [47]. The activity of ROS
within muscle may increase in a hypoxic environment [48].
Also, because ischemia and reperfusion of skeletal muscle
are associated with an increase of ROS release [49], ROS
could be produced when muscle is kept hypoxic and subsequently exposed to reperfusion. Therefore, both loweredand elevated muscle oxygenation levels during RRMBF
may enhance ROS production in skeletal muscle. ROS has
been reported to activate the downstream target of phosphoinositide 3-kinase (PI3K)-Akt signaling [50]. However,RRMBF in the present study did not increase phosphorylation of Akt. Therefore, the basic mechanisms underlying

the enhancement of mTOR signaling pathways following
RRMBF remain to be clarified.
Proteolytic events involve the ubiquitination and subsequent degradation of proteins induced by E3 ligases[51, 52]. Exercise-responsive genes involved in the muscle cell ubiquitin/proteolysis pathway include MuRF-1
and atrogin-1 (muscle atrophy F-box), both of whichshare a common transcription factor, FOXO3a. Atrogin-1
and MuRF-1 negatively regulate muscle mass. Recently,
reduced expression of the proteolysis-related genes
FOXO3a, atrogin-1, MuRF-1, and myostatin has beenreported after acute BFR exercise [9, 10]. Suppression of
myostatin has been found to induce muscle hypertrophy inrodents [53]. Also, immobilization increases the expressionof myostatin in mice, while re-loading muscle decreases
myostatin expression [54]. From these observations, it islikely that BFR combined with exercise inhibits skeletal
muscle protein degradation and promotes myogenesis via
ubiquitin/proteolysis pathways, resulting in increasing
muscle mass. However, Drummond et al. [55] showed thatmRNA expression level for myostatin and MuRF-1 3 hafter performing BFR knee extension at 20 % 1RM was notdifferent from that after control 20 % 1RM knee extension.
In our study using animal model, RRMBF without exercise
did not significantly change the mRNA expression level of
FOXO3a, MuRF-1, and myostatin. Thus, the muscle cell
ubiquitin/proteolysis pathways do not appear to be involvedin the RRMBF-induced decrease of muscle atrophy asreported previously in human studies [11, 12].
Kaatsu training is an exercise training under the conditions with RMBF [5, 6]. The training is distinctive for
producing increases in muscle size and strength throughshort-duration, and low load-intensity training. This training has been reported to enhance protein synthesis throughpost-translation regulation in the Akt/mTOR pathway [8,37]. But, several papers have shown that RRMBF even
without exercises appears to be a novel stimulus of skeletal muscle to induce a net positive protein balance andprevent atrophy. In the present paper, we showed the firstevidence that RRMBF without exercises enhanced mTOR
signaling pathways in skeletal muscle using a rat model.
The hypertrophic effects of KAATSU training cannot be
obtained by the continuous application of RMBF alone inclinical studies [56], suggesting that hypoxia only appears
to be not enough to activate the mTOR pathway. In contrast, RRMBF appears to be a novel stimulus of skeletal
muscle to induce a net positive protein balance and prevent
atrophy. However, the further studies are needed to investigate the potencies of the hypertrophic effects of the RMBF
exercises and RRMBF. In addition, we applied an RRMBF
stimulus comprising an external compressive force of
100 mmHg, and used five repetitions for 5 min, and releaseof pressure for 3 min as described in the previous clinical13

Heart Vessels

studies [11, 12]. Therefore, the further detailed studies
using different protocols of RRMBF including numbers
and duration of RRMBF are needed to clarify the effects of
RRMBF of the mTOR signaling pathways.
Exercise such as aerobic exercise is a well-establishedmethod for improving quality of life, and decreasing cardiovascular risk [57, 58]. However, it is difficult to apply
to bedridden or postoperative patients. On the other hand,
RRMBF can be used in such patients, and may prevent
muscle atrophy in such patients as shown in the previous
papers [11, 12]. But, further clinical studies are needed toclarify this possibility.

Conclusions
RRMBF significantly decreased PmvO2, and enhanced
mTOR signaling pathways in skeletal muscles using a rat
model, which may play a role in preventing muscle atrophy in skeletal muscle under various conditions in humanstudies.
Acknowledgments Dr. Yoshiaki Sato is an inventor of low-load
resistance training with blood flow restriction, so-called Kaatsu training, and the owner of KAATSU Japan Co. Ltd. This work was supported by JSPS KAKENHI Grant Number 24300189 (to T.N.) and
25750288 (to T.Y.). This study was previously presented, in part, inabstract form at the Scientific Sessions, American Heart Association2013 (Dallas, Texas, USA, 2013/11/16-11/20).
Compliance with ethical standards
Conflict of interest There is no conflict of interests to disclose.

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J Appl Physiol 125: 134–145, 2018.
First published March 22, 2018; doi:10.1152/japplphysiol.00972.2017.

RESEARCH ARTICLE

Muscle hypertrophy following blood flow-restricted, low-force isometricelectrical stimulation in rat tibialis anterior: role for muscle hypoxia
Toshiaki Nakajima,1* Seiichiro Koide,2* Tomohiro Yasuda,3 Takaaki Hasegawa,1 Tatsuya Yamasoba,4Syotaro Obi,5 Shigeru Toyoda,1 Fumitaka Nakamura,6 Teruo Inoue,1 David C. Poole,7 and Yutaka Kano2
1

Department of Cardiovascular Medicine, Dokkyo Medical University and Heart Center, Dokkyo Medical University Hospital,
Tochigi, Japan; 2Bioscience and Technology Program, Department of Engineering Science, University of ElectroCommunications, Tokyo, Japan; 3School of Nursing, Seirei Christopher University, Shizuoka, Japan; 4Department ofOtolaryngology, University of Tokyo, Tokyo, Japan; 5Department of Cardiovascular Medicine and Research Support
Center, Dokkyo Medical University, Tochigi, Japan; 6Third Department of Internal Medicine, Teikyo University Chiba
Medical Center, Chiba, Japan; and 7Department of Anatomy, Physiology and Kinesiology, Kansas State University,
Manhattan, Kansas
Submitted 27 October 2017; accepted in final form 14 March 2018

Nakajima T, Koide S, Yasuda T, Hasegawa T, Yamasoba T,
Obi S, Toyoda S, Nakamura F, Inoue T, Poole DC, Kano Y.
Muscle hypertrophy following blood flow-restricted, low-force isometric electrical stimulation in rat tibialis anterior: role for muscle
hypoxia. J Appl Physiol 125: 134 –145, 2018. First published March
22, 2018; doi:10.1152/japplphysiol.00972.2017.—Low-force exercise
training with blood flow restriction (BFR) elicits muscle hypertrophy
as seen typically after higher-force exercise. We investigated theeffects of microvascular hypoxia [i.e., low microvascular O2 partialpressures (PmvO2)] during contractions on muscle hypertrophic signaling, growth response, and key muscle adaptations for increasing
exercise capacity. Wistar rats were fitted with a cuff placed around theupper thigh and inflated to restrict limb blood flow. Low-force
isometric contractions (30 Hz) were evoked via electrical stimulationof the tibialis anterior (TA) muscle. The PmvO2 was determined byphosphorescence quenching. Rats underwent acute and chronic stimulation protocols. Whereas PmvO2 decreased transiently with 30 Hz
contractions, simultaneous BFR induced severe hypoxia, reducing
PmvO2 lower than present for maximal (100 Hz) contractions. Lowforce electrical stimulation (EXER) induced muscle hypertrophy(6.2%, P ⬍ 0.01), whereas control group conditions or BFR alone did
not. EXER⫹BFR also induced an increase in muscle mass (11.0%,
P ⬍ 0.01) and, unique among conditions studied, significantly increased fiber cross-sectional area in the superficial TA (P ⬍ 0.05).
Phosphorylation of ribosomal protein S6 was enhanced by EXER⫹
BFR, as were peroxisome proliferator-activated receptor gamma coactivator-1␣ and glucose transporter 4 protein levels. Fibronectin type III
domain-containing protein 5, cytochrome c oxidase subunit 4, monocarboxylate transporter 1 (MCT1), and cluster of differentiation 147 increased with EXER alone. EXER⫹BFR significantly increased MCT1
expression more than EXER alone. These data demonstrate that microvascular hypoxia during contractions is not essential for hypertrophy.
However, hypoxia induced via BFR may potentiate the muscle hypertrophic response (as evidenced by the increased superficial fiber crosssectional area) with increased glucose transporter and mitochondrial
biogenesis, which contributes to the pleiotropic effects of exercise training with BFR that culminate in an improved capacity for sustained
exercise.
* T. Nakajima and S. Koide contributed equally to this work.
Address for reprint requests and other correspondence: T. Nakajima, Heart
Center, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi, Japan
321-0293 (e-mail: nakat@dokkyomed.ac.jp).
134

NEW & NOTEWORTHY We investigated the effects of low microvascular O2 partial pressures (PmvO2) during contractions on
muscle hypertrophic signaling and key elements in the muscle adaptation for increasing exercise capacity. Although demonstrating thatmuscle hypoxia is not obligatory for the hypertrophic response to
low-force, electrically induced muscle contractions, the reduced
PmvO2 enhanced ribosomal protein S6 phosphorylation and potentiated the hypertrophic response. Furthermore, contractions with bloodflow restriction increased oxidative capacity, glucose transporter, andmitochondrial biogenesis, which are key determinants of the pleiotropic effects of exercise training.
blood flow restriction; COX4; GLUT4, hypoxia; mammalian target of
rapamycin (mTOR); MCT1; microvascular PO2; muscle hypertrophy;
PGC-1␣; rat skeletal muscle; rpS6 phosphorylation

INTRODUCTION

Skeletal muscle is a supremely plastic organ that responds toelevated chronic demands, such as exercise training, by evoking a spectrum of structural and functional adaptations that
increases performance. Structural changes in muscle that underlie the hypertrophic response to isometric exercise training
are facilitated by tipping the net balance between protein
synthesis and degradation (8). An underlying premise herein isthat the hypertrophic response is beneficial, especially in patients and/or elderly individuals whose morbidity/mortality is
increased by muscle atrophy. In general, relatively high muscle
force [e.g., ⱖ70% of the 1-repetition maximum weight (1RM)]
is used to elicit the hypertrophic response (3, 58). However, inpatients with orthopedic or cardiovascular diseases, high-load
exercise may be contraindicated because of various limitations,such as pain or hypertension. On the other hand, several studies
have shown that low loads to failure (42, 43) or low-force(20%–30% 1RM) resistance exercise under blood flow restriction (BFR) can induce muscle hypertrophy and strength increases similar to those resulting from high-force (70% 1RM)
training (30, 62). These studies suggest that the degree ofmuscle hypertrophy is not uniquely determined by mechanicalstress and raise the question as to what other factors might
control or potentiate the hypertrophic response.

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MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODEL

There is experimental support for muscle protein synthesis
and hypertrophy being elicited by exercise training underhypoxic conditions (46, 63). Specifically, Nishimura et al. (46)recruited college-age men to undergo 6 wk of resistancetraining at 70% 1RM in a hypoxic chamber [inspired O2
fraction (FIO2) 0.16] and demonstrated greater muscle hypertrophy of the elbow flexors and extensors compared withnormoxic training. Moreover, D’Hulst et al. (16) found that 4
h of normobaric hypoxia (FIO2 0.11) elevated protein kinase B(Akt) and p70 kDa ribosomal protein S6 (rpS6) kinase(p70S6K, also known as S6K1) phosphorylation in the vastus
lateralis, whereas in normoxia, (FIO2 0.21) this response was
not observed. However, these studies did not show the relationships between molecular changes and muscle hypertrophy. BFR induces skeletal muscle hypoxia and exacerbates
any exercise-induced reduction of muscle oxygenation (35).
Furthermore, Fujita et al. (21) and Fry et al. (19) showedthat the phosphorylation of the mammalian target of rapamycin (mTOR) signaling pathway including mTOR, S6K1,
and rpS6 and muscle protein synthesis were significantly
increased 3 h after low-force (20% 1RM) knee extension
exercise with BFR. Collectively, these observations support
the notion that skeletal muscle hypoxia in combination withmechanical stress may be important mechanistically forstimulating muscle hypertrophy via enhancement of protein
synthesis. However, we are unaware that the relationships
among muscle hypertrophy, muscle oxygenation, and key
molecular control mechanisms have been investigated forexercise under BFR conditions.
The potential for BFR-induced muscle hypoxia in combination with low-force exercise to impact the hypertrophic processes is highlighted by multiple intramyocyte effects that arecommonly found with far-higher-force exercise. For example,
hypoxia challenges ATP production, which elevates the AMP/
ATP ratio and stimulates AMP-activated protein kinase␣-␣(AMPK␣), serving as an intracellular energy sensor (20). In
turn, AMPK␣ moves the glucose transporter 4 (GLUT4) to thecell membrane (25), promoting glucose uptake and sparing
muscle glycogen (23). BFR also increases blood lactate immediately after low-force exercise akin to non-BFR, high-force
exercise (54), and this low-force BFR training for 8 wk
potentiates the extant metabolic changes, perhaps by inducing
an ischemic stimulus that enhances muscle glucose transport
and adenine nucleotide catabolism (12). Furthermore, in addition to muscle strength and hypertrophy, improvement inskeletal muscle endurance and maximum oxygen consumption
has been reported following low-force exercise training with
BFR (1). Thus, it is plausible that low-force exercise training
with BFR may elicit the pleiotropic effects that resemble thosenormally associated with acute or chronic high-force exercise
and in so doing reveal important clues as to the underlying
control mechanisms.
The present investigation created a rat model in which to
study how BFR in combination with low-force muscle contractions stimulates muscle hypertrophy and upregulates key
metabolic pathways that are central to improving muscle functional capacity. Specifically, this model facilitated mimicking
resistance exercise training (22, 33) under control and BFR
conditions combined with measurements of microvascular O2
partial pressures (PmvO2), muscle tension level, and comprehensive muscle analyses. We tested the hypothesis that muscle

135

hypoxia is essential for driving muscle hypertrophy. Moreover,
we sought to determine how the ischemic-hypoxic condition
induced by BFR influences key signaling mechanisms that
determine metabolic function during contraction and which
may be intrinsic to the reduced fatigability and improved
exercise capacity of muscle after training.
MATERIALS AND METHODS

Animals. Male Wistar rats (n ⫽ 74, age 10 –17 wk) were used inthis study (Japan SLC, Shizuoka Laboratory Animal Center). All rats
were housed in a temperature-controlled room at 23 ⫾ 1°C at
55 ⫾ 10% humidity with a light-dark cycle of 12 h and were maintained on rat feed (5L37, PMI Nutrition International, St. Louis, MO)
and water ad libitum. All experiments were conducted under theguidelines established by the Physiological Society of Japan and wereapproved by the University of Electro-Communications Institutional
Animal Care and Use Committee.
Experiment 1-1: acute experimental protocol for muscle contraction.
Under isoflurane anesthesia, rats were secured in a supine position ona hot plate warmed to 37°C (BWT-100, Bio Research Center, Tokyo,
Japan). The right (experimental) leg was attached to the hind limb
movement device (Model RU-72, Motomura Systems, Tokyo, Japan)
at a 90° knee joint angle (Fig. 1A) as previously described (26, 45).
After the incision of the skin, a bipolar electrode TF210 –104 (Unique
Medical, Tokyo, Japan) was connected to the peroneal nerve, andisometric tibialis anterior (TA) contractions were produced by nerve
stimulation (4 – 6 V; 30 Hz or 100 Hz square wave stimuli; 4-ms pulse
duration, 0.7-s stimulus duration). Moreover, to ensure that the exposed surface of the muscle remained moist, the surface was continuously perfused with the Krebs-Henseleit solution (at pH 7.35 andequilibrated with 95% N2-5% CO2 gas). First, we investigated therelationship between muscle tension and stimulus frequency (Hz),in which the tension elicited by 100 Hz was considered to be
maximal (i.e., 100%, Fig. 2A, n ⫽ 3). Judging from this relationship, we defined the high-force condition as notionally equivalent
to 1RM (maximum repetition) and the low-force condition as 50%(i.e., ~50% 1RM) of that which corresponded to the lowest frequency (i.e., 30 Hz) that yielded 48.0 ⫾ 1.2% of the 100-Hz
high-force contraction. To measure acute changes of PmvO2 (Fig.
1B), 30 Hz and 100 Hz were also used as the low- and high-force
contraction, respectively. In total, four sets of contractions (20, 15,
15, and 15 times every 3 s) at 1-min interset intervals were
performed. Torque was monitored by computer using Power Lab/16s (AD Instruments, Colorado Springs, CO) via a strain gaugelinked motor device (Model RU-72, Motomura Systems) during allcontraction bouts.
BFR protocol. BFR to the right lower extremity was induced bycompressing the proximal end of the right thigh with a latex cuff
(overall cuff size: 16-mm width, 90-mm length; Hokanson, Bellevue,WA) as previously described (45, 60). The pressure was set by using
blood pressure meter (mercury blood pressure monitor, Kenz Medico,
Saitama, Japan). This study (n ⫽ 5) determined the relationshipbetween cuff pressure and PmvO2 and resolved that 80 Torr provided
a suitable BFR level at which PmvO2 was lowered considerably but
blood flow was not completely occluded. BFR was started 1 min
before the start of electrical stimulation for each contractions (training) bout.
PmvO2 measurements. Rats were divided into 3 groups (n ⫽ 6each): low (30 Hz) or high (100 Hz) force isometric electricalstimulation exercise (EXER) and EXER under 80 mmHg cuff pressure (EXER⫹BFR). Phosphorescence quenching as described previously (28) was utilized during the BFR protocol to determine thePmvO2 within the medial TA muscle region. A PE-50 catheter filledwith heparinized saline was inserted in the right carotid artery andconnected to a pressure transducer (DX-100, Nihon Kohden, Tokyo,
Japan). This catheter was also used to infuse the phosphorescent probe

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136

MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODEL

A
Tibialis anterior(TA) muscle

Cuff for bloodflow restriction

B

Acute experiment model (Exp.1)
Exp 1-1. PmvO2 measurement

Group 1

Exp 1-2. Muscle sampling (3 hafter EXER or EXER+BFR) forbiochemistry analysis

C

EXER

1 set

2 set

3 set

20 times

15 times

15 times

4 set
30 Hz or 100 Hz
15 times stimulation

Group 2EXER
+BFR

30 Hz stimulation
80 mmHg cuff
pressure

Chronic experiment model (Exp.2)

Muscle sampling (24 h after
9th EXER or EXER+BFR)
for biochemistry andhistochemistry analysis

24 h

1

2

3

4

5

6

7

8

9

Sampling

Training (3 times/week)
Fig. 1. Acute (Exp.1) and chronic (Exp.2) experimental model. A: blood flow restriction (BFR) treatment model using latex cuff. B: acute experimental protocol
in PO2 measurement (Exp. 1–1) and muscle sampling (Exp. 1–2). Exercise (EXER) groups (30-Hz or 100-Hz stimulation) and EXER with BFR groups(EXER⫹BFR). C: chronic experimental protocol (training model, Exp.2). Each set applied acute experimental protocol condition in B. PmvO2, microvascularoxygen partial pressure.

[palladium meso-tetra (4-carboxyphenyl) porphyrin dendrimer (R2)]
at 15 mg/kg. A lateral incision of the skin and overlying fascia wasmade to expose the right TA muscle, and the light source probe/collector of the PMOD 2000 Frequency Domain Phosphorometer(Oxygen Enterprises, Philadelphia, PA) was positioned 2– 4 mmabove the medial TA surface. Excitation light was applied at 524-nm
wavelength; its phosphorescence decay was monitored to measure thelifetime and hence resolve PmvO2. PmvO2 was averaged for 5 s
immediately before the end of contractions when the signal was
stable.
The theoretical basis for phosphorescence quenching has beenreported previously (53, 56). Briefly, the Stern-Volmer relationshipdescribes the quantitative O2 dependence of the phosphorescentprobe. R2 is a nontoxic dendrimer that binds to albumin at 38°C and
pH 7.4 (i.e., under the physiological conditions extant herein) with aquenching constant of 409 mmHg⫺1·s⫺1 and a 601 ␮s decay lifetimein the absence of O2 (31, 50). The net negative charge of R2 also
facilitates restriction of the compound to the vascular space. Thus,
PmvO2 reflects the PO2 within capillary blood, which constitutes theprincipal intramuscular vascular space (50, 52).
Experiment 1-2: acute experimental model for biochemistry analysis.
Electrical stimulation (4 –7 V) was applied to the TA muscle byaffixing a surface electrode to the abraded skin over the right TA(Vitrod A, Nihon Kohden, Tokyo). We used low force (30 Hz) and 80
mmHg applied pressure (i.e., a moderate degree of BFR) to produce
the desired PmvO2 decrease (Fig. 1B, Exp 1-1). In experiments todetermine the phosphorylation response of muscle proteins to asingle bout of contractions (Fig. 1B), the TA muscle was excised
3 h after exercise and immediately frozen in liquid nitrogen, thenstored at ⫺80°C until protein quantification as reported previously

in rat electrical stimulation models (5). The phosphorylation responses of muscle hypertrophy proteins [mTOR, S6K1, rpS6,
extracellular signal-regulated kinase (ERK), and AMPK] were
examined in 11-wk-old rats (n ⫽ 24). Animals were separated into
four groups (n ⫽ 6 each) depending on the presence or absence of
EXER and BFR.
Experiment 2: chronic training model. Rats (n ⫽ 24, 11 wk old)
were divided randomly into 4 groups (n ⫽ 6 each): control (CONT),
low-force electrical stimulation exercise (EXER), exercise under BFR(EXER⫹BFR), and BFR only. For the latter groups, the EXER, BFR,
or EXER⫹BFR conditions were performed three times a week for 3
wk (Fig. 1C). As above, BFR consisted of an external compressive
force of 80 mmHg applied to the proximal portion of the right thigh.
The TA isometric contractions were elicited by electrical stimulation(30 Hz). Rats in each group were killed 24 h after the last training boutto discriminate the “training” effects from those caused by the acuteexercise per se. The entire TA muscle was collected from both theright leg (treated side) and left leg (nontreated side). The isolated
tissue was immediately flash frozen in liquid nitrogen and stored at⫺80°C until analysis.
In chronic training experiments, we measured the force produced
before exercise on the first day and the last day of training andcompared them among groups. The maximal force was measured byapplying 100 Hz electrical stimulation to produce a sustained isometric contraction.
Western blotting analysis. The frozen protein was dissolved in
Lysis buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1
mM EGTA, 1% Nonidet P-40, 10% glycerol, 200 mM NaF, 20 mM
sodium phosphate, and 1 mM NaVO4) and homogenized. Proteins
were separated at 200 V using a 7.5%–10% polyacrylamide gel for

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137

A

C
60

EXER (30 Hz)
EXER (100 Hz)
EXER+BFR

100
50

80

PmvO2 (Torr)

Relative muscle force (%)

MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODEL

60
40
20
0

B

10 20 30 40 50 60 70 80 90 100
Stimulation frequency (Hz)PmvO2 (Torr)

30
20
10

40
30
20

*

10

*

*
*

*

0
Rest

*
*

*

*

* ** **

0

1 set

2 set

3 set

4 set

EXER

30 Hz or 100 Hz
stimulation

EXER
+BFR

30 Hz stimulation
80 mmHg cuff
pressure

Rest 20 40 60 80 100 120 140
Cuff pressure (mmHg)

Fig. 2. Effects of blood flow restriction (BFR) on muscle oxygen partial pressure. A: relationships between muscle tension and the stimulus frequency (Hz).
Tension elicited by 100 Hz was considered as 100% (i.e., equivalent to 1 maximal repetition; n ⫽ 3). B: relationship between cuff pressure (mmHg) and muscle
oxygen partial pressure (PmvO2, Torr). Significantly different between Rest and each condition, *P ⬍ 0.05, **P ⬍ 0.01; n ⫽ 5. C: time courses of alterationsin PmvO2 during muscle contraction induced by 30-Hz or 100-Hz electrical stimulation (EXER) and EXER under 80-mmHg cuff pressure (EXER⫹BFR). Opencircle (30 Hz) and triangle (100 Hz) show EXER, and filled circle shows EXER⫹BFR. Significantly different between groups, *P ⬍ 0.05 vs. 30 Hz EXER, †P ⬍0.05 vs. 100 Hz EXER. Means ⫾ SE; n ⫽ 6/group.

~50 min. Transfer was performed at 72 mA for 60 min using thesemidry method to Amersham High Bond P membrane (GE Healthcare UK, Buckinghamshire, UK). After the transfer, the membrane
was blocked with 2%–3% skim milk in PBS (0.01 M phosphatebuffer, 0.138 M NaCl, 0.027 M KCl, pH 7.4) with 0.1% Tween 30 atroom temperature for 1 h. The membrane was then exposed to
antibodies at the appropriate dilutions in blocking buffer overnight at
4°C. The probed membrane was then washed 3 times in PBS with
0.1% Tween for 15 min each time and was subsequently incubatedwith peroxidase-linked anti-rabbit IgG (Santa Cruz Biotechnology,
Santa Cruz, CA; diluted 1:5,000 with blocking buffer) for 1 h at room
temperature. After three additional washes, bound antibodies weredetected with a Chemi-Lumi One Super kit (Nacalai Tesque, Kyoto,
Japan) and analyzed with an LAS-3000 mini-image analyzer (FujiFilm, Tokyo, Japan). Phosphorylation of Akt on Ser473 was assessedusing anti-phospho-Akt antibody (#4060, Cell Signaling Technology,
Beverly, MA) and anti-total Akt antibody (#4691, Cell Signaling
Technology). Phosphorylation of mTOR on Ser2448 was measured
using anti-phospho-mTOR antibody (#2971, Cell Signaling Technology) and anti-total mTOR antibody (#2972, Cell Signaling Technology). Phosphorylation of p70S6K (S6K1) on Thr389 was determinedusing anti-phospho-p70S6K antibody (#9234, Cell Signaling Technology) and anti-total S6K1 antibody (#2708, Cell Signaling Technology). Phosphorylation of ERK1/2 at Thr202/Tyr204 was measured
using anti-phospho-ERK1/2 antibody (#4370, Cell Signaling Technology) and anti-total ERK1/2 antibody (#4695, Cell Signaling Technology). rpS6 phosphorylation on Ser240/244 was evaluated using
anti-phospho-rpS6 antibody (#5364, Cell Signaling Technology) andanti-total S6 antibody (#2317, Cell Signaling Technology). Antibody
dilutions were 1:1,000 in each case. AMPK phosphorylation on
Thr172 was assessed using anti-phospho-AMPK␣ antibody (#2535,
Cell Signaling Technology) and anti-total AMPK␣ antibody (#2532,
Cell Signaling Technology). Cytochrome c oxidase subunit 4 (COX4,#4850, Cell Signaling Technology), peroxisome proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1␣, ab54481, Abcam,
Cambridge, UK), GLUT4 (BAM1261, R&D Systems, Minneapolis,

MN), fibronectin type III domain-containing protein 5 (FNDC5,
ab174833, Abcam), and anti-hypoxia-inducible factor(HIF)-1␣ antibody (ab1) were purchased from Abcam. Blots were loaded according
to protein concentration (approximately 100 –150 ␮g). To quantify thechange by training, the levels were corrected with GAPDH levels
measured using a GAPDH antibody (GT 239, Gene Tex, CA).
Histological staining. The frozen sample was adhered to a siliconcoated slide glass (s-9441, Matsunami Glass Ind., Osaka, Japan) as atransverse thin section of 10 ␮m at ⫺20°C by cryostat (CM 1510,
LEICA). The staining was performed in hematoxylin-eosin, succinate
dehydrogenase, and slow- and fast-type myosin heavy chain (MHC I,
IIa, and IIb). For succinate dehydrogenase staining, sections were
immersed in 0.2 M sodium phosphate buffer (pH 7.5) containing 0.2
M sodium succinate and 1.2 mM nitroblue tetrazolium at 37°C for 45
min. Mouse monoclonal slow MHC antibody (diluted 1:40 in PBS)
supplied by Novocastrate Laboratories (Leica Microsystems, Wetzlar,
Germany) was used to identify slow-twitch fibers. Mouse fast MHC
monoclonal antibody isoforms were used, which specifically reactwith type IIa (1:1000; SC-71) and IIb (1:100; BF-F3). These were
supplied by Developmental Studies Hybridoma Bank (University of
Iowa, Iowa City, IA). Sections were immersed in PBS solution (pH7.4) at room temperature for 20 min before immersion in primary
antibody at 4°C overnight. Vectastain ABC kit (PK-6102, Vector
Laboratories, Burlingame, CA) was used to elicit an antibody response against MHC antigen. Thereafter, pigment formation was
performed using diaminobenzidine peroxidase substrate kit (SK-4100,
Vector Laboratories) to develop color, and the muscle fiber type wasquantified.
Statistical analysis. All values are expressed as means ⫾ SE. All
statistical analyses were performed in Prism version 6.01 (GraphPad
Software, San Diego, CA). Group differences in PmvO2 during
stimulation, muscle force, and muscle weight data were determined bya two-way analysis of variance and Tukey’s post hoc test. One-way
analysis of variance and Tukey’s post hoc test were used for comparison of Western blotting analysis and histological data. The significance level was set at 0.05.

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138

MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODELRESULTSPmvO2 measurements. When BFR pressure was increased
from 20 mmHg to 140 mmHg at 1-min intervals, PmvO2 decreased in a pressure-dependent manner up until 80 mmHg (Fig.
2B). This was selected as the applied BFR condition.
The average PmvO2 value of TA muscle at rest (baseline) forall measured samples was 27.5 ⫾ 2.0 Torr (Fig. 2C). PmvO2
was decreased to 23.2 ⫾ 4.3 Torr during low-force electricalstimulation (EXER 30 Hz, Fig. 2C) at 1 set, and it gradually
increased to or even above the resting baseline value during theexercise. Application of BFR in combination with 30 Hz (lowforce, EXER⫹BFR) reduced PmvO2 significantly to 7.6 ⫾ 1.9
Torr. This PmvO2 value was lower than that observed duringhigh-force electrical stimulation (i.e., 13.5 ⫾ 3.1 Torr, EXER
100 Hz, Fig. 2C).
Effects of acute isometric electrical stimulation with/without
BFR on mTOR signaling pathways. Phosphorylation of mTOR
on Ser2448, a site directly phosphorylated by Akt, did notincrease in either of these groups (Fig. 3A). The S6K1 phosphorylation at Thr389, a phosphorylation site associated withmaximal activation of the kinase (13), also did not increase inA

p-mTOR/total-mTOR

B

either of these groups (Fig. 3B). On the other hand, rpS6
phosphorylation at Ser240/244, a downstream target of S6K1,
was increased 3 h after EXER⫹BFR compared with CONT,
EXER, and BFR alone (all comparisons P ⬍ 0.05, Fig. 3C).
Given the hypotheses tested herein, of these comparisons, thesignificant difference between EXER and EXER⫹BFR wasnotable.
Mitogen-activated protein kinase cascades are also potential
physiological mechanisms involved in the exercise-induced
regulation of protein synthesis in skeletal muscle (68), andERK1/2 is capable of phosphorylating S6 on its regulatory site(55). However, ERK1/2 phosphorylation at Thr202/Tyr204(Fig. 3D) did not change in any condition. AMPK phosphorylation on Thr172 (Fig. 3E) was also not impacted.
Effects of exercise training with/without BFR on maximal
force, fiber cross-sectional area, and fiber types. The timecourse of alterations in force generated during muscle contractions elicited by 30-Hz electrical stimulation (EXER) andEXER with 80 mmHg BFR (EXER⫹BFR) during the first andninth training bout are shown in Fig. 4A. Note that the force
generated in the first training bout gradually decreased duringp-S6K1/total-S6K1

C

p-mTOR

p-S6K1

p-S6

Total
-mTOR

Total
-S6K1

Total
-S6

CONT

EXER EXER+BFR BFR

2.5

CONT

EXER EXER+BFR BFR

2.0

2.0

p-S6/total-S6

CONT

1.5

EXER EXER+BFR BFR

**

**
**

1.5
1.0

1.5
1.0
1.0

0.5

0.5

0.5
0

0

0

CONT EXER EXER+BFR BFR

D

p-ERK/total-ERK

p-ERK

E

CONT EXER EXER+BFR BFR

p-AMPK/total-AMPK

p-AMPK
Total
-AMPK

Total
-ERK

2.5

CONT EXER EXER+BFR BFR

CONTEXER EXER+BFR BFR

1.5

CONT

EXER EXER+BFR BFR

2.0
1.0

1.5
1.0

0.5
0.5
0

0
CONT EXER EXER+BFR BFRCONT EXER EXER+BFR BFRFig. 3. Effects of EXER or EXER⫹BFR on mTOR signaling pathways. Phosphorylation of mTOR (A) on Ser2448, S6K1 (B) on Thr389, S6 (C) on Ser240/244,
ERK (D) on Thr202/Tyr204, and AMPK on Thr172 (E) in rat tibialis anterior (TA) muscles 3 h after each treatment. Representative immunoblots(phosphorylation and total protein) are shown each group. Proteins with a phosphorylation site are shown as a phospho-to-total ratio. Proteins without a regulatory
phosphorylation site are indicated as total protein content. Means ⫾ SE; n ⫽ 6/group. Significantly different between groups, **P ⬍ 0.01. AMPK,
AMP-activated protein kinase; BFR, blood flow restriction; CONT, control group; EXER, electrical stimulation exercise; mTOR, mammalian target of
rapamycin; S6, ribosomal protein S6 (rpS6); S6K1, p70 kDa ribosomal protein S6 kinase.
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30 Hz muscle force (mNm)

A

B
25

EXER
1st training
9th training

20
15
10
5
0

100 Hz muscle force (mNm)
after 9th training

MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODEL

50

Non-treatedTreated

40

**

30
20
10
0
CONT

EXER EXER+BFR BFR

EXER+BFR

C

20
15
10
5
0
1 5 10 15 20 1 5 10 15 1 5 10 15 1 5 10 15

1 set

2 set

3 set

4 set

Muscle weight (mg)after 9th training

30 Hz muscle force (mNm)

1 5 10 15 20 1 5 10 15 1 5 10 15 1 5 10 15

25

**

650

Non-treatedTreated

600

**

**
Nontreated

550
500
450
400
CONT

Treated139

Fig. 4. Effects of EXER and EXER⫹BFR
training on the exerting tension and muscle
weight. A: time course of alterations in torquegenerated during muscle contraction by 30-Hz
electrical stimulation (EXER) and EXER with
80 mmHg cuff pressure (EXER⫹BFR) at thefirst and ninth training. Open circle shows thefirst training, and filled circle shows the ninth
training. B: muscle force (100 Hz) at the ninth
training session in each group. Open circle
shows the control leg (left side), and filled
circle shows the treated side (right side). C:
muscle wet weight at 24 h after the ninth
training session. Inset: surgically removed
tibialis anterior (TA) muscles from nontreated (left) and treated (right) hindlimbs.
Means ⫾ SE; n ⫽ 6/group. Significantly different between nontreated (left) and treated(right) hindlimbs, **P ⬍ 0.01. There was no
significant difference between the groups on
the treated (right) hindlimbs in the peak tension (EXER vs. EXER⫹BFR, P ⫽ 0.795)
and muscle weight (EXER vs. EXER⫹BFR,
P ⫽ 0.340). BFR, blood flow restriction;
CONT, control group.

EXER EXER+BFR BFR

the repetitive stimulation with and without BFR. However, theforce rapidly decreased and attained a much lower level,
especially during the third and fourth sets in EXER⫹BFR,
compared with EXER alone. The force generated by 30-Hz
electrical stimulation during the ninth training bout was increased in both EXER and EXER⫹BFR, compared with thatduring the first training bout. In Fig. 4B, the absolute maximal
tension (100-Hz stimulation) at the left leg (nontreated side)
was not significantly different among each group. However,the value after the ninth training bout was increased for both
EXER and EXER⫹BFR but not for CONT and BFR groups.
However, there were no statistical differences in maximal force
between EXER and EXER⫹BFR groups after the ninth training bout (P ⫽ 0.340, Fig. 4B).
The effects of EXER with and without BFR on muscle mass
after the ninth training session are shown in Fig. 4C. The
muscle wet weight (left leg, nontreated side) was not significantly different among groups. However, EXER induced muscle hypertrophy (6.2%, P ⬍ 0.01), whereas CONT or BFR
alone did not (Fig. 4C). EXER⫹BFR induced an increase inmuscle mass (11.0%, P ⬍ 0.01), but although numericallygreater, it was not significantly different between EXER andEXER⫹BFR. However, it was notable that there was substantial variability in the response, with the two most hypertrophiedmuscles belonging to the EXER⫹BFR group (Fig. 4C).
In EXER without BFR, fiber cross-sectional area (CSA) was
not increased significantly in the superficial TA (CONT vs.
EXER: P ⫽ 0.094, Fig. 5A). On the other hand, the conditionof EXER⫹BFR led to a statistically significant increase in fiber
CSA in the superficial portion (CONT vs. EXER⫹BFR: P ⫽0.046, Fig. 5A). As expected, type II fibers were dominant in
the superficial portion of TA muscle, but both type I and II
fibers were present in the deep portion. No change in fiber typecomposition was detected under any condition (Fig. 5B).
Effects of exercise training with BFR on lactate transporters(monocarboxylate transporter). EXER and EXER⫹BFR bothenhanced monocarboxylate transporter 1 (MCT1; Fig. 6A) andcluster of differentiation 147 (CD147; Fig. 6C, P ⬍ 0.05) but
not MCT4 (Fig. 6B) expression compared with CONT and
BFR. EXER⫹BFR induced a much larger increase in MCT1
compared with EXER (P ⬍ 0.05).
Effects of exercise training with/without BFR on PGC-1␣
and metabolite transport proteins. EXER⫹BFR, but none ofthe other conditions, significantly increased the critical regulator for mitochondrial biogenesis, PGC-1␣ (Fig. 7A), and also
GLUT4 (Fig. 7B). However, COX4 protein expression, indicative of muscle oxidative capacity, was increased by both
EXER and EXER⫹BFR groups (Fig. 6C). EXER, EXER⫹
BFR, and BFR conditions all enhanced FNDC5 (thought to be
the origin of irisin) protein expression (Fig. 6D).
We also documented the effects of these experimental conditions on a broad spectrum of muscle proteins (Table 1), noneof which was impacted significantly.
DISCUSSION

The foremost original findings of the present investigation
are as follows: 1) Contrary to our hypothesis, muscle hypoxia(i.e., reduced PmvO2) during low-force contractions is not arequisite condition for hypertrophy but, when induced via
BFR, potentiates such hypertrophy. 2) Low-force contractions
with BFR acutely enhance phosphorylation of rpS6. 3) EXER
induced muscle hypertrophy (6.2%, P ⬍ 0.01), but EXER⫹BFR induced an increase in muscle mass (11.0%, P ⬍ 0.01)
and significantly increased CSA preferentially in the superficial
muscle portion (P ⬍ 0.05). 4) Low-force contractions with
BFR enhanced PGC-1␣ protein expression, a critical regulator
for mitochondrial biogenesis, and GLUT4. 5) EXER both withand without BFR elevated muscle oxidative capacity, as reflected by the protein content of COX4, FNDC5, MCT1, andCD147. However, EXER⫹BFR induced a much larger increase in MCT1 compared with EXER alone. These results
provide the first data demonstrating that the reduced PmvO2
accompanying low-force muscle contractions with BFR en-

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140

MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODELA
Muscle fiber CSA (µm2)

Superficial portion
3000

2500

2500

2000

2000

1500

1500

1000

1000

500

500
CONT

B

50

*

0

0

Muscle fiber type (%)

Fig. 5. Effects of EXER and EXER⫹BFR training on muscle fiber cross sectional area (CSA)
and fiber types. A: muscle fiber CSA in TA
muscles into deep and superficial portion. Significantly different between groups, *P ⬍ 0.05
vs. CONT. Mean ⫾ SE; n ⫽ 6/group. B: muscle
fiber composition ratio (%) in each group. Notethat type II fibers were dominant in the superficial portion of TA muscle, but both type I andII fibers coexisted in the deep portion. There
was no significant difference between groups
for each composition. Mean ⫾ SE; n ⫽ 6/group.
BFR, blood flow restriction; CONT, control
group; EXER, electrical stimulation exercise; TA,tibialis anterior.

Deep portion
3000

CONT EXER EXER+BFR BFREXER EXER+BFR BFRDeep portion

100

Superficial portion

40

80

30

60

CONT
EXER
EXER+BFR
BFR

20

40

10

20

0

0
I

IIa

hanced the phosphorylation response of rpS6 in the mTOR
signaling pathways, possibly resulting in the attendant muscle
hypertrophy. Interestingly, these conditions also increased glucose transporter and mitochondrial biogenesis, which may
underly the pleiotropic effects of exercise training with BFR, inwhich the activation of PGC-1␣ is intrinsic to the improved
capacity for sustained exercise.
There is experimental support for muscle protein synthesis
and hypertrophy being elicited by exercise training underhypoxic conditions (8, 9, 11). However, until the present
investigation, the O2 pressures within the intact contracting
muscles and their relationship to candidate mechanisms controlling the hypertrophic response to training (with BFR) had

IIx

I

IIb

B

C

MCT1

MCT4

CD147

GAPDH

GAPDH

GAPDH

CONT

0.4

EXER EXER+BFR BFR

CONT

*

CONT

EXER EXER+BFR BFR

**

*

IIb

EXER EXER+BFR BFR

1.5

2.0

**

IIx

not been determined. PmvO2 was significantly lowered from27.5 mmHg at rest and 23.2 mmHg during blood flow-intact,
low-force electrical stimulation to 7.5 Torr by application of
the 80-mmHg pressure cuff concomitant with electrical stimulation. Indeed, this PmvO2 was significantly lower than that
present during flow-intact, high-force (100 Hz) contractions(13.5 Torr). It is important to note that the level of BFR utilizedherein is not completely occlusive, which would be expected toreduce the PmvO2 to values close to 0 Torr as demonstrated by
Matusmoto et al. (36) using electron paramagnetic resonanceoximetry in mouse quadriceps muscle. Thus, the level of
PmvO2 under the moderate BFR level used in the present
investigation is intermediate between that induced by 100-Hz

A

0.5

IIa

*
1.5

1.0

0.3

*

1.0
0.2

0.5
0.5

0.1
0

0

0
CONT EXER EXER+BFR BFRCONT EXER EXER+BFR BFRCONT EXER EXER+BFR BFRFig. 6. Effects of EXER or EXER⫹BFR training on monocarboxylate (lactate) transporter (MCT) proteins. Effects of EXER or EXER⫹BFR on the expressionof MCT1 (A), MCT4 (B), and its chaperon, CD147, (C) in rat tibialis anterior (TA) muscles 24 h after the ninth training. Representative immunoblots are shownin each group. Expression level was obtained by adjusting each value by the internal control level of GAPDH. Means ⫾ SE; n ⫽ 6/group. Significantly different
between groups, *P ⬍ 0.05, **P ⬍ 0.01. BFR, blood flow restriction; CD147, cluster of differentiation 147; CONT, control group; EXER, electrical stimulation
exercise.
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MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODEL

A

141

B
GLUT4

PGC-1

GAPDH

GAPDH
CONT

CONT

EXER EXER+BFR BFR*

0.5

EXER EXER+BFR BFR

1.5

*

0.4
1.0

0.3
0.2

0.5

0.1
0

0
CONT

EXER EXER+BFR BFR

C

CONT

EXER EXER+BFR BFR

D
COX4

FNDC5

GAPDH

GAPDH
CONT

CONT

EXER EXER+BFR BFR

1.5

**

0.5

**

*

EXER EXER+BFR BFR

*

*

0.4

1.0

0.3

Fig. 7. Effects of EXER and EXER⫹BFR
training on metabolite transport proteins andmitochondria related proteins. A: PGC1␣. B:
GLUT4. C: COX4. D: FNDC5. Data wereobtained from right TA muscle (BFR side).
Protein densities of PGC1␣ (A), GLUT4 (B),
COX4 (C), and FNDC5 (D) are shown. Expression level was obtained by adjusting eachvalue by the internal control level of GAPDH.
Representative immunoblots are shown above
each group. Means ⫾ SE; n ⫽ 6/group. Significantly different between groups, *P ⬍0.05, **P ⬍ 0.01. Significance levels between EXER and CONT were P ⫽ 0.559(PGC1␣) and P ⫽ 0.094 (GLUT 4), respectively. BFR, blood flow restriction; CONT,
control group; COX4, cytochrome c oxidasesubunit 4; EXER, electrical stimulation exercise; FNDC5, fibronectin type III domaincontaining protein 5; GLUT4, glucose transporter 4; PGC-1␣, peroxisome proliferatoractivated receptor gamma coactivator 1-alpha;TA, tibialis anterior.

0.2

0.5

0.1
0

0
CONT

EXER EXER+BFR BFR

CONT

intense muscle contractions and complete blood flow disruption.
By definition, aerobic organisms require O2 to produce
energy, and reduced O2 availability or transient deprivation
causes significant stress in all living cells, including skeletal
muscles. Specifically, hypoxic stress to muscle tissues either
Table 1. Relative expression levels of various proteins ineach group
CONT(n ⫽ 6)SREBP-1(precursor)
SREBP-1 (mature)
REDD1
CD36
IL-6
Myostatin
BDNF (precursor)
HIF-1␣VEGF
Aquaporin-4

0.262 (0.02)
0.238 (0.04)
0.756 (0.07)
0.682 (0.05)
0.258 (0.09)
1.468 (0.15)
1.070 (0.12)
0.608 (0.17)
0.634 (0.07)
0.452 (0.05)

EXER ⫹
EXER (n ⫽ 6) BFR (n ⫽ 6)

BFR (n ⫽ 6)

0.304 (0.03)
0.237 (0.04)
0.689 (0.03)
0.623 (0.06)
0.471 (0.09)
1.262 (0.15)
0.800 (0.06)
0.533 (0.09)
0.675 (0.08)
0.514 (0.05)

0.317 (0.04)
0.187 (0.05)
0.653 (0.04)
0.625 (0.03)
0.492 (0.06)
1.222 (0.13)
0.740 (0.06)
0.652 (0.14)
0.802 (0.08)
0.644 (0.07)

0.328 (0.04)
0.346 (0.04)
0.622 (0.05)
0.597 (0.08)
0.273 (0.03)
1.034 (0.11)
0.730 (0.07)
0.480 (0.07)
0.563 (0.04)
0.433 (0.06)

Data are given as mean (SE). Expression level was obtained by adjusting theinternal control level of GAPDH. Each datum was obtained from six different
rats. BDNF, brain derived neurotrophic factor; BFR, blood flow restrictiongroup; CD36, cluster of differentiation 36; CONT, control group; EXER,
exercise group; EXER⫹BFR, exercise with blood flow restriction group;
HIF-1␣, hypoxia-inducible factor-1␣; IL-6, interleukin-6; REDD1, regulated
in development and DNA damage responses 1; SREPB-1, sterol regulatory
element-binding protein 1; VEGF, vascular endothelial growth factor.

EXER EXER+BFR BFR

suppresses intracellular ATP production (4) or alters metabolic
control [e.g., elevated perturbations of NADH, ADP, phosphocreatine, inorganic phosphate (Pi), or H⫹] as well as increasing
reactive oxygen species (61, 71). An increase of reactive
oxygen species reduces sarcoplasmic reticulum Ca2⫹ release/
reuptake and compromises contractile function (11). Pi accumulation is also considered to be an important contributor tomuscle fatigue (61), as Pi binds to sarcoplasmic reticulum
Ca2⫹ and inhibits muscle contraction (66). When low-force
exercise is performed under BFR (27) or ischemia (65), muscle
fatigability is enhanced and a decrease in the maximum voluntary muscle force and number of repetitions possible occurs
in a similar manner as during high-force exercise. In fact, in
exercise under BFR, the tension production was reduced substantially during the exercise bout because of muscle fatigue.
Note in Fig. 4A that for EXER⫹BFR, tension decreases rapidly
to its nadir compared with that seen for EXER alone. Takaradaet al. (62) determined that this enhanced fatigability induced byexercise with BFR is mechanistically linked to a recruitment oftype II (i.e., higher order) muscle fibers in addition to the typeI fibers normally recruited in the free-flowing condition (24).
This enforced recruitment of both fiber types at contraction
intensities at which they would not normally both be active
provides a putative explanation for the enhanced hypertrophic
response induced by BFR. Such an explanation is also compatible with the present results showing that EXER⫹BFR
increased fiber CSA preferentially in the superficial TA, where

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MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODEL

type II fibers predominate. Interestingly, a significant increasein maximum tension was observed in both EXER andEXER⫹BFR groups (Fig. 4B). Human voluntary contraction
training programs provide evidence that low-force training
with BFR promotes less adaptation of the nervous systemcompared with high-force resistance training (2, 62, 70). Oneof the reasons that a substantial increase of muscle strength wasobserved even at low force herein may be related to theelectrical stimulation condition and enhanced recruitment oftype II fibers. However, the involvement of other mechanisms,
such as exercise-induced metabolites activating motor unit
recruitment (17), cannot be ruled out in the present investigation. Hence, further studies are needed to resolve the precise
mechanisms by which BFR promotes muscle strength andhypertrophy.
The mTOR signaling pathways involving phosphorylationof mTOR and sequential phosphorylation of S6K1/rpS6 play
an essential role in increased muscle strength and hypertrophy(6, 29, 57, 67). Phosphorylation of the mTOR pathways increases within hours of exercise with BFR (19, 21, 44). For
instance, Fujita et al. (21) found S6K1 phosphorylation 3 hfollowing low-force (20% 1RM) knee-extension exercise with
BFR in humans. Likewise, Fry et al. (19) showed that mTOR,
S6K1, and rpS6 phosphorylation and muscle protein synthesis
were increased 1 and 3 h after exercise with BFR. In particular,
rpS6 phosphorylation increased ~17-fold compared with theuntreated CONT group and ~3-fold compared with blood
flow-intact exercise (19). Similarly, in our rat model, rpS6
phosphorylation increased ~13-fold compared with the CONT
group and ~2.6-fold compared with EXER alone. We also
investigated the relationship between PmvO2 and phosphorylation of rpS6 as an index of the muscle hypertrophic signal.
Interestingly, herein no significant change in the muscle hypertrophy signal (rpS6) was induced by BFR alone for 3 wk,
which is inconsistent with our previous findings that BFR alone
induced muscle hypertrophy (59). This disparity may potentially be explained by the longer experimental period (i.e., 6 vs.
3 wk herein) evaluated by Sudo et al. (58). But we did find thatthe low-force exercise condition with BFR herein markedly
enhanced rpS6 phosphorylation. Thus, lowering PmvO2 via
BFR acts to potentiate the protein phosphorylation response
driven by muscle contractions. However, in contrast to humanstudies (19, 21), the present investigation showed that lowforce electrical stimulation with BFR markedly enhanced thephosphorylation of rpS6, which occurred in the absence ofaltered mTOR and S6K1. This finding may have resulted from
evaluating the response just 3 h after the exercise.
Reduced muscle oxygen pressures potentiate the hypertrophic signal within muscle as seen by the Akt, S6K1, andEukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) responses to 4 h to 4 days of hypoxic exposure(FIO2 0.08 or 0.12) (16, 18). HIF-1␣ represents one candidate
signaling mechanism for this response because of its rapid
upregulation during hypoxic stress (34). Surprisingly, however, HIF-1␣ expression was not changed, at least 3 h after the
exercise with BFR (Table 1), suggesting that HIF-1␣ upregulation does not appear to drive the muscle hypertrophic signal(rpS6 phosphorylation). One limitation was that we only obtained tissue samples 3 h after acute exercise and could nottherefore have detected subsequent changes. However, both
rpS6 phosphorylation and hypertrophy occurred in the absenceof a hypoxic signal, suggesting that hypoxia itself, at least at
the muscle microvascular level, is not an obligatory feature ofthese responses. Accordingly, the precise mechanisms controlling the hypertrophic response to low-level contractions with(and without) BFR remain to be resolved.
In marked contrast to the evidence herein, it is consideredthat to induce muscle hypertrophy, resistance exercise training
is generally conducted at or above 70% 1RM (3, 39). The
present investigation utilized neuromuscular electrical stimulation to mimic resistance exercise (22, 33), which has beensuccessful for inducing hypertrophy and strengthening humanmuscles (at 75 Hz, isometric contractions) (22). Herein, lowforce (30 Hz) isometric contractions alone induced a significant
hypertrophic effect (6.2% increase in muscle mass), disputing
the notion that microvascular hypoxia during contractions isessential for muscle hypertrophy and increased maximal tension (100-Hz force production, Fig. 4A). However, in lowforce (30 Hz) isometric contractions alone, the torque generated gradually decreased during the repetitive stimulation (Fig.
4A). Thus, the force production in the present investigation did
induce muscle fatigue, possibly stimulating muscle hypertrophy. On the other hand, a large increase in muscle mass
(11.0%), though it was not statistically greater than found with
EXER alone, and a significant increase in fiber CSA in the
superficial portion were observed after the markedly hypoxic
conditions induced by low-force contractions and BFR over 3
wk of training. This evidence supports the conclusion thathypoxia acts to potentiate the hypertrophic signaling as observed in the elevated rpS6 phosphorylation.
For the chronic exercise training response, as opposed to that
present 3 h after a single bout of contractions (i.e., Fig. 3), no
significant increase in phosphorylation of mTOR, S6K1, andrpS6 was observed in this study (data not shown). The mostplausible explanation for this response is that their phosphorylation response usually reaches peak levels at 3 h after
exercise and subsequently returns to baseline within 24 h.
Second, the training effect itself may cause the muscle hypertrophy signal to gradually reduce (51). In general, the muscle
hypertrophic response in repetitive resistance training increases the CSA and potentially the number of myofibers,
such that the load on the individual muscle fibers suppresses
further signaling and hypertrophy. Ogasawara et al. (48)reported that the phosphorylation response in S6K1 andrpS6, evoked by electrical stimulation (~30 V, 60 Hz) of the
rat gastrocnemius muscle, decreases progressively with subsequent bouts of training. This notion is also supported by
the observation that 9 wk of resistance training in older rats
decreased the phosphorylation responses of Akt and mTOR,
despite significant muscle hypertrophy (48). Interestingly,
however, the phosphorylation response of AMPK␣ wasincreased (32).
In general, high-frequency isometric electrical stimulation(60 –100 Hz) can induce skeletal muscle hypertrophy (48, 64),
whereas lower-frequency electrical stimulation more resembles
endurance-like training (5). However, the imposition of BFR
during low-force isometric electrical stimulation as a training
method herein does not permit discrimination between theeffects of different stimulation frequencies. The low-force
exercise with BFR used herein increases blood lactate immediately after exercise (54), and there is an upregulation of bothglycolytic and aerobic systems after 8 wk of training (12). In

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MUSCLE HYPERTROPHY IN RAT BLOOD FLOW-RESTRICTION MODEL

addition to muscle strength and hypertrophy, there is evidence
for improvement in endurance and maximum oxygen consumption resulting from low-force exercise with BFR training
paradigms (1, 49). We showed that low-force isometric contraction with/without BFR increased COX4, a marker of muscle oxidative capacity (Fig. 7C), and provided the first evidence
that exercise with BFR increases PGC-1␣ protein expression.
PGC-1␣ constitutes a critical master regulator for mitochondrial biogenesis and energy metabolism (69), and PGC-1␣
upregulation may allow greater capacity for modulating metabolic fluxes in skeletal muscle under the low-O2 conditions
imposed by simultaneous low-level contractions and BFR.
Despite the fact that hypoxia is reported to enhance PGC-1␣
expression (47), BFR alone did not increase PGC-1␣ protein
expression herein.
PGC-1␣ induces the expression of multiple genes, including
the substrate transporters GLUT4, FAT/CD36, MCT1, andFNDC5 (7, 10, 41). The concentrations of these substratetransporters, GLUT4 and fatty acid translocase/Cluster of Differentiation 36 (FAT/CD36) as well as MCT1 (9, 10, 37, 38,40), are highly correlated with the oxidative capacities ofskeletal muscle. In the present study, EXER⫹BFR enhanced
GLUT4 protein and PGC-1␣ protein. EXER⫹BFR induced amuch larger increase in MCT1 compared with EXER alone.
FNDC5 and CD147, but not FAT/CD36, all increased with
EXER alone. Benton et al. (7) reported that MCT1 and CD147,
its chaperon, but not MCT4 are regulated by PGC-1␣. Thisfinding supports that BFR via its effect on PGC-1␣ may help
regulate MCT1 protein expression and, in so doing, potentiallyenhance lactate flux across the myocyte sarcolemma. Similarly,
by elevating GLUT4, BFR may increase myocyte glucose
uptake. Indeed, the hypoxic exposure itself raises the AMP/
ATP ratio, thereby activating AMPK␣, which serves as an
intracellular energy sensor moving GLUT4 to the cell membrane (25). In so doing, glucose uptake is promoted by the
GLUT4, and ATP production is sustained/accelerated whilesparing muscle glycogen (23). Thus, exercise under BFR
increased oxidative capacity, glucose transporter, and mitochondrial biogenesis, which may be involved in the pleiotropic
effects of the exercise training under BFR, in which theactivation of PGC-1␣ provides a locus of control. Recently,
Cannavino et al. (14) reported that mitochondrial dysfunction
plays a major role in disuse atrophy, and inducing PGC-1␣
expression could be useful to treat/prevent muscle atrophy.
Thus, low-force, electrically induced exercise with BFR appears to improve muscle mass and prevent muscle atrophy via
the activation of PGC-1␣. In contrast, recent evidence inhumans showed an attenuated expression of all four PGC-1␣
isoforms when endurance exercise is performed with BFR(15), suggesting an exercise paradigm specificity to the BFR
effects that is worthy of further attention.
In conclusion, although demonstrating that muscle hypoxia
is not obligatory for the hypertrophic response to low-force,electrically induced muscle contractions, the reduced PmvO2
induced by BFR during contractions enhanced rpS6 phosphorylation, possibly resulting in the attendant muscle hypertrophy.
Furthermore, in addition to muscle hypertrophy, contractions
with BFR also increased oxidative capacity, glucose transporter, and mitochondrial biogenesis, which are key determinants of the pleiotropic effects of exercise training in which
PGC-1␣ is upregulated.

143

ACKNOWLEDGMENTS
The authors thank Dr. Sir. Y. Sato for fruitful discussions and/or collaborations over the years.
GRANTSThis work was supported by Japan Society for the Promotion of Science
Grants-in-Aid for Scientific Research Grant 16H03203 (to T. Nakajima) andthe Vehicle Racing Commemorative Foundation (to T. Nakajima).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
T.N. and T. Yamasoba conceived and designed research; T.N., S.K., T.
Yasuda, T.H., S.O., and S.T. performed experiments; T.N., S.K., and Y.K.
analyzed data; T.N., T. Yamasoba, T.I., and Y.K. interpreted results ofexperiments; T.N. and Y.K. prepared figures; T.N., F.N., T.I., D.C.P., and Y.K.
drafted manuscript; T.N. edited and revised manuscript; T.N. approved final
version of manuscript.
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Eur J Appl Physiol (2005) 95: 65–73
DOI 10.1007/s00421-005-1389-1

O R I GI N A L A R T IC L E

Haruhito Takano Æ Toshihiro Morita Æ Haruko Iida
Ken-ichi Asada Æ Masayoshi Kato Æ Kansei Uno
Ken Hirose Æ Akihiro Matsumoto Æ Katsu Takenaka
Yasunobu Hirata Æ Fumio Eto Æ Ryozo Nagai
Yoshiaki Sato Æ Toshiaki Nakajima

Hemodynamic and hormonal responses to a short-term low-intensity
resistance exercise with the reduction of muscle blood flow
Accepted: 28 April 2005 / Published online: 15 June 2005
 Springer-Verlag 2005

Abstract We investigated the hemodynamic and hormonal responses to a short-term low-intensity resistance
exercise (STLIRE) with the reduction of muscle blood
ﬂow. Eleven untrained men performed bilateral leg
extension exercise under the reduction of muscle blood
ﬂow of the proximal end of both legs pressure-applied
by a specially designed belt (a banding pressure of 1.3
times higher than resting systolic blood pressure, 160–
180 mmHg), named as Kaatsu. The intensity of STLIRE was 20% of one repetition maximum. The subjects
performed 30 repetitions, and after a 20-seconds rest,
they performed three sets again until exhaustion.
The superﬁcial femoral arterial blood ﬂow andhemodynamic parameters were measured by using theultrasound and impedance cardiography. Serum concentrations of growth hormone (GH), vascular endothelial growth factor (VEGF), noradrenaline (NE),insulin-like growth factor (IGF)-1, ghrelin, and lactate
were also measured. Under the conditions with Kaatsu,
the arterial ﬂow was reduced to about 30% of the control. STLIRE with Kaatsu signiﬁcantly increased GH(0.11±0.03 to 8.6±1.1 ng/ml, P < 0.01), IGF-1(210±40 to 236±56 ng/ml, P < 0.01), and VEGF
(41±13 to 103±38 pg/ml, P < 0.05). The increase in
H. Takano Æ T. Morita Æ H. Iida Æ K. Asada Æ M. Kato
K. Uno Æ A. Matsumoto Æ K. Takenaka Æ Y. Hirata
R. Nagai Æ T. Nakajima
Department of Cardiovascular Medicine,
University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8655, Japan
K. Hirose Æ F. Eto
Department of Rehabilitation, Faculty of Medicine,
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-8655, Japan
Y. Sato Æ T. Nakajima (&)
Department of Ischemic Circulatory Physiology,
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-8655, Japan
E-mail: masamasa@pb4.so-net.ne.jp
Tel.: +81-3-38155411
Fax: +81-3-38140021

GH was related to neither NE nor lactate, but the increase in VEGF was related to that in lactate (r = 0.57,
P < 0.05). Ghrelin did not change during the exercise.
The maximal heart rate (HR) and blood pressure (BP) in
STLIRE with Kaatsu were higher than that without
Kaatsu. Stroke volume (SV) was lower due to the decrease of the venous return by Kaatsu, but, total peripheral resistance (TPR) did not change signiﬁcantly.
These results suggest that STLIRE with Kaatsu signiﬁcantly stimulates the exercise-induced GH, IGF, andVEGF responses with the reduction of cardiac preload
during exercise, which may become a unique method forrehabilitation in patients with cardiovascular diseases.
Keywords Resistance exercise Æ Ischemia Æ
Growth hormone Æ Vascular endothelial growth factor Æ
Hemodynamics Æ Cardiac output Æ Rehabilitation Æ
Blood ﬂow Æ Preload

Introduction
Heavy resistance training has been known to be a potent
stimulus for muscle cell growth and hypertrophy(MacDougall et al. 1997; Staron et al. 1984; Abe et al.
2000), then resulting in improvement of muscle strengthand increased peak exercise capacity. This is due, in part,to the exercise-induced increase of endogenous anabolic
hormones and growth factors such as growth hormone(GH) and insulin-like growth factor-1 (IGF-1) (Kraemer
et al. 1990; Godfrey et al. 2003). The GH and IGF-1
have been also established as a regulator of cardiac
growth, structure and function (Lombardi et al. 1997;
Khan et al. 2002), and GH has been recently applied forthe treatment of congestive heart failure (Fazio et al.
1996; Genth-Zots et al. 1999). However, the exerciseinduced GH elevation depends on speciﬁc exercise
characteristics, and only certain heavy resistance exercise
protocols such as a weight-lifting exercise can induce

66

signiﬁcant elevation in serum GH (Lukaszewska et al.
1976; VanHelder et al. 1984; Godfrey et al. 2003).
Therefore, it is diﬃcult to apply the heavy exercise forpatients, such as those with cardiac diseases. Alternatively, a variety of factors have inﬂuences on the exercise-induced GH responses, i.e. metabolic demands andhypoxia. Low-intensity resistance exercise with tourniquet ischemia or vascular occlusion has been shown to
be a useful method for strength training (Shinohara
et al. 1998; Takarada et al. 2000a; Moore et al. 2004),
where the potent secretion of GH may play a part
(Takarada et al. 2000b). High-intensity exercises [80%of one repetition maximum (RM)] produce a 100-foldincrease in plasma concentration of GH (Kraemer et al.
1990), while a short-term low-intensity resistance exercise (STLIRE) when combined with the reduction ofmuscle blood ﬂow (20% of 1 RM) produces a 290-foldincrease (Takarada et al. 2000b). These results suggestthat STLIRE with the reduction of muscle blood ﬂow
may be a novel method for training patients. However,
the inﬂuence of such kinds of the exercise on the hemodynamics has not been investigated.
High endurance exercise training also stimulates botharteriogenesis and angiogenesis (Yang et al. 1990; Guteet al. 1996). The underlying mechanisms have not been
known exactly. However, reduced oxygen tension and/or related metabolic consequences have been suggested
as possible stimuli, where growth factors such as vascular endothelial growth factor (VEGF) may play anessential role. During exercise, local muscle oxygen
tension falls considerably (Richardson et al. 1995), followed by the secretion of VEGF immediately after asingle bout of exercise in both animals and humans(Breen et al. 1996; Gustafsson et al. 2002). In addition,
exercise (Gustafsson et al. 1999; Amaral et al. 2001;
Gavin and Wagner 2001; Gustafsson et al. 2002) andhypoxia (Shweiki et al. 1992; Minchenko et al. 1994;
Stein et al. 1995) up-regulate the expression of VEGF
messenger RNA. Thus, it is likely that the exercise withthe restricted blood ﬂow reduces local muscle oxygen
tension, and may modulate the exercise-induced VEGF
responses.
Thus, we hypothesized that the hemodynamic
parameters as well as hormonal responses including
VEGF may be altered during STLIRE when combinedwith the reduction of muscle blood ﬂow. Therefore, we
compared the hemodynamic and hormonal responses to
STLIRE with and without the reduction of muscle
blood ﬂow in healthy untrained men.

Methods

medicine. They also had not regularly taken any sports.
The informed consent was obtained prior to the study.
Mean height was 175.8±6.9 cm, and mean weight was
68.1±7.8 kg. The body mass index was 22.1±2.5. The
study protocol was approved by the ethics committee ofthe University of Tokyo.
Exercise protocols
All studies were performed in the afternoon at least 4 hafter the lunch. An indwelling heparin-lock catheter wasinserted into the superﬁcial vein of left arm. After
30 min of rest on supine position, blood samples incontrol were collected. Then, the subject was seatedagainst a backrest, and all subjects were asked to be kept
both arms on the table. After taking rest measurementsof hemodynamic parameters in sitting position for 3 min
by using an impedance method (see below), both legs
were pressure-applied by a special-designed belt, named
as Kaatsu in Japanese (see below). Immediately after
Kaatsu, the subjects performed bilateral leg extension
exercise with the lower extremity positioned at 90
ﬂexion. The intensity of STLIRE was 20% of 1 RM,
which was measured at least 1 week before the experiment. The subjects performed 30 repetitions without
rest, and after a 20-seconds rest, they performed threesets again until exhaustion. All subjects stopped theexercise due to the leg fatigue. Immediately after the
exercise sessions, the banding pressure was released andthen blood samples were obtained at 01, 10, and30 min after the exercise. All blood samples were processed to serum or plasma before storage at 20C until
analysis. Nine men again performed the exercise without
Kaatsu at the same intensity and quality as those for the
exercise with Kaatsu. The sessions of experimental (withKaatsu) and control exercise (without Kaatsu) wereseparated by 2–4 weeks.
Reduction of femoral muscle blood ﬂow by Kaatsu
A method for inducing the reduction of muscle blood
ﬂow was similar as previously reported (Takarada et al.
2000b). Local application of external pressure over bothlegs (a banding pressure of 1.3 times higher than resting
systolic blood pressure, 160–180 mmHg) was used toreduce exercise blood ﬂow. Brieﬂy, both sides of theirthighs were pressure-applied at the proximal ends bymeans of specially designed belts (33 mm in width and880 mm in length) just before the start of the exercise,and the pressure was released immediately after the
exercise.

Subjects
Eleven normal healthy adult men, 26–45 years(34±6 years), participated in this study. All were untrained volunteers without any diseases such as cardiovascular and pulmonary diseases, who did not take any

Measurement of hemodynamic parameters
To evaluate hemodynamic parameters, we used theTask Force Monitor (CNSystems Medizintechnik,67Graz, Austria) (Gratze et al. 1998, 1999; Fortin et al.
1998), which includes surface electrocardiograms(ECG), real time beat-to-beat stroke volume measurements by impedance cardiography (ICG) and beat-tobeat blood pressure measurements by vascularunloading technique (Penaz 1973) so that beat-to-beatchanges of total peripheral resistance can be calculated.
Oscillometric blood pressure was also recorded on theupper arm. ICG was performed by standard methods(Kubicek et al. 1966). A constant sinusoidal alternating
current I0 of 400 lA and 40 kHz is passed through thethorax between a circular electrode placed around theneck and another electrode placed around the lower
thorax aperture. The voltage u(t) is acquired by two
further electrodes placed between the admitting electrodes, each at a distance of at least 3 cm from theouter electrodes to produce an interelectrode homogeneous current. The four electrodes consisted of aluminum tape, which is mounted on adhesive tape. The
detected voltage u(t) is proportional to the thorax
impedance Z (Z(t) = u(t) · I0). The ﬁrst derivative (dZ/d t) of the impedance signal Z(t) is supplied analog
by ICG. The ECG was derived from two separate
adhesive monitoring electrodes that are placed on thethorax to give maximal amplitude of the R wave. The
signal ﬂow, the components of ICG, and calibration of
the ﬁnger blood pressure signal to the oscillometricblood pressure measurement were described (Gratze
et al. 1999). The ECG, impedance signal and beat-tobeat blood pressure were sampled with 1000 Hz each.
These data were used to calculate online all hemodynamic parameters. The measurements of hemodynamic
parameters were heart rate (HR), blood pressure [systolic (sBP), diastolic (dBP) and mean (mBP)], left
ventricular ejection time (LVET), stroke volume (SV),stroke index (SI), cardiac output (CO), cardiac index(CI), total peripheral resistance (TPR) and total
peripheral pressure index (TPRI). The calculation of
SI, CO, CI, TPR and TPRI was as follows.
Fig. 1 Measurement of femoral
artery blood ﬂow. In the pulseDoppler method (A), velocity
time integral (VTI), calculated
as the integral area under thevelocity curve, was measured.
In the 2-dimensional mode,cross sectional area (CSA) was
measured (B). A representative
data recording of blood ﬂow
velocity (A) and diameter (B) of
superﬁcial femoral artery at rest
(Pre-Kaatsu and Post-Kaatsu)

SI ¼ SV=BSA
CO ¼ SV  HR
CI ¼ CO=BSA
TPR ¼ mBP  80=CO
TPRI ¼ mBP  80=CI;
where BSA was body surface area:

Biochemical analyses
Plasma level of lactate was measured at S.R.L. Inc(Tokyo) by the use of an enzyme system employing
lactate oxidase combined with N-ethyl-N-(3-methylphenyl)- N-acetyl ethylenediamine and an auto-analyzer, HITACHI Type 7170. Growth hormone (GH)and insulin-like growth factor (IGF)-1 were measured
with radioimmunoassay (S.R.L Inc., Tokyo). The
VEGF was determined in duplicate by high-sensitivity
an enzyme-linked immunosorbent assay (ELISA) using
speciﬁc anti-VEGF antibody according to the manufacturer’s instructions. Plasma noradrenaline (NOR)
levels were measured in a plasma extract by high-performance liquid chromatography with the use of a cation exchange column, an acetonitrile/phosphate buﬀer
mobile phase, and electrochemical detection. Plasma
ghrelin concentration was measured using ELISA kit
using speciﬁc anti-ghrelin antibody.
Measurement of femoral blood ﬂow
The blood ﬂow of superﬁcial femoral artery was calculated from the cross-sectional area (CSA) of the arteryand velocity time integral (VTI) using Aplio80 (Toshiba,
Tokyo, Japan). The site recorded was 5 cm distal tothe portion of the Kaatsu belt. First, superﬁcial femoral

68artery was identiﬁed in the 2-dimensional mode, andCSA was measured at the end-systolic period (Fig. 1B).
Then, in the pulse-Doppler method (Fig. 1A), VTI,
calculated as the integral area under the velocity curve,
was measured. Adjustment of the angle for the measurement was within 60. Blood ﬂow per minute (ml/min) was obtained by multiplying CSA by VTI andheart rate. The blood ﬂow was obtained from ﬁve out of
11 subjects at rest in sitting position before and after theapplication of Kaatsu, and just before releasing thepressure in the post-exercise.
Data analysis
All values are expressed as means ± SD. Student’s
paired t-test was used to compare two sets of data fromthe same subjects. Comparison of time courses ofparameters was analyzed by one-way ANOVA for repeated measures. When diﬀerences were indicated, aDunnett’s comparison was used to determine signiﬁcance. Spearman rank correlation coeﬃcient (r) wasused to examine the relationship between individual
exercise-induced changes. Diﬀerences were consideredsigniﬁcant if P value was less than 0.05.

with Kaatsu were much larger than those in STLIRE
without Kaatsu. The peak exercise HR reached to109±15 bpm, which equals to 55±12% of target heart
rate calculated from the sex and age. The SBP, dBP, andmBP reached to 182±18, 105±18, and 127±12 mmHg,
respectively.
Figure 3 and Table 1 show the eﬀects of STLIRE on
hemodynamic parameters. In STLIRE with Kaatsu, CO
increased from 5.1±1.5 l/min at rest in sitting position
to 6.2±1.5 l/min (P < 0.01) at the peak exercise. In
STLIRE without Kaatsu, CO increased from 5.2±0.9 to
6.9±1.5 l/min (P < 0.01). The increase in CO was notstatistically diﬀerent between both STLIRE (Fig. 3A,
Table 1). But, SV signiﬁcantly decreased in STLIRE
with Kaatsu, compared with STLIRE without Kaatsu(Fig. 3B and Table 1, P < 0.05). The TPR did notchange signiﬁcantly at the peak exercise of STLIRE
with and without Kaatsu (Fig. 3C). The LVET was
decreased in STLIRE with and without Kaatsu(Fig. 3D, P < 0.05).
Changes in serum concentrations of NOR and lactate
Table 2 shows the time courses of the changes inserum lactate (A) and NOR (B) concentration during

Results
Hemodynamic measurements
Figure 2 shows the eﬀects of Kaatsu on blood ﬂow inthe superﬁcial femoral artery. Application of Kaatsu
signiﬁcantly reduced blood ﬂow at rest from 370±71
to 133±38 ml/min (approximately 30% of the control,n = 5, P < 0.05). The blood ﬂow remained markedly
depressed just before releasing the pressure in the postexercise (195±70 ml/min, P < 0.05).
Table 1 show the eﬀects of STLIRE on HR and BP.
HR, sBP, dBP, and mBP at the peak exercise in STLIRE

Fig. 2 Changes of blood ﬂow of femoral artery. The blood ﬂow ofright superﬁcial femoral artery was obtained at rest before and after
Kaatsu, and immediately after the exercise with Kaatsu. Values aremeans ± SD obtained from ﬁve subjects. * P < 0.05 vs. rest (PreKaatsu)

Table 1 Eﬀects of a short-term low-intensity resistance exercise(STLIRE) with or without Kaatsu on hemodynamic variables
Variables
Heart rate (bpm)With Kaatsu
Without Kaatsu
Systolic blood pressure(mmHg)
With Kaatsu
Without Kaatsu
Mean blood pressure(mmHg)
With Kaatsu
Without Kaatsu
Diastolic blood pressure(mmHg)
With Kaatsu
Without Kaatsu
Cardiac output (l/min)With Kaatsu
Without Kaatsu
Stroke volume (ml)With Kaatsu
Without Kaatsu
Total peripheral resistance(dyn*s/cm5)
With Kaatsu
Without Kaatsu
Left ventricular ejection
time (ms)With Kaatsu
Without Kaatsu

Rest

Peak exercise

73±9
66±9

109±15**]**
96±7**

127±12118±9182±18**]*155±12**

98±18
88±9

127±12**]*
113±27**

86±15
73±9

105±18**]*99±21**

5.1±1.5
5.2±0.96.2±1.5**
6.9±1.5**

71±27
74±20

62±21*]*
74±20

1650±615
1473±327

1554±642
1471±627

315±39314±18271±33*290±33*

Values are mean ± SD (n = 9). * P < 0.05, ** P < 0.01 vs. rest
Signiﬁcant diﬀerences between STLIRE with and without Kaatsu
are also shown. * P < 0.05, ** P < 0.01

69
Fig. 3 Eﬀects of short-term
low-intensity resistance exercise(STLIRE) with and without
Kaatsu on hemodynamic
parameters (CO, SV, TPR, and
LVET). Hemodynamic
parameter at rest in sitting
position and at the peak
exercise are shown in STLIRE
with Kaatsu (blue lines) andwithout (red lines). Values
are means ± SD obtained
from nine subjects. * P < 0.05,** P < 0.01 vs. rest. Signiﬁcantdiﬀerences between STLIRE
with and without Kaatsu arealso shown. * P < 0.05

STLIRE with and without Kaatsu. In STLIRE withand without Kaatsu, lactate signiﬁcantly increased after
the exercise. The increase in lactate concentration after
exercise with Kaatsu was much higher than that without Kaatsu. In STLIRE with Kaatsu, NOR increased
from 0.2±0.06 ng/ml at rest to 0.54±0.14 ng/ml(P < 0.01) immediately after the exercise, and gradually decreased after the exercise. On the other hand, it
increased from 0.15±0.03 to 0.32±0.03 ng/dl (P <0.01) in the control exercise. Thus, the increase in NOR
concentration attained in STLIRE with Kaatsu wasalso signiﬁcantly higher than that without Kaatsu(Table 2).

Table 2 Eﬀects of a short-term
low-intensity resistance exercise(STLIRE) with or without
Kaatsu on hormonal variables

Values are mean ± SD (n = 9).
* P < 0.05, ** P < 0.01 vs. rest
(supine) Signiﬁcant diﬀerences
between STLIRE with andwithout Kaatsu are also shown.
* P<0.05, ** P < 0.01 N.D.
not done

Variables

SupineLactate (mg/dl)
With Kaatsu
11.2±4.5
Without Kaatsu
8.6±2.1
Noradrenaline (ng/ml)
With Kaatsu
0.2±0.06
Without Kaatsu
0.15±0.03
Growth hormone (ng/ml)
With Kaatsu
0.11±0.03
Without Kaatsu
0.16±0.08
IGF-1 (ng/ml)
With Kaatsu
210±40Without Kaatsu
184±25
VEGF (pg/ml)
With Kaatsu
41±13
Without Kaatsu
33±5
Ghrelin (pg/ml)
With Kaatsu
7.1±3.5
Without Kaatsu
N.D.

Eﬀects of STLIRE with Kaatsu on plasma
concentrations of GH, IGF-1, VEGF and ghrelin
Figure 4 and Table 2 show the time courses of plasma
concentrations of GH, IGF-1, and VEGF. After the
exercise with Kaatsu, GH, IGF-1, and VEGF signiﬁcantly increased. The GH increased gradually after the
exercise, and reached to the peak at 30 min after the
exercise (Fig. 4A, Table 2). It increased from 0.11±0.03
to 8.6±1.1 ng/ml (P < 0.01). On the other hand, in
STLIRE without Kaatsu, GH only slightly increased
from 0.16±0.08 to 0.48±0.26 ng/ml (P < 0.05). Thus,
the increase in GH elicited by STLIRE with Kaatsu wasEx

10 min30 min24.1±7.8**]**
15.2±5.7**30.9±12.9**]**
12.6±5.4

16.8±7.2]*
9.7±4.80.54±0.14**]*0.32±0.03**

0.31±0.08**
0.32±0.11**

0.31±0.06**
0.3±0.08**

0.49±0.29
0.31±0.08

3.2±1.45*]*0.48±0.26*

8.6±1.1**]**
0.4±0.2236±56**]*200±32230±40**]*196±36226±58*192±3286±49*]*
49±33

104±24**]**
48±30

103±38**]**
47±18

8.9±2.7
N.D.

3.8±1.8
N.D.

7.4±2.9
N.D.

70

Discussion

Fig. 4 Time courses of changes in plasma concentrations of GH,
IGF-1, and VEGF in STLIRE with Kaatsu (blue lines) and without(red lines). * P < 0.05, ** P < 0.01 vs. rest (supine). Signiﬁcantdiﬀerences between STLIRE with and without Kaatsu are also
shown. * P < 0.05, ** P < 0.01

much higher than that without Kaatsu. The IGF-1 and
VEGF also increased after the exercise with Kaatsu(Fig. 4B, C), and remained high during the recovery of
the exercise. Thus, the increase in IGF-1 and VEGF
elicited in STLIRE with Kaatsu was signiﬁcantly higher
than that without Kaatsu.
Figure 5A and C shows the relationships between thechanges of serum lactate concentrations and those of
VEGF and GH. There were statistical diﬀerences between the changes of serum lactate concentration andthose of VEGF (r = 0.57, P < 0.05, Fig. 5A), but not
GH (Fig. 5C). Figure 5B and D shows the relationships
between the changes of serum NOR concentrations andthose of VEGF and GH. There were no statistical differences between the changes of serum NOR concentration and those of VEGF and GH.
To investigate the possible involvement of ghrelin in
GH release during STLIRE with Kaatus, the serum
concentration of ghrelin was measured. Plasma concentration of ghrelin was not signiﬁcantly altered before
and after STLIRE with Kaatsu (Table 2), indicatingthat ghrelin is not involved in the exercise-induced GH
secretion.

The major ﬁndings of the present study are as follows;(1) STLIRE when combined with Kaatsu signiﬁcantly
stimulates the exercise-induced GH, IGF, and VEGF
responses much higher than that without Kaatsu. (2)The TPR did not signiﬁcantly change, but SV decreased
due to the inhibition of venous return by Kaatsu,
resulting in the reduction of cardiac preload during theexercise. These results suggest that STLIRE with Kaatsu
signiﬁcantly stimulates the exercise-induced GH, IGF,
and VEGF responses with the reduction of cardiac
preload during exercise, which may become a uniquemethod for rehabilitation in patients with cardiovasculardiseases. The GH secretion induced by the exercise isdependent on speciﬁc exercise characteristics, and only
heavy resistance exercise protocols such as a weightlifting exercise can induce signiﬁcant GH secretion(Lukaszewska et al. 1976; VanHelder et al. 1984;
Godfrey et al. 2003). Therefore, it is diﬃcult to apply theheavy exercise for patients, such as aged people andpatients/athletes in rehabilitation programs, who cannot
put high mechanical stress on muscle, tendon and joints.
On the other hand, a variety of factors have inﬂuenceson the exercise-induced GH responses, i.e. metabolic
demands and hypoxia. Low-resistance exercise withtourniquet ischemia or vascular occlusion has beenreported to be a useful method for strength training(Shinohara et al. 1998; Takarada et al. 2000a; Moore
et al. 2004), where the potent secretion of GH is partly
involved (Takarada et al. 2000b). In our study, we used
STLIRE (20% of 1 RM) with Kaatsu. The maximal
heart rate attained during the exercise reached to109±15 bpm, which equals to only 55±12% of the
maximal heart rate adjusted by age and sex. Rate-pressure product, which is accepted as a non-invasive estimate of myocardial oxygen demand during physicalstress, was 198 · 102 mmHg · bpm. Even in spite of such
mild strength of exercise, the increased plasma GH
concentrations after the exercise were approximately
100-times as high as that at rest. The level of the increased GH concentration reached to the level as previously described, where high-intensity exercise (80% 1
RM) was used (Kraemer et al. 1990). Takarada et al.
(2000b) reported the similar results of STLIRE (20% of
1 RM and 14 repetitions · 5 sets, total 70 repetitions),
where by using young men athletes aged 20–22 years,
plasma GH concentration increased 290 times as highas that before exercise. The value was larger than that in
our study. The increased concentrations of NOR andlactate were also much higher than those in our study,
suggesting that the diﬀerence between the level of theincreased GH depends on the strength of the exercise.
No such eﬀect was seen after the exercise without
Kaatsu, indicating that STLIRE with Kaatsu is a useful
method for stimulating GH secretion.
The several mechanisms underlying GH release during STLIRE with Kaatsu may be proposed. Ghrelin has

71Fig. 5 Relation between thechanges of serum VEGF andGH and those of serum lactate
and NOR induced by STRILE
with Kaatsu. Relationshipbetween individual exerciseinduced changes (peak levelof post-exercise—pre-exercise
level) (D VEGF, D lactate,
D GH, and D NOR). (A, C)
Relation between D VEGF/D
GH and D lactate (B, D)
Relation between D VEGF/D
GH and D NOR

been known to potently stimulate GH release (Kojima
et al. 1999; Takaya et al. 2000), and may be involved in
exercise-induced GH elevation (Foster-Schubert at al.
2005). However, plasma concentration of ghrelin was
not signiﬁcantly altered before and after STLIRE with
Kaatsu (Table 2), indicating that ghrelin is not involvedin the exercise-induced GH secretion. Alternatively,
under the conditions with Kaatsu, both lactate andNOR increased after the exercise, compared to thecontrol exercise without Kaatsu. Thus, it is likely thatexercise that produces greater demands on anaerobic
glycolysis may stimulate serum GH elevation. However,since no consistent systematic relationships between GH
and lactate/NOR were observed, a combination ofanaerobic factors such as local ischemia and/or local
accumulation of lactate in legs induced by the restrictionof muscle blood supply may stimulate peripheral aﬀerent nerves, then resulting in enhancement of GHreleasing hormone secretion and/or inhibition ofsomatostatin release from the pituitary gland (Glustina
and Veldhuis 1998; Godfrey et al. 2003). Kaatsu by itself, in the absence of exercise, failed to induce any signiﬁcant GH secretion in healthy males (data not shown),suggesting that exercise is also required. The greater
GH secretion during Kaatsu exercise may be fromaﬀerents originating in fast twitch skeletal muscle ﬁbers(Gosselink et al. 1998) since fast twitch ﬁbers have beenreported to be recruited preferentially during Kaatsu
resistance exercise (Yasuda et al. 2004) or underdynamic ischemic training (Nygren et al. 2000). Thesemechanisms are speculative and further studies areneeded to clarify the basic mechanisms of GH releaseinduced by the Kaatsu exercise.

The IGF-1 as well as GH is involved in various
physiological roles such as cell growth and maintenanceof skeletal muscle. Heavy resistance exercise increases
serum concentration of IGF-1 as well as GH (Kraemer
et al. 1990), and we also showed that STLIRE with
Kaatsu increased plasma IGF-1 concentration. The
circulating GH stimulates synthesis and secretion of
IGF-1 within the muscle, but the time courses in thechanges of serum concentrations of GH and IGF-1 arequite diﬀerent. Thus, the possibility that the elevation of
IGF-1 observed in the present study is induced by theincrease in GH is unlikely.
We also provided new evidence that STLIRE with
Kaatsu increases serum VEGF concentration signiﬁcantly, compared to the control exercise. The increase in
VEGF was related to that in lactate. The VEGF has beenreported to increase immediately after a single bout of
exercise in both animals and humans (Breen et al. 1996;
Gustafsson et al. 2002). In addition, in healthy subjects,
exercise up-regulates the expression of VEGF messenger
RNA (mRNA) (Gustafsson et al. 1999; Amaral et al.
2001; Gavin and Wagner 2001; Gustafsson et al. 2002).
The underlying mechanisms have not been known exactly, but reduced oxygen tension and/or related metabolic consequences have been suggested as possible
stimuli. Hypoxia acts as a stimulus of VEGF secretionand production (Shweiki et al. 1992; Minchenko et al.
1994; Stein et al. 1995), and during exercise, local muscle
oxygen tension falls considerably (Richardson et al.
1995), suggesting that local muscle ischemia may act as a
stimulus of VEGF secretion in the exercise. Thus, it islikely that in STLIRE with Kaatsu, the reduced oxygen
tension and/or related metabolic consequences such as

72

lactate accumulation induced by the restriction of muscle
blood ﬂow may be involved in VEGF secretion. VEGF
has been known to play essential roles in exercise-induced angiogenesis (Amaral et al. 2001), proposing that
STLIRE with Kaatsu may be a method for rehabilitation
exercise to promote angiogenesis. Further clinical studies
are needed to clarify this possibility.
It has been known that moderate to heavy resistance
exercise markedly increases BP (Kilbom and Brundin
1976: Bosisio et al. 1980; Bezucha et al. 1982; Lewis et al.
1983). Heavy leg extension exercise appears to be a
predominately dynamic type of exercise, but it has asubstantial static component (Miles et al. 1987). During
a static exercise, there is a rise in BP caused by an increase in CO, which is due to an increase in HR (Helfant
et al. 1971; Perez Gonzalez 1981). In STLIRE with
Kaatsu, CO increased without signiﬁcant changes in
TPR. The SV rather decreased by about 12%, as compared to control exercise, which was thought to be dueto the reduction of venous return pressure-applied by the
Kaatsu belt. Thus, the increase in BP was largely
dependent on the increase in CO due to a signiﬁcant
increase in HR, but not SV. Therefore, the increase in
BP observed in our exercise was typical of an exercise
with a static component. The inhibition of venous return
during STLIRE with Kaatsu can reduce cardiac preload
during the exercise, which may be useful in rehabilitation in patients with cardiac diseases.
The GH and IGF-1 have been also established as aregulator of cardiac growth, structure, and function(Lombardi et al. 1997; Khan et al. 2002), and GH has
been recently applied for the treatment of congestive
heart failure (Fazio et al. 1996; Genth-Zots et al. 1999).
The STLIRE when combined with Kaatsu appears to bea useful method to induce signiﬁcant exercise-induced
GH responses (EIGHR), while exercise at the same
intensity but without Kaatsu fails to induce it. It remains
unclear whether EIGHR can improve cardiac function
in a similar manner to GH therapy (Fazio et al. 1996;
Genth-Zots et al. 1999). However, GH has been also
well known to increase serum IGF-1 production, which
may also improve cardiac function, but further clinical
trials are needed to clarify this possibility.
In conclusion, STLIRE with Kaatsu signiﬁcantly
stimulates the exercise-induced GH, IGF, and VEGF
responses with the reduction of cardiac preload during
exercise, which may become a unique method for rehabilitation in patients with cardiovascular diseases.

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Scand J Med Sci Sports 2012: ••: ••–••
doi: 10.1111/j.1600-0838.2012.01489.x© 2012 John Wiley & Sons A/S

Effects of low-intensity, elastic band resistance exercise combinedwith blood flow restriction on muscle activation
T. Yasuda1, K. Fukumura1, T. Fukuda1, H. Iida1, H. Imuta1, Y. Sato2, T. Yamasoba1, T. Nakajima1
Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2Department of Basic Sciences in Medicine, Kaatsu
International University, Battaramulla, Sri Lanka
Corresponding author: Tomohiro Yasuda, PhD, Department of Ischemic Circulatory Physiology, Graduate School of Medicine, The
University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81 3 5800 9176, Fax: +81 3 5800 9177, E-mail:yasuda-tomohiro@umin.ac.jp

1

Accepted for publication 16 May 2012

We examined the effects of blood flow-restricted, lowintensity resistance exercise (termed kaatsu) using anelastic band for resistance on muscle activation. Nine men
performed triceps extension and biceps flexion exercises(four sets respectively) using an elastic band for resistance with blood flow restriction (BFR) or CON (unrestricted blood flow). During a BFR session, subjects worepressure cuffs inflated to 170–260 mmHg on the proximal
region of both arms. Surface electromyography (EMG)
was recorded from the triceps brachii and biceps brachii
muscles, and mean integrated EMG (iEMG) was analyzed. Blood lactate concentration was obtained before(Pre) and immediately after two exercises (Post). During

triceps extension and biceps flexion exercises, muscle activation increased progressively (P < 0.05) under BFR(46% and 69%, respectively) but not under CON (12%and 23%, respectively). Blood lactate concentration at
Post was higher (P < 0.05) under BFR than under CON(3.6 and 2.1 mmol/L, respectively). Blood lactate concentration at Post was significantly correlated with increased
iEMG in both triceps extension (r = 0.65, P < 0.01) andbiceps flexion exercises (r = 0.52, P < 0.05). We conclude
that kaatsu training using elastic bands for resistanceenhances muscle activation and may be an effective
method to promote muscle hypertrophy in older adults or
patients with a low level of activity.

Age-related skeletal muscle loss (sarcopenia) inhibits
mobility and increases the risk of developing several
diseases such as diabetes, osteoporosis, and heart disease(Visser et al., 2002; Guillet & Boirie, 2005). Highintensity resistance training can induce muscle hypertrophy and improve insulin resistance and type-2 diabetes
in the elderly (Frontera et al., 1988; Fiatarone et al.,
1990; Dunstan et al., 2002), suggesting that highintensity resistance training leads to prevention and/or
improvement of sarcopenia in the elderly. However, theuse of heavy weights with weight machines/free weights
required for muscle adaptation with traditional resistance exercise may not be practical and may even be
dangerous when carried out without proper supervision.
Thus, the effectiveness of alternative exercise methods
should be investigated.
Elastic bands/tubing have been used widely in rehabilitative medicine and in health enhancement for resistance training (Zion et al., 2003; Ribeiro et al., 2009;
Colado et al., 2010). A previous study reported that ahome-based resistance training program for older adults
using elastic bands could serve as a practical and effective means of improving muscle strength (Mikesky et al.,1994). Elastic bands are also portable and are less expen-

sive and easier to use than weight machines/free weights.
Elastic resistance training has thus been shown to be afeasible alternative to high-intensity resistance training(Colado & Triplett, 2008; Ribeiro et al., 2009; Andersen
et al., 2010). However, as elastic resistance training iscommonly performed at a low-to-moderate intensity
level, this training typically has little or no effect onmuscle hypertrophy (Mikesky et al., 1994; Hostler et al.,
2001; Colado & Triplett, 2008).
In the past decade, several studies have reported thatmuscle hypertrophy can be produced with low-intensity
resistance training [20–30% one-repetition maximum(1RM)] combined with muscular blood flow restriction(BFR), termed “kaatsu training,” regardless of age(Takarada et al., 2000, 2002; Abe et al., 2005; Fujita
et al., 2008). Kaatsu training is also a potentially useful
method for promoting muscle hypertrophy with a low
risk of injury (Nakajima et al., 2006; Madarame et al.,2010; Loenneke et al., 2011; Ozaki et al., 2011). Elastic
resistance training with BFR may thus be an effective
home-based resistance training program for promoting
both muscle strength and hypertrophy. The mechanism
by which BFR potentiates the training effect of lowintensity resistance training remains obscure but appears

1Yasuda et al.

Fig. 1. Illustrations show the body position used for exercises. Triceps extension (a) and biceps flexion (b) were performed with anelastic band.

to be related, in part, to an increase in muscle activation(Moritani et al., 1992; Takarada et al., 2000; Yasuda
et al., 2008, 2009). The purpose of this study was thus to
examine the effect of combined BFR and elastic band
resistance exercise on muscle activation.
Methods
Subjects
Nine healthy men aged 23–41 years with resistance training experience volunteered for the study. All subjects received a verbal andwritten description of the study and provided written, informed
consent prior to participating in the study. The study was approvedby the Ethics Committee of the University of Tokyo.

ProtocolOne week prior to experiments, all subjects completed an orientation session, which included measurement of resting blood pressure, range of motion (ROM), and familiarization with the elastic
band exercises and BFR. During the orientation session, subjects
sat in a chair with the testing arm placed on a table at heart level,and blood pressure was measured after a 3-min rest. The constancyof elbow joint ROM was calculated from coefficients of variation(CVs) of the mean angle values obtained during each exercise. In
both triceps extension and biceps flexion exercises, the ROM offive repetitions was averaged to represent a single datum in eachcase. The CVs (n = 9) for ROM were 2.2% for triceps extension
and 2.6% for biceps flexion exercises.
In an experimental session, subjects performed bilateral triceps
extension and biceps flexion exercises with or without BFR. Subjects participated in two experimental sessions (i.e., one with BFR
and the other without) that were scheduled 1 week apart. The orderof exercises was randomized. Subjects were instructed to refrainfrom ingesting alcohol and caffeine for 24 h before the experimental sessions and from any strenuous exercise for 48 h before thesessions.

Exercises
During triceps extension exercise, subjects were seated comfortably on a rowing chair with the body supported in the vertical2

position (Fig. 1a). Elbow joint ROM during the exercise wasapproximately 140–10° (with 0° being full extension). During
biceps flexion exercise, subjects were seated comfortably on achair (Fig. 1b). Elbow joint ROM during the exercise was approximately 45–140° (with 0° being full extension). Both exercises
were performed using an elastic band. The exercise duration was
2.4 s and included a 1.2-s concentric and 1.2-s eccentric exercise
cycle controlled by a metronome (50 beats/min). The exercise
session (30 repetitions followed by 3 sets of 15 repetitions, with
30 s between sets and exercises) was determined by reference tothe previous studies (Yasuda et al., 2008, 2009).

BFR
In an orientation session, all subjects were trained to wear pressure
cuffs (30-mm width; Kaatsu-Master, Sato Sports Plaza, Tokyo,
Japan) at the most proximal region of both arms. The restriction
pressure intensity of the cuffs (170–260 mmHg) was determinedby ratings of perceived exertion (RPE) in the final set of two
exercises because previous EMG studies using free weights
showed that the value of RPE reached 17–18 in the same exercise
protocol (Yasuda et al., 2008, 2009).
Prior to exercise with BFR, subjects were seated on a chair andthe kaatsu arm cuff was tightened around the arm to a belt pressureof 40 mmHg. The cuff was then inflated to a pressure of
100 mmHg for 30 s and then deflated for 10 s. This procedure wasrepeated, increasing the inflation pressure 20–40 mmHg each time
until the final cuff restriction pressure of 170–260 mmHg wasachieved. Once the cuffs were inflated, they remained so for theentire experimental session, including rest periods between sets
and exercises.

Electromyography (EMG)
The skin was shaved, abraded with a skin preparation gel (Skinpure, Nihon Kohden, Tokyo, Japan), and cleaned with alcohol
wipes. During the experiment, skin impedance was less than 2 kW.
The ground electrode was positioned on the lateral epicondyle.
Bipolar (1-cm center-to-center) surface EMG (sEMG) electrodes(Ag/AgCl; Vitrode F; Nihon Kohden) were placed along the longitudinal axis of the triceps brachii and biceps brachii of the left
upper arm. The electrode placements on the triceps brachii andbiceps brachii were both at 60% of the upper arm limb length,

Blood flow restriction and elastic band
respectively. EMG signals were recorded and collected on a personal computer (T7300 Macintosh, Apple, Tokyo, Japan) for subsequent analysis. All EMG signals were digitized at a sampling
rate of 1024 Hz with a bandwidth of 0 Hz–500 kHz (AB 6216;
Nihon Kohden). To determine integrated EMG (iEMG), signals
were fully rectified and integrated (Power Lab Chart 5 software,
ADInstruments, Nagoya, Japan). During the experimental session,sEMG was recorded continuously, and each repetition was analyzed individually for iEMG. Each iEMG value was divided into
groups of five successive repetitions, and the average for eachgroup of five repetitions was represented as a single data point for
statistical analysis. To determine the iEMG ratio of agonist
muscles, iEMGs during each exercise was normalized to Pre,
which was iEMG without BFR before the first set of each exercise.

Relative exercise intensity
To determine the relative exercise intensity of performing thetriceps extension and biceps flexion exercises using the “extraheavy” bands (i.e., Blue Thera-Bands; Hygenic Corporation;
Akron, Ohio, USA), the iEMGs for the band exercises were compared to the iEMGs of the same exercises using free weights at
predetermined relative exercise intensities (i.e., 10%, 20%, 30%,
40%, and 50% of 1RM). Measurements were also made with thesame elastic band (three to five repetitions) on another experimentday. The order of exercises and loadings was randomized for eachindividual.

Blood lactate concentration
With subjects rested in a seated position, venous blood samples(15–50 mL) were taken from the antecubital vein at baseline (Pre).
Immediately following two exercises, the pressure cuff wasquickly removed, and blood samples were obtained at 0 (Post) and15 min (Post-15) after the two exercises. All samples were analyzed with a rapid lactate analyzer (Lactate Pro, Arkray, Kyoto,
Japan).

Heart rate
Heart rate was measured at baseline (Pre) and immediately
after the last set of each exercise (Post) with a heart ratemonitor (Marquette Dash 3000 Patient Monitor, GE, Milwaukee,
Wisconsin, USA).

RPE
RPE was measured using the Borg scale immediately after the last
set of each exercise (Post) (Borg, 1973).

Statistical analysis
Results are expressed as mean ⫾ standard deviation (SD). A
two-way analysis of variance with repeated measures(condition ¥ time) was used to evaluate the training effects for all
dependent variables. Post-hoc testing was performed using
Tukey’s technique when appropriate. All calculations were madewith JMP statistical software package v.8.0 (SAS Institute Inc.,Tokyo, Japan). Pearson’s product correlation was performed todetermine the relationship between change in iEMG and blood
lactate concentration or RPE. Statistical significance was set at
P < 0.05.

Results
Descriptive characteristics for the subjects are shownin Table 1. None of the subjects had high systolic

Table 1. Descriptive characteristics of nine male subjects

Variable

Mean

SD

Range

Age (years)
Height (cm)Weight (kg)Resting BP (mmHg)
Systolic BP
Diastolic BP
ROM (o)Triceps extension
Biceps flexion
Relative exercise intensity (% 1RM)
Triceps extension
Biceps flexion

29.6
174.7
72.3

7.1
4.4
8.7

23–41
166–180
61–88

117.8
71.8

13.2
8.3

96–127
59–84

119.0
93.4

11.9
10.1

105–144
81–109

15.0
19.9

8.3
6.7

6.0–27.6
10.2–33.6

1RM, one-repetition maximum; BFR, blood flow restriction; BP, bloodpressure; ROM, range of motion; SD, standard deviation.

(ⱖ130 mmHg) or diastolic (ⱖ85 mmHg) blood pressure. During the first five repetitions of each exercise,mean exercise intensity according to normalized iEMG
was approximately 15% of 1RM for triceps extension
and approximately 20% of 1RM for biceps flexion(Table 1).
Figure 2 shows representative EMG traces during
BFR exercises. During the two exercises, all subjects
maintained and completed all the prescribed exercises.
During triceps extension exercise, iEMG increased(P < 0.05) progressively during exercises under BFR(approximately 46%) and was greater (P < 0.05) than
CON under BFR in the last set (Fig. 3a). In biceps
flexion exercise, there was a progressive increase(P < 0.05) in iEMG with BFR (approximately 69%),
such that iEMG was greater (P < 0.05) under BFR vs
CON from the second to the last set (Fig. 3b). No significant changes in muscle activation were observed
under CON during triceps extension (approximately
12%) and biceps flexion exercises (approximately 23%).
At baseline, CON and BFR sessions produced no differences (P > 0.05) in blood lactate concentration(1.0 ⫾ 0.1 and 1.0 ⫾ 0.2 mmol/L, respectively) or heart
rate (67.4 ⫾ 9.6 and 66.0 ⫾ 9.2, respectively). Bloodlactate concentration increased (P < 0.05) in both exercises. Blood lactate concentration at Post was higher(P < 0.05) under BFR than CON (3.6 and 2.1 mmol/L,
respectively). Blood lactate concentration remained
elevated at Post-15 under BFR, but not under CON (1.8
and 1.2 mmol/L, respectively). Following the triceps
extension and biceps flexion exercises, heart rate wasgreater (P < 0.05) under BFR (99 ⫾ 20/min and109 ⫾ 22/min, respectively) than CON (87 ⫾ 15/min
and 92 ⫾ 15/min, respectively), and RPE was greater(P < 0.01) under BFR (17.4 ⫾ 1.6 and 18.7 ⫾ 0.9,
respectively) than CON (12.9 ⫾ 1.6 and 14.6 ⫾ 1.2,
respectively).
Blood lactate concentration at Post was significantly
correlated with increased iEMG in both exercises(Fig. 4). Following each exercise, iEMG was correlated

3

Yasuda et al.

Fig. 2. Representative electromyography tracings from an experimental session with blood flow restriction. The exercises performed
were triceps extension and biceps flexion was performed against elastic band resistance. The experimental session consisted of four setsof each exercise. The time line indicates the time spent performing each exercise and the 30-s rests in between. The total length of theexperimental session was 9.5 min.

Fig. 3. Integrated electromyography (iEMG) ratio of triceps brachii and biceps brachii muscles during triceps extension (a) and biceps
flexion (b) for each set performed. Pre was iEMG without blood flow restriction (BFR) before the first set of each exercise. *Difference
from Pre, P < 0.05. ¶Difference from CON, P < 0.05.

with RPE in triceps extension (r = 0.60, P < 0.01) andbiceps flexion exercises (r = 0.68, P < 0.01).
Discussion
Muscle activation has been shown to increase duringlow-load exercise with BFR (Takarada et al., 2000;

4

Yasuda et al., 2008, 2009). However, it was unknown
whether increased muscle activation could be achieved
during BFR exercise using an elastic band. Our findings
show that muscle activation increased progressively in a
BFR session when exercises were performed at a lowintensity level (approximately 20% 1RM) using an

Blood flow restriction and elastic band

Fig. 4. Relationships between integrated electromyography(iEMG) ratio of agonist muscles for each exercise and blood
lactate immediately after two exercises.

elastic band for resistance. This result was similar to
those in the previously reported studies using freeweights (Yasuda et al., 2008, 2009).
In our study, blood lactate concentration increased
following BFR exercise and was correlated withincreased muscle activation in both triceps extension andbiceps flexion exercises. Previously, it was suggested
that greater muscle activation during low-intensity
resistance exercise with BFR may have taken place tocompensate for a deficit in force development secondary
to changes in energy supply (Bigland-Ritchie et al.,
1986; Moritani et al., 1986). In addition, venous blood
oxygen saturation, oxygen partial pressure, carbon
dioxide, accumulation of blood lactate concentration,and hydrogen ions are significantly changed following
BFR exercises (Takarada et al., 2000; Yasuda et al.,2010), indicating that these changes could potentiallystimulate muscle activation (Leonard et al., 1994). Taken
together, these results suggest that BFR combined withelastic band exercise changes blood flow, energy supply,and venous occlusion sufficiently to induce an increasein muscle activation. A BFR exercise-induced increase inmuscle activation may be one important factor in themuscle hypertrophy seen in active muscle following
low-intensity resistance training with BFR in previous
studies (Takarada et al., 2000; Yasuda et al., 2008, 2009).
Consequently, the results of our study, together withthose of the previous studies, suggest that BFR training

using an elastic band as well as weight machines/freeweights leads to significant muscle hypertrophy.
In general, because elastic resistance training is performed at a low-to-moderate intensity level, the training
program is designed to be a high repetition form of
training. Consequently, most studies have demonstrated
that muscle strength and endurance capacity can be
improved following elastic resistance training (Mikesky
et al., 1994; Rogers et al., 2002; Colado et al., 2010). At
the same time, elastic bands produced less muscle hypertrophy than weight machines (Colado & Triplett, 2008).
Elastic resistance training also induced minor changes inmuscle fiber size and fiber-type composition comparedwith high-intensity resistance training (Hostler et al.,2001). Thus, low-intensity elastic resistance training
combined with BFR may be an effective training
program for promoting muscle hypertrophy in practicalapplications.
Previous studies have demonstrated that elastic resistance training is well tolerated, as indicated by nonexacerbation of chronic disease conditions and lack oftraining-induced injury (Mikesky et al., 1994; Zion
et al., 2003). Home-based resistance training usingelastic bands has therefore been used widely for older
adults and for patients with a lower level of activity(Aniansson et al., 1984; Mikesky et al., 1994; Rogers
et al., 2002; Zion et al., 2003; Colado & Triplett, 2008;
Colado et al., 2010). In the present study, the cuff pressure (170–260 mmHg) produced near exhaustion in subjects, as reported previously (Yasuda et al., 2008, 2009)
because increased iEMG during BFR exercise wasrelated to a high value of RPE. Consequently, highvalues of RPE were observed in both triceps extension
and biceps flexion (17.4 and 18.7, last set, respectively).
However, because RPE was generally lower in BFR
exercises (14.9–15.8, last set) vs high-intensity resistance exercise (17.6–18.7, last set), there were no incidents of any pain reported in kaatsu training (Yasuda
et al., 2010, 2011). Although kaatsu training is performed with restricted venous blood flow and pooling ofblood in the extremities, it has no impact on blood clotting function as assessed by changes in fibrin d-dimer
and fibrin degradation products after exercise or training(Madarame et al., 2010; Clark et al., 2011). Furthermore, serious side effects of kaatsu training have notbeen reported in approximately 13 000 people, including older adults (>80 years old) and patients withvarious physical conditions (Nakajima et al., 2006). All
these findings suggest that elastic resistance training
with BFR is a relatively safe training method, but itshould be noted that a potential for adverse effects
exists, especially when subjects perform until near orcomplete exhaustion.
Two limitations of this study should be mentioned.
First, the material properties of an elastic band are an
important variable for determining exercise intensity.
Previous studies reported that increase in muscle

5

Yasuda et al.
activation depends on the resistance level and stretch
distance of the elastic band/tubing during exercise(Mikesky et al., 1994; Patterson et al., 2001; Andersen
et al., 2010). However, the type of band used in ourstudy (Blue, Thera-band) presented the same resistancelevel, and elbow joint ROM was defined arbitrarily.
There were consequently large individual differences in
the relative exercise intensity.
Second, cuff pressure intensity (170–260 mmHg) forarms was higher than that in the previous studies (Takarada et al., 2000; Yasuda et al., 2008, 2010, 2011), as
discussed earlier. In this study, relative exercise intensities during triceps extension and biceps flexion (15.0%
and 19.9%, respectively) were lower than those in previous EMG studies (20% 1RM; Yasuda et al., 2008,2009). Furthermore, because the same elastic band wasused for all subjects, there were large differences
between individuals in the relative exercise intensity. In
the biceps flexion exercise, cuff pressure intensity was
negatively correlated with relative exercise intensity(r = -0.80, P < 0.05). Taken together, we speculate that ahigh level of cuff pressure intensity is required during
BFR training at low intensity; as a result, the potential
for adverse effects is increased. More work is needed tounderstand how BFR training using an elastic band
would be advantageous for developing safe and effective
methods of promoting muscle hypertrophy in older
adults, and especially in patients capable of tolerating
only low-load resistance exercise.

Perspective
Blood flow-restricted, low-intensity resistance exercise(kaatsu training) using machines/free weights leads toincreased muscle activation, the response to which is an
important factor in muscle hypertrophy. However, as anelastic band is inexpensive, compact, and easy to use
compared with machines/free weights, elastic band
resistance training could be used in home-based training
programs for older subjects or for patients with a lower
level of activity. As in previous BFR studies using
machines/free weights, our results suggest that lowintensity, elastic band resistance exercise combined with
BFR enhances muscle activation. Kaatsu training usingelastic bands may therefore be an effective method topromote muscle hypertrophy in older adults or inpatients capable of tolerating only low-load resistance
exercise.
Key words: vascular occlusion, kaatsu, elastic band,
EMG, upper limb.

Acknowledgements
The authors thank the students who participated in this study. We
also thank Mr. Takayuki Ohtsuka, Mr. Yusuke Uchida, and Mr.
Yugo Chujo (The University of Tokyo) for the technical support.
This study was supported, in part, by Grant-in-Aid (No. 23700713
to T. Y.) from the Japan Ministry of Education, Culture, Sports,
Science, and Technology.

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7

Scand J Med Sci Sports 2013: ••: ••–••
doi: 10.1111/sms.12087© 2013 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd

Muscle size and arterial stiffness after blood flow-restricted
low-intensity resistance training in older adults
T. Yasuda1, K. Fukumura1, T. Fukuda1, Y. Uchida1, H. Iida1, M. Meguro1, Y. Sato2, T. Yamasoba1, T. Nakajima1
Department of Ischemic Circulatory Physiology, University of Tokyo, Tokyo, Japan, 2Department of Basic Sciences in Medicine,
Kaatsu International University, Battaramulla, Sri Lanka
Corresponding author: Tomohiro Yasuda, PhD, Department of Ischemic Circulatory Physiology, Graduate School of Medicine, The
University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81 3 5800 9176, Fax: +81 3 5800 9177, E-mail:yasuda-tomohiro@umin.ac.jp

1

Accepted for publication 30 April 2013

Previous studies have shown that blood flow-restricted
low-intensity resistance training (BFR-RT) causes muscle
hypertrophy while maintaining arterial function in young
adults. We examined the effects of BFR-RT on muscle size
and arterial stiffness in older adults. Healthy subjects(ages 61–84 years) were divided into BFR-RT (n = 9) or
non-training control (CON; n = 10) groups. The BFR-RT
group performed 20% and 30%, respectively, of onerepetition maximal (1-RM) knee extension and leg press
exercises, 2 days/wk for 12 weeks. The BFR-RT groupwore elastic cuffs (120–270 mmHg) on both legs during
training. Magnetic resonance imaging-measured muscle
cross-sectional area (CSA), 1-RM strength, chair stand(CS) test, and cardio-ankle vascular index testing (CAVI),an index of arterial stiffness, were measured before and
3–5 days after the final training session. Muscle CSA of
the quadriceps (8.0%), adductors (6.5%), and gluteus
maximus (4.4%), leg extension and leg press 1-RM
strength (26.1% and 33.4%), and CS performance(18.3%) improved (P < 0.05) in the BFR-RT group, but
not in the CON group. In CAVI testing, there were nochanges in both two groups. In conclusion, BFR-RT
improves muscle CSA as well as maximal muscle
strength, but does not negatively affect arterial stiffnessor humeral coagulation factors in older adults.

Age-related skeletal muscle loss (sarcopenia) inhibits
mobility and increases the risk of developing several
diseases such as diabetes, osteoporosis, and heart disease(Visser et al., 2002; Guillet & Boirie, 2005). Highintensity resistance training (HI-RT) can induce muscle
hypertrophy and improve insulin resistance and type-2
diabetes in the elderly (Frontera et al., 1988; Fiatarone
et al., 1990), suggesting that HI-RT leads to the prevention and/or improvement of sarcopenia in the elderly(Aagaard et al., 2010). However, HI-RT induced about a
20% reduction in arterial compliance in young and older
adults (Miyachi et al., 2003, 2004). In general, reductions
in arterial compliance or increases in arterial stiffness
reduce the arterial buffering function of the pulsation ofblood pressure and blood flow, which contribute to elevations in systolic blood pressure, left ventricular hypertrophy, coronary ischemic disease, and reductions in arterialbaroreflex sensitivity (O’Rourke, 1990; Tanaka et al.,
1998; Monahan et al., 2001). This means that prevention
and treatment of arterial compliance or stiffness are also
important. Thus, even if traditional HI-RT is an effective
tool in reversing sarcopenia and/or osteoporosis, this typeof training may have deleterious effect on arterial compliance or stiffness in older adults.

In the past decade, several studies have reported
that low-intensity resistance training combined withblood flow restriction (BFR-RT), referred to as“KAATSU Training,” elicits muscle hypertrophy andstrength gains similar to those elicited during traditional HI-RT (Takarada et al., 2000; Wernbom et al.,2008; Karabulut et al., 2010). Additionally, previous
studies have reported that BFR-RT could improve
and/or maintain arterial compliance in young adults(Ozaki et al., 2011, 2013). Therefore, BFR-RT may be
a useful method for promoting muscle hypertrophy
with a low risk of increased arterial stiffness in older
adults.
Recently, some studies have demonstrated that sarcopenia is muscle specific and greater quadriceps muscle
loss was found in older adults (Miyatani et al., 2003;
Abe et al., 2011). However, no previous studies haveexamined the effect of BFR-RT on lower body muscle
size in older adults, and only a single study has investigated changes in skeletal muscle size with BFR-RT in
older adults (Takarada et al., 2000). Thus, the purpose of
the present study was to examine the effects of BFR-RT
on thigh muscle size and arterial stiffness in older
adults.

1

Yasuda et al.
Methods

Blood flow restriction

Participants

During the training sessions, subjects wore a specially designed
elastic pressure cuff (50 mm width, KAATSU Master, Sato Sports
Plaza, Tokyo, Japan) around the most proximal portion of the bothlegs. On the first day of training, the cuff was set at 120 mmHg.
The pressure was increased by 10–20 mmHg at each subsequent
training session until a pressure of approximately 270 mmHg wasreached. The restriction pressure was selected in accordance withprevious studies (Yasuda et al., 2012a). Immediately after the two
exercises, the pressure cuff was quickly removed. The amount oftime under moderate blood flow restriction was approximately
11 min.

Twenty-one older men and women (aged 61–84 years) volunteered to participate in the study and were selected according to the
exclusion criteria used to define “medically stable” older participants for exercise studies proposed by Greig et al. (1994). In
addition, volunteers who suffered from a chronic disease such as
severe hypertension, orthopedic disorders, deep venous thrombosis, peripheral vascular disease, or cognitive dysfunction were
excluded from the study. None of the participants had participatedin resistance-type training for a minimum of 3 years prior to thestudy. All participants were free of overt chronic disease as
assessed by medical history, physical examination, and complete
chemistry and hematologic evaluation. Subjects in the nontraining control (CON) group continued their daily physical activity, but no additional exercise routine was imposed. All
participants were informed of the risks associated with themethods, procedures and risks, and signed an informed consent
document before participation. The principles of the World
Medical Association Declaration of Helsinki and the American
College of Sports Medicine Guidelines for Use of Human Subjects
were adopted in this study. Twenty-one individuals (5 men, 16
women) enrolled in the study, but two participants dropped out
following randomization to the BFR-RT group because of reasons
unrelated to the research study. Consequently, 19 participants wererandomized to either the BFR-RT group {3 men, 6 women: n = 9;age [mean ⫾ standard deviation (SD) ]: 71.3 ⫾ 7.1 years} or the
CON group (2 men, 8 women: n = 10; age: 67.7 ⫾ 6.0 years).

Training protocol
To develop the thigh muscles especially for quadriceps muscles,
the participants in the BFR-RT group performed bilateral knee extension and leg press exercise training 2 days/week for 12 weeks. This
training was performed under the close supervision of those withtechnical knowledge in BFR training. One week before the start of the
training study, both groups performed practice sessions for the functional ability test and one-repetition maximum (1-RM) test. In addition, BFR-RT participants were familiarized with the BFR stimulus.
Three or four days before training, the 1-RM of both exercises wasdetermined. Training intensity and volume were set at 20% or 30% of
1-RM and 75 repetitions (30, 20, 15, and 10 reps, with around 30-s
rests between sets, respectively) for knee extension and leg press
exercises (90-s rests between exercises), respectively. This protocol istypical of submaximal BFR studies (Abe et al., 2005; Yasuda et al.,2010, 2012b). Once the cuffs were inflated, they remained so for thetwo exercises, including rest periods between sets and exercises.
During knee extension and leg press exercises, participants wereseated comfortably on isotonic knee extension (13260, VR1, Cybex
International, Inc., Medway, Massachusetts, USA) and leg pressmachines (Pro 1 Seated Leg Press, Life Fitness, Schiller Park, Illinois,
USA), with the body supported in a vertical position. Knee joint rangeof motion (ROM) was approximately 90-0° and hip joint ROM wasmaintained at 110° (with 180° being full extension) during knee
extension exercises, while knee joint ROM and hip joint ROM wereapproximately 90-0° and 125-70°, respectively during leg press exercises. The exercise duration was 2.0 s (1.0-s concentric and 1.0-s
eccentric exercise cycle) for knee extension exercises and 2.6 s (1.3-sconcentric and 1.3-s eccentric exercise cycle) for leg press exercises.
During all training sessions, heart rate was recorded at baseline (pre)and immediately after the last set of each exercise (post; Model 9560,
Onyx II, Nonin Medical Inc., Plymouth, Minnesota, USA). Ratingsof perceived exertion, calculated on a scale (6–20) to measure subjective feelings of exertion and fatigue, were recorded immediately
after the last set of each exercise (Borg, 1982). The training loads ofeach exercise for the BFR-RT group were adjusted based on 1-RM
testing performed every 3 weeks.

2

Measurements schedule
Subject testing took place before the start of the study (pre) and
3–7 days after (post) the 12-week training period. The orders ofmeasurements were magnetic resonance imaging (MRI), venous
blood samples, arterial function [flow-mediated dilatation (FMD),
cardio-ankle vascular index testing (CAVI), and ankle brachialpressure index (ABI) ] tests, functional ability test, and 1-RM
strength measurements. The MRI measurement was obtained
between 11:00 and 12:00 h. Venous blood samples and arterial
function tests (after 6–7 h fast) or functional ability test and 1-RM
strength were determined on separate days (few days interval). The
subjects were instructed to refrain from ingesting alcohol andcaffeine for 24 h prior to pre- and post-training measurements.

MRI-measured muscle CSA
Muscle CSA was obtained using a MRI scanner (1.5-T MRI,
Hitachi, Tokyo, Japan). A T-1 weighted spin-echo axial plane
sequence was performed with a 540-ms repetition time and a 20-ms
echo time. Subjects rested quietly in the magnet bore in a supine
position with their legs extended. The top edge of the great trochanter was used as the origin point, and continuous transverse
images with 10-mm slice thickness (0-mm interslice gap) wereobtained from the top edge of the great trochanter to the lateralcondyle of femur at pre- and post-training measurements. All MRI
data were transferred to a personal computer for analysis using
specially designed image analysis software (sliceOmatic, Tomovision Inc., QC, Canada). Skeletal muscle tissue cross-sectional area
(CSA) data for the quadriceps, adductors and hamstrings at 50% of
thigh length (Fig. 1) and for the gluteus maximus at the top edge ofthe great trochanter were digitized. The coefficient of variation ofthis measurement was less than 1.0% (Yasuda et al., 2012b).

Estimation of 1-RM strength
One RM was estimated by the 10-RM method (Baechle & Earle,2008) using a weight stack machine. Bilateral knee extension andleg press maximum dynamic strength (1-RM) were assessed using
an isotonic knee extension (VR1, Cybex International, Inc.) andleg press machines (Seated Leg Press, Life Fitness). After
warming up, the testing load was set (approximately 80% of predicted 1-RM). Each subject reached muscular failure for the load,and partial repetitions (where participants failed to lift through theentire ROM) did not count as RMs. If a subject had to perform agiven repetition number for a given condition again, as a result ofease in obtaining the desired repetitions or failure to attain therepetition number, a 5-min rest period was given and the condition
was attempted again at an altered load. No participant had toperform a given repetition number test condition more than threetimes. Each participant performed the knee extension exercise,rested for 5 min, and then performed the leg press exercise. During
estimated 1-RM testing as well as training sessions, the parallel leg

Blood flow restriction and older adults
Pretraining

Posraining
Anterior

Anterior

Posterior

PosteriorFig. 1. Typical magnetic resonance images showing transverse sections of the thigh taken before (pre) and after (post) 12 weeks of leg
extensions and leg presses with blood flow restriction. The images show identical sections at the mid-thigh in the same subjects (YN).
stance width was set at 100% of the shoulder-width for leg press
exercises.

Arterial function tests
FMD, CAVI and ABI measurements were conducted in the supine
position. The participants were instructed to fast 6–7 h before
testing and refrain from ingesting alcohol, caffeine for at least 12 hprior to testing. After the participants were asked to rest in thelying position in a quiet, dark, air-conditioned room (23–25°C) for
5 min, a standard cuff was positioned around the right arm, 2–3 cm
below the antecubital fossa and their systolic and diastolic bloodpressures were assessed using oscillometric methods (UA-767PC,
A&D Co., Ltd, Tokyo, Japan). Then, after the participants had
rested again for at least 15 min in a supine position in the sameroom, endothelium-dependent FMD of the brachial artery wasmeasured using an established noninvasive method (Corretti et al.,2002). Using a 10-MHz linear array transducer probe, the longitudinal image of the right brachial artery was recorded at baseline
and then continuously from 30 sec before to at least 2 min after the
cuff deflation that followed syprasystolic compression (50 mmHg
above systolic blood pressure) of the right forearm for 5 min. The
diastolic diameter of the brachial artery was determined semiautomatically using an instrument equipped with software formonitoring the brachial artery diameter (UNEX EF, Unex Co. Ltd,
Nagoya, Japan). %FMD was calculated as reported previously(Tomiyama et al., 2008; Yeboah et al., 2009). Then, after a 20–30min rest, CAVI and ABI were measured noninvasively using a
VS-1500 system (Fukuda Denshi Co., Ltd, Tokyo, Japan). CAVI
was obtained by substituting the stiffness parameter into an equation for determining vascular elasticity (Shirai et al., 2006).

Blood sampling and biochemical analyses
Venous blood samples were obtained from the antecubital vein andmeasured for fibrin/fibrinogen degradation products (FDP),
d-dimer and creatine kinase (CK). The plasma concentrations ofthese samples were measured at a commercial laboratory (SRL
Inc., Tokyo, Japan) by following latex immunoassay for FDP andd-dimer and spectrophotometry for nicotinamide adenine dinucleotide phosphate formed by a hexokinase and d-glucose-6phosphate-dehydrogenase-coupled enzymic system for CK.

Functional ability test
A chair-stand test required participants to stand up from a seatedposition, as many times as possible, within 30 s (Rikli & Jones,
1990).

Statistical analyses
Results are mean ⫾ SD. Statistical analysis was performed by a
two-way analysis of variance (ANOVA) with repeated measures[trials (BFR-RT vs CON) ¥ time (pre vs post)]. Post-hoc testing
was performed using Tukey’s test when a significant F-value was
detected. Percent changes from pre were also compared between
groups using Tukey’s test. Statistical significance was set at
P < 0.05.

Results
Before training, there were no significant differences
between the two groups for age and anthropometric variables except for systolic blood pressure (Table 2). Afterthe training program, mid-thigh girth was increased(P < 0.01) in the BFR-RT group, but not in the CON
group (Table 1). There were no changes in body mass,
BMI and lower leg girth in both groups. During training
sessions in the BFR-RT group, heart rates were slightly
higher (P < 0.05) in the leg press exercise [118 ⫾ 18
beats per minute (BPM)] than in the knee extension(112 ⫾ 19 BPM) exercise. The ratings of perceived exertion tended to be higher (P = 0.09) in the knee extension
exercise (15.3 ⫾ 1.5) than in the leg press (14.3 ⫾ 1.8)
exercise. During both exercises, the participants did not
perform contraction efforts until exhaustion.
After 12 weeks of BFR training, CSA was increasedby 8.0% (pre, 44.0 ⫾ 9.5 cm2; post, 45.1 ⫾ 9.4 cm2) inthe quadriceps, 6.5% in the adductors (pre, 22.2 ⫾8.4 cm2; post, 22.6 ⫾ 8.2 cm2) and 4.4% in the gluteus
maximus (pre, 37.5 ⫾ 7.3 cm2; post, 39.8 ⫾ 4.4 cm2),
but not in the hamstrings (pre, 21.1 ⫾ 4.6 cm2; post,
21.1 ⫾ 4.1 cm2) in the BFR-RT group (Fig. 2A–D). In
the CON group, no change was observed in each muscle
CSA (pre, 43.5 ⫾ 9.5 cm2; post, 42.7 ⫾ 9.0 cm2 forquadriceps, pre, 21.2 ⫾ 8.6 cm2; post, 21.0 ⫾ 8.6 cm2
for adductors, pre, 19.9 ⫾ 3.6 cm2; post, 20.3 ⫾ 3.6 cm2for hamstrings and pre, 36.4 ⫾ 7.2 cm2; post, 35.6 ⫾7.5 cm2 for gluteus maximus; Fig. 2A–D). Knee extension and leg press 1-RM strength were also increased
26.1% (pre, 50 ⫾ 20 kg; post, 64 ⫾ 26 kg) and 33.4%(pre, 145 ⫾ 47 cm2; post, 191 ⫾ 56 kg) in the BFR-RT
group but not in the CON group (pre, 52 ⫾ 26 kg; post,
55 ⫾ 27 kg for knee extension and pre, 143 ⫾ 56 kg;
post, 142 ⫾ 51 kg for leg press; Fig. 3A,B).
There were no changes (P > 0.05) between pre- andpost-training in heart rate, systolic and diastolic blood3

Yasuda et al.
Table 1. Changes in anthropometric variables and skeletal muscle size after 12 weeks of training period

BFR-RT
Pre
Anthropometric variables
Age, years
Standing height, mBody mass, kg
BMI, kg/m2
Mid-thigh girth, cm
Lower leg girth, cm

CON
Post

71 (7)
1.61 (0.08)
53.9 (9.3)
20.8 (2.6)
44.0 (3.7)
33.7 (3.0)

54.0 (9.0)
20.9 (2.5)
44.7 (1.5)**
33.5 (3.1)

%

Pre

Post

%

0.4
0.4
1.5##
-0.7

68 (6)
1.58 (0.06)
53.4 (9.1)
21.3 (2.9)
46.5 (3.7)
34.0 (2.9)

53.4 (9.0)
21.3 (2.8)
46.3 (3.9)
33.9 (2.9)

0.1
0.1
-0.5
-0.4

Notes: Data are given as mean (⫾standard deviation). BFR-RT, blood flow-restricted resistance training; BMI, body mass index; CON, non-resistancetraining; mid-thigh girth, at 50% thigh length; lower leg girth, at 30% lower leg length. **P < 0.01, Pre vs Post; ##P < 0.01, BFR-RT vs CON.

(a)

(b)

Quadriceps
20

**

12
8
4
0

12
8
4
0

4

4

8

8

Hamstrings

(c)

*

16
Change in muscle CSA (%)

16
Change in muscle CSA (%)

Adductors
20

Gluteus maximus

(d)

8

16

*

0

4

8

Change in muscle CSA (%)

Change in muscle CSA (%)

12
4

8

4
0
4
8

12

12

Fig. 2. Percent changes in quadriceps (a), adductors (b), hamstrings, (c) and gluteus maximus (d) muscle cross-sectional area (CSA).
Data are given as mean (⫾standard deviation). **P < 0.01, *P < 0.05. Blood flow-restricted resistance training (filled symbols) vsnon-resistance training (unfilled symbols).

pressures, CAVI, ABI, FDP, d-dimer and CK for eithergroup; however, the BFR-RT group tended to improve(P = 0.09) in FMD, whereas the CON group did notchange (Table 2).
Chair-stand performance improved (P < 0.05) 18.3%
in the BFR-RT group (pre, 14.8 ⫾ 3.1 times; post,
17.4 ⫾ 4.2 times), but not in the CON group (pre,18.0 ⫾ 3.3 times; post, 18.4 ⫾ 3.9 times). The change inthe chair-stand test results correlated with the change inmuscle CSA for the quadriceps (r = 0.53, P < 0.05) andgluteus maximus (r = 0.50, P < 0.05), but not for the
adductors (r = 0.27, P > 0.05), as well as changes inmuscle strength for knee extension (r = 0.55, P < 0.05)
and leg press (r = 0.47, P < 0.05).

4

Discussion
It has previously been observed that BFR-RT leads toincreased muscle size and maintenance of arterial compliance in young adults (Ozaki et al., 2013). However,there are no published data investigating thigh muscle
size and arterial stiffness following BFR-RT in older
adults. Our findings show that low-intensity knee extension and leg press training with BFR can lead to a significant increases in thigh (quadriceps and adductors)
and hip (gluteus maximus) muscle CSA as well as
maximal contractile strength in older adults. In addition,
we observed no changes in hemodynamic parameters(heart rate, systolic and diastolic blood pressures), arte-

Blood flow restriction and older adults(a)Knee extension

(b)

40

Leg press
60**
Change in 1-RM strength (%)

Change in 1-RM strength (%)

**
30

20

10

0

50
40
30
20
10
0

Fig. 3. Percent changes in knee extension (a) and leg press (b) one-repetition maximal (1-RM) strength. Data are given as mean (⫾standard
deviation). **P < 0.01, Blood flow-restricted resistance training (filled symbols) vs non-resistance training (unfilled symbols).
Table 2. Changes in hemodynamic parameter, arterial function, coagulation system and muscle damage after 12 weeks of training period

BFR-RT

Heart rate, bpm
Systolic BP, mmHg
Diastolic BP, mmHg
CAVI, m/sec
ABI, unit
FMD, %
FDP, 10-5 g/L
D-dimer, 10-5 g/L
CK, IU/l

CON

Pre

Post

Pre

Post

62 (11)151 (15)##90 (9)
9.1 (1.4)
1.13 (0.07)
2.8 (2.0)
2.9 (1.1)
0.5 (0.4)
165 (145)

62 (8)
143 (20)#91 (11)9.0 (1.5)
1.15 (0.06)
4.4 (2.5)§
3.7 (3.0)
1.2 (1.6)
137 (63)

58 (7)
126 (10)79 (10)8.7 (0.8)
1.13 (0.10)
4.4 (1.8)
2.7 (0.7)
0.3 (0.3)
108 (53)59 (7)
121 (12)80 (12)8.5 (1.1)
1.13 (0.09)
3.9 (2.5)
3.0 (2.0)
0.4 (0.2)
115 (54)

Notes: Data are given as mean (⫾ standard deviation). BFR-RT, blood flow-restricted resistance training; CON, non-resistance training; BP, blood pressure;
CAVI, cardio-ankle vascular index; ABI, ankle-brachial pressure index; FMD, flow-mediated dilation; FDP, fibrin/fibrinogen degradation products; CK,
creatine kinase. ##P < 0.01, #P < 0.05, BFR-RT vs CON; §P, 0.09, Pre vs Post.

rial stiffness (CAVI), coagulation factors (FDP andd-dimer) and muscle damage (CK), suggesting that
BFR-RT was an useful method for preventing and/or
improving sarcopenia in old healthy adults.
In this study, BFR-RT (at 20–30% 1-RM) produced a
hypertrophic potential of 0.33% per session (8.0%
increase in quadriceps muscle CSA over 24 training sessions), which is similar to that observed following HI-RT
at 80% 1-RM (0.26–0.45%) in elderly adults (Frontera
et al., 1988; Fiatarone et al., 1990). Additionally, theobserved gains in knee extension and leg press 1-RM
strength (1.09% and 1.39% per session, respectively)
were comparable with the previous BFR-RT study(Karabulut et al., 2010) at 20% 1-RM (1.06% and 1.07%
per session, respectively), which thus appears equallyeffective as HI-RT at 80% 1-RM for improving thighmuscle strength in older adults. Therefore, our data suggested that BFR-RT (at 20–30% 1-RM) as well as HI-RT(at 80% 1-RM) can provide an effective hypertrophic
stimulus on selected thigh muscles in older adults.
Few studies have attempted to elucidate the cellularand molecular mechanisms of adaptation in skeletal
muscle as well as the cardiorespiratory system in
response to low-intensity BFR exercise (Manini &Clark, 2009). Previous studies demonstrated that a single
session of low-intensity (at 20% 1-RM) knee extension

exercise with BFR increased both vastus lateralis (VL)
muscle protein synthesis (40–50% at 3 h post-exercise)and the Akt/mammalian target of rapamycin (mTOR)
signaling pathway in young and older men (Fujita et al.,2007; Fry et al., 2010). These anabolic responses may
contribute significantly to BFR training–induced muscle
hypertrophy and strength gain. On the other hand, thesame laboratory using the same technique reported thathigh-intensity (at 70% 1-RM) knee extension exercise
increased VL muscle protein synthesis (48% at 2 h postexercise) through the mTOR pathway in young men(Dreyer et al., 2006). This means that increases in postexercise muscle protein synthesis are probably similar
between high-intensity resistance exercise and lowintensity BFR resistance exercise. Recently, Nielsen
et al. (2012) revealed that BFR-RT (23 training sessions)leads to marked proliferation of myogenic stem cells andresulting myonuclei addition in skeletal muscle, which isaccompanied by substantial myofiber hypertrophy.
Therefore, BFR-RT as well as HI-RT indicates that myogenic stem cell-derived myonuclei provides an improved
capacity for myofibrillar gene transcription, which islikely to contribute to an enhanced activity of muscle
protein synthesis.
Previous cross-sectional studies found that individuals
who performed HI-RT on a regular basis demonstrated

5

Yasuda et al.
lower levels of arterial compliance than their sedentary
peers (Bertovic et al., 1999; Miyachi et al., 2003). Consistent with the cross-sectional studies, 8–16 weeks of
HI-RT induced approximately 20% reductions in arterial
compliance (Miyachi et al., 2004). On the other hand,
our results show that arterial stiffness was maintained
following 12 weeks of BFR-RT in older adults. The
finding is consistent with previous observations of anunaffected arterial stiffness following BFR-RT in young
adults (Ozaki et al., 2013). It is not clear what physiological mechanisms explain the reduced arterial compliance following resistance training, but previous
HI-RT and BFR-RT studies reported that resistancetraining-reduced arterial compliance was associated withelevations of systolic arterial pressure during training
sessions (London & Guerin, 1999; Ozaki et al., 2013).
The training load, the number of repetitions, and the rest
time between sets during BFR training sessions weresimilar between this study and a previous BFR-RT study(Ozaki et al., 2013). Therefore, we speculate that themagnitude of change in blood pressure responses during
BFR exercise is an influencing factor for resistancetraining-induced arterial compliance in older adults aswell as young adults.
Recently Yoshizawa et al. (2009) demonstrated thatmoderate-intensity resistance training (at 60% 1-RM) did
not increase arterial stiffness in middle-aged women,
which may have great importance for health promotion
with resistance training. However, they did not mention
the changes for muscle size. In addition, the magnitude ofincrease in 1-RM leg press strength following training
period was less than one-half that reported for current
study (14.8 vs. 33.4%) although the training frequency
and period (2 days/week for a 12-week period) were same
between two studies. This means that moderate-intensity
resistance training is not enough method for preventing
and/or improving sarcopenia in old healthy adults.
Arterial compliance is influenced by vascular endothelial function (Wilkinson et al., 2004). In general, vascular endothelial cells play an important role in theregulation of vascular activity by producing vasoactive
substances such as nitric oxide (NO), but the endothelial
function is not improved by HI-RT (Okamoto et al.,2009). In this study, NO-dependent brachial artery FMD
tended to improve following BFR-RT. Moreover, a previous study demonstrated that NO production in muscle
is enhanced following BFR exercise (Larkin et al.,2012). Therefore, there is a high possibility that BFR-RT
has a beneficial effect on endothelial function, unlike
HI-RT. In this study, interestingly, brachial artery FMD
was tended to improve following leg exercise training.
This is in agreement with previous study showing thatcycle exercise improves brachial artery FMD (Schmidt
et al., 2002). Previously, Madarame et al. (2008) demonstrated that “cross-transfer” effect for the endogenous
anabolic hormones of blood flow-restricted muscles wasobserved in non-restricted muscles. These findings indi-6cate that a beneficial effect on endothelial function following BFR-RT could be expected to affect both blood
flow-restricted and non-restricted sites.
Previous studies reported that resistance training
increases muscle size and strength, and improves functional performance in daily tasks for older adults (Hunter
et al., 2001; Suetta et al., 2004; Bottaro et al., 2007;
Kryger & Andersen, 2007). Additionally, it is wellknown that knee extension muscle CSA and strength
play important role in the chair-stand performance forolder adults (Corrigan & Bohannon, 2001; Takai et al.,2009). In the present study, we showed that 12-week
BFR-RT led to improved chair-stand performance where
the magnitude of improvement was associated with thechange in the muscle CSA and strength for both thequadriceps and gluteus muscles, respectively. Recently,
Yoshioka et al. (2012) revealed that hip extensors(gluteus maximus, etc.) as well as knee extensors arefundamental muscles in the chair-stand task. Taken
together, the present improvement in the chair-stand task
likely was due to the observed increases in muscle sizeand strength for the quadriceps and gluteus maximus.
The present results showed that muscle hypertrophy
occurring not only in the thigh muscles directly affected
BFR, but also in the gluteus maximus muscle proximal tothe area directly affected by BFR. This finding is consistent
with that of previous investigations in young adults (Abeet al., 2005; Yasuda et al., 2010). The mechanisms behindtrunk (non-restricted blood flow) muscle hypertrophy following BFR-RT are not completely known, but have been
hypothesized to occur from an accumulation of metabolites
leading to increased muscle fiber recruitment (Yasuda
et al., 2009) and the “cross-transfer” effect for the growthof restricted-blood flow skeletal muscles (Madarame et al.,2008) in older adults as well as young adults.
Some potential limitations of this study may be mentioned. We measured CAVI, which reflects changes inboth central and peripheral muscle arterial compliance,
although previous studies measured central and/or
peripheral arterial compliance. Hence, more work isneeded to understand the relationship between BFR-RT
and arterial function.
In conclusion, low-intensity knee extension and legpress training with BFR elicited marked gains in thighmuscle CSA and strength, and did not negatively affectarterial stiffness in older healthy adults. Also, chair-standability was improved by this training, which may bemainly due to an increase in quadriceps and gluteus
maximus muscle size. Thus, our results demonstrated
that low-intensity resistance training with BFR was an
useful method for preventing and/or improving sarcopenia in old healthy adults.
Perspective
BFR-RT leads to improve lower body muscle sizeand strength and improve and/or maintain arterial

Blood flow restriction and older adults
compliance in young healthy adults. However, the effectof BFR-RT on lower body muscle size and arterial function in old healthy adults was unclear. As previous
BFR-RT studies in young healthy adults, our results suggested that BFR-RT (20–30% of 1-RM) could improvelower body muscle size and maintain arterial stiffness in
old healthy adults. Thus, BFR-RT is an useful method
for preventing and/or improving not only sarcopenia in
old healthy adults, but also disuse muscle atrophy inelderly patients capable of tolerating only low-load resistance training (i.e., multiple sclerosis patients, hip/knee
arthritis patients, etc).

Key words: sarcopenia, vascular occlusion, muscle
hypertrophy, arterial stiffness, strength.

Acknowledgements
The authors thank the participants who participated in this study.
We also thank Dr. Hideo Tsuneyoshi, Mr. Kei Hattori, Mr.
Hiroyuki Oka, Mr. Masahiko Tsuneki (Tokyo Hitachi Hospital),Dr. Nobuhiko Haga, Mr. Kazuhiko Yokota, Mr. Takayuki Ootsuka
and Mr. Yugo Chujo (The University of Tokyo) for technicalsupport. This study was supported, in part, by Grant-in-aid(#50227790 to TN and #23700713 to TY) from the Japan Ministryof Education, Culture, Sports, Science, and Technology.

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Eur J Appl Physiol
DOI 10.1007/s00421-014-3073-9

ORIGINAL ARTICLE

Effect of low‑load resistance exercise with and without blood flow
restriction to volitional fatigue on muscle swelling
Tomohiro Yasuda · Kazuya Fukumura · Haruko Iida ·Toshiaki Nakajima

Received: 5 February 2014 / Accepted: 2 December 2014
© Springer-Verlag Berlin Heidelberg 2014

Abstract
Purpose The effects on muscle swelling were compared
between low-load resistance exercise to exhaustion with
(BFR) and without blood flow restriction (NBFR).
Methods Ten young men [aged 27 (SD 5) years, standing height 1.74 (SD 0.05) m, body mass 70.3 (SD 4.3) kg]
performed 20 % of one repetition maximal dumbbell curl
exercise to exhaustion (four sets, rest intervals were 30 s
for BFR and/or 3 min for NBFR, respectively). One arm
was randomly chosen for BFR exercise and the other arm
performed NBFR exercise. During the BFR exercise session, an elastic cuff was worn proximally on the testingarm at 160 mmHg. Electromyography (EMG) signals wererecorded from surface electrodes placed on the biceps brachii muscle and analyzed for integrated EMG (iEMG).
Biceps brachii muscle thickness (MTH) was measured
using B-mode ultrasound.
Results The total number of exercise repetitions was
greater (p < 0.01) in NBFR (221 ± 67 reps) than in BFR(111 ± 36 reps). During the exercise session, iEMG for
biceps brachii muscles increased (p < 0.01) during BFR and
NBFR (3.94 and 4.45 times of baseline value). Immediately
after the exercise, MTH sharply increased (p < 0.01) with
BFR and NBFR (1.21 and 1.20 times of baseline value).
These results demonstrate that both BFR and NBFR exercises
lead to pronounced muscle activation and muscle swelling.
Conclusion Low-load resistance exercise to exhaustion is an effective method for promoting muscle swelling
Communicated by William J. Kraemer.
T. Yasuda (*) · K. Fukumura · H. Iida · T. Nakajima
Department of Ischemic Circulatory Physiology, Graduate Schoolof Medicine, The University of Tokyo, 7‑3‑1, Hongo, Bunkyo‑ku,
Tokyo 113‑8655, Japane-mail: yasuda‑tomohiro@umin.ac.jp

regardless of BFR. Furthermore, our data indicate that theincrease in muscle swelling for both NBFR and BFR is
maintained even 60 min after the exercise.
Keywords Muscle thickness · Electromyography ·Vascular occlusion · Biceps brachii · Metabolite
Abbreviations
1-RM	One repetition maximum
BFR	Blood flow restriction
HL	High-load resistance training
iEMG	Integrated electromyography
MTH	Muscle thickness
NBFR	No blood flow restriction

Introduction
In the past decade, numerous studies have reported that
low-intensity resistance training [20–30 % one-repetition
maximum (1-RM)] combined with blood flow restriction (BFR) elicits muscle fatigue and hypertrophy similar
to that induced by traditional high-load resistance training(HL, >70 % 1-RM), regardless of age (Abe et al. 2005;
Karabulut et al. 2010; Loenneke et al. 2012d; Takaradaet al. 2000; Yasuda et al. 2009, 2010a, 2014). BFR training
was originally developed in Japan and it is better known as
KAATSU training (Sato 2005). This technique may serveas an alternative training method to improve muscle sizeand strength in elderly patients who are capable of tolerating only low-load resistance training (i.e., multiple sclerosis patients, arthritis patients, etc.).
Recently, low-load (30 % 1-RM) resistance exercise tovolitional fatigue was reported to stimulate muscle protein
synthesis for a longer duration than HL (90 % 1-RM) or

13

Eur J Appl Physiol

work-matched resistance exercise (Burd et al. 2010). In
addition, Ogasawara et al. (2013) revealed that low-load(30 % 1-RM) bench press training to volitional fatigue
results in muscle hypertrophy similar to HL (75 % 1-RM)
bench press training. Therefore, there is a high possibility
that low-load resistance training to volitional fatigue is aneffective method for the promotion of muscle protein synthesis and hypertrophy, regardless of whether or not BFR isapplied.
Acute cell swelling has been shown to stimulate protein synthesis and suppress proteolysis (Berneis et al.
1999; Häussinger et al. 1993). A previous study showedthat increased leg circumference, an index of muscle
swelling, was more pronounced in BFR than in non-BFR
immediately after low-intensity knee extension exercise(Fry et al. 2010). Interestingly, following a single bout of
low-intensity BFR bench press exercise, acute changes inmuscle size were observed in both the blood flow restricted
triceps muscle as well as the blood flow non-restrictedchest muscle. The muscle cross-sectional area of both thetriceps and chest muscles increased following BFR benchpress training (Yasuda et al. 2010b). Therefore, it appears
that BFR training-induced muscle cell swelling may contribute significantly to the anabolic benefits of BFR (Loenneke et al. 2012a; Yasuda et al. 2012). However, previous
BFR or NBFR studies (Fahs et al. 2014; Martín-Hernández
et al. 2013; Yasuda et al. 2012) have only evaluated muscle
swelling at the beginning and end of the resistance exercise, giving no inference as to the time-course of change.
We hypothesized that low-load resistance training to volitional fatigue is an effective method for the promotion ofmuscle swelling regardless of BFR, and the time-course of
the increase in muscle swelling will be similar for both conditions. Thus, the purpose of the present study was to investigate the effect of low-load resistance exercise to volitional
fatigue with and without BFR on muscle swelling.

experience and performed upper body, but they were notprofessionally trained. Each subject was informed of therisks associated with the exercise, measurements to betaken and the purpose of the study, which conformed to
the Declaration of Helsinki and was approved by the Ethics Committee for Human Experiments, University ofTokyo. Written informed consent was obtained from eachsubject prior to participation.

Methods

Exercise

Subjects

The subjects performed four sets of arm curl exercise without BFR (NBFR, with 3 min rest period between sets) andwith BFR (with 30 s rest period between sets). In each
set of exercise, the subjects repeated the movements until
exhaustion, which was defined as failure to keep up withthe metronome. This protocol is typical of previously
reported BFR and NBFR studies (Kubo et al. 2006; Ogasawara et al. 2013). Exercise intensity was 20 % of the predetermined 1-RM. During each exercise condition, subjects
sat on the arm curl bench, with their arm positioned in frontof their body such that the shoulder was supported at 45°
flexion. The range of elbow joint motion during exercise
was completed from 0° to 150° (0° being full extension).

Ten healthy young men volunteered for the study. A priori sample size estimation indicated that eight subjects
would be needed to detect a group by time interaction
for measurements of muscle size with an effect size of
1.5–1.8, alpha level of 0.05, and a power of 0.80. Subjects
were excluded if they were hypertensive (blood pressure> 140/90 mmHg) or obese (BMI > 30 kg/m2). The subjects were classified as “recreationally active”; three of ten
participated in regular aerobic type exercises (jogging, or
cycling; 2–3 times/week for approximately 30 min). Threeother subjects had light to moderate resistance training

13

ProtocolOne week prior to experiments, all subjects completed anorientation session which included measurement of restingblood pressure and familiarization with arm curl exercise
and BFR. During the orientation session, subjects sat in achair with the testing arm placed on a table at heart level,and blood pressure was measured after 3 min rest. Then,
1-RM for each arm was determined. Subjects performed
5–6 unilateral arm curls with a low load (approximately
30–40 % predicted 1-RM) as a warm-up and to familiarize subjects with the arm curl exercise. After the warm-up
period, the intensity was set at about 80 % of predicted
1-RM. Following each successful lift, the intensity wasincreased by about 5 % until the subject could not complete
the lift through the entire range of motion. A test was considered valid only when the subject used the proper formand completed the entire lift in a controlled manner without assistance. On average, five trials were necessary tocomplete a 1-RM test (2–3 min rest between each attempt)(Yasuda et al. 2008, 2009, 2010a, 2012).
In the experiments, the subjects randomly performed
unilateral arm curl exercises with two different exercise
conditions that were scheduled 1 week apart (Visit 1 andVisit 2). The order of exercise conditions was randomized.
Subjects were instructed to refrain from drinking alcoholand caffeine for 24 h before the sessions and from performing any strenuous exercise for 48 h before the sessions.

Eur J Appl Physiol
Fig. 1  Experimental timeline

Resistance exercise 䠄BFR or NBFR䠅
1st set2nd set3rd set4th set

Pre

Post

15min

30min

60min

UltrasoundBlood sampling
Electromyography
Heart rate

Contraction duration was 2.4 s with a 1.2:1.2 s concentriceccentric contraction duty cycle controlled by a metronome(50 beats per min) (Yasuda et al. 2008, 2009). One arm was
randomly chosen to perform BFR exercise, while the otherarm performed NBFR exercise, but the use of dominant or
non-dominant arm was randomized between subjects. The
protocols are summarized in Fig. 1.
Blood flow restriction
Before the experiment, all subjects were familiarized withthe specialized pressure cuff (30 mm width, Kaatsu–Master, KAATSU Japan Co., Ltd, Tokyo, Japan). The pressure was set to 160 mmHg, according to previous studies (Yasuda et al. 2008, 2009) for the upper arm which
reported that 160 mmHg is the optimal level of BFR for
altering blood flow, energy supply, and increasing muscle
activation when the predetermined exercise protocol is
the same among all BFR conditions. The restriction pressure intensity was applied to the upper arms as previously
described (Yasuda et al. 2009, 2010a, 2011). During acclimatization, no sign of discomfort or pain was observedin the subjects. In the BFR session experiment, subjects
were seated on a chair and the cuff was tightened aroundthe arm to a “belt pressure” (i.e., the pressure the cuff isapplying to the arm prior to inflation) of 30 mmHg on themost proximal region of the testing arm. The cuff wasthen inflated to 160 mmHg (Yasuda et al. 2009, 2010a,
2011). In the BFR session, the cuff was inflated for theentire exercise session including the rest periods between
sets and contractions.
Ultrasound‑measured muscle thickness
The muscle thickness of the elbow flexors was measured
using B-mode ultrasound (Acuson Sequoia 512, Siemens,
Tokyo, Japan) at the biceps brachii muscle (at 60 % distal between the lateral epicondyle of the humerus and theacromial process of the scapula). Briefly, the measurements were carried out while the subjects stood with theirelbows extended and relaxed. A 10.0 MHz scanning head
(5.5 cm length probe) was placed on the skin perpendicular
to the tissue interface. The scanning head was coated with awater-soluble transmission gel to facilitate acoustic contact
without depressing the dermal surface. The subcutaneous
adipose tissue-muscle interface and the muscle-bone interface were identified from the ultrasonic image. The perpendicular distance from the adipose tissue-muscle interface
to the muscle–bone interface was taken as muscle thickness (MTH). Ink markers on the elbow flexors were used
to ensure similar positioning over repeated MTH measurements (Yasuda et al. 2012). Multiple images were recordedby the same investigator (TY) each time and printed foranalysis. Then, each image analysis was performed by thesame investigator who was blinded to the both condition
and time assignments of the subjects. Test–retest reliabilityof MTH measurements using intraclass correlation coefficient (ICC3,1) was 0.97. The MTH was recorded before
the resistance exercise (pre), during rest periods between
sets (1st, 2nd and 3rd set), immediately after the resistance
exercise (post), and at 15, 30 and 60 min after the resistance exercise (Fig. 1).
Electromyography (EMG)
The skin was shaved, abraded with a skin preparation gel(Skinpure, Nihon Kohden, Japan), and cleaned with alcohol wipes. During the experiment, skin impedance wasless than 2 kΩ. The ground electrode was positioned on
the lateral epicondyle. Bipolar (2-cm center-to-center) surface EMG (sEMG) electrodes (Ag/AgCl; Vitrode F; Nihon
Kohden; Tokyo, Japan) were placed over the muscle belly(mid-portion) along the longitudinal axis of the biceps brachii of the testing upper arm (Yasuda et al. 2008, 2009).
The electrode placement on the biceps brachii was at 60 %of the upper arm limb length. EMG signals were recorded
and collected on a personal computer (T7300 Macintosh,
Apple, Japan) for subsequent analysis. All EMG signals were digitized at a sampling rate of 1,024 Hz with abandwidth of 0 Hz to 500 kHz (AB 6216; Nihon Kohden;
Tokyo, Japan). The load cell signal was low-pass filteredwith a 10 Hz cutoff. Raw EMG signals were digitized andstored on hard disk in a computer using the Chart software
program (LabChart 7 software, ADInstruments, Japan).
To determine integrated EMG (iEMG), signals were fullyrectified and automatically integrated (“Integral” function

13

Eur J Appl Physiol

##

150

BFR
NBFR

125

Exercise repeonsin LabChart 7 software) on the same computer. During theexperimental session, sEMG was recorded continuously
and each iEMG value was divided into groups of five successive repetitions (12 s). When the last iEMG group ofeach set was less than five repetitions, the iEMG value wasdivided according to the number of repetitions. The highestof iEMG group over each entire set was represented as asingle data point for statistical analysis. iEMG during each
set was normalized to pre, which was iEMG of the same
exercise without BFR (three to five repetitions) before thefirst set of each visit day. The coefficient of variation (CV)for this measurement from test to retest was 5.7 %.

100

#
**

75

**

50

**

25

**

0

**

**

Blood sampling and biochemical analyses

Heart rate
During two exercise sessions, heart rate was measured during each set (Model 9560, Onyx II, Nonin Medical Inc.,
Plymouth, MN, USA).

5.0

Muscle thickness (cm)

Venous blood samples (2 mL) were obtained from theantecubital vein and measured for hematocrit, lactate
concentration (n = 10), and creatine kinase (CK, n = 3).
Hematocrit and lactate concentration were obtained before(pre), immediately after [post (without cuff)], and at 15, 30
and 60 min after the resistance exercise (Fig. 1). CK was
obtained at pre, post, and daily for 4 days after the resistance exercise. Lactate concentration was analyzed with arapid lactate analyzer (Lactate Pro, Arkray, Tokyo, Japan)
and hematocrit and CK were measured at a commercial
laboratory (SRL Inc., Tokyo, Japan).

Fig. 2  Exercise repetitions during each set. **p < 0.01 vs. 1 set;##p < 0.01, #p < 0.05 vs. BFR

4.5

**

**

**

**

**

**

**

4.0
3.5

**

**

**

3.0
2.5

**

**

**

**
BFR
NBFR

Pre

1st set2nd set 3rd set Post

15 min 30 min 60 min

Fig. 3  Change in biceps brachii muscle thickness during and immediately after exercise. **p < 0.01 vs. pre

Ratings of perceived exertion (RPE)
Statistical analysis
RPE was measured using the Borg scale (6–20) every 10
repetitions and immediately after each set (Borg 1973).
Visual analog scale (VAS)
VAS, drawn as a 100-mm line with 0 mm indicating “nopain” and 100 mm indicating “extremely sore”, was used
to quantify soreness levels. The subject was instructed tomark a point on the line describing their soreness after
they palpated their upper arm with their fingers (palpationof ~5 mm skin indention), while the investigator passively
extended and flexed the subject’s forearm. The highest
value of soreness from these three methods for each subject was used for muscle soreness analysis. VAS was measured before, immediately after (without cuff), and daily for
4 days after the exercise bout of each arm (Thiebaud et al.
2013). VAS of each subject was measured at the same timeof day throughout the investigation.

13

Results are expressed as mean ± standard deviation(SD). Two-way ANOVA with repeated measures (condition × time) was used to evaluate the training effects for all
dependent variables. When significant main effects and/orinteraction were observed, post hoc testing was performed
using the Tukey technique. Statistical significance was set at
p < 0.05. Effect sizes (ESs, Cohen’s d) in MTH and lactate
concentration were calculated with the following formula: [(αmean − pre mean)/pre SD, α = 1st set, 2nd set, 3rd set, post,
15, 30, or 60 min; d = 0.2–0.5 is a small effect, d = 0.5–0.8 isa moderate effect, and d > 0.8 is a large effect] (Cohen 1988).

Results
The mean age, height, body mass and BMI for the subjects
were 27 ± 5 years, 173.6 ± 4.9 cm, 70.3 ± 4.3 kg andEur J Appl Physiol

**

**

5

**

6
**

iEMG rao

5

BFR
NBFR

4
3
2

**

1

**

**

**

3rd set4th set0Pre

1st set2nd setFig. 4  Change in integrated EMG (iEMG) during each set.
**p < 0.01 vs. pre

23.3 ± 1.6, respectively. On each visit day, there were nodifferences (p > 0.05) between BFR and NBFR for 1-RM
(13.6 ± 2.5 and 13.7 ± 2.1 kg), heart rate (67.4 ± 8.0 and
64.7 ± 11.0 BPM), systolic (124 ± 7 and 120 ± 8 mmHg)
and diastolic blood pressures (75 ± 9 and 71 ± 13 mmHg).
Exercise repetitions decreased progressively (p < 0.01)
in the two conditions for arm curl exercise from the 1st to
4th set and NBFR was greater (p < 0.01) than BFR at the
1st and 2nd sets. The total number of (4 sets) exercise repetitions was greater (p < 0.01) in NBFR (221 ± 67 reps) thanin BFR (111 ± 36 reps) (Fig. 2). MTH for biceps brachii
increased (p < 0.01) with BFR and NBFR (1.21 and 1.20fold the baseline value), which was similar from the 1st
set to 60 min (Fig. 3). All ESs for the differences in MTH
were large for BFR (0.88–1.51 from 2nd set to 60 min) and
NBFR (0.84–1.81 from 1st set to 60 min) except for 1st
set for BFR (0.71). During the exercise session, iEMG for
biceps brachii muscles increased (p < 0.01) progressively
in BFR and NBFR (3.94 and 4.45 times baseline value); theiEMG increases for BFR and NBFR were similar from the
1st to 4th sets (Fig. 4).
Immediately after the exercise session, the lactate concentration was similarly increased with both conditions(Fig. 5). Immediately after the exercise session, hematocrit was increased with both BFR (pre: 46.4 ± 2.5 %,post: 48.4 ± 2.7 %) and NBFR (pre: 46.6 ± 1.7 %, post:
48.2 ± 2.0 %) to similar levels. During the exercise session, the heart rate increased progressively similarly inboth BFR and NBFR from the 1st (96 ± 10 and 95 ± 13
BPM), 2nd (96 ± 10 and 97 ± 15 BPM), 3rd (93 ± 8 and
99 ± 12 BPM), and 4th set (93 ± 7 and 99 ± 17 BPM). All
ESs for the differences in lactate concentration were large
for BFR (0.8–10.4 from post to 60 min) and NBFR (1.6–
10.9 from 1st set to 60 min) except for 60 min for NBFR
(0.64).

Lactate concentraon (mmol/L)

7

**
BFR

4

NBFR
3

2

**
1

0

Pre

Post

15min

30min

60min

Fig. 5  Change in lactate concentration immediately after exercise.
**p < 0.01, vs. pre

In summation of four sets, high RPE score (morethan 15) showed a longer duration (p < 0.01) in NBFR
(130 ± 56 reps) than in BFR (90 ± 39 reps). In both
BFR and NBFR, VAS significantly increased: 39 ± 27
and 47 ± 23 mm at 24 h, 54 ± 26 and 69 ± 23 mm at
48 h, 50 ± 22 and 58 ± 17 mm at 72 h, and 28 ± 21 and
32 ± 17 mm at 96 h. There was no significant difference in
VAS between the two conditions in any set.
In both BFR and NBFR, CK gradually increased:
165 ± 73 and 160 ± 74 U/L at pre, 169 ± 72 and
162 ± 78 U/L at post, 420 ± 429 and 583 ± 559 U/L
at 24 h, 3,668 ± 5,442 and 3,825 ± 3,767 U/L at 48 h,
9,102 ± 7,267 and 8,788 ± 7,570 U/L at 72 h, and13,415 ± 7,267 and 11,305 ± 8,712 U/L at 96 h.
Discussion
The main findings of the present study were: (1) increased
muscle swelling following exercise and increased muscle
activation during resistance exercise did not differ between
BFR and NBFR, and, (2) time-course of the increase inmuscle swelling was similar between two conditions, (3)low-load resistance exercise to volitional fatigue induced
an increase in muscle swelling 15 min after exercise, which
was mainly dependent on muscle damage or inflammationof the muscle tissues regardless of BFR.
It is known that acute cell swelling due to osmotic water
shifting into the cell stimulates anabolic processes, boththrough an increase in protein synthesis and a decrease inproteolysis (Berneis et al. 1999; Häussinger et al. 1993).
Recent BFR studies (Martín-Hernández et al. 2013; Loenneke et al. 2012a; Yasuda et al. 2012) suggest that BFR
training leads to pronounced acute changes in muscle size,

13

Eur J Appl Physiol

an index of muscle swelling, the response to which may
be an important factor for promoting muscle hypertrophy.
However, recent studies (Mitchell et al. 2012; Ogasawara
et al. 2013) have reported that NBFR training to volitional
fatigue results in muscle hypertrophy similar to high-loadtraining, but their studies were unclear regarding the relationship between NBFR and muscle swelling. In the present study, we revealed the effect size for muscle swelling
was similar in both BFR and NBFR exercises [1.5 (large)
and 1.8 (large) for post, respectively]. Therefore, it would
appear that low-load resistance exercise to volitional
fatigue could stimulate muscle protein metabolism inducedby muscle swelling. On the other hand, Fahs et al. (2014)
demonstrated that BFR training induced a greater increasein muscle size compared with non-BFR training althoughsimilar muscle swelling was observed following low-load
resistance training to volitional fatigue with and without
BFR. In addition, Loenneke et al. (2012b) observed that theinduced increase in muscle size after a brief application of
BFR (in the absence of exercise) may have been mediatedthrough an acute fluid shift. Taken together, these findings
suggest that acute muscle swelling may be a requisite factor for muscle hypertrophy but by itself is not enough.
In previous BFR studies, greater muscle activation during low-load BFR resistance exercise was hypothesized tooccur as a compensation for a deficit in force development,
secondary to changes in energy supply; these changes
resulted from the decreased oxygen available to the muscle and an accumulation of metabolites (Bigland-Ritchie
et al. 1986; Moritani et al. 1986; Yasuda et al. 2010a). In
this study, muscle activation during the exercise session
increased progressively in both BFR and NBFR conditions,although the number of exercise repetitions was approximately two-fold greater in NBFR than in BFR. Additionally, the magnitude of the increased blood lactate concentration and hematocrit following exercise was similar
between the two conditions. Therefore, it can be speculated
that increased muscle activation during NBFR was also
caused by a mismatch in energy demand/energy supply,
although the metabolic product per unit exercise repetition
with NBFR was approximately one-half that with BFR.
Taken together, muscle swelling and muscle activation during low-load resistance exercise to volitional fatigue could
reach a plateau with NBFR as well as with BFR, eventhough the number of exercise repetitions was approximately two-fold greater in NBFR than in BFR.
Previous studies (Loenneke et al. 2012a, c; Yasuda et al.
2012) reported that an increase in muscle swelling with
BFR was due to a fluid shift from the plasma into the muscle under BFR. In the present study, however, the increased
muscle swelling with both NBFR and BFR remained atleast 60 min post-exercise whereas plasma volume andblood lactate concentration returned to baseline at 15 min

13post-exercise. On the other hand, increased muscle soreness scores (assessed by VAS) with NBFR and BFR (54and 69 mm, respectively) were very high score comparedwith a previously reported BFR study (20 mm; Thiebaud
et al. 2013). In addition, muscle damage (CK, n = 3) gradually increased to 13,415 U/L for BFR and 11,305 U/L for
NBFR at 96 h post-exercise. These low-intensity exercise
results suggest that muscle soreness and muscle damage
with BFR and NBFR were comparable with that reportedwith a high-intensity exercise study (Nosaka and Newton2002), which performed maximal eccentric exercise of unilateral elbow flexors (3 sets of 10 reps). In contrast, previous BFR studies of low-load BFR exercise not to volitional fatigue reported that there are no changes in markers
of muscle damage between before and after an acute boutof exercise (Abe et al. 2006; Fujita et al. 2008). Taken
together, it is speculated that low-load resistance exercise
to volitional fatigue induced an increase in muscle swelling 15 min after exercise, which was mainly dependent
on muscle damage or inflammation of the muscle tissues
regardless of BFR.
Some limitations of this study should be discussed.
First, the rest period between sets was different between
NBFR (3 min rest period between sets) and BFR (30 s rest
period between sets). Based on previous studies (Stull and
Kearney 1978; Salles et al. 2009), it can be speculated that
NBFR with 30 s rest periods between sets recovered maximal strength and exercise repetitions were approximately
twice as much as 3 min rest periods between sets for theupper bodies. Therefore, it is likely that increased MTH
in NBFR was a little suppressed after the 2nd set when
NBFR with 30 s rest periods between sets was applied. In
this study, the highest effect size in MTH was 1.5 for BFR
and 1.8 for NBFR (at the 3rd set and post, respectively),
but MTH at the 1st set of NBFR already reached a large
effect size (1.3). Taken together, there is a high possibility
that increased muscle swelling between the two conditions
with 30 s rest periods between sets are also similar. Second,
because the number of repetitions at the 1st set (67 reps)
were higher compared with a previous BFR study (25 reps)(Kubo et al. 2006), it appears that the optimal level of BFR
was higher than 160 mmHg in this study. Notably, thisstudy used an arbitrary pressure. Previous studies (Loenneke et al. 2012b, 2013; Yasuda et al. 2008) reported thatdifferences in limb size do result in differences in BFR,
thus it is always necessary to pay attention to the relationship between the level of BFR and the exercise and/or
training effect. Third, NBFR exercise was limited to highly
motivated individuals who are capable of tolerating the perceptual response of the exercise session because the highRPE score (more than 15) was approximately a 1.5-foldlonger period in NBFR than in BFR. Fourth, our results
were acute and may not necessarily be translated to chronicEur J Appl Physiol

adaptation. Hence, more studies are necessary to understand the relationship between NBFR exercise and safety
and/or arterial function.
In conclusion, low-load resistance exercise to volitional
fatigue is an effective method to promote muscle swellingand muscle activation regardless of BFR, and the timecourse of the increase in muscle swelling was similar forboth conditions. Furthermore, our data indicate that theincrease in muscle swelling for both NBFR and BFR is
maintained even 15–60 min after the exercise, which may
be mainly dependent on muscle damage or inflammation of
the muscle tissues.
Acknowledgments The authors thank the participants who participated in this study. We also thank Yusuke Uchida, Seiya Oosumi,
Kenji Kinpara, and Shinpei Sugimoto (Okamoto-Ishii Hospital, Shizuoka, Japan). This study was supported, in part, by Grant-in-aid(#25750288 and #20549604 to TY) from the Japan Ministry of Education, Culture, Sports, Science, and Technology, and the DescenteFoundation. Our department is funded by KAATSU Japan Co., Ltd.

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