Effectiveness of Combined Aerobic and Strength Training in Acute and Chronic Adaptations in Patients With Heart Failure
Phase: NA
Conditions: Chronic Heart Failure, Fragility
Sponsor: University of Lisbon

 
 
 
EFFECTIVENESS OF COMBINED 
AEROBIC AND STRENGTH 
TRAINING IN ACUTE AND 
CHRONIC ADAPTATIONS IN 
PATIENTS WITH HEART FAILURE 
      
 
Date: 19/10/2017 
 
Study Protocol and Statistical Analysis Plan 

1 
 
PROTOCOL 
 
 
 
Effectiveness of combined aerobic and strength training in acute and chronic adaptations in 
patients with heart failure 
 
 
 
Patients with chronic heart failure (CHF) that underwent to a hospital-based cardiac 
rehabilitation (CR) program in the Lisbon district Hospitals will be recruited. The study will be 
performed in the Cardiovascular Rehabilitation Center of the University of Lisbon (CRECUL) at the 
Lisbon University Stadium (EUL). The participants will be randomized into one of the following 
exercise groups: A) combined exercise training with more aerobic training and less strength training 
(CAT); B) combined exercise training with more strength training and less aerobic training (CST);  
Inclusion criteria: CHF patients; receiving optimal medical therapy for CHF (including an 
angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and a beta-blocker 
unless a contraindication is evident) with a stable condition for more than 1 month (no 
hospitalization for heart failure (HF), no change in medication, and no change in New York Heart 
Association (NYHA) functional class. Exclusion criteria: if they are younger than 18 years or are 
unable to sign informed consent; unstable angina pectoris; and orthopedic or neurological 
limitations to exercise. Patients will be stratified (by age and etiology) and randomized 
consecutively to CAT or CST in the beginning of the exercise at community. There will be 2 
assessment moments (M): M0) before starting the exercise training (ExT) program (baseline) and 
M1) 3 month after starting the ExT. 
Sample size was calculated (G-Power,Version3.1.3) assuming a difference in carotid intima-
media thickness (IMT) between groups of 5%  to be a clinical important difference with a SD of 
0.16, α=0.05, 1-β=0.95 and an expected dropout rate of 26%. The calculations yielded a total 
minimum sample size of 28 participants (14 in each group). 
 
Title 
Recruitment 
Participants 

2 
 
 
 
Participants with established CHF after finishing in average a 3-month hospital based CR 
program at the Hospital will be invited and recruited to start a community based CR program at the 
EUL. The Clinical Director of the CR program at the Pulido de Valente Hospital and the Clinical 
Director of the community based CR program at the EUL, will make one of the connections to invite 
all the patients with the mentioned inclusion criteria to join the community based program. All 
patients will have access to informed consent (is attached the file of informed consent) where the 
entire project will be clearly explained.  
Other forms to promote the recruitment in other Hospitals in the Lisbon district will be the 
distribution of a leaflet, with the contacts and brief information about the community based 
program. It will be presented and asked to each of the Clinical Director of the CR program at the 
Hospitals in Lisbon district the authorization to give to all the patients who completed the hospital 
based program the information leaflet. 
All the information provided at the flyer will be online at the website of the University of 
Lisbon, Faculty of Human Kinetics – University of Lisbon (FMH-UL) and Faculty of Medicine – 
University of Lisbon. 
 
 
 
 
 

3 
 
 
INTRODUCTION 
 
CHF is the major public health problem in the world [1], highly prevalent in older 
individuals and a major cause of disability, hospitalizations, morbidity and mortality [2]. Generally, 
CHF patients have reduced exercise capacity, with main symptoms of effort intolerance, early fatigue 
and breathlessness [3], also exhibiting increased peripheral and central chemosensitivity, and 
impaired sympathovagal balance with sympathetic activation (SA) predominance [4].  
Understanding the oxidative metabolism and intracellular energy transfer in both skeletal and 
cardiac muscle, mechanisms of endothelial dysfunction, and the role of SA and inflammatory cytokines 
provide possible mechanistic explanations of the pathophysiologic factors involved in the development 
of exercise intolerance [5, 6]. It has been shown in CHF patients that increased arterial stiffness is 
associated with cardiovascular morbidity and mortality [7]. There are evidences that increased arterial 
stiffness predicts exercise intolerance in CHF patients [8]. 
Increased carotid IMT is associated with subclinical left ventricular (LV) myocardial dysfunction, 
suggesting a possible role of carotid IMT in HF risk determination [9]. CHF is associated too with 
endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FMD). 
Since endothelial function is thought to play an important role in coordinating tissue perfusion and 
modulating arterial compliance, interventions to improve endothelial dysfunction are imperative.  
Systemic vasoconstriction and impaired peripheral perfusion are hallmarks in advanced CHF. 
While a number of factors, including increased sympathetic tone and an activated renin-angiotensin 
system, have been proposed to be involved in the reduced arterial vasodilatory capacity in HF, the 
pivotal role of the endothelium in coordinating tissue perfusion has now been recognized.  
Several clinical studies have documented endothelial dysfunction of large conduit and small 
resistance vessels in patients with CHF. Endothelial dysfunction may affect the cardiovascular system in 
two ways: first, endothelial dysfunction of resistance vessels may impair peripheral perfusion, and, 
second, endothelial dysfunction of large conduit vessels may limit the increase in blood flow provided 
by the supplying large vessels and may increase impedance of the failing LV and consequently impair LV 
ejection fraction (LVEF). An important functional consequence of endothelial dysfunction is the inability 
to release nitric oxide (NO) in response to physiological stimuli such as increases in flow, reflecting 
impaired FMD [10]. Conversely, chronically increased blood flow enhances the release of NO in 
experimental models, by upregulation of NO synthase, the enzyme that uses L-arginine to generate NO. 
Project 

4 
 
The intermittent increases of blood flow by physical training may increase the capability of the 
endothelium to release NO and therefore may restore endothelial function in patients with CHF who 
are usually subjected to a limited degree of physical activity[5]. The dysfunctional endothelium 
contributes to increased vascular stiffness and impaired arterial distensibility, augmenting myocardial 
damage [10]. 
The direct relationship between exercise and vascular health is certain, but the complex set of 
metabolic pathways, haemodynamic effects of exercise on cardiovascular cells/tissues, and the 
regulation of genetic expression activated by exercise is still largely undefined [11]. The effects of 
aerobic and resistance exercise on clinical blood pressure might be different, because they have 
different mechanical characteristics. Aerobic training (AT) is characterized by the execution of cyclic 
exercises, carried out with large muscle groups contracting at mild to moderate intensities for a long 
period of time. On the other hand, strength training (ST) is characterized by the execution of exercises 
in which muscles from a specific body segment are contracted against a force that opposes the 
movement[12]. 
Aerobic capacity is directly related to arterial function, including endothelial function, arterial 
stiffness and wave reflection. In addition, coupling of arterial and cardiac function is a major 
determinant of aerobic capacity. Thus, poor resting arterial function likely limits aerobic capacity, but it 
is also possible that changes in arterial function during acute exercise may play a role. Arterial function 
is not only associated with aerobic capacity, but is also an independent predictor of mortality[5].  
Controlled clinical trials have shown that in HF patients ExT programs improve peripheral and 
cardiac adaptations and also the aerobic capacity, delay the onset of anaerobic metabolism, and 
improve the autonomic balance [1, 13]. Apart from adaptation in maximal cardiac output, heart 
contractility, and stroke volume, aerobic ExT is also able to promote amelioration in the peripheral 
microvascular background by reducing resistance to flow, increasing the compliance of the arteries and 
endothelial function [13]. Abnormalities in endothelium and FMD are a key phenomenon in the blunted 
vasodilatory response in CHF patients. ExT enables the improvement of both basal endothelial NO 
formation and agonist-mediated FMD of the skeletal muscle (SM) vasculature in CHF patients. The 
correction of endothelial dysfunction is associated with a significant improvement in exercise capacity 
evidenced by a 26% increase in peak oxygen uptake (VO2peak) [14].  
Previous studies in HF have been show that 16.4% of 171 patients had cachexia, and the 
mortality at 18 months of follow-up was as high as 50% in the subset of patients with cachexia 
compared with 17% in those without cachexia. Cardiac cachexia is defined as an advanced stage of HF 

5 
 
associated with involuntary loss of at least 5% of non-oedematous body weight. And muscle wasting, 
also known as sarcopenia, is the loss of muscle mass (MM) and strength, whereas cachexia describes 
loss of weight. Distinction of the two clinical conditions might also be challenging, because cachexia and 
muscle wasting can co-exist in the same patient. Indeed, cachexia might lead to muscle wasting and vice 
versa, although muscle wasting can occur earlier in the course of the disease[15].   
SM strength, in upper and lower limbs, are parameters that independently predict survival [16, 
17, 18]. This alternative treatment should focus on increasing MM, strength and power in the limbs to 
improve functionality and performance [19]. SM dysfunction includes reduced cardiac contractile 
performance that contributes to changes in SM physiology, muscle atrophy, weakness and reduced 
oxidative capacity [20]. Muscle function is also enhanced in response to ST in CHF patients, including 
myofilament function and whole muscle [21] as well as SM oxidative capacity [21].  
It’s crucial that the ExT in such patients should be train the peripheral muscles effectively 
without producing great cardiovascular stress. An alternative treatment approach should focus on the 
application of specific resistance exercise program to improve body composition [22], increase the 
crosssectional area, muscle fibre [23], all of which counteract muscle wasting and may be cornerstone 
in the prevention of sarcopenia and cardiac cachexia in CHF patients [24]. 
ExT is a major component of rehabilitation/secondary prevention interventions, inducing 
significant beneficial changes in mechanisms of pathophysiology, exercise tolerance, functional capacity 
and QoL, while a positive impact on hospitalization and mortality reduction. There has been growing 
interest in the characteristics and modalities of exercise training able to induce optimal benefits. High 
intensity and interval mode have been shown to induce greater benefits than moderate intensity and 
continuous mode regimes. Considering the current body of evidence of high-intensity interval training 
(HIIT) in CHF, HIIT demonstrated to be more efficient, result in long term adherence, which be an 
important practical aspect to consider during the ExT and consequently optimized improvements in 
central and peripheral adaptations [25]. More studies are needed to proof their safety and benefits on 
this type of patients. 
Additionally, there has been sound rationale for the inclusion of ST to the HIIT, which has been 
also shown able to yield benefits in terms of exercise capacity and QoL. It is well known that combined 
AT and ST is the preferred exercise intervention to reverse or attenuate the loss of MM and improve 
exercise and functional capacity, muscle strength in this individuals [19]. But there are underlying 
mechanisms from the ST in the CHF patient’s peripheral capacity that remains unidentified. And isn’t 
known what is the benefits of combine different proportions of AT and ST. 

6 
 
For that reason, the investigators will test two proportions in combined training, CAT and CST. 
There haven't been any data on the so called combined regimes, which include both aerobic exercise 
with HIIT and ST and the investigators will evaluate the effects of acute and chronic response.  
PURPOSE 
 
 
The research project will contribute to a better understanding in several aspects that are 
unexplained by scientific research. The purpose of this research project are: 
1) To determine the effectiveness of a ExT programme with different proportions of CAT and 
CST in promoting cumulative effects in acute and chronic adaptations in CHF patients;  
2) To identify the mechanisms of the potential improvement in effectiveness promoted by ST;  
This research project is going to employ state of the art methods focusing peripheral 
adaptations analysis in both groups namely in echocardiography variables, cardiopulmonary exercise 
testing, arterial stiffness, functional physical fitness, QoL and body composition in 2 distinguished 
moments: M1) baseline and M2) 3 month.  
 
 
This project will assess the acute and chronic effects in central and peripheral adaptations of a 
combined training to patients with CHF would address a number of important breaches in scientific 
knowledge with potential clinical benefits. 
 
STUDY DESIGN 
 
 
 
A longitudinal randomized control trial (RCT) research design using two distinct ExT 
prescriptions (CAT and CST) will be applied in CHF patients. All the same assessments will be done in 
two moments: M0 - baseline and M1 - 3 months after starting the ExT. The patients will be 
randomized into either one of the two ExT group.  
Recruitment and screening will  last  9  months  (September 2017  to  May  2018)  and the  
patient  assessment will  last  until August 2018. It is expected to finish the project with peer-review 
redaction submitted and/or accepted  in December 2018 (time line attached). 
The following assessments on the 4 moments will be performed at the Pulido Valente 
Hospital, FMH-UL and Academia de Fitness at EUL: Echocardiogram (Echo) (MyLab Alpha, ESAOTE); 
Plan and Methods 

7 
 
cardiopulmonary exercise test (CPET) (Ergostik, Geratherm Respiratory GmbH, Bad Kissingen); 
arterial stiffness - Complior Analyse (ALAM Medical); Intima-media thickness - ultrasound (ESAOTE 
MyLanOne); body composition - dual energy radiographic absorptiometry (DXA, Hologic Explorer-
W); functional physical fitness - Fullerton Functional Fitness Test; isometric strength – portable hand 
dynamometer JAMAR plus digital (Sammons Preston); maximal strength – 1RM and QoL 
questionnaire. 
All assessment moments will be done in 5 days: 
Day 1  – Echo will be performed at the Pulido Valente Hospital; 
Day 2 and 3 – during one day and time of the ExT session at the EUL, the patient will perform 
the functional physical fitness tests; maximal strength; isometric strength and QoL questionnaire. In 
other day the investigators will perform the arterial stiffness and the IMT before the session in rest 
and after the ExT; 
Day 4 – In FMH, the CPET and dual energy radiographic absorptiometry (DXA) exam. 
Individual reports will be sent by email or delivered on paper. During the 1-year project the 
multidisciplinary team will have bimonthly meetings to update the study information and discuss 
the patient’s progress. 
 
TASK  DENOMINATION 
 
 
1. ECHOCARDIOGRAM 
 
 
A resting transthoracic echocardiogram will be performed with MyLab Alpha, ESAOTE, Italy. 
The exam will be performed by the echocardiography laboratory cardiologists, who will be blinded 
to experimental protocol and group randomization, with the usual measurements of systolic and 
diastolic function, particularly the calculation of LVEF by Simpson`s formula, telediastolic and 
telessystolic volumes and diameters, doppler analysis of the transmitral flow, tissue doppler and 
quantification of mitral valve regurgitation. 
 
2. CARDIOPULMONARY EXERCISE TEST  
 
CPET is the best technique to obtain the maximal functional capacity. This test will be 
performed with the subjects in a non-fasting condition and under the regular medication. 
Symptom-limited exercise test 

8 
 
A symptom-limited ramp incremental CPET, will be performed on a cycle ergometer 
(Ergostik, Geratherm Respiratory GmbH, Bad Kissingen, Germany) with breath-by-breath gas 
exchange measurements. For cardiorespiratory recording will be used a mask that does not 
interfere with breathing and can cause discomfort. Gas exchange analysis provides a highly 
reproducible measurement of exercise limitation and insights into the differentiation between 
cardiac or respiratory cause of dyspnea, assesses ventilator efficiency and carries prognostic 
information. After 2 minutes rest followed by 3 minutes unloaded pedaling, each patient will be 
encouraged to exercise to exhaustion, as defined by intolerance, leg fatigue or dyspnea unless 
clinical criteria for test termination occurred. Patients will continue seated on the cycle ergometer 
as soon as they stop, while recovery measurements are taken. Blood pressure will be recorded at 
baseline, during each  stage, at peak exercise and during recovery. Peak oxygen capacity will be 
considered the highest attained VO2 during the final 30 sec. of exercise and ventilator AT will be 
estimate by the V-slope method. Heart Rate (HR) recovery as a simple marker of parasympathetic 
activity will be calculated as the difference between peak HR and HR one minute later. The recovery 
period will continue until 6 minutes after peak effort. Chronotropic response (ChR) to exercise will 
be evaluated by the % of HR reserve (HRR) used at peak exercise. ChR= [peak HR – resting HR/(220 – 
age – resting HR)x100]. A failure to use 80% of the HRR is defined as chronotropic incompetence. All 
patients should achieve a respiratory exchange ratio of >1.1, an indicator of maximal effort in the 
CPET. The CPET will provide clinical information to patient screening and exercise intensity 
prescription. 
The investigators will study, the HR max and recovery at 1st and 3rd minutes, the VO2 peak, 
respiratory exrespiratory exchange ratios,  respiratory quotient, ventilatory anaerobic threshold, the 
ventilatory equivalent for O2  and C O2 . 
 
3. ARTERIAL STIFFNESS 
 
 
Arterial stiffness will be measured by pulse wave velocity (PWV) obtained by applanation 
tonometry will be measured during a 15 and 30-minute rest. A single operator locates the carotid, 
femoral, radial and distal posterial tibial arteries on the right side of the body and mark the point for 
capturing the corresponding pressure curves with two specific pressure sensitive transducers. The 
distance between the carotid and femoral, radial and distal posterial tibial arteries will be measured 
directly and entered into the Complior Analyse software (ALAM Medical, Paris, France). Right 
brachial blood pressure will be measured and entered into the Complior Analyse software, and then 

9 
 
signal acquisition is launched. The operator position the carotid sensor with the help of its specific 
holder and manually held the femoral sensor on the femoral artery and the distal sensor in the distal 
posterial tibial artery. When the operator observes 10 carotid pulse waveforms of at least 90% 
quality showed on the software, simultaneous carotid and femoral, radial and distal posterial tibial 
pressure curves will be recorded for 10 pulse waveforms. The time delay (aortic transit time) 
between the two pulse waveforms is then calculated automatically. Values obtained from the carotid 
to femoral artery, carotid to radial artery and carotid to distal posterial tibial artery are taken as 
indices of central/aortic, upper and lower limb arterial stiffness, respectively. The investigators will 
study the pulse pressure (PP), the carotid stiffness index β, augmentation index (Aix), and peak wave 
velocity (PWV) 
 
4. INTIMA-MEDIA THICKNESS 
 
Carotid intima media thickness (cIMT) will be defined as the distance between the leading edge 
of the lumen–intima interface to the leading edge of the media–adventitia interface of the far wall of 
the right carotid artery using an ultrasound scanner equipped (ESAOTE MyLanOne) with a linear 13 MHz 
probe and implemented with a previously validated radiofrequency-based tracking of arterial wall that 
allows a real-time determination of common carotid far-wall thickness with high spatial and temporal 
resolution [26]. cIMT is automatically measured, and distension curves are acquired within a segment of 
the carotid artery about 1 cm before the flow divider, where the operator places the region of interest. 
The coefficients of variation for repeated measurements in our laboratory for cIMT and diameter are 
reported elsewhere [26]. 
To evaluate the acute effects of ExT, at the pre-exercise measurement at 15 and 30-minutes 
rest, blood pressure (BP) was measured twice on the right upper arm using an automatic cuff in a dorsal 
decubitus position. If the difference in systolic BP (SBP) between the two measurements was larger 
than 10 mmHg, another BP measurement was performed. The final measured value was used for the 
analysis. Immediately after measuring BP. Post-exercise measurement was carried out with the same 
methods.  
From this test, the investigators will study the diameter and distensibility of the artery, intima–
media thickness in the carotid arteries (cIMT), PWV, brachial blood pressure, and the alpha and beta 
index. 
 
5. BODY COMPOSITION -  DUAL ENERGY RADIOGRAPHIC ABSORPTIOMETRY  

10 
 
 
 
All the patients will be tested in the morning with a 12-h fasted no caffeine and alcohol, 
refrained from the moderate to vigorous exercise at least 24-h. Total and regional body mass (bone 
mineral content, lean soft- tissue and fat mass) is estimated using dual energy radiographic 
absorptiometry (DXA) (Hologic Explorer-W, fan-beam densitometer, software QDR for windows 
version 12.4, Hologic, USA). The attenuation of x-rays pulsed between 70 and 140 KV synchronously 
with the line frequency for each pixel of the scanned image. This technique uses RX with a low 
radiation dose (1-3μSv / test), much lower than usual exposure to our natural involvement (5-8μSv / 
day) or RX to the chest (50-150μSv / test). The same lab technician will perform the scans, and 
execute the analyses according to the standard analysis protocol. Total body skeletal muscle mass 
(TBSMM) will be calculated as TBSMM = (1.13 ALST) – (0.02 age) + (0.61 sex) + 0.97, where ALST 
means appendicular lean soft tissue. Skeletal muscle mass (kg) will be normalized by height (kg/m2) 
and termed skeletal muscle index to verify the level of physical disability risk. Height will be 
measured to the nearest 0.5 cm with a stadiometer (SECA, Hamburg, Germany), body weight (SECA, 
Hamburg, Germany) and body mass index (BMI) (kg/m2) will be calculate for height and body weight 
from the DXA. Body circumferences at the waist will also be measured using an inelastic flexible 
metallic tape (Lufkin W606PM, Vancouver, Canada), to the nearest 0.1cm. All anthropometric 
procedures will be led by the same certified technician. 
The investigators will study the bone mineral content, lean soft- tissue and fat mass, total and 
regional body mass. 
 
6. OBJECTIVE MEASURED PHYSICAL ACTIVITY 
 
 
Each participant will use the ActiGraph GT3X+ and given oral and written instructions on how 
to wear the accelerometers for the following 7 days. The ActiGraph GT3X+ (AG; ActiGraph, 
Pensacola, FL) is able to  assess acceleration in the vertical, antero-posterior and medio-lateral axes. 
It is a reliable instrument with high inter-instrument reliability and intra-instrument reliability within 
frequencies that are common in human activities. This device has been widely used in research, with 
good validity for measuring physical activity levels. The ActiGraph GT3X+ will be attached to an 
elastic waist belt and placed in line with the axillary line of the right iliac crest. Participants will be 
asked to wear the accelerometer from the moment they wake up until they go to bed at night, and 
requested to remove it only during water-based activities such as showering and swimming and 

11 
 
when they go to bed. ActiGraph GT3X+ will be initialized using a sample rate of 30 Hz and then 
downloaded using the low filter extension option in Actilife5 Software v5.7.4 (ActiGraph, Pensacola, 
FL). The cut off points previously used in an older sample of adults to calculate daily times in each 
activity intensity band will be: sedentary (<1.5 MET) 0–199 counts per minute (cpm); light (1.5– 3 
MET) 200–1998 cpm; moderate to vigorous physical activity (>3 MET): ≥1999 cpm. Sensitivity 
analyses will also be performed using a more conservative cut point of zero cpm to differentiate 
sedentary time from activity. All physical activity variables will be converted to time (in minutes) per 
valid day. 
 
7. FUNCTIONAL PHYSICAL FITNESS  TESTS 
 
The functional physical fitness tests are a simple, reproducible, readily available tool 
frequently employed to assess submaximal functional capacity and evaluate the response to 
intervention. The six minute walking test (6MWT) will be performed indoors, along a long flat, 
straight, enclosed 20-meter corridor with a hard surface that is seldom. Patients will be instructed to 
walk at their own pace according to their tolerance to exercise for 6 minutes, with rest stops as 
needed. The final result will be the distance in meters covered in the 6 minutes. Total distance during 
the test will be recorded. Because the body weight of patients directly affect the energy and work 
required to walk, it will be used the body weight-walking distance (body weight × walking distance) 
to assess the walking capacity of subjects. The aim of the 6MWT is to assess aerobic endurance. The 
30-second chair stand, assesses the lower body strength, needed for numerous tasks such as 
climbing stairs or walking. Patients will be instructed to sit and stand as faster as they can in 30 
seconds with arms folded across chest. The 8-foot (2.44 meters) up and go test evaluates the 
agility/dynamic balance, which is important in tasks that require quick maneuvering. It will be 
evaluated the time in seconds that the participant needed to get up, walk the distance of 2.44 
meters and return to the initial position. For the flexibility, it will be assessed in both upper and 
lower body. The chair sit-and-reach aim to assess the lower body flexibility from a sitting position at 
front of a chair with the leg extended and hands reaching toward the toes, the number of cm 
between extended fingers and tip toes (+ or -) will be measured. To assess the upper body (shoulder) 
flexibility, it will be used the back scratch test with one hand reaching over the shoulder and one up 
the middle of the back, it will be taken the number of cm between extended middle fingers (+ or -). 
 
8. ISOMETRIC STRENGTH 
 
 
 

12 
 
Handgrip strength will be assessed by a portable hand dynamometer JAMAR plus digital 
(Sammons Preston, Bolingbrook, IL). Subjects will be assessed on both hands alternately. Handgrip 
assessment will be conducted with the patients in a seated comfortable position, with the shoulder 
adducted and close to, but not supported by, the trunk. The elbow of the assessed limb should be 
flexed to 90 degrees and the forearm should be in a neutral position (halfway between supine and 
pronation position). A variation of 0-30 degrees in the wrist extension will be allowed. Each subject 
will be assessed in three attempts for both hands alternately. In each attempt the subject will exert 
the maximal grip strength on the hand dynamometer with the assessed limb during 5 seconds. After 
each attempt, there will be a resting period of 60 seconds that will be used both for recovery and for 
changing the handgrip dynamometer to the opposite hand. All patients  will be instructed not to 
perform a Valsalva manoeuvre during the tests. 
 
9. MAXIMAL STRENGTH 
 
 
Maximal strength will be assessed by 1RM test for each of six weight exercises on variable 
resistance machines (Life Fitness) available at the EUL as follows, leg press, leg extension, leg curl, 
low row, chest press and lat pull down. The protocol test of 1RM was determined as previously 
described in our prior studies[27]. The protocol will include four pre-test sessions to familiarize each 
patient with the test procedures. Correct exercise and breathing techniques (avoidance of the 
Valsalva manoeuvre) will be practiced. Prior to the 1RM determination, each subject warmed-up for 
15 min on a treadmill at 50% of HRR and then performed ten stretching exercises. To warm-up 
before using a machine, each patient will be asked to perform eight repetitions using a relatively 
light resistance, followed by a 30 second rest. A second set of four repetitions using a moderate 
resistance will be then used, followed by a 1 minute rest. After that each patient will be asked to 
perform single repetitions until the 1RM was reached. The rests between attempts will be 1–2 min. 
The resistance will be increased by approximately 5 kg, or by 2.5 kg when the subject was near his 
maximum. Strength will be recorded as the maximal number of kilograms lifted in one full range of 
motion. The order of the tests will be the same for all patients, and these exercises will be the same 
as those used for the ExT. 
 
10. QUALITY OF LIFE  QUESTIONNAIRE 
 
 
The Short Form-36 Health Survey (SF-36) is a self-assessment health status questionnaire 

13 
 
composed of 36 questions about socio-demographic, health and personal behavior[28]. It was 
designed for use in clinical practice and research, health policy evaluations and general population 
surveys. The 36 questions in the SF- 36 survey capture the subject’s perception of their general 
health by sorting them into multi-item scales that assess 8 concepts. The 8 subscales are as follows: 
physical functioning (10 questions); role/physical (4 questions); bodily pain (2 questions); general 
health (10 questions); vitality/energy (4 questions); social functioning (2 questions); role/emotional 
(3 questions); mental health/emotional wellbeing (5 questions). The SF-36 also provides 2 important 
summery measures of health-related QoL: physical component summary and mental component 
summary scales. The strength of both scales lies in their ability to distinguish a physical from a 
mental outcome. The items and dimensions in SF-36 were constructed using the likert method of 
summated ratings. This questionnaire has been used in CR programs[29]. A Portuguese validated 
version of SF-36 is available[30]. 
 
11. EXERCISE TRAINING PROGRAM 
 
 
The ExT program will be carried out mostly in groups at the EUL gymnasium, 3 or 2 times a 
week (depending on the availability of the patient for complete the 90% of prescribed sessions), 60 
minutes per session, on non-consecutive days and supervised for both groups. All sessions will 
include 10 minutes of warm up and cool down standardized for both groups. The warm up will focus 
on pulse raising, mobility and preparatory stretching for the conditioning component. Cool down will 
include transition from conditioning component to the stretching phase, which comprises static and 
dynamic stretching exercises  for all major muscle groups. Muscle strength is intentionally performed 
before the aerobic exercises to maximize training effects. Sessions will be deemed completed when 
at least 90% of the prescribed exercises have been successfully performed. 
All patients will do in the strength part the same 6 machines (3 to the upper limbs and 3 for 
de lower limbs): leg press, leg extension, leg curl, low row, chest press and lat pull down. The 
periodization created allows for a slow progressive increase in strength exercise intensity, volume 
and density(effort/rest). 
CAT group: The subjects will perform in ST part, always only 1 set in the 6 machines early 
mentioned. During the first and second week they will do 12 repetitions at 40% - 50% of 1 RM. In the 
third and fourth week progress to 10 repetitions at 60%-70% of 1 RM, and in the second and third 
month, 8 repetitions at 70%-80% of 1 RM. In the AT part the HIIT protocol is based on a ratio 2 min : 
1 min. Consisted of 10 interval training periods (2 min of high intensity at 85% - 90% of heart rate 

14 
 
reserve (HRreser) and 9 pauses (1 min in passive pause) between interval training periods. During the 
first week of training will start with a continuous training, in the second week the investigators will 
start with 5 intervals of HIIT, and in the second and third months they are doing the 10 stages of HIIT. 
CST group: During the first and second week subjects will perform 1 sets with 12 repetitions 
at 40% - 50% of 1 RM in the 6 machines mentioned before. In the third and fourth week strength 
exercises progress to 2 sets of 10 repetitions, at 60%-70% of 1 RM, and in the second and third 
month consists of 3 sets at 8 repetitions, at 70%-80% of 1 RM.  . In the AT part the HIIT protocol is 
based on a ratio 2 min : 1 min. Consisted of of 5 interval training periods (2 min of high intensity: 85% 
- 90% of HRreser) and 4 pauses (1 min in passive pause) between interval training periods. During the 
first week of training will start with a continuous training, in the second week we will start with 3 
intervals of HIIT, and after the third/fourth week they are doing the 5 stages of HIIT. 
The patients will be instructed in correct exercise techniques and to avoid the Valsalva 
maneuver. All patients will be continuously monitored using telemetry (NORAV) during the execution 
of the exercise session in order to achieve the HR training. Blood pressure will be assessed before 
and after completing each session. If necessary, the blood pressure will be measured during the ExT 
session. 
 
12. DATA BASE MANAGEMENT AND  REPORTS 
 
 
This task includes the treatment of the variables obtained during the data collection period. 
In order to assure the confidentiality of the participants an ID code will be attributed to each 
participant in the database and all the equipment’s and sheets used. All personal data (identification 
documents) of the participants will be destroyed after the passage to the unknown database. A 
single researcher will perform the database management. 
Patient’s individual reports will be completed within 2 weeks after evaluation, including 
quantitative and qualitative information on all assessments made at M0 and M1. 
 
13. STATISTICAL ANALYSIS 
 
Data will be analyzed in M0 and M1. It will be tested the data for normality and 
homogeneity of variance with the Shapiro Wilk and Levene’s tests, respectively. Data analysis will 
be described according   to the established purposes for this project (descriptive values: mean, 
standard deviation, range, % change) and comparisons of means will be used for all purposed 

15 
 
outcomes intra and inter groups. Baseline characteristics between groups will be evaluated with 
oneway ANOVA. Mixed between within subjects ANOVA will be conducted in a 2 (pre vs post ExT) 
design to assess efficiency of the program. When a significant interaction is observed, t tests, or 
Wilcoxon signed-rank tests will be used to determine where the interaction occurred. 
M0 versus M1 will be compared to evaluate the changes in patients and trace the necessary 
timespan for such changes using General Linear Mixed Model Analysis for repeated measures with 
Tukey’s posthoc procedure for the mean comparisons. Pearson product moment correlation 
coefficient or Spearman's rank correlation coefficient will be used to study the relationship 
between different variables by group and correlation coefficients will be compared between 
groups. Statistical significance will be set at an alpha level of 0.05. Other statistical procedures can 
be done. 
Statistical analyses will be conducted using Statistical Package for the Social Sciences (SPSS) 
22.0 (IBM SPSS Statistics, Chicago, IL, USA). 
Data analysis will allow peer reviews publication, slide presentations and oral 
communications in national and international conferences, during year of 2018 and beginning of 
2019 to present all the results of the project. 
 
 
 
 
 
 
 
 
1. R. Belardinelli, D. Georgiou, G. Cianci and A. Purcaro, 10-year exercise training in chronic heart 
failure: A randomized controlled trial, J Am Coll Cardiol 60 (2012), no. 16, 1521-1528. 
2. G. Loncar, S. Fülster, S. von Haehling and V. Popovic, Metabolism and the heart: An overview of 
muscle, fat, and bone metabolism in heart failure, Int J Cardiol 162 (2013), no. 2, 77-85. 
3. J. Y. Tabet, P. Meurin, A. B. Driss, H. Weber, N. Renaud, A. Grosdemouge, F. Beauvais and A. 
Cohen-Solal, Benefits of exercise training in chronic heart failure, Arch Cardiovasc Dis 102 
(2009), no. 10, 721-730. 
4. J. H. Caldwell, J. M. Link, W. C. Levy, J. E. Poole and J. R. Stratton, Evidence for pre- to 
postsynaptic mismatch of the cardiac sympathetic nervous system in ischemic congestive heart 
failure, J Nucl Med 49 (2008), no. 2, 234-241. 
5. J. Downing and G. J. Balady, The role of exercise training in heart failure, J Am Coll Cardiol 58 
(2011), no. 6, 561-569. 
REFERENCES 

16 
 
6. R. Belardinelli, Arrhythmias during acute and chronic exercise in chronic heart failure, Int J 
Cardiol 90 (2003), no. 2-3, 213-218. 
7. D. W. Kitzman, D. M. Herrington, P. H. Brubaker, J. B. Moore, J. Eggebeen and M. J. Haykowsky, 
Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart 
failure and preserved ejection fraction, Hypertension 61 (2013), no. 1, 112-119. 
8. H. Ooi, W. Chung and A. Biolo, Arterial stiffness and vascular load in heart failure, Congest Heart 
Fail 14 (2008), no. 1, 31-36. 
9. V. S. Effoe, C. J. Rodriguez, L. E. Wagenknecht, G. W. Evans, P. P. Chang, M. C. Mirabelli and A. 
G. Bertoni, Carotid intima-media thickness is associated with incident heart failure among 
middle-aged whites and blacks: The atherosclerosis risk in communities study, J Am Heart Assoc 
3 (2014), no. 3, e000797. 
10. C. N. Marti, M. Gheorghiade, A. P. Kalogeropoulos, V. V. Georgiopoulou, A. A. Quyyumi and J. 
Butler, Endothelial dysfunction, arterial stiffness, and heart failure, J Am Coll Cardiol 60 (2012), 
no. 16, 1455-1469. 
11. J. J. Whyte and M. H. Laughlin, The effects of acute and chronic exercise on the vasculature, Acta 
Physiol (Oxf) 199 (2010), no. 4, 441-450. 
12. C. G. Cardoso, R. S. Gomides, A. C. Queiroz, L. G. Pinto, F. da Silveira Lobo, T. Tinucci, D. Mion 
and C. L. de Moraes Forjaz, Acute and chronic effects of aerobic and resistance exercise on 
ambulatory blood pressure, Clinics (Sao Paulo) 65 (2010), no. 3, 317-325. 
13. D. Acanfora, P. Scicchitano, G. Casucci, B. Lanzillo, N. Capuano, G. Furgi, C. Acanfora, M. 
Longobardi, R. A. Incalzi, G. Piscosquito and M. M. Ciccone, Exercise training effects on elderly 
and middle-age patients with chronic heart failure after acute decompensation: A randomized, 
controlled trial, Int J Cardiol 225 (2016), 313-323. 
14. R. Hambrecht, E. Fiehn, C. Weigl, S. Gielen, C. Hamann, R. Kaiser, J. Yu, V. Adams, J. Niebauer 
and G. Schuler, Regular physical exercise corrects endothelial dysfunction and improves exercise 
capacity in patients with chronic heart failure, Circulation 98 (1998), no. 24, 2709-2715. 
15. S. von Haehling, N. Ebner, M. R. Dos Santos, J. Springer and S. D. Anker, Muscle wasting and 
cachexia in heart failure: Mechanisms and therapies, Nat Rev Cardiol (2017). 
16. A. Casas-Vara, F. Santolaria, A. Fernández-Bereciartúa, E. González-Reimers, A. García-Ochoa 
and A. Martínez-Riera, The obesity paradox in elderly patients with heart failure: Analysis of 
nutritional status, Nutrition 28 (2012), no. 6, 616-622. 
17. M. Hülsmann, M. Quittan, R. Berger, R. Crevenna, C. Springer, M. Nuhr, D. Mörtl, P. Moser and 

17 
 
R. Pacher, Muscle strength as a predictor of long-term survival in severe congestive heart 
failure, Eur J Heart Fail 6 (2004), no. 1, 101-107. 
18. S. D. Anker, P. Ponikowski, S. Varney, T. P. Chua, A. L. Clark, K. M. Webb-Peploe, D. Harrington, 
W. J. Kox, P. A. Poole-Wilson and A. J. Coats, Wasting as independent risk factor for mortality in 
chronic heart failure, Lancet 349 (1997), no. 9058, 1050-1053. 
19. S. Mandic, J. Myers, S. E. Selig and I. Levinger, Resistance versus aerobic exercise training in 
chronic heart failure, Curr Heart Fail Rep 9 (2012), no. 1, 57-64. 
20. C. Zizola and P. C. Schulze, Metabolic and structural impairment of skeletal muscle in heart 
failure, Heart Fail Rev 18 (2013), no. 5, 623-630. 
21. M. J. Toth, M. S. Miller, P. VanBuren, N. G. Bedrin, M. M. LeWinter, P. A. Ades and B. M. Palmer, 
Resistance training alters skeletal muscle structure and function in human heart failure: Effects 
at the tissue, cellular and molecular levels, J Physiol 590 (2012), no. Pt 5, 1243-1259. 
22. R. W. Braith, M. A. Welsch, M. S. Feigenbaum, H. A. Kluess and C. J. Pepine, Neuroendocrine 
activation in heart failure is modified by endurance exercise training, J Am Coll Cardiol 34 
(1999), no. 4, 1170-1175. 
23. K. A. Volaklis and S. P. Tokmakidis, Resistance exercise training in patients with heart failure, 
Sports Med 35 (2005), no. 12, 1085-1103. 
24. S. Cohen, J. A. Nathan and A. L. Goldberg, Muscle wasting in disease: Molecular mechanisms 
and promising therapies, Nat Rev Drug Discov 14 (2015), no. 1, 58-74. 
25. P. Meyer, M. Gayda, M. Juneau and A. Nigam, High-intensity aerobic interval exercise in chronic 
heart failure, Curr Heart Fail Rep 10 (2013), no. 2, 130-138. 
26. AACVPR, Guidelines for cardiac rehabilitation and secondary prevention programs 5th edition 
with web resource2013. 
27. H. Santa-Clara, B. Fernhall, M. Mendes and L. B. Sardinha, Effect of a 1 year combined aerobic- 
and weight-training exercise programme on aerobic capacity and ventilatory threshold in 
patients suffering from coronary artery disease, Eur J Appl Physiol 87 (2002), no. 6, 568-575. 
28. J. E. Ware and C. D. Sherbourne, The mos 36-item short-form health survey (sf-36). I. Conceptual 
framework and item selection, Med Care 30 (1992), no. 6, 473-483. 
29. K. Brown, A review to examine the use of sf-36 in cardiac rehabilitation, Br J Nurs 12 (2003), no. 
15, 904-909. 
30. P. L. Ferreira, [development of the portuguese version of mos sf-36. Part i. Cultural and linguistic 
adaptation], Acta Med Port 13 (2000), no. 1-2, 55-66. 

18