The Effect Of An Expanded Long Term Periodization Exercise Training In Patients With Cardiovascular Disease: Central And Peripheral Adaptations
Phase: NA
Conditions: Cardiovascular Diseases, Coronary Artery Disease
Sponsor: University of Lisbon

 
 
 
  
STUDY PROTOCOL AND STATISTICAL ANALYSIS 
The Effect Of An Expanded Long Term Periodization 
Exercise Training In Patients With Cardiovascular Disease: 
Central And Peripheral Adaptations 
Date: 24/09/2019 

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The Effect Of An Expanded Long Term Periodization Exercise Training In Patients 
With Cardiovascular Disease: Central And Peripheral Adaptations 
BACKGROUND 
Cardiovascular Disease (CVD) remains the main cause of death in most European countries accounting for over 
four million deaths (47% of all deaths) each year1,2. In Portugal CVD is among the main causes of morbidity, 
mortality and disability3.  
Cardiac Rehabilitation (CR) of patients with CVD has been practiced in Europe to varying degrees since the 
early 1970s1. Coronary heart disease (CHD), if left untreated, is a progressive disease and individuals with CHD 
are at high risk for recurrent events4. CR is a comprehensive, long-term program involving medical evaluation, 
prescribed exercise training (ET), cardiac risk factor modification, education and counselling. These programs 
are designed to limit the physiologic and psychological effects of cardiac illness, reduce the risk for sudden 
death or re-infarction, control cardiac symptoms, stabilize or reverse the atherosclerotic process, and enhance 
the psychosocial and vocational status of selected patients5. Furthermore, it is a safe, useful and an effective 
treatment for patients with coronary artery disease (CAD)6,7, particularly after myocardial infarction (MI), but 
also for patients with cardiac interventions and chronic stable heart failure8,9. Being a Class I recommendation 
from the American Heart Association, the American College of Cardiology, and the European Society of 
Cardiology, with exercise therapy consistently identified as a central element, guidelines recommend that 
patients with acute coronary syndromes should be offered comprehensive CR services in order to reduce risk 
factors that may have an impact on future cardiovascular complications10. 
Exercise adherence after a hospital-based CR program is reported to be poor with only 30% to 60% of those 
who complete a phase II CR program are still exercising 6 months later and after 12 months, up to 50 to 80% 
of participants failing to adhere to exercise11-14. Despite the benefits associated with regular ET, adherence 
with supervised exercise-based CR remains low15. More studies are needed to assess interventions that may 
help patients adhere to regular and effective ET after ending a hospital-based CR exercise program.  
A brief review of meta-analysis studies that assess the impact of different types of exercise in short term 
outcomes for participants of CR will now be presented. The findings of a meta-analysis in 2015 indicated that 
high intensity interval training (HIIT) is more effective than moderate continuous training (MCT) for the 
improvement of both VO2 peak and the anaerobic threshold (AT) in patients with stable CAD 16. The greater 
improvement in VO2 peak following HIIT compared to MCT (4.6 ± 3.1 versus 2.8 ± 2.4 ml/kg/min) is important 
in the context of a 10-25% survival advantage with every 3.5 ml/kg/min improvement in VO2 peak17. 
Another meta-analysis in 2016, compared HIIT and MCT in their ability to improve patients aerobic exercise 
capacity and various cardiovascular risk factors. Ten studies with 472 patients were included for analyses (218 
HIIT, 254 MCT) and the main conclusions were that HIIT improves the mean VO2 peak in patients with CAD 
more than MCT, although MCT was associated with a more pronounced numerical decline in patients resting 
heart rate (HR) and body weight18.  
Current CR guidelines recommend the inclusion of a standardized resistance training (RT) program10,19. A 
recent meta-analysis of ET programs in patients with CAD revealed that the addition of RT training to MCT led 
to superior improvements in body composition, muscle strength, peak work capacity, and a trend for greater 

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increases in VO2 peak20. Similar to HIIT, RT has not been shown to compromise patient safety or program 
adherence20. 
Less is known about central and peripheral adaptations during long term effects on HIIT, MCT or even aerobic 
combined training with RT. In 2016, a systematic review and meta-analysis with a total of 63 studies with 
14,486 participants with CHD median follow-up of 12 months were included21. It was concluded that exercise-
based CR reduces cardiovascular mortality and provides important data showing reductions in hospital 
admissions and improvements in quality of life21. Madssen et al22, showed that a 12-month maintenance 
exercise program consisting of infrequent supervised exercise sessions did not result in improved adherence 
to exercise or increased VO2 peak in CAD patients compared to usual care. One monthly session during a year 
of HIIT was not enough to improve or maintain exercise capacity. In the literature there is a lack of evidence 
on the effects in exercise capacity, muscle strength and body composition in long term weekly supervised 
exercise sessions on a maintenance exercise program in CVD patients.  
Current exercise guidelines for CR focus on moderate intensity steady state exercises, with walking and cycling 
being the most recommended types of ET10. The repetitive nature of this type of activity can become 
monotonous for the patient, affecting exercise adherence, compliance and training outcomes. Multiple 
training variables can be manipulated during exercise prescription, including repetitions, interval length, rest 
period length and intensity of resistance. In this regard, much insight could be gained from approaches used 
in sport conditioning, where exercise prescription is designed to be physiologically and psychologically 
sustainable using periodization.  
Periodization was developed in the 1960’s by the Russian physiologist Leo Matveyev23 and is defined as an 
organized cyclic program that uses planned variations in intensity, volume, and specificity to minimize fatigue 
and maximize performance outcomes24. Periodized programs are composed of macrocycles, mesocycles and 
microcycles. The largest cycle or macrocycle is 1 year in length, each macrocycle is then broken into 
mesocycles, traditionally 1 to 3 months in length. Finally, each mesocycle is broken into individual 
microcycles23. In healthy or trained populations, periodization aims to optimize ET adaptations as compared 
with non periodized training, to prevent overtraining and to avoid plateauing of training adaptations25,26. The 
classical approach to periodization is linear periodized training, consisting in promoting wave-like progression, 
typically moving from general training (high volume/low intensity) towards specific training (low volume/high 
intensity)27. Periodized methods are considered to be superior to nonperiodized methods in trained 
populations25 and appears to be superior in inactive adults28. Interestingly, a recent study investigated the 
effect of 22 weeks of 2 different types of periodization and 1 non periodization RT protocols on a 
comprehensive range of physical function and health outcomes in apparently healthy untrained older adults29. 
Contrary of what was hypothesised, all three training models were equally effective for promoting significant 
improvements in various physical function and physiological health outcomes through RT in this population29.  
In most of the CR programs there are no periodization or exercise progression during medium to long term 
interventions. Further randomized controlled trials (RCT) are necessary to evaluate long-term periodization 
outcomes and assess the length of change observed in supervised CR programs. 
 
 
 

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PURPOSE 
To overcome the lack of knowledge regarding the physiological effects after hospital-based CR program, a 12 
month RCT study will be performed. This study will hopefully contribute to generate evidence-based exercise 
prescription approaches to prolong the ET after the end of hospital-based CR programs. 
The purpose of this research project is twofold:  
1) To conduct a 12-month randomized control trial to evaluate the effects of periodized ET regime versus a 
non periodized ET regime on VO2 peak, maximal strength, body composition, functionality and quality of life 
in CVD patients.  
2) to differentiate the effects of a 12-month periodized ET regime versus a non periodized ET regime on the 
different components of the oxygen kinetics response and oxidative adaptations in CVD patients. 
The primary end points for aim 1 are: cardiopulmonary exercise testing (CPET) variables such as VO2 peak, AT, 
peak work rate, ventilatory equivalent of carbon dioxide (VE/VCO2), ventilatory equivalent of oxygen 
(VE/VO2), minute ventilation (VE), one repetition maximum (1RM), total body bone mineral content, lean and 
fat tissue mass and percentage of body fat mass, quality of life and functional physical fitness tests. The 
primary end points for aim 2 are oxygen kinetics and muscle deoxygenation dynamics of the vastus lateralis 
muscle at the submaximal test.  
The hypothesis for this study are: 1) considering that this type of periodization exerts higher stress on the 
cardiovascular and neuromuscular systems, so that there could be greater adaptations, leading to higher 
increases in VO2max, muscle strength, body composition and functionality compared to non periodized ET 
regime; 2) there will be a better improvement microvascular O2 delivery in the exercise transient in response 
to periodized ET regime that would be associated with a faster adjustment of pulmonary VO2 kinetics than in 
non periodized group. Improvements in microvascular O2 delivery would be indicated by a better matching 
between the rate of adjustment of muscle deoxygenation relative to phase II pulmonary VO2, which 
represents a decreased reliance on O2 extraction for a given pulmonary VO2. 
 
METHODS 
PARTICIPANTS 
Patients with CVD that underwent to a hospital-based 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: 1) periodized group; 2) non periodized group following the American College of Sports and 
Medicine (ACSM) guidelines30. Patient’s eligibility will be assessed according to the risk stratification criteria 
for patients with CVD for low and/or moderate risk stratification from the American Association of 
Cardiovascular and Pulmonary Rehabilitation 31. Male and female participants, ≥ 18 years of age, who had an 
established history of the following conditions or procedures will be included: MI, or coronary 
revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or 
coronary artery stent), angina pectoris or coronary artery disease defined by angiography. Exclusion criteria 

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will be participants who had heart failure, heart transplants with either cardiac resynchronization therapy or 
implantable defibrillators; inability to comply with guidelines for participation in exercise testing and 
training30; and significant limiting and/or unstable comorbidities that would prevent full participation. 
Sample size was calculated (G-Power, Version 3.1.3) assuming a difference in peak oxygen uptake (VO2 peak) 
between groups of 3 ml/kg/min to be a clinical important difference with a SD of 3.5 ml/kg/min, α=0.05, 1-
β=0.80 and an expected dropout rate of 37%. The calculations yielded a total minimum sample size of 50 
participants (25 in each group). 
STUDY DESIGN 
A longitudinal RCT research design using two distinct ET prescriptions (periodization vs non periodization) will 
be applied in CVD patients. Briefly, following the informed consent process, patients will be randomized and 
stratified (by gender and age) to periodization or non periodization groups. The randomization code will be 
developed with a computer random-number generator to select random permuted blocks. Participants will 
exercise for a period of 12 months. All the same assessments, except the echocardiogram that will be done in 
M0 and M3 (for risk stratification), are going to be taken in 4 different time points during a year: M0 - baseline, 
M1 - 3 months after starting the ET, M2 - 6 months after starting the ET and M3 - 12 months after starting the 
ET. The patients will be randomized into either one of the two ET group. Recruitment and screening will last 
12 months (September 2017 to September 2018) and the patient assessment will last until September 2019. 
It is expected to finish the project with peer-review redaction submitted and/or accepted in December 2019.  
The following assessments on the 4 time points will be performed at the Pulido Valente Hospital, FMH-UL and 
Academia de Fitness at EUL: Echocardiogram (Echo) (MyLab Alpha, ESAOTE); cardiopulmonary exercise test 
(CPET) (Ergostik, Geratherm Respiratory GmbH, Bad Kissingen); skeletal muscle deoxygenation dynamics 
(NIMO, Nirox srl); body composition - dual energy radiographic absorptiometry (DXA, Hologic Explorer-W); 
objective measured physical activity - accelerometer (ActiGraph GT3X+); functional physical fitness - Fullerton 
Functional Fitness Test; isometric strength – portable hand dynamometer JAMAR plus digital (Sammons 
Preston); maximal strength – 1RM and Quality of Life questionnaire. 
All assessment moments will be done in 1 to 2 weeks: 
Day 1 – Echo and CPET will be performed at the Pulido Valente Hospital;  
Day 2 and 3 – during the day and time of the ET session at the EUL, the patient will perform: functional physical 
fitness tests; maximal strength; isometric strength and Quality of Life questionnaire;  
Day 4 – In FMH, the dual energy radiographic absorptiometry (DXA) exam and the activation of the 
accelerometer to measure the objective measured physical activity will be done. 
Day 5 – Submaximal CPET with the skeletal muscle deoxygenation dynamics at the Pulido Valente Hospital. 
Individual reports will be sent by email or delivered on paper. During the 3-year project the multidisciplinary 
team will have bimonthly meetings to update the study information and discuss the patient’s progress. 
 
 

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MEASUREMENT PROCEDURES 
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 left ventricular ejection fraction by Simpson`s formula, telediastolic and telessystolic volumes 
and diameters, doppler analysis of the transmitral flow, tissue doppler and quantification of mitral valve 
regurgitation.  
EXPECTED RESULTS 
The variables measured in this task will provide clinical information to patient screening. Most of the human 
and animal studies demonstrated that post-MI physical exercise training results in positive effect on 
myocardial remodeling32. These beneficial effects include improved cardiac function, mitigated interstitial 
myocardial fibrosis, and enhanced physical capacity. It is expected a positive effect on myocardial remodeling 
in both exercise training groups. It is important to note that the existing studies have only investigated the 
effects of endurance exercise on post-MI remodeling; therefore, the effects of post-MI resistance training or 
combined endurance and resistance training have yet to be systematically examined to identify a better 
exercise mode.  
2. CARDIOPULMONARY EXERCISE TEST 
CPET is the best technique to obtain the maximal and submaximal functional capacity. Those tests will be 
performed with the subjects in a non-fasting condition and under the regular medication.  
Symptom-limited exercise test 
A symptom-limited ramp incremental CPET, in accordance with the Clinician’s Guide to Cardiopulmonary 
Exercise Testing in Adults33, will be performed on a cycle ergometer (Ergostik, Geratherm Respiratory GmbH, 
Bad Kissingen, Germany) with breath-by-breath gas exchange measurements. 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 2 minutes unloaded pedaling and 2 more minutes at rest, each patient will be 
encouraged to exercise to exhaustion (20 Watt+20 Watt/min or 15 Watt+15Watt/min or 10 Watt+10 
Watt/min), 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. Twelve-lead ECG will be recorded continuously and blood pressure will be recorded 
at baseline, every two minutes, at peak exercise and during recovery. Peak oxygen capacity will be considered 
the highest attained VO2 during the final 30s of exercise and ventilator AT will be estimate by the V-slope 
method. 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 (CR) to exercise will be evaluated by the % of HR reserve (HRR) used at peak exercise. 
CR= [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 

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maximal effort in the CPET. The CPET will provide clinical information to patient screening and exercise 
intensity prescription. 
Submaximal exercise test 
On a separate day to the maximal test, patients will be recruited for a constant load exercise test. The test 
load is set at 80% of the value of the work rate corresponding to the AT detected in the maximum test, which 
was performed first, or 50% of VO2 peak, if the AT could not be adequately determined.  Cardiopulmonary 
data will be recorded for 5 minutes at rest followed by 1 minute unloaded pedaling. After unloaded pedaling, 
patients will perform the constant load test for 6 min at the work rate described above, followed by unloaded 
pedaling for 5min. To improve the confidence of the kinetic parameter determination, this test will be 
performed three times and the averaged profile will be used for the kinetic analysis. 
Curve fitting will be performed with Graphics software Origin version 7.0 (Microcal Software Inc., 
Northampton, Massachusetts, USA) using iterative techniques. The kinetics of the oxygen uptake response to 
the constant workload exercise will be analyzed by the sequent separate phases. 
Before each maximal and submaximal test, the gas analyzer will be calibrated using ambient air and standard 
calibration gases of known concentration (16.7% O2 and 5.7% CO2). The calibration of the turbine flowmeter 
will be performed using a 3l syringe (Quinton Instruments, Seattle, Wash.) Twelve-lead ECGs, blood pressure, 
and ratings of perceived exertion will be recorded during each exercise stage. 
EXPECTED RESULTS 
The CPET will provide fundamental information to exercise intensity prescription and is a primary endpoint for 
purpose 1 and 2. We expect increases in VO2max in both training regimes from 5%–15% after 12 months of 
physical conditioning, with the greatest improvements in the periodized training group. 
It is expected that there would be an improved microvascular O2 delivery in the exercise transient in response 
to both training groups that would be associated with a faster adjustment of VO2 kinetics, with the greatest 
improvements in the periodized training group. 
3. SKELETAL MUSCLE DEOXYGENATION DYNAMICS 
The muscle deoxygenation dynamics of the Vastus Lateralis muscle will be evaluated throughout the 
submaximal CPET. Deoxyhaemoglobin [HHb], oxyhaemoglobin [HbO2], and total haemoglobin [HbT] 
concentrations will be quantified with a continuous-wave tissue oximeter (NIMO, Nirox srl, Brescia, Italy), 
based on the Near-infrared Spectroscopy (NIRS) system, which provides continuous, non-invasive monitoring 
of the relative concentration changes in these variables during rest and exercise. Brieﬂy, this system is based 
on the oxygen dependency of absorption changes for near infra-red light in haemoglobin and myoglobin and 
it consists on an emission probe which emits three wave lengths (685, 850 and 905 nm) and a photon detector. 
The intensity of incident and transmitted light will be record continuously at 40 Hz and used to estimate the 
concentrations changes relative to baseline for oxygenated, deoxygenated and total haemoglobin. To account 
for the possible influence of the local fat layer on NIRS a real-time correction using an algorithm included in 
the software program v2.0 supplied with the spectrometer (Nimo Data Analysis Peak) will be used. Since the 
HHb signal is less dependent of changes in blood flow it can be used as an indicator of fractional O2 extraction 
within the microvascular level. This task will be performed at rest, during and immediately following the 

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submaximal CPET. The off- oxygen consumption and HHb kinetics will be determined using a monoexponential 
model which incorporates an amplitude, time constant and time delay.  
EXPECTED RESULTS 
The off- oxygen consumption and HHb kinetics will be determined using a mono-exponential model which 
incorporates an amplitude, time constant and time delay. As the recovery of muscle and total 
body oxygenation from both maximal and submaximal exercise is delayed in sedentary participants, it is 
expected that the exercise training, in particular the periodized training group, induces a decrease of the time 
constant of the exponential decrease of these parameters.  
4. BODY COMPOSITION - DUAL ENERGY RADIOGRAPHIC ABSORPTIOMETRY (DXA) 
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. 
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. 
EXPECTED RESULTS 
DXA provides descriptive data on the body composition of all patients from the studied groups and will be 
important to monitor the changes in body composition over time and to quantify the intervention effects 
particularly regarding fat free mass and muscle wasting. It will also allow adjustments to the expected 
differences between groups at the end of the study. It is not probable to find exercise-related changes in body 
weight but small reductions in percent total body and regional fat are desirable, as well as increases in lean 
soft tissue of the lower limbs in the exercise groups. The variables obtained in this task are primary endpoints 
of purpose 1 and secondary endpoints of purpose 2. We expect small reductions in regional fat layer thickness 
in the exercise groups, especially in periodized training group.  
5. 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 

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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 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. 
EXPECTED RESULTS 
This assessment will be used as a control of the physical activity or inactivity of the participants. The ones who 
reported at least moderate-intensity cardiorespiratory exercise training for ≥ 30 minutes per day on ≥ 5 days 
a week for a total of ≥ 150 minutes per week, vigorous-intensity cardiorespiratory exercise training for ≥20 
minutes per day on ≥ 3 days a week (≥75 minutes per week), or a combination of moderate and vigorous 
intensity exercise to achieve a total energy expenditure of ≥ 500-1000 MET minutes per week, consistent with 
the recommendations of the American College of Sports Medicine34, will be classified as active. Those not 
meeting this criterion will be considered inactive. We expect increases in time spent in moderate-to-vigorous 
physical activity from M0 to M3 in both exercise groups. 
6. 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 -). 
 

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EXPECTED RESULTS 
The variables measured in this task are primary end-points of purpose 1. We expect gradual improvements of 
the functional fitness test scores from M0 to M3 in both exercise groups, in particular the periodized training 
group. 
7. ISOMETRIC STRENGTH 
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. 
EXPECTED RESULTS 
The variables measured in this task are secondary aims of the project. It remains to be determined whether a 
training protocol that specifically focuses on increasing hand grip strength would have a greater impact on 
overall functional status. Maximal isometric strength is not expected to decrease in both exercise groups.  
8. 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 studies35. 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 ET. 
EXPECTED RESULTS 
The variables measured in this task are primary endpoints of aim 1. Significant improvements in maximal 
strength are possible as high from 50 and 69% of 1-RM among middle-aged CAD participants and over 80% of 
1- RM in elderly CAD participants36. 

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9. QUALITY OF LIFE QUESTIONNAIRE  
The Short Form-36 Health Survey (SF-36) is a self-assessment health status questionnaire composed of 36 
questions about socio-demographic, health and personal behavior37. 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 quality of life: 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 programs38. A Portuguese validated version of SF-
36 is available39. 
EXPECTED RESULTS 
The variables measured in this task are primary endpoints of aim 1 of the project, it is expected improvements 
in the quality of life for both exercise training groups and a bi-directional relationship with increased physical 
activity and vocational status40. 
10. EXERCISE TRAINING PROGRAM 
The ET program will be carried out mostly in groups at the EUL gymnasium, 3 times a week (60 minutes per 
session) on non-consecutive days for 48 weeks and supervised for both groups. To ensure that total training 
loads (i.e., volume x intensity) were similar in both groups despite differences in intensity, it will be used the 
training impulses (TRIMP) method from Edwards41 for the aerobic component and the volume load method 
for the RT component42,43. 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. In every 10 exercise sessions, 
it will be prescribed multifunctional exercise with the aim to develop other fitness components such as agility, 
flexibility and balance. In total, approximately 14 multifunctional exercise sessions will be prescribed during 
48 weeks. Sessions will be deemed completed when at least 90% of the prescribed exercises have been 
successfully performed. 
Periodized group: the exercise prescription will be gradually progressed through various combinations of 
duration, frequency and/or intensity of training. Over the first 15 exercise sessions, it will be prescribed 
continuous ET: 20 minutes on an ergometer with the intensity of the first AT (AT1) measured on the CPET or 
50-60% of the HRR, if the AT could not be adequately determined44, Borg Rating of Perceived Exertion (RPE) 
equivalent 9-11; and anatomical RT adaptation (2 sets of 15-20 repetitions 50% 1RM); from the 16th session 
until the 30th session, it will be prescribed combined ET with HIIT45: 4 interval training periods of 2 minutes 
(AT2 intensity or 80-90% HRR, if AT2 could not be determined44, RPE 15-17) and 4 active pauses of 2 minutes 
(below AT1 or 40-50% HRR, RPE 6-9) between interval training periods; and hypertrophy (2 sets 8-12 
repetitions at 60% 1RM). From the 31st until the 45th exercise session, after the adjustments of the 
respectively time point assessments, it will be done 20 minutes of MCT with the intensity between AT1 and 

11 
 
AT2 or of 60-70% HRR, RPE 12-13 and maximal strength (2 sets of 6-8 repetitions at 80% 1RM).  From the 46th 
until the 60th exercise sessions, it will appear again the HIIT with the same pause intensities but different work 
intensities (above AT2 intensity or > 90% HRR, RPE 17-19 and active pauses at AT1 or 50-60% HRR, RPE 9-11) 
with hypertrophy (2 sets 8-12 repetitions 60% 1RM). At the end of the 60th session, the same exercise 
prescription will start over again, MCT with maximal strength, HIIT with hypertrophy, MCT with maximal 
strength and HIIT with hypertrophy until the 134th session. The 2 types of RT prescribed will focus on the 
major trunk, upper and lower body muscle groups in circuit weight training 46 and/or machines (Life Fitness, 
Rosemont, IL, USA). The patients will be instructed about the correct exercise techniques and to avoid the 
Valsalva maneuver. 
Non periodized group: in accordance with the ACSM Guidelines 2014 30 for CVD, participants will do a 
combined ET regime (aerobic and RT). Aerobic component: combine moderate (40% HRR) to vigorous (75% 
HRR) exercises 3 d.wk-1 on nonconsecutive days, for 20 min per session, involving major muscle groups using 
the available ergometers (treadmill, indoor row and cycle ergometer) to perform continuous and rhythmic 
activities in nature. Resistance component: RT should be performed after the aerobic component of the 
exercise session to allow for adequate warm-up. Initial load should be trained initially with one set of 10–15 
repetitions that can be lifted without straining (~30%–40% 1RM for the upper body; ~50%–60% 1 RM for the 
lower body). Low-risk patients may progress to 2–4 sets with 8–12 repetitions with a resistance of ~60%–80% 
1RM with a rest interval of 2–3 min between sets. Each major muscle group (i.e., chest, shoulders, arms, 
abdomen, back, hips, and legs) should be trained initially with one set; multiple set regimens may be 
introduced later as tolerated. Perform 8–10 exercises of the major muscle groups. 
By design, the non periodized group involves an identical total training volume and time commitment but 
differed regarding metabolic stress induced by the periodized group. All patients will be monitored with a HR 
monitor (H7 Polar, Electro, Kempele, Finland) 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 ET session. 
11. TRIMP CALCULATIONS 
The quantification of the training load in the aerobic component by the Edwards method41 will be performed 
from the division of intensity zones related to maximal HR (HRmax) -  Zone 1: 50 at 60% of HRmax; Zone 2: 60 
at 70% of HRmax; Zone 3: 70 at 80% of HRmax; Zone 4: 80 at 90% of HRmax; Zone 5: 90 at 100% of HRmax. 
Since the HR prescription that are being used is in % HRR, it will be converted % HRmax to % HRR as it is 
possible to observe in Table 1. For estimation of the Edwards method, the time accumulated in each zone was 
multiplied by its value and the results obtained will be summed (Table 2). 
 
 

12 
 
Table 1: Methods of Estimating Intensity of Cardiorespiratory Exercise (Adapted from Garber et all34) 
Intensity 
%HRR or %VO2R 
%HR max 
Edwards method Zone 
Very light 
< 30 
< 57 
1 
Light 
30 - < 40 
57 - < 64 
2 
Moderate 
40 - < 60 
64 - < 76 
3 
Vigorous 
60 - < 90 
76 - < 96 
4 
Near maximal to maximal 
≥ 90 
≥ 96 
5 
HRmax, maximal heart rate; HRR, heart rate reserve; VO2R, oxygen uptake reserve.  
Table 2: Intensity and duration, as quantified by daily trimp per every 15 exercise sessions during the training 
period for the periodized group and the non-periodized group. 
 
 
The equation for calculating the volume load for the RT is accomplished by multiplying the number of 
repetitions by the percentage of 1-RM43. This equation is represented as the following: Volume load (kg) = 
number of sets x number of repetitions x %1RM. In both groups, TRIMP is similar (Periodized: 12820 vs Non 
Periodized: 12790). 
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. A single researcher will perform the database management. 
EXPECTED RESULTS 
We expect to add the data collected at M0, M1, M2 and M3 to the database within 2 weeks of the end of the 
respective evaluation moment, and store it at the FMH-UL web server allowing detailed progress reports and 
back-ups when needed. Individual reports will be delivered within 2 weeks of the end of the respective 
evaluation moment. 
Aerobic Component 
 
 
Linear Periodized Group 
Non Periodized Group 
Number of 
sessions 
total 
time 
work 
sets 
work 
(min) 
rest 
sets 
rest 
(min) 
work 
(zone) 
rest 
(zone) 
extra 
(min) 
extra 
(zone) 
TRIMP 
daily 
work 
sets 
work 
(min) 
work 
(zone) 
TRIMP 
daily 
1 to 15 
20 
1 
20 
0 
0 
2 
0 
0 
0 
40 
1 
20 
2 
40 
16 to 30 
20 
4 
2 
4 
2 
4 
2 
4 
1 
60 
1 
20 
3 
60 
31 to 45 
20 
1 
20 
0 
0 
3 
0 
0 
0 
60 
1 
20 
3 
60 
46 to 60 
20 
4 
2 
4 
2 
5 
3 
4 
1 
60 
1 
20 
3 
60 
61 to 75 
20 
1 
20 
0 
0 
3 
0 
0 
0 
60 
1 
20 
3 
60 
76 to 90 
20 
4 
2 
4 
2 
4 
2 
4 
1 
60 
1 
20 
3 
60 
91 to 105 
20 
1 
20 
0 
0 
3 
0 
0 
0 
60 
1 
20 
3 
60 
106 to 120 
20 
4 
2 
4 
2 
5 
3 
4 
1 
60 
1 
20 
3 
60 
121 to 135 
20 
1 
20 
0 
0 
3 
0 
0 
0 
60 
1 
20 
3 
60 
 
 
 
 
 
 
 
 
 
 
520 
 
 
 
520 

13 
 
13. STATISTICAL ANALYSIS 
Data will be analyzed in M0, M1, M2 and M3. 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 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 ET) 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, M0 versus M2, M0 versus M3, M1 versus M2, M2 versus M3 and M1 versus M3 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 redaction, slide presentations and oral communications in national and 
international conferences at the end of 2017 beginning of 2018.  
 
 

14 
 
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