the acute physiological response to high-intensity ......the acute physiological response to...
TRANSCRIPT
The Acute Physiological Response to High-intensity Interval Exercise in Patients with Coronary Artery Disease
by
Vanessa Dizonno
A thesis submitted in conformity with the requirements for the degree of Master of Science
Graduate Department of Exercise Sciences University of Toronto
© Copyright by Vanessa Dizonno (2017)
ii
The acute physiological response to high-intensity interval exercise in
patients with coronary artery disease
Vanessa Dizonno
Master of Science
Graduate Department of Exercise Sciences University of Toronto
2017
Abstract
High-intensity interval exercise (HIIE) elicits quicker and more substantial improvements in
aerobic capacity compared to moderate-intensity continuous exercise (MICE), but the protocol
that optimizes the physiological stimulus and patient preference is undetermined. Fifteen patients
with coronary artery disease (CAD) underwent physiological assessment during 3 different HIIE
protocols and MICE. The 4x4 protocol elicited a greater physiological stimulus, as indicated by
heart rate (HR), oxygen uptake (VO2), rating of perceived exertion (RPE), and blood pressure
responses, but was the least preferred HIIE protocol. The 10x1 protocol was most preferred, it
was comparable to MICE, and should be considered a timesaving alternative. TRIP proved to be
a strong physiological stimulus and may be a viable choice opposed to long duration intervals,
for its similar HR response and RPE at a higher VO2 compared to MICE. These results indicate
that HIIE is an efficient and well-tolerated exercise prescription for CAD patients.
iii
Acknowledgments
First and foremost, I would like to thank my supervisor, Dr. Jack Goodman, for his mentorship
and continued support throughout my undergraduate and graduate experience, and I am
extremely grateful for the academic resources and opportunities made available to me. This
thesis project would not have been possible without his expertise and guidance. A special thank
you to Dr. Katharine Currie who has been another academic mentor, and has taught me many of
the skills required of this thesis. I would also like to acknowledge my other committee members,
Dr. Scott Thomas and Dr. Paul Oh, who have contributed valuable insight over the past two
years.
I would like to pay special mention to my family members and friends who have been my
irreplaceable support network, and have provided continuous encouragement throughout my
entire academic career. Thank you to my lab colleagues for allowing me to practice and refine
my skills and assisting during data collection.
Departmental funding and scholarships I received from the university and generous donors
allowed me to focus my efforts on my research and academic success, and I am thankful for this
financial support.
Finally, I appreciate the time and hard work put forth by my study participants, who were a
pleasure to have a part of the study.
iv
Table of Contents
ACKNOWLEDGMENTS ........................................................................................................................ III
LIST OF TABLES ...................................................................................................................................VII
LIST OF FIGURES ............................................................................................................................... VIII
LIST OF APPENDICES .......................................................................................................................... IX
LIST OF ABBREVIATIONS .................................................................................................................... X
– INTRODUCTION AND RATIONALE ..........................................................................1
1.1. INTRODUCTION ...............................................................................................................................1
1.2. RATIONALE .....................................................................................................................................3
1.3. AIMS................................................................................................................................................4
1.3.1. Primary aim .............................................................................................................................4
1.3.2. Secondary aim .........................................................................................................................4
1.4. EXPERIMENTAL APPROACH .............................................................................................................4
1.5. STUDY HYPOTHESES .......................................................................................................................6
1.5.1. Primary hypothesis ..................................................................................................................6
1.5.2. Secondary hypothesis ..............................................................................................................6
– REVIEW OF LITERATURE ..........................................................................................7
2.1. INTRODUCTION ...............................................................................................................................7
2.2. CHRONIC RESPONSE TO HIGH-INTENSITY INTERVAL TRAINING ......................................................8
2.2.1. Effect of HIIT on maximal aerobic capacity ...........................................................................9
2.2.2. Effect of HIIT on cardiac structure and function ..................................................................12
2.2.3. Effect of HIIT on QoL, adherence and safety ........................................................................14
2.3. ACUTE RESPONSE TO HIGH-INTENSITY INTERVAL EXERCISE ........................................................16
2.3.1. Effect of HIIE on the acute cardiorespiratory response ........................................................16
2.4. HIIE PROTOCOL OPTIMIZATION ....................................................................................................17
2.4.1. Work interval .........................................................................................................................18
2.4.2. Recovery interval ...................................................................................................................18
2.4.3. HIIE optimization summary ..................................................................................................20
2.5. MECHANISMS ................................................................................................................................20
2.5.1. Chronic exercise ....................................................................................................................20
2.5.2. Acute exercise ........................................................................................................................21
2.6. SUMMARY OF REVIEW OF LITERATURE .........................................................................................22
v
– METHODOLOGY AND METHODS ..........................................................................23
3.1. STUDY OVERVIEW .........................................................................................................................23
3.2. PARTICIPANTS ...............................................................................................................................23
3.2.1. Participant inclusion and exclusion criteria .........................................................................23
3.2.2. Standard of care ....................................................................................................................23
3.2.3. Recruitment ...........................................................................................................................24
3.3. STUDY VISITS ................................................................................................................................25
3.3.1. Visit 1 – Consent and familiarization ....................................................................................25
3.3.1. Visits 2-5 – Exercise interventions ........................................................................................25
3.4. STUDY MEASURES .........................................................................................................................29
3.4.1. Resting phenotypic characteristics ........................................................................................29
3.4.2. HR, BP, RPE, VO2 .................................................................................................................29
3.4.3. Participant exercise preference .............................................................................................30
3.5. DATA AND STATISTICAL ANALYSES .............................................................................................30
3.5.1. Sample size calculation .........................................................................................................30
3.5.2. Data analysis .........................................................................................................................30
3.5.3. Statistical analysis .................................................................................................................31
– THE ACUTE PHYSIOLOGICAL RESPONSE TO HIGH-INTENSITY
INTERVAL EXERCISE IN PATIENTS WITH CORONARY ARTERY DISEASE ........................32
ABSTRACT ............................................................................................................................................32
INTRODUCTION ..................................................................................................................................32
MATERIALS AND METHODS ............................................................................................................33
RESULTS ...............................................................................................................................................38
DISCUSSION .........................................................................................................................................41
CONCLUSION .......................................................................................................................................45
ACKNOWLEDGEMENTS ....................................................................................................................45
– CONCLUSION ...............................................................................................................46
5.1. EXTENDED DISCUSSION ................................................................................................................46
5.1.1. Clinical implications .............................................................................................................47
5.1.2. Patient preferences ................................................................................................................48
5.2. STUDY LIMITATIONS .....................................................................................................................49
5.3. FUTURE DIRECTIONS .....................................................................................................................51
5.4. CONCLUSION .................................................................................................................................52
REFERENCES ..........................................................................................................................................54
vi
APPENDIX A: RECRUITMENT SCRIPT ............................................................................................67
APPENDIX B: SCREENING FORM .....................................................................................................70
APPENDIX C: RECRUITMENT POSTER ...........................................................................................71
APPENDIX D: CONSENT FORM ..........................................................................................................72
APPENDIX E: BORG RATING OF PERCEIVED EXERTION ........................................................80
APPENDIX F: MEDICAL HISTORY QUESTIONNAIRE .................................................................81
APPENDIX G: EXTENDED TECHNICAL PROTOCOLS .................................................................83
APPENDIX H: PRE-VISIT CHECKLIST .............................................................................................92
APPENDIX I: DATA COLLECTION SHEETS ....................................................................................93
APPENDIX J: HIIE QUESTIONNAIRE .............................................................................................101
APPENDIX K: ADDITIONAL RESULTS ...........................................................................................104
vii
List of Tables
Table 1. Summary of HIIT studies examining aerobic capacity in patients with CAD.
Table 2. Detailed description of HIIE protocols.
Table 3. Participant characteristics.
Table 4. Detailed description of HIIE protocols for manuscript.
Table 5. Study results.
Table 6. Additional results.
viii
List of Figures
Figure 1. Intermittent versus continuous exercise training variables, format, and associated adaptations.
Figure 2. Variables that can be manipulated in a HIIE session.
Figure 3. Familiarization protocol schematic.
Figure 4. 4x4 protocol schematic.
Figure 5. 10x1 protocol schematic.
Figure 6. TRIP schematic.
Figure 7. MICE schematic.
Figure 8. Exercise protocol schematics for manuscript.
Figure 9. VO2 response to exercise protocols.
Figure 10. HR response to exercise protocols.
Figure 11. Group average SBP and DBP responses to the exercise protocols.
ix
List of Appendices
Appendix A: Recruitment Script
Appendix B: Screening Form
Appendix C: Recruitment Poster
Appendix D: Consent Form
Appendix E: Borg Rating of Perceived Exertion
Appendix F: Medical History Questionnaire
Appendix G: Extended Technical Protocols
Appendix H: Pre-visit Checklist
Appendix I: Data Collection Sheets
Appendix J: HIIE Questionnaire
Appendix K: Additional Results
x
List of Abbreviations
AT Anaerobic Threshold AUC Area Under the Curve BLa Blood Lactate BMI Body Mass Index BNP B-type Natriuretic Peptide BP Blood Pressure CABG Coronary Artery Bypass Graft CAD Coronary Artery Disease CPA Cardiopulmonary Assessment CR Cardiac Rehabilitation CRS Cardiac Rehabilitation Supervisor cTn Cardiac Troponin CV Cardiovascular CVD Cardiovascular Disease DBP Diastolic Blood Pressure ECG Electrocardiogram EDV End-Diastolic Volume EF Ejection Fraction eNOS Endothelial Nitric Oxide Synthase ESV End-Systolic Volume FMD Flow-Mediated Dilation HF Heart Failure HIIE High Intensity Interval Exercise HIIT High Intensity Interval Training HR Heart Rate HRpeak Peak Heart Rate HRR Heart Rate Reserve KT Knowledge Translation LV Left Ventricle MI Myocardial Infarction MICE Moderate Intensity Continuous Exercise MICT Moderate Intensity Continuous Training NO Nitric Oxide PCI Percutaneous Coronary Intervention PCr Phosphocreatine QoL Quality of Life RCT Randomized Controlled Trial RPE Rating of Perceived Exertion RPP Rate Pressure Product RR Risk Ratio SIT Sprint Interval Training TRI Toronto Rehabilitation Institute TRIP Toronto Rehabilitation Institute Protocol TTE Time to Exhaustion TWH Toronto Western Hospital
xi
UHN University Health Network VAT Ventilatory Anaerobic Threshold VO2 Oxygen Uptake VO2max Maximal Oxygen Uptake VO2peak Peak Oxygen Uptake VO2R Oxygen Uptake Reserve
1
– Introduction and Rationale
1.1. Introduction
An aging population is associated with higher chronic disease morbidity prevalence, particularly
cardiovascular (CV) disease. Coronary artery disease (CAD) continues to be one of the leading
causes of death worldwide [1] and is characterized by plaque development (atherosclerosis) in
the coronary arteries, resulting in ischemia from compromised coronary blood flow. CV risk
factors include: hypercholesterolemia, hypertension, obesity, Type II diabetes mellitus, and
physical inactivity. These are associated with a chronic inflammatory state in the vasculature,
leading to impaired vasodilatory capacity and endothelial dysfunction of peripheral vessels [2,
3]. Furthermore, aerobic fitness is a main prognostic indicator for CAD patients [4, 5]; thus,
interventions that aim to improve peak oxygen uptake (VO2peak) and CV health in CAD patients
are of particular relevance.
Exercise training has proven to be an effective and safe therapeutic intervention to improve
health outcomes in patients with CAD, potentially acting to impede atherosclerosis development
and enhance endothelial function [6]. Cardiac rehabilitation (CR) programs involving exercise
training have shown greater reductions in overall and CV disease (CVD) mortality compared to
usual care [7]. Physical activity levels and CV fitness are important correlates of CV endpoints in
both healthy and CVD populations [8], so the standard of care for CR involves 30-60mins of
moderate-intensity continuous exercise (MICE) (40-85% heart rate reserve (HRR)) utilizing
large muscle groups [9-11]. Conventional aerobic exercise training improves endothelial
dysfunction in individuals with CAD, and may attenuate the age-related decline in vascular
function [12]. Despite these clear benefits, one of the main barriers to CR adherence is a
perceived lack of time [13], so the development of shorter but effective exercise prescriptions
that elicit clinically-relevant improvements in physiological outcomes are desired.
In contrast to continuous exercise, intermittent/interval exercise involves alternating bouts of
intense exertion followed by short periods of rest, and has been widely used in athletic training
models for almost a century. It has become widely advocated as a strategy to improve VO2peak
rapidly and more significantly in many controlled studies [14-16]. Various types or sub-
categories of interval exercise exist, including sprint interval training (SIT) and high-intensity
2
interval training (HIIT), whereby SIT involves supra-maximal efforts (i.e., a pace equal or
greater than what would elicit maximal VO2 [VO2max]) and HIIT near-maximal (i.e., 85-95%
VO2max). Rest periods typically allow for a partial, but not complete, recovery and can be
passive (complete rest) or active (light-moderate intensity) in nature. SIT, while effective in
some contexts, is both physically and mentally demanding, and thus, is not generalizable to all
individuals. In contrast, working at high, but sub-maximal, intensities during HIIT makes it both
feasible and a potentially safer alternative.
Figure 1. Intermittent versus continuous exercise training variables, format, and associated adaptations. Taken from MacInnis and Gibala [17].
High-intensity interval exercise (HIIE) allows for the greater achievement of total time spent at
high workloads than otherwise possible with continuous exercise, facilitating substantial
improvements in aerobic capacity in both healthy and clinical populations. It allows individuals
to train at workloads above the anaerobic threshold (AT) but below maximal exercise capacity,
producing similar or superior improvements in VO2peak [16, 18-21], AT [18-20], cardiac
function [18], endothelial function [18, 22, 23], exercise adherence and quality of life [20, 21,
24] compared to moderate-intensity continuous training (MICT). In addition, HIIT is an
attractive training model as the time period required for each exercise session can be markedly
reduced (i.e., low-volume HIIT). A recent meta-analysis [25] found that HIIT was superior to
3
MICT as it increased VO2peak by 1.78 ml·kg-1·min-1 greater in those with CAD. Additionally,
HIIT induces a larger improvement in endothelial-dependent function compared to MICT [22].
HIIE has been used in various clinical populations including heart failure (HF) [26, 27] and CAD
[18, 20] without adverse outcomes in both supervised and home-based rehabilitation settings
[28-30]. Therefore, it is now accepted to be a safe, efficacious alternative to high-volume aerobic
exercise training in the general community and within CR programs. A recent retrospective study
demonstrated that there was a low risk of CV events with both HIIT and conventional MICT in
4,846 patients with CAD in a CR setting (1 fatal cardiac arrest during 129,456 hours of MICE
and 2 nonfatal cardiac arrests during 46,364 hours of HIIE) [31]. Leaders in the field of CR, such
as the Mayo Clinic and the Toronto Rehabilitation Institute (TRI), are in the process or have
already adopted HIIT as standard of care treatment for all patients [32]. Originally described by
Wisloff et al. in HF patients, the HIIT protocol adopting four, 4-min intervals of high-intensity
with 3-mins of moderate-intensity recovery has been extensively studied in the literature, and has
proven to elicit superior gains in aerobic fitness compared to MICT matched for total work [27].
However, patients have to be highly compliant and motivated to complete this particular
regimen. Gibala et al. described a practical, low-volume HIIE protocol that is time-efficient and
more widely applicable to patient populations [33, 34]. This protocol, consisting of ten, 1-min
high-intensity intervals with 1-min of low-intensity recovery, has proven to be effective in
patients with CAD [23]. In response to the overwhelming amount of favourable research for
HIIT in clinical cohorts, the TRI has developed a unique interval-continuous exercise hybrid
protocol that is prescribed to eligible and willing patients in the CR program.
1.2. Rationale
HIIT has the potential to improve VO2peak and its limiting factors [35], which are observably
impaired in clinical populations compared to healthy and athletic individuals. Despite the
growing acceptance of HIIT for select patient groups, a protocol that optimizes patient outcomes
(i.e., VO2peak, CV end-points) has not yet been determined. Numerous HIIE protocols have
been developed, using various combinations of interval and recovery durations/intensities, but
largely based on data from athletic populations [36-38]. Little is known about the degree to
which varying protocols perturb the CV system or challenge energy production systems for
patient populations, and this response will be influenced by CAD pathophysiology and arguably
4
unlike that observed in healthy and athletic cohorts. The magnitude of CV stimulus, and
consequently, the potential for adaptation from long-term exercise training can be determined
from an acute study investigating different exercise protocols on physiological parameters.
Different combinations of intensity and duration of both interval and recovery phases elicit
unique, acute physiological responses [33], so careful consideration of these variables is needed
to optimize tolerability and pleasure, if patients are to truly adhere to and benefit from HIIT [39].
1.3. Aims
1.3.1. Primary aim
Therefore, the primary aim of this investigation was to examine the acute physiological effects of
3 HIIE protocols compared to MICE in patients with CAD. Exercise intensities that correspond
to a high oxygen uptake (VO2) maximally stress oxygen transport and utilization systems;
therefore, the accumulated time spent at this high VO2 may determine associated physiological
benefits [36, 37, 40-42]. Interval exercise has been shown to result in a longer time spent at a
high %VO2max compared to MICE [43], so the optimal protocol may be one that allows long
periods of time to be spent near or at VO2peak. Accordingly, the primary outcome was chosen to
be time spent at a high VO2, and more specifically, above 90%VO2 reserve (VO2R). Clinically
meaningful improvements in CV adaptations should be observed if exercising above this
threshold.
1.3.2. Secondary aim
A secondary objective was to quantitatively assess participant exercise preference for each
exercise protocol.
Overall, results from this study will help to determine a HIIE protocol that is both effective and
preferred by CAD patients.
1.4. Experimental approach
This investigation provides novel insight into the acute physiological response to 4 exercise
protocols that are currently adopted in CR patients. The study used a crossover design to allow
the comparison of 3 HIIE protocols to 30 mins of MICE. The 4x4 protocol (four, 4-min high-
intensity intervals with 3-min moderate-intensity recovery) was chosen as it has consistently
5
proven to elicit superior and rapid improvements in aerobic capacity in a variety of healthy and
clinical populations. Selected for its low-volume design, the 10x1 protocol (ten, 1-min high-
intensity intervals with 1-min low-intensity recovery) can be a timesaving alternative to higher-
volume continuous exercise, while achieving physiological responses of equal magnitude. The
TRI protocol (TRIP), a hybrid of interval and continuous exercise employing short-duration
intervals (30-sec) and moderate-intensity bouts (3-min), is an example of a site-specific exercise
prescription that has yet to be formally investigated. Lastly, 30 mins of MICE was included as
the control condition to represent conventional exercise prescription and current standard of care
in CR [11]. With the exception of TRIP, these protocols have been studied as part of chronic
exercise training studies, but their acute physiological effects are less well-known. Few acute
HIIE studies in clinical populations exist, and a comprehensive examination of the physiological
response to the aforementioned exercise protocols is lacking. This thesis project adds valuable
and duly warranted insight to expand the current knowledge base that exists for HIIE in CR.
Exercise intensity was prescribed using heart rate (HR), specifically %HRR, because it is
considered the gold-standard for indirect intensity assessment by the ACSM [9] and for its
widespread use in CR settings. In addition, rating of perceived exertion (RPE) was used in
conjunction with HR monitoring for its general ease of use and practicability during interval
exercise [44]. Participants performed exercise sessions on the treadmill so that study results
could be translatable to modes frequently used in CR and outside of the laboratory. Data was
analyzed in reference to the achievement of certain intensities, specifically above thresholds
corresponding to the MICE average and 90% VO2R. Values attained during the MICE session
can be considered the characteristic stimulus during a CR exercise session, so working above this
threshold should theoretically induce greater adaptations than typically observed, whereas time
spent near VO2peak (i.e., >90%VO2R) has been suggested to elicit improvements in maximal
aerobic capacity [43, 45]. A greater improvement in VO2max with training was observed with
HIIE eliciting a longer time spent ≥VO2max [46], but empirical evidence to support this in
clinical cohorts is lacking. Though the exact exercise intensity threshold to elicit improvements
in VO2peak for cardiac patients is currently undetermined [47], 90-100% of VO2max has been
found to increase VO2max to the greatest extent [15, 48, 49], providing a logical threshold for
investigation.
6
1.5. Study hypotheses
1.5.1. Primary hypothesis
It was hypothesized that the 4x4 protocol would result in a greater time spent at a high VO2 (i.e.,
>90%VO2R) relative to MICE because of its long duration intervals and moderate-intensity
recovery periods. In addition, 10x1 and TRIP were hypothesized to be comparable to
conventional MICE, owing to its short-duration intervals and low-intensity recovery periods.
These hypotheses are supported by a study that examined the acute CV response to long (4-min)
intervals, short (20-sec) intervals, and 28 mins MICE in CR patients. Peak VO2 values were
higher during the long-duration interval protocol compared to both short-duration intervals and
MICE [50]. Although time spent at high %VO2peak was not measured, it is plausible that it
would be greatest with intervals of long duration. This is also supported findings by Meyer et al.
in HF patients [51].
1.5.2. Secondary hypothesis
A secondary hypothesis was that patients would prefer the 10x1 protocol, for its short interval
duration, low-intensity recovery, and total time.
7
– Review of Literature
2.1. Introduction
The benefits of exercise have long been supported in the literature, with higher levels of fitness
reducing the risk of acute myocardial infarction (MI) or sudden cardiac death [52], outweighing
any potential risk associated with exercise participation [53]. Exercise-based CR is standard of
care, eliciting reductions in CV and overall mortality (13 and 26%, respectively) [7] through
improvements in VO2peak, quality of life (QoL), and reductions in hospital admissions and
associated costs [54-56]. Mechanisms that these improvements can be attributed to include:
increased myocardial perfusion [6], reduced CV risk factors (i.e., body fat percentage, lipid
profile, blood biomarkers, blood pressure [BP] regulation), improved endothelial function,
inflammation, and sympathovagal balance, and favourable cardiac remodeling and enhanced
function [57-59]. Conventional aerobic exercise training has been shown to improve vascular
health in individuals with CAD [6], and may attenuate the age-related decline in vascular
function in men [12]. It is considered a safe and effective therapeutic intervention for patients
participating in a CR program.
Typically, 30-60 minutes of MICE (40-85%HRR) on most days of the week [9] is prescribed to
CR patients, in line with current Canadian exercise recommendations [10]. Improvements in
aerobic capacity and vascular structure and function in the CAD population have been seen with
12 weeks of MICE [60, 61], but regressed with a period of detraining [62]. Those with lower
baseline fitness and poorer CV health likely experience the greatest benefits [63], making it
crucial to advocate for daily exercise participation in CAD patients. Since VO2peak has
prognostic value for patients with CVD [5], and each 1 ml·kg-1·min-1 increase equals a 15%
decline in all-cause mortality [4], the exercise training program that elicits the greatest increase
in VO2peak should be adopted. It is pertinent to find an effective exercise intervention, especially
considering results from HF-ACTION, a multi-centre randomized controlled trial (RCT), show
that MICT in HF patients increased VO2peak <1 ml·kg-1·min-1 with suboptimal adherence rates
[64].
Exercise volume is a key parameter that affects the magnitude of improvement in aerobic
capacity with chronic training, dependent on the intensity, duration, and frequency of each
8
exercise session. Specifically, aerobic exercise intensity, rather than duration or frequency, is the
main factor to influence the training response and cardioprotective effects [10, 65-71]. A review
of epidemiological studies and clinical trials found that vigorous, compared to moderate-
intensity, exercise had greater cardioprotective effects by reducing CVD risk and improving
aerobic capacity, diastolic BP (DBP), and glucose regulation to a greater extent [65]. Data
suggests that intensity effectively improves VO2max [72], with a greater magnitude of
improvement with increasing exercise intensity between 50-100% VO2max [48]. Moreover,
high-intensity exercise (>90%VO2max) produces a potent metabolic signal promoting
mitochondrial biogenesis [17], and high-level muscle fibre recruitment that subsequently
improves the aerobic potential of type II fibres [73]. Exercise intensity may not only dictate the
magnitude of improvement in a dose-response manner, but the achievement of certain intensity
thresholds may be a requirement for particular physiological adaptations [68].
2.2. Chronic response to high-intensity interval training
Coaches have been using interval training for almost a century because it is an effective way to
optimize an athlete’s training program and maximize improvements in physical performance. In
order to compete at a high level in competitive events, endurance athletes aim to have a high
VO2max and the ability to maintain a high %VO2max for extended periods. Training regimes
must elicit sustained intensities representative of competition in order to improve lactate kinetics,
muscle fibre recruitment, fatigue resistance, and thus, athletic performance [74].
Interval exercise allows for a longer time to be spent in high-intensity zones compared with
continuous exercise, eliciting more substantial improvements in VO2max [14, 75]. HIIT consists
of short bursts or intense intervals separated by periods of lower intensity active or passive
recovery. It allows individuals to train at workloads above the AT, but below VO2max, and has
been shown to improve both submaximal and maximal exercise capacities [36]. HIIT is a potent
stimulus to perturb both central and peripheral systems, surpassing the beneficial adaptations
observed with MICT [76]. A variety of modes can be practiced, including: incline walking,
running, swimming, cycling, and rowing. In fact, only one HIIE session per week may be all that
is needed to reduce CV mortality risk in men (risk ratio [RR]=0.61) and women (RR=0.49), with
no added benefit of increasing the duration or number of sessions [66]. Since one of the main
barriers to exercise adherence is a perceived lack of time [13], it is desirable to integrate HIIT
9
into exercise programs to induce beneficial adaptions and maximize adherence. This preliminary,
yet promising, research has sparked interest for further investigation in patient populations. Since
the seminal work by Wisloff et al. in HF patients [27], many others have sought to investigate
the physiological effects of HIIT in other clinical cohorts, such as those with CAD.
2.2.1. Effect of HIIT on maximal aerobic capacity
HIIT elicits superior increases in maximal exercise capacity compared to MICT, with a 46%
increase in VO2peak (vs. 14%) reported in HF patients who participated in a 12-week training
program [27]. This impressive improvement was likely due to low baseline fitness (VO2peak=13
ml·kg-1·min-1) and the specific HIIT protocol employed (4x4: four, 4-min intervals at 90-95% of
peak HR [HRpeak] interspersed with 3-min active recovery periods at 50-70% HRpeak). Studies
utilizing this protocol in CAD patients have still shown HIIT to be superior to MICT, but not to
the same extent as in the HF population. Rognmo et al. recruited 21 patients with stable CAD
and found that 10 weeks of HIIT, specifically treadmill walking, elicited an increase in VO2peak
of 17.9% (vs. 7.9% with MICT) [77], findings consistent with other investigations using the
same HIIT protocol [78-81]. In a longer-term training study with coronary artery bypass graft
(CABG) patients, both HIIT and MICT had comparable increases in VO2peak after 4 weeks
(HIIT: 27 vs. 30, MICT: 26 vs. 29 ml·kg-1·min-1), but the HIIT group continued to improve while
the MICT group had similar VO2peak values at the 6-month time point (32 vs. 30 ml·kg-1·min-1,
p<0.05, respectively) [82]. This is particularly meaningful because 6 months consisted of home-
based exercise, whereby participants were asked to exercise 3-4 times per week at home,
confirmed with exercise diaries.
The limitation of most previous work is that studies have been small, single-centre trials. The
SAINTEX-CAD study aimed to investigate the efficacy and safety of HIIT in 200 CAD patients
[83]. Participants randomized to 12 weeks of either HIIT or MICT experienced comparable
increases in VO2peak at both the 6- (+15% vs. +13%, respectively) and 12-week (+23% vs.
+20%, respectively) time points. The similar, rather than superior, improvements in VO2peak
contrast previous results, likely because 4-min intervals at 90-95% HRpeak were not feasible for
study participants. Training intensity was often reduced to avoid hyperventilation or volitional
fatigue; thus, the average intensity of the HIIT group was lower than the prescribed intensity
10
(88% HRpeak). Additionally, participants in the MICT group were able to exercise at intensities
averaging 80% HRpeak, which is at the upper-end of moderate-intensity prescription.
A different HIIT protocol (2-min intervals at 85-95% HRR/VO2R with 2-min recovery periods at
35-45% HRR/VO2R) increased VO2peak to a similar extent compared to MICT in high-
functioning men with CAD [28]. Both exercise protocols were designed to maintain an average
training intensity of 65% VO2R to reflect the training intensity used by the athletic population,
whereas comparatively, the average training intensity of the 4x4 protocol is significantly higher.
However, a variation of the aforementioned HIIT protocol (2 mins at 90% HRmax, followed by
2 mins at 60% HRmax) induced superior increases in VO2peak, compared to maintenance in
MICT and deterioration in control [84]. Another study found similar increases in VO2peak with
HIIT (3-min intervals at the respiratory compensation point with 3-min recovery at the
ventilatory anaerobic threshold [VAT]) and MICT (50 mins at VAT) [85]. It could be that
exercising at intensities greater than the VAT provides no additional benefit; however, not all
data is in agreement with this [86]. A recently published study, which used 20-sec intervals at
50% of maximum workload with 40-sec recovery at 10%, found 8 weeks of training to increase
VO2peak more so than MICT (+4.5 vs. +2.5 ml·kg-1·min-1, respectively) in ischemic heart
disease patients [30].
Thus far, the popular 4x4 protocol has been compared to isocalorically-matched MICT, but low-
volume HIIT has surfaced to address the difficulties associated with intervals of long duration.
The development of a practical, low-volume HIIE protocol that is time-efficient and more widely
applicable to patient populations was sought after [33, 34]. This 10x1 protocol, consisting of ten,
1-min high-intensity intervals with 1-min of low-intensity recovery, has elicited comparable
increases in VO2peak compared to MICT participants who performed twice as much work
(HIIT: 20 vs. 25, MICT: 19 vs. 23 ml·kg-1·min-1) [23]. Patients with lower baseline fitness and/or
motivation may find the 10x1 protocol to be more manageable. Fortunately, a randomized RCT
in UK CR centres is currently underway, with participants in the HIIT group performing low-
volume HIIT [87]. This will provide valuable insight into the efficacy of low-volume HIIT in the
CR setting, through the pragmatic examination of its physiological, psychological, and economic
impact.
11
Due to the variety of interval protocols in the literature, recent meta-analyses and systematic
reviews have aimed to compare the effectiveness of HIIT to MICT in aerobic capacity. Cornish
et al. [18] conducted a systematic review and found HIIT to increase VO2peak to a greater extent
compared to MICT in CAD patients, despite the methodological limitations in all of the
reviewed studies. A 2015 meta-analysis, consisting of six RCTs, found HIIT to be superior to
MICT as it increased VO2peak by 1.5 ml·kg-1·min-1greater in those with CAD [19], similar to
results found in another meta-analysis [25]. Twenty-one studies, totaling 736 cardiac patients,
were considered in a recently published systematic review and meta-analysis, which aimed to
compare the effects of HIIT and MICT on the main outcome of aerobic fitness [88]. Again, HIIT
improved VO2peak to a greater extent compared to MICT (+1.76 ml·kg-1·min-1, p<0.001), but
improvements in essentially all other physiological outcomes (i.e., BP, weight, lipids, endothelial
and cardiac function) were comparable between interventions. The authors suggested peripheral
mechanisms to contribute to the greater improvement in aerobic capacity, including: increased
activation of PGC-1α (influences substrate utilization and mitochondrial biogenesis), improved
Ca2+ handling, enhanced peripheral blood flow, and gains in skeletal muscle capacity. Although
these findings coincide with earlier reports, the studies included were significantly heterogeneous
(i.e., population studied, duration of intervention, exercise protocol utilized). Refer to Table 1 for
a summary of HIIT studies in CAD patients.
It appears that HIIT elicits comparable, if not superior, improvements in VO2peak while
reducing the time commitment required of patients. Specifically, it is likely that superior training
adaptations are observed with the 4x4 protocol compared to isocalorically-matched MICE, and
comparable if prescribing the 10x1, low-volume HIIT protocol [17].
12
Table 1. Summary of high-intensity interval training (HIIT) studies examining peak oxygen uptake (VO2peak) in patients with coronary artery disease (CAD). VO2peak results are presented as the percent increase from baseline (HIIT vs. moderate-intensity continuous training [MICT]), and the superior, inferior, or equal effect of HIIT compared to CONT (i.e., MICT/control).
2.2.2. Effect of HIIT on cardiac structure and function
Increased arterial stiffness from atherosclerotic development in the coronary vasculature can lead
to myocardial ischemia, owing to a decrease in coronary perfusion and concomitant increase in
myocardial oxygen demand. Accordingly, the effect of HIIT on cardiac structure and function is
of interest in the cardiac patient population. Wisloff et al. found that 12 weeks of HIIT, and not
MICT, resulted in smaller left ventricle (LV) systolic and diastolic diameters (-15% and -12%,
Author (year)
Participants
Duration
(weeks)
Intervention HIIT
CONT
VO2peak results
Superior Inferior
Equal
Rognmo et al.
(2004)
21 CAD 10 4x4 85/55%VO2peak
41min 50-60%VO2peak
+18% vs +8% Superior
Warburton et
al. (2005)
14 CAD 16 2x2 90/40%HRR
30min 65%HRR
Not available Superior
Amundsen et
al. (2008)
17 CAD 10 4x4 85/55%VO2peak
41min 50-60%VO2peak
+17% vs +8% Superior
Moholdt et al. (2009)
59 CABG 4 + 26 4x4 90/70%HRmax 46min 70%HRmax
4w: +12% vs +9% 26w: +6% vs +4%
Equal Superior
Munk et al.
(2009)
40 PCI 26 4x4 85/65%HRmax
usual care
+17% vs +8% Superior
Moholdt et al.
(2012)
89 MI 12 4x4 90/70%HRpeak
usual care
+14% vs +8% Superior
Rocco et al.
(2012)
37 CAD 13 7x3 RCP/VAT
50min VAT
+25% vs +23% Equal
Currie et al.
(2013)
22 CAD 12 10x1 89/10%PPO
30-50min 58%PPO
+24% vs +19%
Equal
Keteyian et al.
(2014)
39 CR
patients
10 4x4 85/65%HRR
40min 60-80%HRR
+16% vs +8%
Superior
Conraads et al. (2015)
200 CAD 12 4x4 90/60%HRpeak 47min 70-75%HRpeak
+23% vs +20%
Equal
Kim et al. (2015)
28 MI/PCI 6 4x4 90/60%HRR 45min 70-85%HRR
+22% vs +8%
Superior
Cardozo et al.
(2015)
71 CAD 16 2x2 90/60%HRmax
30min 70-75%HRmax control
+18% vs 0% vs
-14%
Superior
Jaureguizar et
al. (2016)
72 CAD 8 20s/40s 50/10%Wmax
30min VT
+23% vs +12% Superior
CABG, coronary artery bypass graft, CAD, coronary artery disease, CR, cardiac rehab, HRmax, maximum heart rate, HRpeak, peak heart rate, HRR, heart rate reserve, VAT, ventilatory anaerobic
threshold, VT, ventilatory threshold, Wmax, maximal workload
13
respectively) and LV end-systolic and end-diastolic volumes (ESV/EDV) (-24% and -18%,
respectively), indicative of reverse LV remodeling in HF patients [27]. Measures of systolic (i.e.,
LV ejection fraction [EF], stroke volume, contractility) and diastolic (i.e., Ea) function improved
in the HIIT group, with no significant changes observed in MICT and control groups. In
addition, HIIT elicited a 40% reduction in proB-type natriuretic peptide (BNP), a biomarker of
cardiac hypertrophy (i.e., released in response to elevated filling pressures and indicative of
cardiac stress). Using a post-MI rat model, HIIT led to greater increases in exercise capacity and
cardiac function (i.e., LVEF, fractional shortening) and similarly attenuated apoptosis compared
to MICT [89]. However, superior cardiac adaptations with HIIT have not been consistently
observed. The SMARTEX study, a randomized multicenter trial including 261 HF with reduced
EF patients, found the change in LV end-diastolic diameter to be similar between HIIT and
MICT groups [90]. It follows that the improvement in VO2peak was also similar between groups,
but could be owing to the suboptimal exercise intensity in the HIIT group while MICT exercised
above target. In fact, deleterious cardiac remodeling may occur with HIIT, as evidenced by an
increase in LV mass, no fibrosis regression, and increased BNP in rodents with hypertension-
induced HF [91].
A study that used a CAD cohort found LV filling speed and diastolic relaxation to be improved
with HIIT, using tissue Doppler to compare 10 weeks of either HIIT or MICT on indices of LV
function [78]. However, systolic function (i.e., resting EF) did not seem to change post-training
in either group. Moreover, HIIT has been seen to improve LV compliance, contributing to the
observed increase in systolic ejection volume, stroke volume, and cardiac output [84]. HIIT may
even help with the age-associated decline in cardiac function in older adults. Not only was an 8-
week HIIT program safe and feasible, but also effective at improving aerobic fitness and resting
LVEF (+4%, p=0.001), compared to unchanged values in MICT and control groups [92]. While
LV morphology and diastolic function remained unchanged in this group of healthy sedentary
older adults, another study found diastolic function at rest and both systolic and diastolic reserve
during exercise to improve [93]. It is likely that the opportunity for positive remodeling in
pathological hearts is greater.
It is important to consider the length of the exercise intervention, especially in the context of
cardiac remodeling. Improvements in peak aerobic capacity observed after short-term HIIT or
MICT are not likely from central adaptations. Measures of systolic and diastolic function (i.e.,
14
resting EF, EDV, ESV) were essentially unchanged after a 4-week intervention [82], suggesting
that the similar increase in VO2peak between groups was due to peripheral mechanisms;
however, this was not measured. There also seems to be an intensity-dependent effect on
cardiomyocytes, whereby higher intensity exercise resulted in better cardiomyocyte hypertrophic
responses/contractile parameters (i.e., fractional shortening, Ca2+ handling, myofilament
responsiveness to Ca2+) compared to low- or moderate-intensity exercise [72].
Therefore, considering the paucity of data available in the CAD population, it is difficult to draw
a definitive conclusion. Evidence in HF patients suggests HIIT elicits positive central
adaptations, but its superiority in other populations is not well-substantiated. Long-duration
interventions are needed to more clearly illustrate exercise-induced cardiac remodeling in the
CAD population.
2.2.3. Effect of HIIT on QoL, adherence and safety
Although a higher risk of CV events has been suggested with higher intensity exercise [52], HIIT
has been used in various clinical populations including HF [26, 27, 90] and CAD [18, 20]
without adverse outcomes in both supervised and home-based rehabilitation settings [28-30].
Therefore, it may be regarded as a safe, efficacious alternative to high-volume aerobic exercise
in the general community and within CR programs [94]. A retrospective study demonstrated that
there was a low risk of CV events after both HIIT and conventional MICT in 4,846 patients with
CAD in a CR setting (1 fatal cardiac arrest during 129,456 hours of MICE and 2 nonfatal cardiac
arrests during 46,364 hours of HIIE) [31]. However, in a 2015 systematic review that evaluated
the safety of HIIE in individuals with cardiometabolic disease, the rate of adverse events (~8% of
patients) was higher than previously documented for MICE, despite all of which being non-fatal
[95]. Furthermore, a dose-response relationship may exist for high-intensity exercise and
increased risk of percutaneous coronary intervention (PCI, RR=1.05, p=0.047), as found in a
systematic review and meta-regression [96]. It should be noted that only 3 of the 8 included trials
prescribed exercise in the form of intervals and the intensity was lower than what is typically
found in the HIIT literature. As such, caution should be exercised when performing HIIE in
clinical populations, but overall, the risk of complication is low in patients absent of
contraindications. Confirmation of eligibility and initial supervision are encouraged upon
incorporating HIIE into a patient’s exercise program.
15
Home-based interval training studies have aimed to determine if patients can adhere to and
perform vigorous exercise without the occurrence of adverse events, and further, its effect on
health-related QoL. Moholdt et al. randomized 30 CABG patients to either home-based HIIT or
residential CR and found similar increases in VO2peak (+4 vs. +5 ml·kg-1·min-1, respectively)
and QoL at 6-months follow-up [97]. Despite being an underpowered study, adherence rates
were acceptable for the interventions, with 7 out of 12 participants reporting ≥2 interval sessions
per week for the whole 6-month period. There was one fatal adverse event whereby a patient in
the residential group died during the warm-up of a low-intensity skiing session. Another study
implemented a 12-week HIIT program, either hospital- (treadmill or group) or home-based in
patients with CAD [29]. There were no reports of adverse events (i.e., cardiac arrest, acute MI),
aside from an ankle sprain and Achilles tendonitis during group exercise. Treadmill exercise
elicited a significantly greater increase in VO2peak compared to home-based exercise (+1.6
ml·kg-1·min-1, p=0.02); however, there were no other differences between groups. Exercise
adherence was lower in the home-based HIIT group, as 4 participants in this group did not reach
≥70% of the recommended exercise sessions, and thus, could possibly explain its ineffectiveness
to increase VO2peak to the same extent. Participants were then followed up 1 year later to
evaluate long-term adherence. VO2peak and health-related QoL were significantly above
baseline values, with no significant differences between the three groups [98]. The home-based
exercise group trended towards having higher levels of physical activity, but 94.5% of
participants were meeting exercise guidelines, performing at least 30 mins of daily physical
activity. It may be that the number of HIIE sessions performed is important for maintenance, as 1
monthly supervised plus 3 at-home interval sessions for 12 months was not enough to improve
exercise adherence or VO2peak. Despite the lack of apparent improvement when discharged
from the CR program, aerobic fitness did not deteriorate in these CAD patients [99]. QoL
followed the same trend, where it increased significantly after the intervention and was
maintained at follow-up. Most studies have found an equal [30, 83, 100] or superior [27] effect
of HIIT compared to MICT on QoL. However, results published from the SMARTEX study are
not in line with previous findings. QoL was unchanged after both HIIT and MICT interventions,
probably owing to the study’s suboptimal outcomes [90].
16
Home-based HIIT appears to be an effective and safe alternative to supervised cardiac
rehabilitation, and provides the added benefit of being a low-burden intervention that may
promote better long-term exercise adherence [101].
2.3. Acute response to high-intensity interval exercise
The high rate of ATP utilization with interval exercise is met with activation of the body’s
energy production systems and muscle recruitment patterns. The specific CV and muscular
stimuli during acute exercise induce advantageous physiological adaptations with chronic
exposure (i.e., repeated perturbations in homeostasis). It is crucial to consider the acute response
to exercise because the transient metabolic challenge is indicative of the adaptive process to
occur with repeated stimulus exposure. Despite the logical relationship between the acute
response to exercise and consequential adaptations, little is known about the degree to which
HIIE perturbs the CV system or challenges energy production systems.
2.3.1. Effect of HIIE on the acute cardiorespiratory response
The limited research available on acute cardiac and respiratory responses to HIIE has been done
mostly in HF patients. Data suggests an improvement in LV systolic and diastolic function from
decreased systemic vascular resistance and/or enhanced myocardial contractility [102]. Meyer et
al. found LV function to be maintained in both HF and CAD patients during and after HIIE and
MICE sessions, indicative of a greater peripheral stimulus (i.e., increasing blood lactate [BLa]
levels) with interval exercise and no detriment to cardiac function [103]. The acute
cardiorespiratory response (i.e., time spent >90%VO2peak, HR, RPE) seemed to be similar
between HIIE (30-sec intervals) and MICE sessions in HF patients, but the higher efficiency and
adherence rates observed during HIIE made it the protocol of choice [104]. Following moderate-
and high-intensity exercise in HF patients, there was a greater reduction in HR and arrhythmias
and increased HR variability with HIIE, likely due to improved sympathovagal balance. The
lower rate pressure product (RPP) observed with HIIE implies a smaller myocardial oxygen
demand despite higher achieved workloads [105], sufficiently perturbing the peripheral
musculature as seen by higher BLa levels. RPE and dyspnea for HIIE (15-sec intervals) were
found to be lower while time to exhaustion (TTE) greater compared to isocaloric MICE in a
CAD cohort [67]. Also, mean ventilation and VO2 were lower with HIIE and did not induce
exercise-related myocardial injury [67]. Other studies have explored cardiac stress and injury
17
(i.e., cardiac troponin (cTn) and BNP) in HF and control participants before and after low-
volume HIIE and MICE [106]. As expected, cTn and BNP at baseline were higher than controls.
The exercise-induced increase in cTn and BNP were comparable after HIIE and MICE, but
greater increases in BNP were observed in HF participants. Not all studies have found increased
cTn after exercise, as others have found unchanged cTn levels immediately and 24 hours after
HIIE and MICE sessions [67, 104, 107].
It can be argued that HIIE does not negatively affect cardiac function or induce cardiac injury in
the heart disease population; however, the particular exercise protocol investigated may be of
relevance.
2.4. HIIE protocol optimization
The athletic population has purposefully manipulated key exercise variables to create training
programs to achieve performance goals. The acute physiological response during exercise and
the recovery period is determined by the exercise load and can be changed through the
manipulation of nine variables: intensity and duration of work and recovery intervals, number of
intervals, the number of series and between-series recovery durations and intensities (see Figure
3) [37]. In addition, Tschakert and Hofmann have suggested mean workload as a relevant
variable to take into account [108]. Interval exercise has been shown to result in a longer time
spent at a high VO2 compared to MICE [43], so the optimal HIIE protocol for athletes is one that
allows longer periods of time to be spent near or at VO2max. It is likely that the accumulated
time spent at these high intensities will determine associated physiological benefits [36, 37, 40-
42].
Particular interval protocols determine the acute physiological response, and consequently,
specific long-term adaptations from chronic exposure [108], so determining an optimal protocol
that is effective yet safe is of great value [50]. Despite the growing acceptance of HIIE for select
patient groups, the protocol that optimizes patient outcomes has not yet been determined. Careful
consideration of interval duration and intensity is needed to optimize tolerability and pleasure, if
patients are to truly adhere to and benefit from HIIT [39]. Improving VO2peak is of paramount
importance, as aerobic fitness is the strongest predictor of mortality in clinical populations [8,
109]. Ten minutes near or at VO2max has been suggested as a target in order to achieve
improvements in aerobic capacity [37], and shown to be achievable in a HIIE session [37, 110].
18
Figure 2. Variables that can be manipulated in a HIIE session. Taken from Buchheit and Laursen [37].
2.4.1. Work interval
Astrand et al. were one of the first groups to publish work investigating the acute physiological
response to intermittent exercise, specifically, short (30-sec) and long (3-min) intervals in a well-
trained male subject [41]. Short intervals elicited low BLa levels and were perceived to require
less effort. The authors suggested that short work intervals allowed for the achievement of heavy
workloads with large muscle groups but minimal strain on the cardiorespiratory system, whereas
longer intervals stressed the aerobic system to a greater extent. Other early studies are in
agreement with these findings; long work intervals substantially increase BLa and produce large
VO2 oscillations, while shorter intervals minimally increase BLa and show small oscillations of
VO2 [42]. Longer intervals (i.e., 4-10 mins) may allow for more time to be spent at a high
%VO2max, because a high VO2 can be reached by the end of each interval rather than the steady
increase over time with shorter intervals [37]. In agreement with data from athletes, higher acute
metabolism and peak cardioventilatory measures (i.e., workload, HR, VO2, BLa) were observed
with long duration intervals (4-min) compared to short (20-sec) intervals or MICE in CR patients
[50].
2.4.2. Recovery interval
The type of recovery undoubtedly influences the acute metabolic load placed on the body.
Passive, rather than active, recovery seems to be preferred as it allows a longer TTE in CAD
patients [110], potentially because of the opportunity for phosphocreatine (PCr) restoration
19
[111]. It follows that longer recovery periods allow for greater intramuscular PCr restoration,
improving endurance performance [112]. Active recovery facilitates a quicker achievement of
VO2max during a work interval, but as a result, can lead to suboptimal work capacity or
premature fatigue during subsequent intervals due to an impingement on muscle metabolic
recovery [108, 113, 114]. 15-sec intervals and passive recovery was superior in those with CAD
compared to combinations using 60-sec intervals and active recovery when considering RPE,
time spent >80% VO2max, and TTE [110]. The optimal protocol in HF patients appears to
follow a similar design – 30-sec intervals with passive recovery compared to combinations using
90-sec intervals and active recovery, with no adverse outcomes reported [115]. PCr kinetics may
be dependent on the interaction between the work-to-rest ratio and recovery type, as TTE was
negatively influenced by active recovery but only in intervals of short duration [116]. PCr
reconstitution was lower in short intervals with active recovery, with the observed impairment in
endurance performance possibly a result of PCr’s main role as an energy source during initial
exercise (<30 secs) [112]. However, longer TTE may not necessarily translate to greater time
spent at a high VO2, as both active and passive recoveries resulted in similar time spent >90%
VO2max, despite passive allowing longer TTE [117]. It should be noted that only HIIT with
active recovery increased VO2max after 7 weeks. A similar study found total time spent >90%
VO2max to be comparable using either type of recovery, but when TTE was taken into account,
active recovery allowed a greater percentage of the session to be spent at a high %VO2max
[118].
Reviews have been published in attempt to synthesize the vast array of data available. Midgley et
al. [40] recommend work and recovery durations between 15-30s and active recovery (below
lactate threshold) to maximize time spent near or at VO2max. However, it is not clear if this
protocol design translates into long-term health benefits if implemented into CR. In a 2016
review article by Hussain et al. [119], the authors surmise that the 4x4 HIIE protocol may be
most effective, as it has consistently elicited superior physiological benefits. This parallels
Hofmann and Tschakert’s argument, that mean intensity and total duration of an exercise session
are the main determinants of exercise load (which are maximized in 4x4 HIIE protocol compared
to 10x1) [120].
20
2.4.3. HIIE optimization summary
Evidence supports long-duration, high-intensity intervals to be a strong physiological stimulus,
with shorter intervals eliciting comparable responses to continuous exercise [121]. However, the
preferred protocol in patients is one with short duration intervals and passive recovery periods
[110], and may not come at the expense of a lower VO2 response [122]. The prescription of
longer intervals can be considered for the improvement and maintenance of physical capacity in
individuals of a higher fitness level [123]. Notwithstanding this evidence, it would be imprudent
to conclude one protocol’s effectiveness over another, as the optimal HIIE protocol may be
different for each clinical population. A systematic approach to HIIE prescription is warranted,
to maximize health benefits and minimize risk.
2.5. Mechanisms
2.5.1. Chronic exercise
Numerous mechanisms have been proposed to account for the HIIE-induced adaptations in
exercise capacity, including associated changes in endothelial function. Decreases in oxidative
stress, inflammation, and sympathetic tone, with concomitant increases in nitric oxide (NO)
bioavailability and vagal influence may all act to improve vascular tone and stiffness [89, 124].
MiR-126, a specific microRNA linked to an atheroprotective state, was found to be higher after 4
weeks of MICT and progressive HIIT (adding 1 interval per week), and may explain HIIT’s
effectiveness as a secondary prevention intervention. Increased NO release with regular aerobic
exercise has been shown to improve endothelial-dependent vasorelaxation in hypertensive
patients [125], with greater endothelial NO synthase (eNOS) and NO metabolite levels seen after
HIIT in healthy and infarcted rats [126, 127] In further support of this suggested mechanism,
endothelial dysfunction with reduced eNOS expression and increased vascular stiffness
biomarkers was improved with HIIT in a HF rat model [128].
Peripheral adaptations also play a role in the beneficial physiological changes observed with
chronic exercise training. Skeletal muscle membrane excitability and contractile function in type
II fibres was improved after a 12-week HIIT intervention in older adults, coincident with
improved performance outcomes [129]. Additionally, an upregulation of PGC-1α may play an
important role in aerobic fitness improvements following HIIT [27, 33, 94]. In support of this,
21
skeletal muscle oxidative capacity was found to increase after 8 weeks of HIIT, but MICT
increased capillary density to a greater extent [76]. Moreover, the VO2 efficiency slope increased
alongside improvements in aerobic fitness with both HIIT and MICT, representing a lower
ventilatory demand for a given submaximal workload [130]. This indirect measure of
cardiopulmonary function provides insight into skeletal muscle adaptations, as increases in
mitochondrial and capillary density and peripheral blood flow will attenuate the exercise-induced
increase in metabolic acidosis, which is linked to the ventilatory response. Observed central
adaptations are probably related to hematological factors during submaximal work, while
maximal improvements require a training period of substantial length [17].
2.5.2. Acute exercise
Acute exercise is associated with increased oxidative stress, which may temporarily reduce NO
production and bioavailability and impair endothelial function (i.e., flow-mediated dilation
[FMD]). This would explain the ‘biphasic FMD response’ to acute exercise, whereby arteries are
in an imbalanced pro-oxidant state immediately after exercise, until antioxidant levels increase
during the recovery period [131]. Results have shown that higher intensity exercise is associated
with greater oxidative stress [132], however, there are studies which are not in support of this
[133]. An increase in blood flow during exercise elicits a comparative increase in antegrade
shear, thus, promoting NO-mediated vasodilation [134]. In contrast, the decrease in FMD
immediately post-exercise may not represent impaired endothelial vasodilation, but rather the
dilated artery’s diminished dilator capacity; however, most data does not support impaired FMD
from a smaller shear stimulus during reactive hyperemia [132, 135, 136]. Furthermore, the
increase in sympathetic vasoconstrictor activity and norepinephrine with strenuous exercise is
associated with a decrease in FMD [137]. Moreover, CAD patients may even experience a
paradoxical vasoconstriction effect with increased blood flow [3]. Inflammation has also been
suggested to influence endothelial function after exercise [50, 138, 139]. HIIE (15-60-sec
intervals) was shown to increase biomarkers of inflammation and muscle damage immediately
after exercise, albeit in healthy males [140]. In contrast, another study favoured HIIE over MICE
to elicit an anti-atherogenic profile, as measured by brain-derived neurotrophic factor,
adiponection, and plasminogen inhibitor-1 [141]. Guiraud et al. [107] found biological markers
associated with endothelial function to be unchanged after HIIE in physically active men with
CAD, however, this could be due to the short intervals employed (15-sec) with passive recovery.
22
The physiological demand during HIIE is high, so motor unit recruitment increases and ATP use
exceeds production to create an environment with excessive levels of metabolic byproducts,
acting to impair skeletal muscle contraction. These metabolites (i.e., Pi, AMP, ADP) accumulate
during long intervals and active recovery that eventually increase the concentration of hydrogen
ions and lactate production. If consistently repeated, the ensuing fatigue will lead to chronic
training adaptations. The brief periods of recovery during interval exercise allow for PCr
resynthesis and fatigue-related metabolite clearance, to delay the attainment of exhaustion
compared to MICE. In addition, the role of myoglobin has been hypothesized as a potential
oxygen store during initial exertion (<30 secs), which is why shorter intervals may not place a
substantial demand on circulatory and respiratory systems [41, 142].
2.6. Summary of review of literature
Empirical evidence supports HIIT’s potential to improve aerobic fitness with chronic training,
often to a greater and more rapid extent than MICT. Various HIIE protocols have been
investigated in the literature, but one that optimizes both the physiological response and
preference has yet to be recommended. Furthermore, the acute physiological stimulus of these
protocols in patient populations is unclear. This information would inform the evidence-based
prescription of an effective HIIE protocol, and thus, warrants future attention.
23
– Methodology and Methods
3.1. Study overview
This investigation employed a within-subject, repeated measures design, and involved five study
visits in total. The first study visit took place at the TRI or Toronto Western Hospital (TWH),
and Visits 2-5 at the Dr. Terry Kavanagh Heart Health Laboratory in the University of Toronto’s
Goldring Centre for High Performance Sport. Visit 1 involved consent and familiarization, and
Visits 2-5 involved one of 4 randomized exercise protocols with assessment of physiological
parameters. Within each participant, all study visits were scheduled at the same time of day (i.e.,
morning or afternoon) to standardize the effect of beta-blockers and minimize the influence of
diurnal rhythms on BP [143]. Participants were instructed to abstain from vigorous exercise for
24 hours, caffeine and alcohol consumption for 12 hours, tobacco use for 6 hours, and to eat a
similar meal no less than 3 hours prior to each visit [144, 145]. Participants were encouraged to
maintain their daily routine, including participation in CR classes, medications, diet, and sleep
until all study visits were completed.
3.2. Participants
3.2.1. Participant inclusion and exclusion criteria
Men and post-menopausal women (≥12 consecutive months since last menses) with documented
CAD (i.e., history of MI, CABG, PCI, or stable angina) in sinus rhythm were recruited. Patients
were either current participants or graduates of the University Health Network (UHN)’s CR
program. Exclusion criteria included: a major musculoskeletal, pulmonary, or severe cognitive
impairment precluding exercise participation, history of HF, unstable angina, significant
arrhythmia, diabetes, high risk for falls, and/or evidence of ischemia or significant arrhythmia
during cardiopulmonary assessment (CPA).
3.2.2. Standard of care
Patients were enrolled in (or completed) UHN’s 6-month CR program, including aerobic and
resistance exercise training, education, and one-on-one counseling. Upon referral, patients
completed an initial assessment that included: a medical and family history questionnaire, resting
electrocardiogram (ECG), body composition, and CPA. Patients attended weekly sessions at the
24
TRI or TWH and were also asked to complete 4 aerobic and 2 resistance exercise sessions per
week at home. Resistance training was introduced during the first half of the program. All
subjects completed weekly paper diaries of their exercise activities, HR and symptoms. Each
group class began with an interactive education session, followed by warm-up and stretching
routine, and then personalized exercise session. At TRI, exercise was performed either inside
(track, treadmill, or cycle) or on the outdoor track, weather-permitting. Patients at TWH
exercised in the gym, where there was treadmill, bike, and arm ergometer access. Exercise
prescription was based on patient medical history and fitness level (from CPA results), and
intensity prescribed from a combination of 3 criteria: 1) 60-80% VO2peak, 2) 70-80% HRR, 3) at
or below AT, 4) below any signs or symptoms of ischemia, and 5) RPE 11-14. Patients were
prescribed an initial prescription of 0.5 to 1 mile at the lower end of the intensity range. Distance
was progressed by 0.5 to 1 mile every 2 weeks as indicated. Exercise was continually progressed,
with the goal of exercising for 30-60 mins, 5 days per week, at the top end of the intensity range.
Patient tolerability and willingness were considered before intervals of higher intensity (>80%
HRR) were prescribed for brief periods, usually a faster walking pace.
3.2.3. Recruitment
Participants were recruited from UHN’s CR program, at various stages throughout the program.
The study coordinator gave a brief talk outlining the main study details and inclusion criteria
before the beginning of the CR class (Appendix A). Interested participants were encouraged to
inquire further and ask questions during or after class, and a copy of the consent form was
provided for each prospective participant to keep. For patients who gave consent to be screened
for research studies, the study coordinator used the patient’s file and a preliminary screening
form (Appendix B) to screen for patients with contraindications to HIIE. The CR supervisor
(CRS) and/or study physician verified patient eligibility. The CRS asked eligible patients if they
would be interested in speaking to the study coordinator regarding potential participation in a
research study, and introduced the study coordinator with the patient’s verbal agreement. The
first study visit was scheduled for those who were interested and met the inclusion/exclusion
criteria (as confirmed by their patient file). Posters (Appendix C) were posted around the TRI to
assist with recruitment. Participants were recruited on a rolling basis.
25
This study was discussed at the Cardiac Department’s team meetings at the TRI and TWH.
Members in attendance included both clinical and research staff. Potential patient burden and
recruitment strategy was discussed.
3.3. Study visits
3.3.1. Visit 1 – Consent and familiarization
Eligible patients completed the consent and familiarization process during one of their weekly
CR classes (but still attended the education component of class). Written informed consent was
obtained in person by the study coordinator after the study was explained in detail and all
questions were answered (Appendix D). The main objectives of the visit were to: 1) obtain
consent, 2) accustom participants to treadmill exercise (i.e., start/stop, speed up/slow down,
straddle), and 3) determine treadmill speeds corresponding to the target intensities through
%HRR and RPE (Appendix E). Treadmill speed was increased every 5 seconds until a maximal
safe walking speed was attained. If the target HR was not met, the incline was increased until the
desired intensity was achieved. Results from the patient’s most recent CPA served to inform this
process. Refer to Figure 3 for the familiarization schematic. The speed/incline combinations
were used during Visits 2-5. Participants were also asked to fill out a medical history
questionnaire (Appendix F). The medical history questionnaire inquired about CV health,
alcohol intake, prescription and non-prescription drugs, smoking status, and family history of
disease or sudden death.
3.3.1. Visits 2-5 – Exercise interventions
This study employed 4 different exercise protocols on a motorized treadmill, randomized for
order. Participants underwent anthropometric and resting hemodynamic measures (baseline)
before completion of the exercise protocol with physiological assessment.
A single-lead ECG was applied on bare, cleaned and abraded skin. BP was measured at specific
time points using a motion-tolerant monitor (Tango M2, SunTech Medical, Morrisville, NC,
USA). Participants used a mouthpiece and nose clip to allow the measurement of breath-by-
breath samples of expired air, which was analyzed by an automated system (Vmax 2900,
BD&Co., US) to determine the volume of air expired and its gas content. From this information,
the oxygen cost of each exercise protocol was calculated (Appendix G).
26
Figure 3. Familiarization protocol. Dark grey: high-intensity (85-95% HRR/RPE 17-19), grey: moderate-intensity (60-70% HRR, RPE 14-15), light grey: low-intensity (20% HRR, RPE≤11). A 5-min warm-up (w/u) from 0-5mins (30-40% HRR/RPE 11-12), a 5-min passive rest period from 14-19mins, and 3-min cool-down (c/d) from 35-38mins (20% HRR, RPE≤11).
Treadmill exercise was chosen so that study results could be translatable to exercise modes
typically performed in the CR setting. Exercise intensity was prescribed as %HRR (desired HR =
desired intensity × (HRpeak - HRrest) + HRrest) and RPE. Intervals were prescribed using a
combination of %HRR and RPE because it is a feasible method that can be used by staff and
patients in the CR setting, and is recommended by the Canadian Association for Cardiac
Prevention and Rehabilitation. Each exercise protocol began with a 5-min warm-up at 30-40%
HRR/RPE 11-12 and concluded with a 3-min cool-down at 20% HRR/RPE ≤11. Treadmill speed
and incline was continually adjusted to ensure that target HRs were achieved and maintained
during the exercise session. The details of each exercise protocol can be found in Table 2 and
Figures 3-6.
The following were criteria to terminate exercise, as recommended by the American College of
Sports Medicine [9]:
• Exercise SBP >250mmHg and/or DBP >115mmHg
• Drop in SBP of >10mmHg, accompanied by other evidence of ischemia
• Signs/symptoms of exercise intolerance: moderate-severe angina, dyspnea,
dizziness/syncope, cyanosis/pallor
• Sustained ventricular tachycardia
• Participant’s request to stop
27
Table 2. Exercise protocol details.
Figure 4. 4x4 exercise protocol. Dark grey: high-intensity interval (85-95% HRR, RPE 17-19), grey: moderate-intensity recovery (60-70% HRR, RPE 14-15). A 5-min warm-up (w/u) from 0-5mins (30-40% HRR/RPE 11-12) and 3-min cool-down (c/d) from
33-36mins (20% HRR, RPE ≤11). BP, HR, and RPE values at 9, 12, 16, 26, and 30 minutes (represented by ♥).
Protocol name
WORK INTERVAL RECOVERY INTERVAL Protocol
duration (min)
Series repetitions
Duration (min)
Intensity (% HRR)
Intensity (RPE)
Duration (min)
Intensity (% HRR)
Intensity (RPE)
4x4
10x1 TRIP
1
2
1+2
MICE
4
10 4
1
4
1
4
1 0.5
3
7
30
85-95
85-95 85-95
60-70
-
60-70
17-19
17-19 17-19
14-15
14-15
3
1 0.5
-
-
-
60-70
≤20 ≤20
-
-
-
14-15
≤11 ≤11
-
-
-
28
20 -
-
28
30
10x1, low-volume interval protocol, MICE, moderate intensity continuous exercise, 4x4, Norwegian interval protocol, % HRR, percentage of heart rate reserve, RPE, rating of perceived exertion, TRIP, Toronto
Rehabilitation Institute protocol
28
Figure 5. 10x1 exercise protocol. Dark grey: high-intensity interval (85-95% HRR, RPE 17-19), light grey: low-intensity recovery (20% HRR, RPE ≤11). A 5-min warm-up (w/u) from 0-5mins (30-40% HRR, RPE 11-12) and 3-min cool-down (c/d)
from 25-28mins (20% HRR, RPE ≤11). BP, HR, and RPE values at 8, 11, 14, 21, and 24 minutes (represented by ♥).
Figure 6. TRIP. Dark grey: high-intensity interval (85-95% HRR, RPE 17-19), grey: moderate-intensity interval (60-70% HRR, RPE 14-15), light grey: low-intensity recovery (20% HRR, RPE ≤11). A 5-min warm-up (w/u) from 0-5mins (30-40% HRR, RPE 11-12) and 3-min cool-down (c/d) from 33-36mins (20% HRR, RPE ≤11). BP, HR, and RPE values at 9, 12, 16, 26, and 30
minutes (represented by ♥).
29
Figure 7. MICE protocol. Grey: moderate-intensity (60-70% HRR/RPE 14-15). A 5-min warm-up (w/u) from 0-5mins (30-40% HRR, RPE 11-12) and 3-min cool-down (c/d) from 35-38mins (20% HRR, RPE≤11). BP, HR, and RPE values at 12, 20, and 35
minutes (represented by ♥).
3.4. Study measures
3.4.1. Resting phenotypic characteristics
Height and mass were measured at the start of each session, with light exercise clothing but
without shoes. Body mass index (BMI, kg·m-2) was subsequently calculated. Participants quietly
lay supine for 10 minutes in a dimly lit room. Four BP measurements were taken from the right
arm positioned at heart level, at 1-min intervals using an automated device (BpTRU model
BPM-100, BpTRU Medical Devices, Coquitlam, BC, Canada), and the average of the last 3
measures were used as resting BP and HR values (Appendix H).
3.4.2. HR, BP, RPE, VO2
HR was recorded continuously by monitoring R-R intervals (Polar V800, Polar Electro Oy,
Kempele, Finland) during exercise. BP and RPE were taken during the early, mid, and late
portion of the exercise session. BP was also taken immediately after exercise (<2 mins post)
(Appendix I).
30
3.4.3. Participant exercise preference
At the end of Visit 5, participants were asked to complete a questionnaire based on their
experience of all exercise protocols (Appendix J). This questionnaire was specifically developed
for assessing participant HIIE preference, modified from one previously used [146]. Participants
were asked to rank the exercise protocols (4x4, 10x1, TRIP, MICE) in order of preference, from
most to least preferred.
3.5. Data and statistical analyses
3.5.1. Sample size calculation
An a priori sample size calculation using the primary outcome of time spent above 90% VO2R
resulted in a sample requirement of 8 participants to detect differences with a chosen α of 0.05
and β of 0.8. While the duration at a high %VO2max an individual should exercise in order to
achieve optimal aerobic improvements remains unknown, a minimum of 10 minutes near or at
VO2max is suggested to lead to cardiopulmonary adaptations [37]. Acute HIIE studies that have
measured VO2 would suggest this amount of time is achievable with an interval exercise session
[110, 147]. It was hypothesized that the 4x4 protocol would elicit 10 minutes above 90% VO2R
compared to 0 minutes during 30 mins of MICE. The standard deviation from a previous study
was used [110]. As the thesis project was a part of a larger research study, 17 participants were
successfully recruited in order to satisfy the sample size calculation for FMD.
3.5.2. Data analysis
The physiological response to each exercise protocol was quantified after the exclusion of warm-
up and cool-down periods. Three-breath and five-beat rolling averages were computed from
breath-by-breath VO2 and R-R interval data, respectively, with erroneous data points (i.e.,
arrhythmias, erratic breaths) eliminated before the calculation of average and peak values from
each protocol. RPP was calculated as the product of peak HR and BP values during exercise.
Area under the curve (AUC) was determined (GraphPad Software Inc., La Jolla, CA, USA)
above standing VO2 and HR values (Appendix K), and change (Δ) in HR and VO2 values were
calculated as the percent change from early to late portions of the exercise session. Early was
identified as 15% (or 25% for MICE) protocol completion while late as 90-100% completion.
The proportion of the exercise session spent above specific thresholds was determined using time
31
and AUC, and also represented as a percentage of the total session to control for differences in
protocol duration. The thresholds examined were the average VO2 of a participant’s MICE
session and 90% VO2R (VO2R = intensity × (VO2peak - VO2rest) + VO2rest). Time spent above
the MICE average VO2 and 90% VO2R were calculated by summing the time blocks
corresponding to values above each threshold. Exercise protocol preference was determined by
assigning numerical values (1-4) to the exercise protocols based on its ranking. The most
preferred protocol was given a value of 1 and 4 for least preferred. Rankings were summed, with
the most preferred protocol having the lowest total value.
3.5.3. Statistical analysis
Analyses were performed using IBM SPSS Statistics (Version 25, IBM Corp, Armonk, NY). The
Shapiro-Wilk test was used to test normality of data, and a one-way repeated measures ANOVA
or Friedman test was performed as appropriate, to test the null hypothesis that HIIE was not
different than MICE. Greenhouse-Geisser correction was used when data violated the
assumption of sphericity with Mauchly’s W test. If significant main effects were observed, post-
hoc analyses were conducted by pair wise comparisons or Wilcoxon signed-rank test with
Bonferroni correction. Results are expressed as mean ± standard deviation and statistical
significance was accepted at a p<0.05.
32
– The acute physiological response to high-intensity interval exercise in patients with coronary artery disease
This chapter is a modified version of a manuscript to be submitted for review and publication.
ABSTRACT
High-intensity interval exercise (HIIE) elicits quicker and more substantial improvements in
aerobic capacity compared to moderate-intensity continuous exercise (MICE), but the protocol
that optimizes the physiological stimulus and patient preference is undetermined. Fifteen patients
with coronary artery disease (CAD) (9 males, 67 ± 6 years) underwent physiological assessment
during 3 different HIIE protocols and MICE. The 4x4 protocol (four, 4-min intervals) elicited a
greater physiological stimulus, as indicated by heart rate (HR), oxygen uptake (VO2), rating of
perceived exertion (RPE), and blood pressure responses (p<0.05), but was the least preferred
HIIE protocol. The 10x1 protocol (ten, 1-min intervals) was most preferred, it was comparable to
MICE, and should be considered a timesaving alternative. TRIP (30-sec intervals) proved to be a
strong physiological stimulus and may be a viable choice opposed to long duration intervals, for
its similar HR response and RPE at a higher VO2. These results indicate that HIIE is an efficient
and well-tolerated exercise prescription for CAD patients.
INTRODUCTION
Coronary artery disease (CAD) continues to be one of the leading causes of death worldwide [1],
and since aerobic capacity is a main prognostic indicator for CAD patients [4, 5], therapeutic
interventions that aim to improve aerobic fitness are of particular value. It is not surprising that
exercise-based cardiac rehabilitation (CR) is current standard of care, eliciting reductions in
cardiovascular (CV) and overall mortality [7] through improvements in exercise capacity, quality
of life, and reductions in hospital admissions and associated costs [54-56]. Typically, 30-60
minutes of moderate-intensity continuous exercise (MICE) on most days of the week is
prescribed to CR patients [9, 10], in line with current Canadian exercise recommendations [11].
Despite the irrefutable benefits of exercise-based CR, one of the main barriers to CR adherence
is a perceived lack of time [13], so the development of shorter but effective exercise
prescriptions that elicit clinically-relevant improvements in physiological outcomes are desired.
33
High-intensity interval exercise (HIIE) allows for the greater achievement of total time spent at
high workloads than commonly performed with continuous exercise, facilitating substantial
improvements in aerobic capacity in both healthy and clinical populations. Compared to
moderate-intensity continuous training (MICT), high-intensity interval training (HIIT) has been
shown to produce similar, if not superior, improvements in peak oxygen uptake (VO2peak) [77-
80, 82, 83], anaerobic threshold [20], cardiac function [78, 84], endothelial function [83, 100],
exercise adherence and quality of life [30, 83, 97, 100]. HIIE has also been used in various
clinical populations without adverse outcomes in both supervised and home-based rehabilitation
settings [29, 30]. Therefore, it may be regarded as a safe, efficacious alternative to high-volume
aerobic exercise in the general community and within CR programs.
Despite the growing acceptance of HIIT for select patient groups, there is no consensus on which
protocol is optimal. Numerous HIIE protocols have been developed, using various combinations
of interval and recovery durations and intensities, but little is known about the degree to which
various protocols perturb CV and energy production systems. Different combinations of intensity
and duration of both interval and recovery phases elicit unique, acute physiological responses
[33], so careful consideration of these variables is needed to optimize tolerability of exercise, and
has implications for training adherence [39]. While few studies have examined HIIE in CAD
patients [50, 67, 110], its acute physiological effects are not as well understood as conventional
MICE. Protocols previously investigated are limited in number and the cardiopulmonary and
hemodynamic responses are not comprehensively examined. Therefore, the purpose of the study
was to examine the acute physiological effects of 3 HIIE protocols frequently used in CR
compared to the standard of care (i.e., MICE) in patients with CAD. It was hypothesized that the
protocol employing long-duration intervals (4-min) would provide the greatest physiological
stimulus, as determined by time spent at a high VO2, and the protocols employing shorter
duration intervals would be comparable to MICE.
MATERIALS AND METHODS
Participants. Seventeen patients (11 males) with documented, stable CAD were recruited from
the University Health Network (UHN)’s CV Prevention and Rehabilitation Program (Toronto,
Canada). All patients were diagnosed with CAD, defined as having at least one of the following:
history of myocardial infarction (MI), percutaneous coronary intervention, coronary artery
34
bypass graft procedure, or stable angina. Patients with a history of heart failure, diabetes
mellitus, significant arrhythmia, unstable angina, or other contraindication to HIIE were
excluded. In addition, only post-menopausal women (≥12 months since last menses) were invited
to participate. Eligibility was determined with patient health records and verbal confirmation.
VO2peak and heart rate (HR) peak were obtained from routine cardiopulmonary assessments, as
part of a patient’s care in the CR program. The study protocol was reviewed and approved by
UHN’s Research Ethics Board before informed consent was obtained in writing by patients prior
to participation. Participant characteristics can be found in Table 3.
Study design. A randomized, crossover design was chosen as the experimental approach,
involving 5 visits in total. The first visit included consent, medical history, and a familiarization
protocol to determine the treadmill speeds and inclines needed to achieve the target HR zones
based on results from patients’ routine cardiopulmonary assessments. The other 4 visits involved
an exercise protocol and assessment of physiological parameters. Participants completed 3 HIIE
and 30-min MICE protocols, randomized for order. Within each participant, all study visits were
scheduled at the same time of day to standardize the effect of beta-blockers and to minimize the
influence of diurnal rhythms on blood pressure (BP) [143], and visits were scheduled at least 48
hours apart. Participants were instructed to abstain from vigorous exercise for 24 hours, caffeine
and alcohol consumption for 12 hours, tobacco use for 6 hours, and to eat a similar meal no less
than 3 hours prior to each session. Participants were encouraged to maintain their daily routine,
including participation in CR classes, medications, diet, and sleep until all study visits were
completed. Anthropometric and resting supine BP and HR measurements (BpTRU model BPM-
100, BpTRU Medical Devices, Coquitlam, BC, Canada) were taken at the start of each
laboratory visit. Study participation was concluded with a questionnaire to assess exercise
protocol preference, whereby participants were asked to rank the protocols from most to least
preferred.
Exercise protocols. Exercise was performed on a motorized treadmill and prescribed as a
percentage of HR reserve (% HRR) (desired HR = desired intensity × (HRpeak - HRrest) +
HRrest) and rating of perceived exertion (RPE) using the Borg (6-20) scale [148]. Treadmill
speed and incline was continually adjusted to ensure that target heart rates were achieved and
maintained during the exercise session. A standardized 5-min warm up at 30-40% HRR and 3-
min cool down at ≤20% HRR were included in each exercise session. HR was calculated from
35
continuously recorded R-R intervals (Polar V800, Polar Electro Oy, Kempele, Finland) and a
motion-tolerant BP monitor (Tango M2, SunTech Medical, US) was used for BP measurements
during the early, mid, and late portion of each exercise protocol, as well as immediately after
exercise cessation. Participants used a mouthpiece and nose clip to allow the measurement of
breath-by-breath samples of expired air, which was analyzed by an automated system (Vmax
2900, BD&Co., US) to determine VO2. The exercise protocol was terminated if any of the
following criteria were observed: abnormal BP response, signs of exercise intolerance, or patient
request to stop.
Table 3. Participant characteristics.
Variable N=14
Sex (%)
Male Female
Age (years) Height (m)
Weight (kg) BMI (kg·m
-2)
Supine systolic blood pressure (mmHg) Supine diastolic blood pressure (mmHg) Supine heart rate (bpm)
VO2peak (ml·kg-1
·min-1
) Peak heart rate (bpm) CV event (%)
Angina
CABG
MI
PCI Time since most recent CV event (years)
Pacemaker (%) Smoking status (%) Current
Previous Non-smoker
Medications (%) ACE inhibitor/ARB
Acetylsalicylic acid
Alpha-blocker Anti-arrhythmic
Beta-blocker
Blood thinner
Ca2+
channel blocker
Statin
8 (47) 6 (43) 67 ± 6
1.7 ± 0.09
74.7 ± 13.1 25.5 ± 2.8 112 ± 13 70 ± 5 60 ± 8
31.3 ± 9.7 140 ± 20
1 (7) 2 (14)
8 (57) 11 (79)
2.0 ± 1.8
1 (7)
0 (0) 8 (57) 6 (53)
8 (57)
14 (100)
1 (7) 2 (14) 9 (64) 8 (57) 1 (7)
13 (93) Data presented as mean ± standard deviation. ACE, angiotensin converting enzyme, ARB, angiotensin II receptor blocker, bpm, beats per minute, BMI, body mass index, CABG, coronary artery bypass graft, CV, cardiovascular, MI, myocardial
infarction, PCI, percutaneous coronary intervention
36
Schematics of each exercise protocol can be found in Figure 8 and their descriptions in Table 4.
The 4x4 [77-83, 100] and 10x1 [23, 87] protocols were selected for examination because of their
previous use in CAD patients and positive outcomes observed in the literature. TRIP (Toronto
Rehabilitation Institute protocol), a site-specific protocol, is currently prescribed to select
patients at the site of recruitment but has yet to be formally investigated. Lastly, MICE was used
as a control condition to represent standard exercise prescription in CR [11]. It is recognized that
the aforementioned protocols are neither isovolumic nor isocaloric, but the study’s rationale was
based upon the comparison of habitually used exercise protocols that are not necessarily matched
for total work performed.
Data analysis. The physiological response to each exercise protocol was quantified after the
exclusion of warm-up and cool-down periods. Three-breath and five-beat rolling averages were
computed from breath-by-breath VO2 and R-R interval data, respectively, with erroneous data
points (i.e., arrhythmias, erratic breaths) eliminated before the calculation of average and peak
values from each protocol. Rate pressure product (RPP) was calculated as the product of peak
HR and BP during exercise. Area under the curve (AUC) was determined (GraphPad Software
Inc., La Jolla, CA, USA) above standing VO2 and HR values, and change (Δ) in HR and VO2
values was calculated as the percent change from early to late portions of the exercise session.
Early was identified as 15% (or 25% for MICE) protocol completion while late as 90-100%
completion. The proportion of the exercise session spent above specific thresholds was
determined using time and AUC, and also represented as a percentage of the total session to
control for differences in protocol duration. The thresholds examined were the average VO2 of a
participant’s MICE session and 90% VO2R (VO2R = intensity × (VO2peak - VO2rest) + VO2rest)
The first threshold was selected on the premise that MICE represents the current standard of care
in CR [11], so time spent exercising above this threshold may provide a more potent stimulus,
and further, an intensity near or at VO2max (i.e., 90% VO2R) is suggested to be required for
improvements in aerobic fitness [43, 149]. Time spent above the MICE average VO2 and 90%
VO2R were calculated by summing the time blocks corresponding to values above these
threshold.
37
Figure 8. Exercise protocol schematics. See Table 4 for protocol details.
Table 4. Exercise protocol details.
Statistical analysis. Statistical analyses were performed using IBM SPSS Statistics (Version 25,
IBM Corp, Armonk, NY). The Shapiro-Wilk test was used to test normality of data. One-way
repeated measures analyses of variance or Friedman tests were performed on normally and non-
normally distributed data, respectively, and significant main effects were examined post-hoc
(compared to MICE) by pairwise comparisons or Wilcoxon signed-rank tests using Bonferroni
correction. Results are expressed as mean ± standard deviation and statistical significance was
accepted at a p<0.05.
4x4
time
10x1
TRIP MICE
inte
nsit
y
time
time
time
inte
ns
ity
inte
nsit
y
inte
ns
ity
Protocol name
WORK INTERVAL RECOVERY INTERVAL Protocol
duration (min)
Series
repetitions
Duration
(min)
Intensity
(% HRR)
Intensity
(RPE)
Duration
(min)
Intensity
(% HRR)
Intensity
(RPE)
4x4
10x1 TRIP
1
2
1+2
MICE
4
10 4
1 4
1
4
1 0.5
3 7
30
85-95
85-95 85-95
60-70 -
60-70
17-19
17-19 17-19
14-15
14-15
3
1 0.5
- -
-
60-70
≤20 ≤20
- -
-
14-15
≤11 ≤11
- -
-
28
20 -
- 28
30
10x1, low-volume interval protocol, MICE, moderate intensity continuous exercise, 4x4, Norwegian interval protocol, % HRR, percentage of heart rate reserve, RPE, rating of perceived exertion, TRIP, Toronto
Rehabilitation Institute protocol
38
RESULTS
Two male participants dropped out of the study due to time constraints, leaving 15 participants
who completed all study visits. Out of the 15 participants, one requested to prematurely end the
4x4 and TRIP protocols due to volitional fatigue, so his data for all analyses were excluded. In
addition, two female participants did not complete the ergospirometry assessments due to
extreme discomfort, so VO2 data is presented on 12 men and women. It should be noted that
there were no serious adverse events during the study, however, one participant experienced mild
angina (≤ 3/10) during the 10x1 protocol. There were no significant differences in
anthropometrics or resting BP and HR between study visits, thus, values were averaged and are
presented in Table 3. Standing VO2 and HR prior to the start of exercise were also similar
between visits (data not shown). Study results are presented in Table 5.
VO2 responses. Sample VO2 responses for one participant during each of the four protocols and
the group average are presented in Figure 9. Both 4x4 and TRIP protocols were greater than
MICE for average %VO2R achieved, with 10x1 trending significance (p=0.081). The peak
%VO2R achieved during 4x4, 10x1, and TRIP were all greater than MICE. The same trends
emerged when analyzed as relative VO2 values. The ΔVO2 for the 3 HIIE protocols were not
different than MICE, and total AUC was smaller for 10x1 compared to MICE. The AUC >MICE
values were greater in 4x4 and TRIP compared to MICE, but when analyzed >90% VO2R, no
protocol was significantly different to MICE. However, 4x4 approached significance (p=0.084).
The time spent >MICE was greater in the 4x4 and TRIP protocols; however, when expressed as
a percentage of the total exercise session, TRIP approached significance (p=0.057). Similar
observations were observed for time and percentage of session spent >90% VO2R, except TRIP
failed to reach statistical significance (p=0.084).
39
Table 5. Exercise protocol results.
HR responses. Sample HR responses for one participant during each of the four protocols and the
group average are presented in Figure 10. There was a main effect for average %HRR, whereby
MICE had a lower average than 4x4 and was trending to be lower than TRIP (p=0.057). Peak
%HRR also had a main effect, with all HIIE protocols having greater peak values than MICE.
When average and peak HR values were expressed as beats per minute, all results remained,
except TRIP’s average HR became significantly greater than MICE. The ΔHR was similar
between groups, and total AUC for the 10x1 protocol was smaller compared to MICE.
Variable PROTOCOL
P value 4x4 10x1 TRIP MICE
Oxygen uptake
Average (% VO2R) Average (ml·kg
-1·min
-1)
Peak (% VO2R)
Peak (ml·kg-1
·min-1
)
Δ (%)
AUC
Total >MICE
>90% VO2R
Time (min)
>MICE
>90% VO2R Time (% of session)
>MICE
>90% VO2R
Heart rate
Average (% HRR) Average (bpm)
Peak (% HRR)
Peak (bpm)
Δ (%)
AUC Total
Blood pressure (mmHg)
Peak SBP
Peak DBP
Post 1 min SBP Post 1 min DBP
Peak RPP
RPE
72 ± 19‡
24.1 ± 6.0†
102 ± 25‡
32.9 ± 9.1†
10 ± 7
532 ± 146
106 ± 68*
13 ± 29
22.7 ± 4.6*
6.0 ± 8.0*
81 ± 17*
21 ± 29*
77 ± 12†
122 ± 17‡
104 ± 17‡
142 ± 18‡
12 ± 7
1601 ± 429
186 ± 31‡
88 ± 15
136 ± 30
68 ± 12 26436 ± 5543‡
16 ± 2*
65 ± 18 21.9 ± 4.6
96 ± 27†
30.8 ± 6.9†
22 ± 24
350 ± 102‡
43 ± 31
6 ± 18
12.4 ± 3.9
2.1 ± 4.4
64 ± 21
10 ± 22
68 ± 1 114 ± 16
94 ± 10‡
136 ± 21‡
12 ± 10
1018 ± 300*
175 ± 40
79 ± 9
139 ± 43
74 ± 14 23950 ± 6378†
15 ± 1
67 ± 23*
22.4 ± 5.3†
93 ± 31*
28.5 ± 6.6†
20 ± 19
493 ± 160
61 ± 39*
14 ± 30
20.8 ± 5.7*
4.9 ± 9.1
74 ± 20
18 ± 33
69 ± 7
116 ± 15†
95 ± 9‡
136 ± 20‡
16 ± 6
1351 ± 441
176 ± 28
80 ± 16
139 ± 47
66 ± 17 24011 ± 5305†
14 ± 1
58 ± 16 20.2 ± 4.8
82 ± 24
26.6 ± 5.1
5 ± 16
479 ± 165
23 ± 14
2 ± 4
14.9 ± 2.1 1.5 ± 3.4
52 ± 4
5 ± 11
60 ± 9
110 ± 16
80 ± 11 125 ± 19
11 ± 7
1417 ± 589
153 ± 24
76 ± 14 126 ± 25
67 ± 13
19119 ± 4214 14 ± 1
p≤0.001 p≤0.001 p≤0.001
p≤0.001
p=0.158
p≤0.001 p=0.004
p=0.028
p≤0.001
p≤0.001
p=0.004
p≤0.001
p≤0.001 p≤0.001
p≤0.001
p≤0.001
p=0.158
p≤0.001
p=0.003
p=0.034
p=0.531 p=0.035
p≤0.001
p=0.003
Data presented as mean ± standard deviation and P values for main effects.
AUC, area under the curve, bpm, beats per minute, Δ, delta, DBP, diastolic blood pressure, 10x1, low volume
interval protocol, MICE, moderate-intensity continuous exercise, 4x4, Norwegian interval protocol, % HRR,
percentage of heart rate reserve, % VO2R, percentage of oxygen uptake reserve, RPE, rating of perceived exertion, RPP, rate pressure product, SBP, systolic blood pressure, TRIP, Toronto Rehabilitation Institute protocol
Different from MICE at *p<0.05, †p<0.01, ‡ p<0.001
40
BP, RPP, RPE, and protocol preference. Peak systolic BP (SBP) was higher during 4x4
compared to MICE and diastolic BP (DBP) trended significance (p=0.066). Both SBP and DBP
values taken immediately after the HIIE protocols were not found to be statistically different
from MICE. Peak RPP values during HIIE were greater than MICE. A main effect of protocol on
RPE was observed, whereby 4x4 was perceived to be harder than MICE, and 10x1 trended
significance (p=0.078). When participants ranked the protocols in order from most to least
preferred, 10x1 ranked first, followed by TRIP, 4x4, and then MICE.
Figure 9. Typical oxygen uptake (VO2) response from one participant (left side) and for the group average with standard deviation bars (right side). The lower dotted line represents MICE VO2 average and the upper dashed line 90% VO2 reserve (VO2R). 4x4, Norwegian interval protocol, 10x1, low-volume interval protocol, TRIP, Toronto Rehabilitation Institute protocol, MICE, moderate intensity continuous exercise.
Figure 10. Typical heart rate (HR) response from one participant (left side) and for the group average with standard deviation bars (right side). Dashed lines represent 40% and 80% HR reserve (HRR). 4x4, Norwegian interval protocol, 10x1, low-volume interval protocol, TRIP, Toronto Rehabilitation Institute protocol, MICE, moderate intensity continuous exercise.
0 10 20 300
10
20
30
time (min)
VO
2 (m
L/k
g/m
in)
4x4
0 10 20 300
10
20
30
time (min)
VO
2 (m
L/k
g/m
in)
TRIP
0 5 10 15 200
10
20
30
time (min)
VO
2 (m
L/k
g/m
in)
10x1
0 10 20 300
10
20
30
time (min)
VO
2 (m
L/k
g/m
in)
MICE
0 50 1000
1040
60
80
100
% of session
%V
O2R
4x4
10x1
TRIP
0 10 20 3050
75
100
125
150
175
time (min)
Hea
rt r
ate
(b
pm
)
4x4
0 10 20 3050
75
100
125
150
175
time (min)
He
art
ra
te (b
pm
)
TRIP
0 5 10 15 2050
75
100
125
150
175
time (min)
Hea
rt r
ate
(b
pm
)
10x1
0 10 20 3050
75
100
125
150
175
time (min)
He
art
ra
te (b
pm
)
MICE
0 50 1000
1040
60
80
100
% of session
%H
RR
4x4
10x1
TRIP
41
DISCUSSION
This investigation aimed to elucidate differences in the acute physiological response to HIIE
protocols compared to MICE in patients with CAD. The study’s hypotheses that 4x4 and 10x1
protocols would elicit greater and comparable physiological stimuli, respectively, compared to
MICE were confirmed. However, TRIP, a unique site-specific protocol employing short-duration
intervals, unexpectedly proved to be a more potent stimulus relative to conventional MICE and
may provide another option for HIIE prescription. HIIE was effective, well-tolerated, and
preferred so its prescription should be considered in eligible and willing CR patients.
Although this investigation is not the first to examine the acute physiological response to HIIE in
CR patients, it furthers our understanding by way of a comprehensive cardiorespiratory
examination of protocols employed in CR. Our study has demonstrated that the 4x4 protocol
provided the greatest CV stimulus based on the HR, VO2 and BP responses. This is in agreement
with previous findings, but time spent at a high VO2 during the HIIE protocols was not examined
[50]. Though the present observations would suggest 4x4 to be the optimal protocol, it had the
highest RPE and was ranked the lowest HIIE protocol for preference by study participants. The
10x1 protocol was most preferred, but it was the least effective HIIE protocol when considering
average VO2 and time spent at a high VO2. An advantage of the 10x1 protocol is that it is a low-
volume alternative to standard of care that elicits a comparable physiological response. TRIP, a
novel site-specific protocol, proved to be a strong physiological stimulus and may be a viable
alternative to long duration intervals, for its similar HR response and RPE but greater time spent
above MICE VO2 compared to standard of care. Similar to the present study, Guiraud et al. [110]
concluded short duration intervals (15-sec) with passive recovery to be the optimized HIIE
prescription for those with CAD, as it allowed for a greater number of intervals to be completed
and a similar time spent at a high VO2 with lower RPE compared to other combinations of longer
durations (60-sec) and active recovery. These and previous results highlight the effectiveness of
HIIE in eliciting a potent physiological stimulus relative to MICE.
It is noteworthy that TRIP, a protocol utilizing short-duration intervals and low-intensity
recovery, resulted in a greater average VO2 and time spent above MICE VO2 compared to the
MICE protocol, findings also observed when exercising with longer duration intervals and
moderate-intensity recovery (i.e., 4x4). Earlier studies have found short work intervals to
42
facilitate the achievement of heavy workloads with large muscle groups but minimally strain the
cardiorespiratory system, whereas longer intervals stress the aerobic system to a greater extent
[41, 42]. This is supported by our observation of a high-intermediate level of cardiac stress with
the 4x4 protocol compared to intermediate during 10x1 and TRIP, indicated by peak RPP values.
For example, long work intervals have been shown to elicit higher acute metabolic and peak
cardiorespiratory changes (i.e., blood lactate, HR, VO2) compared to short intervals (20-sec) or
MICE in CR patients [50], potentially due to a more substantial anaerobic glycolytic system
contribution. Results from the present study and others [50, 121] show minor HR and VO2
oscillations with intervals of short duration, which explains the maintenance of a high VO2
during TRIP despite frequent recovery periods. Furthermore, the work-to-rest ratio and recovery
intensity may be important parameters to consider. Data from athletes suggests a ratio >1 should
result in more time spent at a high VO2 [150], and would explain why the 10x1 protocol was
comparable to MICE for average VO2 and time spent above the thresholds, while 4x4 and TRIP
were superior. A study investigating a 10x1 protocol observed higher average HR and VO2
responses when an active recovery was used compared to a passive recovery [151]. While the
physiological response of the 10x1 protocol was inferior to the other HIIE protocols in the
present study, it should not be discounted as a possible HIIE prescription based on the
observation that it was comparable to MICE.
Time spent near or at maximal VO2 (VO2max) is a potent stimulus for cardiorespiratory fitness
adaptations, with a suggested target of 10 accumulated minutes at this intensity in order to infer
improvements in VO2max [37]. Accumulated time spent at high intensities maximally stresses
the oxygen transport and utilization systems, and therefore, may determine associated
physiological benefits [36, 37, 40-42]. Interval exercise has been shown to result in a longer time
spent at a higher %VO2max compared to MICE [43], so the optimal HIIE protocol may be one
that allows for greater periods of time to be spent near or at VO2max. In the present study,
approximately 6 and 5 minutes were spent above 90% VO2R during 4x4 and TRIP, respectively.
This is in line with previous findings in CAD patients [110], but below the 10-minute target.
However, these times were significantly greater and approximately double the amount of time
spent above 90% VO2R during 10x1 and MICE. Even when expressed as absolute time and
percentage of the total exercise session, the 10x1 protocol was comparable to MICE, yet 10
minutes less to complete. It could be speculated that the addition of work/rest series to match the
43
total exercise duration of the other protocols would increase its physiological stimulus to become
superior to MICE. In addition, the physiological response to a typical CR session was quantified
and used as a threshold, whereby exercising above this would arguably lead to superior CV
improvements. Results for time spent above MICE VO2 suggest both 4x4 and TRIP to be
superior to MICE, demonstrating that these protocols elicit larger aerobic stimuli compared to
traditionally prescribed continuous exercise. Peak VO2 was greater in all HIIE protocols
compared to MICE, which was expected given that each HIIE protocol prescribed 85%-95%
HRR for the high-intensity intervals. Finally, average VO2 values complement the time spent
above MICE VO2 observations, with 4x4 and TRIP having higher values than MICE. Hence,
average VO2 and time spent above MICE indicate 4x4 and TRIP are more potent stimuli
compared to MICE, while 10x1 is comparable. However, in order to spend a greater amount of
time at intensities near or at VO2peak, it is necessary to perform the 4x4 protocol.
The changes in VO2 and HR from early to late exercise suggest a gradual increase in VO2 and
HR occurred for all protocols, as evident by positive ΔVO2 and ΔHR values. While this finding
was expected, the magnitude of increase that occurred during the HIIE sessions seemed to be
comparable to MICE. AUC analysis revealed that the 10x1 protocol produced lower cumulative
HR and VO2 stimuli compared to MICE, likely owing to its shorter exercise time. Observations
for VO2 AUC above MICE parallel findings for time spent above this threshold, but since time
spent above 90%VO2R was minimal, it was not sufficient to elucidate differences. AUC is a
useful comparative method to quantify the cumulative exercise stimulus for protocols employing
differing work-to-rest ratios, recovery intensities, and exercise durations. Our investigation
builds upon existing literature by using AUC to elucidate differences in the cumulative exercise
stimulus, which validates trends observed for time spent above MICE and possibly for time spent
above 90% VO2R. It is unclear what this information translates to exactly, but may provide
further support to trends observed for time spent above certain intensities.
The recommended exercise intensity for aerobic exercise in CR patients is 40-85% HRR or an
RPE of 12-16 [10]. In the present study, mean %HRR and RPE were higher during the 4x4
protocol compared to MICE, however, all exercise protocols elicited values within
recommendations. As expected, higher peak HR values were observed during the HIIE protocols
compared to MICE. While the 4x4 protocol elicited a higher BP response, regardless of protocol,
44
BP remained within an acceptable range during exercise (i.e., SBP <250 mmHg and/or DBP
<115 mmHg) [9]. However, exaggerated blood pressure (EBP) responses (SBP >210 mmHg)
[152] were documented during certain HIIE sessions (4x4: n=2, 10x1: n=4, TRIP: n=1). EBP
during exercise is associated with an increased risk of future hypertension and/or CV
events [153, 154]; thus, these observations may be clinically relevant, but could also be product
of higher exercise intensities during HIIE and their associated VO2 costs. It follows that
myocardial oxygen demand (i.e., RPP) was greater during HIIE compared to MICE, which may
be an important consideration before its prescription in patients with compromised coronary
blood flow. Moreover, BP immediately after exercise may be of additional clinical relevance, as
post-2 min SBP predicted risk of acute MI [155]. In the present study, no differences in post-
exercise BP were apparent, yet, 3 cases of elevated SBP (≥195mmHg) immediately after
exercise were observed (1 case per HIIE protocol). Finally, no significant adverse events
occurred during the exercise sessions, supporting HIIE and its low risk of associated CV events
[31].
Limitations. It is recognized that the present study has limitations. We did not measure local
metabolites or metabolic by-products (i.e., phosphocreatine, blood lactate), which would have
helped to elucidate the contribution of the aerobic and anaerobic energy production systems to
meet ATP demand during the various exercise protocols. The inclusion of stable CAD patients,
free of other comorbidities (i.e., diabetes mellitus, heart failure), limits the applicability of study
findings to the representative CR population. Our participants were already engaging in CR
(n=8) or were graduates of the program (n=6) and had higher fitness levels than patients with
additional comorbidities and/or naïve to CR [156]. Although 6 women were successfully
recruited for participation and provides a larger female representation than previous studies [50,
67, 110], this did not provide enough statistical power to evaluate potential sex-based
differences. An exploratory analysis did not reveal an effect of sex on time spent >90%VO2R
(p=0.683), so one may surmise that there are no differences in the acute physiological response
to HIIE between males and females; however, these results should be interpreted with caution.
Finally, while numerous combinations of work-to-rest ratios and exercise intensities for HIIE
prescription could be examined, the intent of the study was to examine 2 HIIE protocols
previously employed in longitudinal training studies and a novel site-specific HIIE protocol.
45
CONCLUSION
This study demonstrated that 3 HIIE protocols, using different work-to-rest ratios and recovery
intensities, had distinct physiological responses appropriate for training in CR. The 4x4 protocol
was the most potent CV stimulus, but its higher perceived difficulty and lack of preference
should be considered before its prescription. While the 10x1 protocol was comparable MICE, it
was the most preferred amongst our participants, and would be a pragmatic choice to achieve a
similar stimulus to the current standard of care in a shorter period of time. Moreover, TRIP, a
novel protocol, elicited a comparable HR and RPE response for a higher VO2 relative to MICE,
indicating it is both effective and tolerable and should be examined in a longitudinal training
study. The present investigation has confirmed that HIIE prescription is well tolerated, effective,
and is preferred over a traditional MICE protocol.
ACKNOWLEDGEMENTS
The authors would like to thank the participants for their time and effort, and acknowledge the
CR clinical and research staff at UHN for their assistance with study recruitment.
46
– Conclusion
5.1. Extended discussion
The purpose of this study was to examine the acute physiological response to HIIE protocols in
patients with stable CAD, and identify a protocol that was both effective and preferred by CR
patients. The current investigation provides novel insight into the acute physiological stimulus of
3 habitually prescribed HIIE protocols, by way of a comprehensive CV assessment and the
comparison to a MICE session representative of standard of care. Study hypotheses were
confirmed, whereby the 4x4 protocol resulted in a potent CV stimulus, as evident by greater HR,
VO2, and BP responses relative to traditional MICE, but despite this, was the least preferred
HIIE protocol. Comparatively, the 10x1 protocol ranked highest for preference and provided a
comparable physiological stimulus to standard of care with the advantage of a markedly lower
exercise time. In contrast to what was hypothesized, TRIP elicited a greater average and peak
VO2 for comparable HR and RPE response compared to MICE, and may provide an effective
alternative for HIIE prescription. Overall, the investigated HIIE protocols were comparable or
superior, well tolerated, and favoured over conventional MICE. On the whole, findings from the
present investigation confirm longitudinal training study observations and expand our current
understanding of HIIE in the CAD population.
The time at which peak values occurred provides additional information on cardiorespiratory
parameters over the course of the exercise sessions. Peak HR occurred during the latter portion
of the exercise session for all protocols while peak VO2 seemed to generally occur earlier. This
suggests that HR continues to rise throughout the course of the exercise session, while VO2
reaches a plateau sometime after the session’s midpoint, a trend that can be confirmed upon
graphical examination of Figures 9 and 10. It is also interesting to consider the BP trend during
the investigated protocols. It appears that SBP increased noticeably from rest at exercise onset,
declined during the first half of exercise, and then reached a plateau during the latter half, while a
clear trend for the DBP response was not apparent (Appendix K).
An increase in coronary blood flow accompanies exercise in order to meet myocardial metabolic
demand, but this capacity is reduced in those with obstructive CAD and/or poor coronary
vascular function. The RPP is representative of myocardial oxygen demand, which was observed
47
to be greater with HIIE compared to MICE. However, with repeated exposure over time, the RPP
at a given work rate is typically reduced after HIIT [157]. The greatest improvements may be
associated with a low initial fitness level, as previous work has revealed higher fitness CAD
patients did not decrease resting or peak RPP after HIIT [20], likely because of a higher achieved
work rate. The differences observed in RPP with a given exercise protocol may be of clinical
importance for ischemic patients, supporting short duration intervals to generate a lower
myocardial oxygen cost.
5.1.1. Clinical implications
This study has important clinical implications for both staff and patients involved in CR. CR
staff, who recognize HIIT’s effectiveness and desire its incorporation into the care of eligible
patients, have little empirical evidence to inform HIIE prescription that yields the most
efficacious adaptive stimulus in addition to patient compliance and preference. Findings support
HIIE’s low-risk of associated serious adverse events in the CAD population [158], but an
episode of mild angina during the 10x1 protocol (1/42 HIIE sessions or 2%) during this
investigation is higher than the <1% target for CR-related adverse events. This would be of
concern for CR staff considering HIIE prescription. Moreover, the assessment of physiological
parameters during exercise has provided detailed information on the cardiorespiratory demands
of various exercise regimens. We observed that mean HR and RPE values were within exercise
intensity recommendations [9], in compliance with CR guidelines [10]. All exercise BP values
were below the criteria for exercise termination, with a few EBP responses observed during
HIIE. The higher peak RPP observed during HIIE compared to MICE is indicative of greater
cardiac stress, whereby values fell in the intermediate (10x1 & TRIP) to high-intermediate (4x4)
range. This supports the 4x4 protocol as a strong CV stimulus requiring a substantial myocardial
oxygen cost, and warrants consideration before its prescription in those with compromised
coronary blood flow. While this demonstrates HIIE to be a more potent physiological stimulus
than MICE, the CV response is not necessarily adverse. These results further reinforce the
importance of conducting a maximal exercise test on patients before initiating HIIT, to
accurately determine target intensities, and confirm the absence of exercise intolerance at high
intensities (i.e., ischemia). Clinical staff can then be assured that patients are exercising at safe
levels because high-intensity intervals are prescribed at submaximal intensities and do not
require supramaximal efforts.
48
While HIIT’s superiority in eliciting greater VO2peak improvements compared to MICE is
considered clinically significant (+1.78 ml·kg-1·min-1) [25], the difference in magnitude of
improvement between various HIIE protocols employed with chronic training may not be. In
other words, although one HIIE protocol provides a greater acute physiological stimulus
compared to the others, its superiority with long-term adaptations may be marginal. Further,
differences in morbidity and morality rates are likely negligible. However, it is fathomable that
differences would arise with a protocol that elicits higher adherence rates, which may be
influenced by perceptions of enjoyment and preference. It has also been argued that the savings
in time accumulated with HIIT are actually rather small [159], thus, it is important to
qualitatively assess perceived barriers to exercise participation.
Finally, it is imperative to consider HIIT within the context of broader public health initiatives
[160]. Effective public health strategies aim to make small changes to elicit clinically meaningful
results across a large population. HIIT is not only valuable to athletes wishing to improve
performance, but relevant to the general population, as interval exercise is representative of
many activities of daily living (i.e., walking up stairs, catching the bus), and warrants its
advocacy within public health strategies. At present, HIIT produces substantial health
improvements in a select subset of CR patients but has yet to have wide-reaching impact. Its
successful implementation in the CR setting requires additional time and personnel, which may
not be a judicious use of resources. One should also be critical of HIIT interventions intended to
increase exercise participation. HIIT’s unsuccessful adoption may not be due to HIIT itself, but
the failure to adequately address and target barriers to physical activity in general. Consideration
of HIIT is justified when the focus is to optimize exercise prescription in compliant individuals;
however, attention should be placed on examining its effectiveness in a sedentary population
with the intent of increasing physical activity levels.
5.1.2. Patient preferences
Theoretical frameworks such as Social Cognitive Theory [161] and Theory of Planned
Behaviour [162] offer psychological determinants that influence exercise behaviour, and how
perceived barriers and exercise enjoyment act to influence these factors. HIIE may increase
exercise self-efficacy through the accomplishment of multiple high-intensity bouts [146], and
further, exercise enjoyment may predict attitudes and future intentions to engage in HIIE [163].
49
While studies have shown in-task affect during HIIE to be similar or more negative than
continuous exercise, the post-exercise response was similar [164]. In line with the present
study’s results, previous work has shown an equal or greater preference for HIIE compared to
continuous exercise [146]. Future intentions and behaviour (i.e., exercise adherence) for HIIE
may not be as straightforward compared to continuous exercise due to the intermittent nature of
HIIE and its purposeful recovery periods. HIIE may elicit a negative in-task affect but positive
rebound; however, the predictive power for future exercise behaviour is unclear. This
investigation found the 10x1 protocol to be most preferred, followed by TRIP, 4x4, and MICE
(Appendix K). Anecdotally, majority of participants disliked the 4x4 protocol because of its long
interval duration, and those who selected it as their most preferred protocol did on the basis that
they perceived to have worked the hardest. In line with previous suggestions [123], the 4x4
protocol can be prescribed to willing and/or highly functional patients who wish to incur further
improvements in aerobic fitness. However, participants who most preferred the 4x4 protocol
were not necessarily of the highest fitness level or with the most CR participation/HIIE
experience, which challenges the notion that longer duration intervals should only be prescribed
to the ‘ideal’ patient. Intervals of shorter duration, as in 10x1 and TRIP, were found to be
preferred over 4x4 and MICE protocols, and may be suitable for patients in the early stages of
CR and/or of limited aerobic capacity. Participants commented that short duration intervals (≤60-
sec) allowed the achievement of high workloads that contributed to feelings of accomplishment,
and was manageable with the anticipation of an approaching recovery period. Furthermore, there
were no apparent trends in protocol preference between sexes. Individualized exercise
prescription should be encouraged in CR settings because it is clear that protocol preference is
patient-dependent.
5.2. Study limitations
Our sample was limited to recruiting patients currently participating in the CR or graduate
programs, which yielded few female participants. Few were deemed to be suitable for study
participation, as diabetes mellitus and musculoskeletal impairments were the most prevalent
comorbidities, especially in this post-menopausal cohort. Though recruiting solely female CAD
patients proved to be unfruitful, this highlights unique challenges that accompany studies that
aim to elucidate sex-based differences. Although 6 women were successfully recruited for
participation and provides a larger female representation than previous studies [50, 67, 110], this
50
did not provide enough statistical power to evaluate potential sex-based differences. An
exploratory analysis did not reveal an effect of sex on reported physiological measures, including
the main outcome of time spent >90%VO2R (p=0.683). This may suggest that there are no
differences in the acute physiological response to HIIE between males and females; however,
these results should be interpreted with caution.
Another limitation was the use of treadmill exercise, which limits the study’s generalizability to
those using cycle ergometry. Treadmill exercise was chosen since it is the most common
modality in North American CR programs, and can be used without the need for costly cycle
ergometers. Patients who could not comfortably perform exercise on a treadmill were excluded,
yet many patients uncomfortable on the treadmill may indeed be less challenged while walking
on a track. Following the notion of applicability to CR programs, exercise was prescribed as
%HRR rather than workload or %VO2peak, as both patients and CR staff can readily prescribe
and monitor exercise intensity using HR zones. However, HR for exercise prescription has been
subject to criticism in the HIIE literature because of its nonlinear relationship to work rate at high
intensities, and further, the HR ‘lag’ may result in inaccurate estimations of exercise intensity
especially during short-duration intervals [37]. Moreover, workload adjustments due to HR drift
during HIIE are required in order to stay within target HR zones and may result in suboptimal
training adaptations. Exercise intensity prescription becomes further complicated for patients
with reduced inotropic and chronotropic reserve (i.e., beta-blocker use) [143, 165], which
compromised over half of study participants. While exercising at workloads corresponding to AT
have been favoured [166, 167], HR may still be an appropriate method of exercise intensity
prescription [167, 168]. In the current study, it was ensured that patients were consistent with
their medication routine and that all study visits were conducted at the same time of day to
ensure intra-individual reliability.
The CPA from which VO2peak and HRpeak were obtained may have inherent errors. Since
patients were recruited at all points of participation or graduation from the CR program (due to
difficulties in the initial recruitment strategy), only 5 had CPAs conducted within 3 months of
study participation. Additionally, patients from TWH did not undergo expired gas assessment
during maximal exercise testing, so their VO2peak was estimated using the Bruce protocol
equation (n=4). It appears that their VO2peaks may be over-estimated because essentially no time
was spent above 90%VO2R for any of these participants. Ideally, patients would have performed
51
a maximal treadmill exercise test with ergospirometry assessment prior to study participation,
except this would have required additional time, personnel, and patient burden. However, owing
to the study’s crossover design, within-subject comparisons are not subject to this limitation.
Lastly, it should be mentioned that the intensities achieved during the HIIE protocols were in the
moderate to vigorous range and may not be considered high-intensity. Peak values demonstrate
that participants were able to achieve high intensities, so this limitation is likely due to study
design. Despite partaking in a familiarization session, participants performed these protocols in
their entirety for the first time. Additional sessions would improve familiarity and comfort,
which would potentially allow for the achievement of higher exercise intensities for a longer
period of time. However, the beneficial effect of HIIT may not be solely attributed to its high-
intensity prescription, but the intermittent nature may provide an independent and additive effect.
Preliminary work investigating moderate-intensity interval training is intriguing and may be an
appropriate pre-HIIT step or as an alternative for those deterred from or ineligible for HIIE
[169].
5.3. Future directions
First and foremost, longitudinal training studies are required to compare the efficacy of the
protocols used in this study and verify if acute physiological responses predict long-term gains in
aerobic fitness. Since an acute study has shown promising results for 15-sec intervals [110], a
longitudinal study should consider investigating a HIIE protocol with short duration intervals
(i.e., ≤30-sec) and determine related training adaptations. Long-term interventions (>6 months)
should be employed, as it could be possible that both HIIT and MICT induce the same
magnitude of improvement, but MICT requires a longer time course for adaptations [73]. Results
from training studies should be applied to the examination of safety and long-term adherence,
and ultimately, on CV end-points (i.e., morbidity and mortality). Future analyses should also
consider the most appropriate way to represent and quantify the physiological stimulus, as this
may be different than the method in which exercise is prescribed. The present investigation
selected time spent >90%VO2R as the main outcome to compare protocols, but its relationship to
VO2peak improvement needs to be confirmed. While the current investigation used treadmill
exercise, exploring multiple exercise modalities for patient preference may be of merit (i.e., track
52
walking, cycling, outdoor activities). It is with this systematic approach that the optimal exercise
protocol can be determined.
Though sex-specific data on CV disease is growing [170, 171], an inadequate representation of
females undermines the our ability to ascribe evidence-based sex-specific recommendations in
CR. Research on the effects of HIIE in patients with CAD have been based on mostly male
participants [20, 23, 77, 78, 83, 85]; thus, these studies were not adequately powered to report
sex-specific results. Future work should focus on purposefully recruiting a greater proportion of
female patients so that the optimal exercise prescription for both men and women in CR may be
formally investigated.
Lastly, knowledge translation (KT) involving CR staff and patients is paramount if HIIT is to
become regularly prescribed in the CR setting. Health care professionals within a patient’s circle
of care may be hesitant to advocate for and incorporate HIIE into a patient’s exercise program,
on account of unfamiliarity with its prescription, lack of knowledge, and worry of patient safety.
Well-informed KT experts should share research that clearly illustrates its effectiveness,
highlighting its low risk of serious adverse events, and address both staff and patient concerns. A
succinct message that can be offered to CR staff and patients based on the present investigation’s
findings would recommend the initial prescription of shorter duration intervals (i.e., ≤60-sec)
with low-intensity recovery and then progressively increase work duration and/or recovery
intensity. It may be worthwhile to consider advocating for higher intensity interval exercise for
patients who are hesitant or find HIIE intolerable. In addition, prescribing HIIE to naïve CR
patients is resource-intensive (i.e., additional time and supervision), so thoughtful consideration
of addressing these challenges is needed before HIIT is to become standard of care.
5.4. Conclusion
The present results are congruent with the overwhelming body of literature in favour of HIIE
over conventional MICE. While the 4x4 protocol proved to elicit a potent physiological stimulus,
its preference was limited to few participants. In contrast, the well-received 10x1 protocol was
only as good as conventionally prescribed MICE. TRIP had a greater average and peak VO2
response for a similar average HR to MICE, so may be a viable option opposed to long duration
interval protocols. However, the 10x1 protocol may be used as a low-volume, pragmatic
alternative that is more enjoyable than conventional MICE. These results lend support to a
53
paradigm shift in CR standards of care, calling for both high-volume continuous exercise and
HIIE as effective and patient-preferred modes of exercise.
54
References
1. WHO. The top 10 causes of death. 2017 Jan 2017 [cited 2017 Aug 13].
2. Liebermen, E.H., et al., Flow-Induced Vasodilation of the Human Brachial Artery is
Impaired in Patients <40 Years of Age with Coronary Artery Disease. American Journal of Cardiology, 1996. 78: p. 1210-1214.
3. Brunner, H., et al., Endothelial function and dysfunction. Part II: Association with
cardiovascular risk factors and diseases. A statement by the Working Group on
Endothelins and Endothelial Factors of the European Society of Hypertension. Journal of Hypertension, 2005. 23: p. 233-246.
4. Keteyian, S.J., et al., Peak aerobic capacity predicts prognosis in patients with coronary
heart disease. Am Heart J, 2008. 156(2): p. 292-300.
5. Kavanagh, T., et al., Prediction of Long-Term Prognosis in 12 169 Men Referred for
Cardiac Rehabilitation. Circulation, 2002. 106(6): p. 666-671.
6. Gielen, S., G. Schuler, and R. Hambrecht, Exercise Training in Coronary Artery Disease
and Coronary Vasomotion. Circulation, 2001. 103: p. e1-e6.
7. Heran, B.S., et al., Exercise-based cardiac rehabilitation for coronary heart disease. Cochrane Database Syst Rev, 2011(7): p. CD001800.
8. Myers, J., et al., Exercise capacity and mortality among men referred for exercise testing. N Engl J Med, 2002. 346(11): p. 793-801.
9. ACSM's Resource manual for guidelines for exercise testing and prescription. 2013, Wolters Kluwer: Lippincott Williams and Wilkins: Baltimore.
10. Mezzani, A., et al., Aerobic exercise intensity assessment and prescription in cardiac
rehabilitation: a joint position statement of the European Association for Cardiovascular
Prevention and Rehabilitation, the American Association of Cardiovascular and
Pulmonary Rehabilitation and the Canadian Association of Cardiac Rehabilitation. Eur J Prev Cardiol, 2013. 20(3): p. 442-67.
11. Stone, J.A. and H.M. Arthur, Canadian guidelines for cardiac rehabilitation and
cardiovascular disease prevention, second edition, 2004: executive summary. Can J Cardiol, 2005. 21(Suppl D): p. 3D-19D.
12. DeSouza, C.A., et al., Regular Aerobic Exercise Prevents and Restores Age-Related
Declines in Endothelium-Dependent Vasodilation in Healthy Men. Circulation, 2000. 102: p. 1351-1357.
13. Barbour, K.A. and N.H. Miller, Adherence to exercise training in heart failure: a review. Heart Fail Rev, 2008. 13(1): p. 81-9.
55
14. Helgerud, J., et al., Aerobic high-intensity intervals improve VO2max more than
moderate training. Med Sci Sports Exerc, 2007. 39(4): p. 665-71.
15. Thomas, T.R., S.B. Adeniran , and G.L. Etheridge, Effects of different running programs
on VO2 max, percent fat, and plasma lipids. Can. J. Appl. Sport Sci., 1984. 9(2): p. 55-62.
16. Milanovic, Z., G. Sporis, and M. Weston, Effectiveness of High-Intensity Interval
Training (HIT) and Continuous Endurance Training for VO2max Improvements: A
Systematic Review and Meta-Analysis of Controlled Trials. Sports Med, 2015. 45(10): p. 1469-81.
17. MacInnis, M.J. and M.J. Gibala, Physiological adaptations to interval training and the
role of exercise intensity. J Physiol, 2017. 595(9): p. 2915-2930.
18. Cornish, A.K., S. Broadbent, and B.S. Cheema, Interval training for patients with
coronary artery disease: a systematic review. Eur J Appl Physiol, 2011. 111(4): p. 579-89.
19. Elliott, A.D., et al., Interval training versus continuous exercise in patients with coronary
artery disease: a meta-analysis. Heart Lung Circ, 2015. 24(2): p. 149-57.
20. Warburton, D.E., et al., Effectiveness of high-intensity interval training for the
rehabilitation of patients with coronary artery disease. Am J Cardiol, 2005. 95(9): p. 1080-4.
21. Moholdt, T., et al., Long-term follow-up after cardiac rehabilitation: A randomized study
of usual care exercise training versus aerobic interval training after myocardial
infarction. Int J Cardiol, 2011. 152(3).
22. Ramos, J.S., et al., The impact of high-intensity interval training versus moderate-
intensity continuous training on vascular function: a systematic review and meta-
analysis. Sports Med, 2015. 45(5): p. 679-92.
23. Currie, K.D., et al., Low-volume, high-intensity interval training in patients with CAD. Med Sci Sports Exerc, 2013. 45(8): p. 1436-42.
24. Guiraud, T., et al., High-intensity interval training in cardiac rehabilitation. Sports Med, 2012. 42: p. 587-605.
25. Liou, K., et al., High Intensity Interval versus Moderate Intensity Continuous Training in
Patients with Coronary Artery Disease: A Meta-analysis of Physiological and Clinical
Parameters. Heart Lung Circ, 2016. 25(2): p. 166-74.
26. Meyer, K., et al., Comparison of Left Ventricular Function During Interval Versus
Steady-State Exercise Training in Patients With Chronic Congestive Heart Failure. American Journal of Cardiology, 1998. 82: p. 1382-1387.
56
27. Wisloff, U., et al., Superior cardiovascular effect of aerobic interval training versus
moderate continuous training in heart failure patients: a randomized study. Circulation, 2007. 115(24): p. 3086-94.
28. Safiyari-Hafizi, H., et al., The Health Benefits of a 12-Week Home-Based Interval
Training Cardiac Rehabilitation Program in Patients With Heart Failure. Can J Cardiol, 2016. 32(4): p. 561-7.
29. Aamot, I.L., et al., Home-based versus hospital-based high-intensity interval training in
cardiac rehabilitation: a randomized study. Eur J Prev Cardiol, 2014. 21(9): p. 1070-8.
30. Jaureguizar, K.V., et al., Effect of High-Intensity Interval Versus Continuous Exercise
Training on Functional Capacity and Quality of Life in Patients With Coronary Artery
Disease: A RANDOMIZED CLINICAL TRIAL. J Cardiopulm Rehabil Prev, 2016. 36(2): p. 96-105.
31. Rognmo, O., et al., Cardiovascular risk of high- versus moderate-intensity aeroibc
exercise in coronary heart disease patients. Circulation, 2012. 126: p. 1436-1440.
32. Pack, Q.R., et al., Safety of early enrollment into outpatient cardiac rehabilitation after
open heart surgery. Am J Cardiol, 2015. 115: p. 548-552.
33. Gibala, M.J., et al., Physiological adaptations to low-volume, high-intensity interval
training in health and disease. J Physiol, 2012. 590(5): p. 1077-84.
34. Gibala, M.J. and A.M. Jones, Physiological and performance adaptations to high-
intensity interval training. Nestle Nutr Inst Workshop Ser, 2013. 76: p. 51-60.
35. Daussin, F.N., et al., Improvement of VO2max by cardiac output and oxygen extraction
adaptation during intermittent versus continuous endurance training. Eur J Appl Physiol, 2007. 101(3): p. 377-83.
36. Laursen, P.B. and D.G. Jenkins, Scientific Basis for High-Intensity Interval Training. Sports Med, 2002. 32(1): p. 53-73.
37. Buchheit, M. and P.B. Laursen, High-intensity interval training, solutions to the
programming puzzle: Part I: cardiopulmonary emphasis. Sports Med, 2013. 43(5): p. 313-38.
38. Buchheit, M. and P.B. Laursen, High-intensity interval training, solutions to the
programming puzzle. Part II: anaerobic energy, neuromuscular load and practical
applications. Sports Med, 2013. 43(10): p. 927-54.
39. Martinez, N., et al., Affective and Enjoyment Responses to High-Intensity Interval
Training in Overweight-to-Obese and Insufficiently Active Adults. J Sport Exerc Psychol, 2015. 37(2): p. 138-49.
40. Midgley, A.W., L.R. McNaughton, and M. Wilkinson, Is there an optimal training
intensity for enhancing the maximal oxygen uptake of distance runners? Empirical
57
research findings, current opinions, physiological rationale and practical
recommendations. Journal of Sports Medicine, 2006. 36(2): p. 117-132.
41. Astrand, I., et al., Intermittent Muscular Work. Acta Physiologica Scandinavica, 1960. 48: p. 448-453.
42. Saltin, B., B. Essen, and B.K. Pedersen, Intermittent exercise: its physiology and some
practical applications, in Advances in exercise physiology. 1976, Karger Publishers. p. 23-51.
43. Demarie, S., J.P. Koralsztein, and V. Billat, Time limit and time at VO2max during a
continuous and an intermittent run. J Sports Med Phys Fitness, 2000. 40: p. 96-102.
44. Ciolac, E.G., et al., Rating of perceived exertion as a tool for prescribing and self
regulating interval training: a pilot study. Biol Sport, 2015. 32(2): p. 103-8.
45. Dupont, G., N. Blondel, and S. Berthoin, Time spent at VO2max: a methodological issue. Int J Sports Med, 2003. 24: p. 291-297.
46. Turnes, T., et al., Interval training in the boundaries of severe domain: effects on aerobic
parameters. Eur J Appl Physiol, 2016. 116(1): p. 161-169.
47. Swain, D.P. and B.A. Franklin, Is there a threshold intensity for aerobic training in
cardiac patients? Med Sci Sports Exerc, 2002. 34(7): p. 1071-1075.
48. Wenger, H.A. and G.J. Bell, The interactions of intensity, frequency and duration of
exercise training in altering cardiorespiratory fitness. Sports Med, 1986. 3: p. 346-356.
49. Thomas, T.R., et al., Effects of interval and continuous running on HDL-cholesterol,
apoproteins A-1 and B, and LCAT. Can J Appl Sport Sci, 1985. 10(1): p. 52-59.
50. Tschakert, G., et al., Acute Physiological Responses to Short- and Long-Stage High-
Intensity Interval Exercise in Cardiac Rehabilitation: A Pilot Study. Journal of Sports Science and Medicine, 2016. 15: p. 80-91.
51. Meyer, K., et al., Interval training in patients with severe chronic heart failure: analysis
and recommendations for exercise procedures. Med Sci Sports Exerc, 1997. 29(3): p. 306-312.
52. Thompson, P.D., et al., Exercise and acute cardiovascular events placing the risks into
perspective: a scientific statement from the American Heart Association Council on
Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology. Circulation, 2007. 115(17): p. 2358-68.
53. Britain, G., At least five a week: Evidence on the Impact of Physical Activity and Its
Relationship to Health: a Report from the Chief Medical Officer. Department of Health, 2004.
58
54. Andersen, T.J., et al., Close Relation of Endothelial Function in the Human Coronary
and Peripheral Circulations. Journal of the American College of Cardiology, 1995. 26(5): p. 1235-1241.
55. Pattyn, N., et al., Aerobic interval training vs. moderate continuous training in coronary
artery disease patients: a systematic review and meta-analysis. Sports Med, 2014. 44(5): p. 687-700.
56. Swift, D.L., et al., Physical Activity, Cardiorespiratory Fitness, and Exercise Training in
Primary and Secondary Coronary Prevention. Circulation Journal, 2013. 77(2): p. 281-292.
57. Vanhees, L., et al., Importance of characteristics and modalities of physical activity and
exercise in the management of cardiovascular health in individuals with cardiovascular
disease (Part III). Eur J Prev Cardiol, 2012. 19(6): p. 1333-56.
58. Linke, A., S. Erbs, and R. Hambrecht, Exercise and the coronary circulation-alterations
and adaptations in coronary artery disease. Prog Cardiovasc Dis, 2006. 48(4): p. 270-84.
59. Pedersen, B.K. and B. Saltin, Exercise as medicine - evidence for prescribing exercise as
therapy in 26 different chronic diseases. Scand J Med Sci Sports, 2015. 25 Suppl 3: p. 1-72.
60. Edwards, D.G., et al., Effect of exercise training on endothelial function in men with
coronary artery disease. Am J Cardiol, 2004. 93(5): p. 617-20.
61. Edwards, D.G., et al., Effect of exercise training on central aortic pressure wave
reflection in coronary artery disease. Am J Hypertens, 2004. 17(6): p. 540-3.
62. Vona, M., et al., Impact of physical training and detraining on endothelium-dependent
vasodilation in patients with recent acute myocardial infarction. Am Heart J, 2004. 147(6): p. 1039-46.
63. Luk, T.H., et al., Effect of exercise training on vascular endothelial function in patients
with stable coronary artery disease: a randomized controlled trial. Eur J Prev Cardiol, 2012. 19(4): p. 830-9.
64. O'Conner, C.M., et al., Efficacy and Safety of Exercise Training in Patients with Chronic
Heart Failure: HF-ACTION randomized controlled trial. JAMA, 2009. 301(14): p. 1439-1450.
65. Swain, D.P. and B.A. Franklin, Comparison of cardioprotective benefits of vigorous
versus moderate intensity aerobic exercise. Am J Cardiol, 2006. 97(1): p. 141-7.
66. Wisloff, U., et al., A single weekly bout of exercise may reduce cardiovascular mortality:
how little pain for cardiac gain? 'The HUNT study, Norway'. Eur J Cardiovasc Prev Rehabil, 2006. 13: p. 798-804.
59
67. Guiraud, T., et al., Acute Responses to High-Intensity Intermittent Exercise in CHD
Patients. Med Sci Sports Exerc, 2011. 43(2): p. 211-7.
68. Kemi, O.J. and U. Wisloff, High-intensity aerobic exercise training improves the heart in
health and disease. J Cardiopulm Rehabil Prev, 2010. 30: p. 2-11.
69. Lee, I.M., Relative Intensity of Physical Activity and Risk of Coronary Heart Disease. Circulation, 2003. 107(8): p. 1110-1116.
70. Slattery, M.L., D.R. Jacobs Jr., and M.Z. Nichaman, Leisure time physical activity and
coronary heart disease death. The US Railroad Study. . Circulation, 1989. 79: p. 304-311.
71. Shephard, R.J., Intensity, duration and frequency of exercise as determinants of the
response to a training regime. Int Z angew Physiol einschl, 1968. 26: p. 272-278.
72. Kemi, O.J., et al., Moderate vs. high exercise intensity: differential effects on aerobic
fitness, cardiomyocyte contractility, and endothelial function. Cardiovasc Res, 2005. 67(1): p. 161-72.
73. Gibala, M.J., High-intensity Interval Training: A Time-efficient Strategy for Health
Promotion? Curr Sports Med Rep, 2007. 6(4): p. 211-213.
74. Hawley, J.A., et al., Training techniques to improve fatigue resistance and enhance
endurance performance. J Sports Sci, 1997. 15(3): p. 325-33.
75. Helgerud, J., et al., Aerobic endurance training improves soccer performance. Med Sci Sports Exerc, 2001. 33(11): p. 1925–1931.
76. Daussin, F.N., et al., Effect of interval versus continuous training on cardiorespiratory
and mitochondrial functions: relationship to aerobic performance improvements in
sedentary subjects. Am J Physiol Regul Integr Comp Physiol, 2008. 295(1): p. R264-72.
77. Rognmo, O., et al., High intensity aerobic interval exercise is superior to moderate
intensity exercise for increasing aerobic capacity in patients with coronary artery
disease. European Journal of Cardiovascular Prevention & Rehabilitation, 2004. 11(3): p. 216-222.
78. Amundsen, B.H., et al., High-intensity aerobic exercise improves diastolic function in
coronary artery disease. Scand Cardiovasc J, 2008. 42(2): p. 110-7.
79. Kim, C., H.E. Choi, and M.H. Lim, Effect of High Interval Training in Acute Myocardial
Infarction Patients with Drug-Eluting Stent. Am J Phys Med Rehabil, 2015. 94(10 Suppl 1): p. 879-86.
80. Keteyian, S.J., et al., Greater improvement in cardiorespiratory fitness using higher-
intensity interval training in the standard cardiac rehabilitation setting. J Cardiopulm Rehabil Prev, 2014. 34(2): p. 98-105.
60
81. Munk, P.S., et al., High-intensity interval training may reduce in-stent restenosis
following percutaneous coronary intervention with stent implantation A randomized
controlled trial evaluating the relationship to endothelial function and inflammation. Am Heart J, 2009. 158(5): p. 734-41.
82. Moholdt, T.T., et al., Aerobic interval training versus continuous moderate exercise after
coronary artery bypass surgery: a randomized study of cardiovascular effects and quality
of life. Am Heart J, 2009. 158(6): p. 1031-7.
83. Conraads, V.M., et al., Aerobic interval training and continuous training equally improve
aerobic exercise capacity in patients with coronary artery disease: the SAINTEX-CAD
study. Int J Cardiol, 2015. 179: p. 203-10.
84. Cardozo, G.G., R.B. Oliveira, and P.T. Farinatti, Effects of high intensity interval versus
moderate continuous training on markers of ventilatory and cardiac efficiency in
coronary heart disease patients. ScientificWorldJournal, 2015. 2015: p. 192479.
85. Rocco, E.A., et al., Effect of continuous and interval exercise training on the PETCO2
response during a graded exercise test in patients with coronary artery disease. Clinics, 2012. 67(6): p. 623-627.
86. Moholdt, T., et al., The higher the better? Interval training intensity in coronary heart
disease. J Sci Med Sport, 2014. 17(5): p. 506-10.
87. McGregor, G., et al., High-intensity interval training versus moderate-intensity steady-
state training in UK cardiac rehabilitation programmes (HIIT or MISS UK): study
protocol for a multicentre randomised controlled trial and economic evaluation. BMJ Open, 2016. 6(11): p. e012843.
88. Xie, B., et al., Effects of High-Intensity Interval Training on Aerobic Capacity in Cardiac
Patients: A Systematic Review with Meta-Analysis. Biomed Res Int, 2017. 2017: p. 5420840.
89. Lu, K., et al., Effects of high-intensity interval versus continuous moderate-intensity
aerobic exercise on apoptosis, oxidative stress and metabolism of the infarcted
myocardium in a rat model. Mol Med Rep, 2015. 12(2): p. 2374-82.
90. Ellingsen, O., et al., High-Intensity Interval Training in Patients With Heart Failure With
Reduced Ejection Fraction. Circulation, 2017. 135(9): p. 839-849.
91. Holloway, T.M., et al., High intensity interval and endurance training have opposing
effects on markers of heart failure and cardiac remodeling in hypertensive rats. PLoS One, 2015. 10(3): p. e0121138.
92. Hwang, C.L., et al., Novel all-extremity high-intensity interval training improves aerobic
fitness, cardiac function and insulin resistance in healthy older adults. Exp Gerontol, 2016. 82: p. 112-9.
61
93. Molmen-Hansen, H.E., et al., Aerobic interval training reduces blood pressure and
improves myocardial function in hypertensive patients. Eur J Prev Cardiol, 2012. 19(2): p. 151-60.
94. Kessler, H.S., S.B. Sisson, and K.R. Short, The potential for high-intensity interval
training to reduce cardiometabolic disease risk. Sports Med, 2012. 42(6): p. 489-509.
95. Levinger, I., et al., What Doesn't Kill You Makes You Fitter: A Systematic Review of
High-Intensity Interval Exercise for Patients with Cardiovascular and Metabolic
Diseases. Clin Med Insights Cardiol, 2015. 9: p. 53-63.
96. Abell, B., P. Glasziou, and T. Hoffmann, The Contribution of Individual Exercise
Training Components to Clinical Outcomes in Randomised Controlled Trials of Cardiac
Rehabilitation: A Systematic Review and Meta-regression. Sports Med Open, 2017. 3(1): p. 19.
97. Moholdt, T., et al., Home-based aerobic interval training improves peak oxygen uptake
equal to residential cardiac rehabilitation: a randomized, controlled trial. PLoS One, 2012. 7(7): p. e41199.
98. Aamot, I.L., et al., Long-term Exercise Adherence After High-intensity Interval Training
in Cardiac Rehabilitation: A Randomized Study. Physiother Res Int, 2016. 21(1): p. 54-64.
99. Madssen, E., et al., Peak oxygen uptake after cardiac rehabilitation: a randomized
controlled trial of a 12-month maintenance program versus usual care. PLoS One, 2014. 9(9): p. e107924.
100. Moholdt, T., et al., Aerobic interval training increases peak oxygen uptake more than
usual care exercise training in myocardial infarction patients: a randomized controlled
study. Clin Rehabil, 2012. 26(1): p. 33-44.
101. Dalal, H.M., et al., Home based versus centre based cardiac rehabilitation: Cochrane
systematic review and meta-analysis. BMJ, 2010. 340: p. b5631.
102. Tomczak, C.R., et al., Effect of acute high-intensity interval exercise on postexercise
biventricular function in mild heart failure. J Appl Physiol (1985), 2011. 110(2): p. 398-406.
103. Meyer, K., et al., Comparison of left ventricular function during interval versus steady-
state exercise training in patients with chronic congestive heart failure. The American Journal of Cardiology, 1998. 82(11): p. 1382-1387.
104. Normandin, E., et al., Acute responses to intermittent and continuous exercise in heart
failure patients. Can J Cardiol, 2013. 29(4): p. 466-71.
105. Meyer, K., et al., Physical response to different modes of interval exercise in patients
with chronic heart failure - application to exercise training. European Heart Journal, 1996. 17: p. 1040-1047.
62
106. Benda, N.M., et al., Changes in BNP and cardiac troponin I after high-intensity interval
and endurance exercise in heart failure patients and healthy controls. Int J Cardiol, 2015. 184: p. 426-7.
107. Guiraud, T., et al., A single bout of high-intensity interval exercise does not increase
endothelial or platelet microparticles in stable, physically fit men with coronary heart
disease. Can J Cardiol, 2013. 29(10): p. 1285-91.
108. Tschakert, G. and P. Hofmann, High-Intensity Intermittent Exercise: Methodological and
Physiological Aspects. International Journal of Sports Physiology and Performance, 2013. 6: p. 600-610.
109. Halcox, J.P.J., et al., Prognostic Value of Coronary Vascular Endothelial Dysfunction. Circulation, 2002. 106(6): p. 653-658.
110. Guiraud, T., et al., Optimization of high intensity interval exercise in coronary heart
disease. Eur J Appl Physiol, 2010. 108(4): p. 733-40.
111. Yoshida, T., H. Watari, and K. Tagawa, Effects of active and passive recoverings on
splitting of the inorganic phosphate peak determined by 31P-Nuclear magnetic
resonance spectroscopy. NMR in biomedicine, 1996. 9(1): p. 13-19.
112. Chidnok, W., et al., Muscle metabolic responses during high-intensity intermittent
exercise measured by (31)P-MRS: relationship to the critical power concept. Am J Physiol Regul Integr Comp Physiol, 2013. 305(9): p. R1085-92.
113. Chidnok, W., et al., Exercise tolerance in intermittent cycling: application of the critical
power concept. Med Sci Sports Exerc, 2012. 44(5): p. 966-76.
114. Kriel, Y., et al., The Effect of Active versus Passive Recovery Periods during High
Intensity Intermittent Exercise on Local Tissue Oxygenation in 18 - 30 Year Old
Sedentary Men. PLoS One, 2016. 11(9): p. e0163733.
115. Meyer, P., et al., High-intensity interval exercise in chronic heart failure: protocol
optimization. J Card Fail, 2012. 18(2): p. 126-33.
116. Barbosa, L.F., B.S. Denadai, and C.C. Greco, Endurance Performance during Severe-
Intensity Intermittent Cycling: Effect of Exercise Duration and Recovery Type. Front Physiol, 2016. 7: p. 602.
117. Abderrahman, A.B., et al., Effects of recovery mode (active vs. passive) on performance
during a short high-intensity interval training program: a longitudinal study. Eur J Appl Physiol, 2013. 113(6): p. 1373-83.
118. Thevenet, D., et al., Influence of recovery mode (passive vs. active) on time spent at
maximal oxygen uptake during an intermittent session in young and endurance-trained
athletes. Eur J Appl Physiol, 2007. 99(2): p. 133-42.
63
119. Hussain, S.R., A. Macaluso, and S.J. Pearson, High-Intensity Interval Training Versus
Moderate-Intensity Continuous Training in the Prevention/Management of
Cardiovascular Disease. Cardiol Rev, 2016. 24(6): p. 273-281.
120. Hofmann, P. and G. Tschakert, Intensity- and Duration-Based Options to Regulate
Endurance Training. Front Physiol, 2017. 8: p. 337.
121. Tschakert, G., et al., How to Regulate the Acute Physiological Reponse to "Aerobic"
High-Intensity Interval Exercise. Journal of Sports Science and Medicine, 2015. 14: p. 29-36.
122. Guiraud, T., et al., High-Intensity Interval Training in Cardiac Rehabilitation. Sports Med, 2012. 42(7): p. 587-605.
123. Ribeiro, P.A., et al., High-intensity interval training in patients with coronary heart
disease: Prescription models and perspectives. Ann Phys Rehabil Med, 2016.
124. Seals, D.R., Edward F. Adolph Distinguished Lecture: The remarkable anti-aging effects
of aerobic exercise on systemic arteries. J Appl Physiol (1985), 2014. 117(5): p. 425-39.
125. Higashi, Y., et al., Regular aerobic exercise augments endothelium-dependent vascular
relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived
nitric oxide. Circulation, 1999. 100: p. 1194-1202.
126. Fallahi, A.A., et al., Alteration in cardiac uncoupling proteins and eNOS gene expression
following high-intensity interval training in favor of inreasing mechanical efficiency. Iran J Basic Med Sci, 2016. 19(258-264).
127. Fallahi, A., et al., Cardioprotective effect of high intensity interval training and nitric
oxide metabolites (NO2-, NO3-. Iran J Public Health, 2015. 44(9): p. 1270-1276.
128. Adams, V., et al., High-intensity interval training attenuates endothelial dysfunction in a
Dahl salt-sensitive rat model of heart failure with preserved ejection fraction. J Appl Physiol (1985), 2015. 119(6): p. 745-52.
129. Wyckelsma, V.L., et al., Intense interval training in healthy older adults increases
skeletal muscle [3H]ouabain-binding site content and elevates Na+,K+-ATPase alpha2
isoform abundance in Type II fibers. Physiol Rep, 2017. 5(7).
130. Prado, D.M., et al., Effects of continuous vs interval exercise training on oxygen uptake
efficiency slope in patients with coronary artery disease. Braz J Med Biol Res, 2016. 49(2): p. e4890.
131. Silvestro, A., et al., Vitamin C prevents endothelial dysfunction induced by acute exercise
in patients with intermittment claudication. Atherosclerosis, 2002. 165: p. 277-283.
132. Johnson, B.D., J. Padilla, and J.P. Wallace, The exercise dose affects oxidative stress and
brachial artery flow-mediated dilation in trained men. Eur J Appl Physiol, 2012. 112(1): p. 33-42.
64
133. McClean, C., et al., Effects of Exercise Intensity on Postexercise Endothelial Function
and Oxidative Stress. Oxid Med Cell Longev, 2015. 2015: p. 723679.
134. Tinken, T.M., et al., Impact of shear rate modulation on vascular function in humans. Hypertension, 2009. 54(2): p. 278-85.
135. Birk, G.K., et al., Effects of exercise intensity on flow mediated dilation in healthy
humans. Int J Sports Med, 2013. 34(5): p. 409-14.
136. Harris, R.A., et al., The flow-mediated dilation response to acute exercise in overweight
active and inactive men. Obesity (Silver Spring), 2008. 16(3): p. 578-84.
137. Dyson, K.S., J.K. Shoemaker, and R.L. Hughson, Effect of acute sympathetic nervous
system activation on flow-mediated dilation of brachial artery. Am J Physiol Heart Circ Physiol, 2006. 290(4): p. H1446-53.
138. Munk, P.S., et al., High intensity interval training reduces systemic inflammation in post-
PCI patients. Eur J Cardiovasc Prev Rehabil, 2011. 18(6): p. 850-7.
139. Morikawa, Y., et al., Aerobic interval exercise training in the afternoon reduces attacks
of coronary spastic angina in conjunction with improvement in endothelial function,
oxidative stress, and inflammation. Coron Artery Dis, 2013. 24(3): p. 177-82.
140. Cipryan, L., IL-6, Antioxidant Capacity and Muscle Damage Markers Following High-
Intensity Interval Training Protocols. J Hum Kinet, 2017. 56: p. 139-148.
141. Santos, C.C., et al., Influence to high-intensity intermittent and moderate-intensity
continuous exercise on indices of cardio-inflammatory health in men. J Exerc Rehabil, 2016. 12(6): p. 618-623.
142. Christensen, E.H., R. Hedman, and B. Saltin, Intermittent and Continuous running. Acta Physiologica Scandinavica, 1960. 50: p. 269-286.
143. Gordon, N.F. and J.J. Duncan, Effect of beta-blockers on exercise physiology:
implications for exercise training. Med Sci Sports Exerc, 1991. 23(6): p. 668-676.
144. Corretti, M.C., et al., Guidelines for the Ultrasound Assessment of Endothelial-
Dependent Flow-Mediated Vasodilation of the Brachial Artery. Journal of the American College of Cardiology, 2002. 39(2): p. 257-265
145. Van Bortel, L.M., et al., Expert consensus document on the measurement of aortic
stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens, 2012. 30(3): p. 445-8.
146. Jung, M.E., J.E. Bourne, and J.P. Little, Where Does HIT Fit? An Examination of the
Affective Response to High-Intensity Intervals in Comparison to Continuous Moderate-
and Continuous Vigorous- Intensity Exercise in the Exercise Intensity- Affect Continuum. PLoS One, 2014. 9(12): p. e114541.
65
147. Buchheit, M., et al., Physiological strain associated with high-intensity hypoxic intervals
in highly training young runners. Journal of Strength and Conditioning Research, 2012. 26(1): p. 94-105.
148. Borg, G., Borg's perceived exertion and pain scales. 1998, Champaign, IL: Human Kinetics.
149. Billat, V.L., Interval Training for Performance: A Scientific and Empirical Practice. Sports Medicine, 2001. 31(2): p. 75-90.
150. Millet, G.P., et al., VO2 responses to different intermittent runs at velocity associated
with VO2max. Can J Appl Physiol, 2003. 28(3): p. 410-423.
151. Rozenek, R., et al., Acute Cardiopulmonary And Metabolic Responses To High-Intensity
Interval Training (Hiit) Protocols Using 60s Of Work And 60s Recovery. J Strength Cond Res, 2016.
152. Fletcher, G.F., et al., Exercise standards for testing and training: a scientific statement
from the American Heart Association. Circulation, 2013. 128(8): p. 873-934.
153. Bouzas-Mosquera, C., A. Bouzas-Mosquera, and J. Peteiro, Prognostic value of the
increase in systolic blood pressure with exercise in patients with hypertension and known
or suspected coronary artery disease. Medicina Clínica (English Edition), 2017. 148(2): p. 51-56.
154. Keller, K., et al., Impact of exaggerated blood pressure response in normotensive
individuals on future hypertension and prognosis: Systematic review according to
PRISMA guideline. Adv Med Sci, 2017. 62(2): p. 317-329.
155. Laukkanen, J.A., et al., Systolic blood pressure during recovery from exercise and the
risk of acute myocardial infarction in middle-aged men. Hypertension, 2004. 44(6): p. 820-5.
156. Alter, D.A., et al., Relationship between cardiac rehabilitation participation and health
service expenditures within a universal health care system. Mayo Clin Proc, 2017. 92(4): p. 500-511.
157. Gaeini, A.A., A.A. Fallahi, and F. Kazemi, Effects of aerobic continuous and interval
training on rate-pressure product in patients after CABG surgery. J Sports Med Phys Fitness, 2015. 55(1-2): p. 76-83.
158. Rognmo, O., et al., Cardiovascular risk of high- versus moderate-intensity aerobic
exercise in coronary heart disease patients. Circulation, 2012. 126(12): p. 1436-40.
159. Hardcastle, S.J., et al., Why sprint interval training is inappropriate for a largely
sedentary population. Front Psychol, 2014. 5: p. 1-3.
66
160. Biddle, S.J. and A.M. Batterham, High-intensity interval exercise training for public
health: a big HIT or shall we HIT it on the head? Int J Behav Nutr Phys Act, 2015. 12: p. 95.
161. Bandura, A., Self-efficacy: the exercise of control. 1997, New York: Freeman.
162. Ajzen, I., The theory of planned behaviour. Organ Behav Hum Decis Process, 1991. 50(2): p. 179-211.
163. Stork, M.J. and K.A. Martin Ginis, Listening to music during sprint interval exercise:
The impact on exercise attitudes and intentions. J Sports Sci, 2016. 35(19): p. 1940-1946.
164. Stork, M.J., et al., A scoping review of the psychological responses to interval exercise: is
interval exercise a viable alternative to traditional exercise? Health Psychol Rev, 2017: p. 1-21.
165. Tabet, J.V., et al., Determination of exercise training level in coronary artery disease
patients on beta blockers. Eur J Cardiovasc Prev Rehabil, 2008. 15: p. 67-72.
166. Wonisch, M., et al., Influence of beta-blocker use on percentage of target heart rate
exercise prescription. Eur J Cardiovasc Prev Rehabil, 2003. 10(4): p. 296-301.
167. Chaloupka, V., et al., Exercise Intensity Prescription After Myocardial Infarction in
Patients Treated With Beta-blockers. J Cardiopulm Rehabil, 2005. 25: p. 361-365.
168. da Cunha, F.A., T. Farinatti Pde, and A.W. Midgley, Methodological and practical
application issues in exercise prescription using the heart rate reserve and oxygen uptake
reserve methods. J Sci Med Sport, 2011. 14(1): p. 46-57.
169. Jimenez-Pavon, D. and C.J. Lavie, High-intensity intermittent training versus moderate-
intensity intermittent training: is it a matter of intensity or intermittent efforts? Br J Sports Med, 2017. 51(18): p. 1319-1320.
170. Bairey Merz, C.N., et al., Insights from the NHLBI-Sponsored Women's Ischemia
Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation,
diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis
and macrovascular and microvascular coronary disease. J Am Coll Cardiol, 2006. 47(3 Suppl): p. S21-9.
171. Shaw, L.J., et al., Insights from the NHLBI-Sponsored Women's Ischemia Syndrome
Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors,
symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol, 2006. 47(3 Suppl): p. S4-S20.
67
Appendix A: Recruitment Script
Recruitment script
Study investigator to examine patient file (in those who have not opted out of “Consent to
Screen”) prior to recruitment to determine eligibility, and will be reviewed by Cardiac Rehab
Supervisor (CRS).
CRS or other rehab staff member will introduce patient to study investigator once patient gives
verbal consent to be approached.
My name is ___________ and I am one of the researchers working at the Toronto Rehab. Your CRS and I have reviewed your file, and you are eligible to volunteer for a study we are currently recruiting for. Would now be a good time to discuss some details of the study? If yes, proceed. If not, ask when an appropriate time would be.
We are trying to find the most effective type of exercise for improving fitness by examining how different bouts of fast and slow walking affect the health of blood vessels in patients with coronary artery disease. Therefore, we are investigating the effects of different ways to do aerobic exercise. As an example, 1 would involve walking as quickly as you can for 1 minute, alternating with 1 minute of slow walking. This would be repeated 10 times for a total of 20 minutes. There are 3 other different combinations outlined in this form that I will go over with you. We would be performing measurements before, during, and shortly after each of these 4 different exercise bouts. Participation in this study is completely voluntarily and will in no way affect the care you receive here. If you choose to participate, the extra time commitment (approximately 11 hours) will include 5 visits in total, scheduled weekly, starting after you complete your 3-month assessment. The first visit will be done at TR, and the last 4 will be done at the University of Toronto’s Goldring Centre for High Performance Sport near St. George Station. Visits 2-5 will replace 4 of your recommended at-home exercise sessions, and each visit will last approximately 2.5h each. You would not miss any of your rehab classes. You will be compensated for transportation costs. Visit 1 – Will occur during one of your CR classes. I will review the consent form with you, obtain your written consent if you agree to participate, and complete the familiarization session. On a treadmill, we will determine treadmill speed and incline (like walking up a slight hill) combinations to achieve target heart rates determined from your exercise test. Visits 2-5 – These visits will consist of 1 of 4 exercise sessions (randomized for order), with measurements done before, during, and after treadmill exercise. Three of the protocols will be high-intensity interval exercise. The protocols will have various combinations of interval duration and intensity. The fourth protocol will be 30 mins of moderate intensity continuous exercise that is similar to what you have been doing on the track as a part of your CR. [At this point, will show participant figures of exercise protocols and explain in detail].
68
Risks of exercise: Performing exercise carries risk, albeit minimal, even with high-intensity interval exercise. We have reviewed your file to check for anything that might increase your cardiovascular event risk while participating in high-intensity interval exercise. You will be monitored carefully and can stop at any point during testing. Visits will be scheduled during clinic hours so there will be a physician on-site. With treadmill exercise, there is a risk that you may fall. This risk will be minimized during the first visit, where you will become familiar with starting/stopping, and slowing down/speeding up on the treadmill. You can press the emergency stop button on the treadmill to bring the treadmill to a stop. A clip will be attached to you and will halt the treadmill in the event that you get too far down the treadmill belt. Measurements:
1) bFMD – this is a noninvasive measurement to determine how big your artery gets with an increase in blood flow, and is a good indicator of vascular health. A blood pressure cuff is used to inhibit blood flow to the forearm for 5 mins. You may temporarily experience a tingly feeling. Blood flow increases when the blood pressure cuff is released, and an ultrasound wand is used on your upper arm to measure the changes in the artery.
2) cfPWV – this is a noninvasive measurement to determine stiffness of arteries, and is a
good indicator of vascular health. A pen-like probe (like a wand) is placed over the area where the artery in your neck and leg are located, and measures how long it takes for your pulse to travel from the neck area to the leg area. Stiffer arteries will cause the pulse to travel faster in your arteries, while a more compliant, healthier artery will cause the pulse to travel slower.
3) Heart rate, blood pressure, and oxygen consumption will be measured before, during, and
after exercise. For oxygen consumption, you will be wearing a mask over the nose and mouth just as you did during your exercise test here at the rehab centre. You will be breathing normally during this test.
4) Preference and enjoyability questionnaires will be given during exercise, and at the end
of the study to assess which protocol is preferred. Benefits: Four of the study visits will replace four of your recommended at-home exercise sessions. Most of the research done in this area has been in men, with few female volunteers. This study will help us determine the most effective and enjoyable exercise protocol for women with coronary artery disease. The results from this study will help change cardiac rehab, with specific consideration of the benefits for women. You will not be asked to do any aspect of the study you are not completely comfortable with. I or a colleague will always meet you at the front doors and escort you to the appropriate testing site.
69
The results of these tests will remain completely confidential and you may withdraw from the study at any time. If you decide NOT to participate, you will continue with your current exercise program. If you are interested in participating, I will give you a consent form to look over, and if you wish, discuss with family, friends, or your physician. You can choose to take the form home with you and we will call you in a couple of days to confirm your involvement in this study. If you need any other information you can contact us at the number provided [circle on consent form]. Your decision to participate will not affect the care provided to you in the program.
70
Appendix B: Screening form
Eligibility checklist After preliminary screening, to confirm eligibility for recruitment
Inclusion criteria:
☐ man or post-menopausal woman (≥12 consecutive months since last menses) ☐ documented CAD (history of MI, CABG, PCI, or stable angina) in sinus rhythm ☐ currently participating in or have completed CR program
Absolute Exclusion criteria: ☐ major MSK, pulmonary, or cognitive impairment ☐ recent CV event (<6weeks) ☐ history of heart failure ☐ hypertrophic cardiomyopathy ☐ symptomatic aortic stenosis ☐ CCSC Class II-IV (unstable) angina ☐ significant arrhythmia ☐ evidence of ischemia during 3-month CPA (>1mm horizontal or down-sloping ST-segment depression) ☐ TIDM or TIIDM ☐ symptomatic cerebrovascular disease (<6months) ☐ uncontrolled HT (>180/100mmHg) ☐ high-risk for falls ☐ submaximal 3-month CPA (<anaerobic threshold) ☐ <30mins MICE ☐ cannot understand or follow instructions given in English
Relative Exclusion criteria:
☐ vascular aneurysm/spontaneous coronary artery dissection ☐ implantable cardioverter-defibrillator Notes:
Next: Meet with patient to recruit/consent
Patient eligible? YES NO
71
Appendix C: Recruitment Poster
72
Appendix D: Consent form
CONSENT FORM TO PARTICIPATE IN A RESEARCH STUDY
Study Title: Acute physiological response to high-intensity interval exercise in patients
with coronary artery disease
Principal Investigator:
Paul Oh, MD, Medical Director Cardiovascular Prevention and Rehabilitation Program, Toronto Rehabilitation Institute P: 416-597-3422 x5263, E: [email protected]
Co-investigators:
Jack Goodman, PhD, Supervisor Faculty of Kinesiology and Physical Education, University of Toronto P: 416-978-6095, E: [email protected] Vanessa Dizonno, B.Kin., Graduate student and study coordinator Faculty of Kinesiology and Physical Education, University of Toronto P: 416-946-5487, E: [email protected]
Introduction:
You are being asked to take part in a research study; however, participation in any research study is voluntary. Please read the information about the study presented in this form, as it includes the purpose, procedures, possible benefits, discomforts, risks and precautions, so that you can make an informed decision. You should take as much time as you need to make your decision and should not sign this form until you are sure you understand the information. You have the right to refuse to participate or withdraw from the study at any time. If you have any questions, you should ask the study coordinator to explain anything that requires further clarification. Before you make your decision, you may wish to discuss the study with your family doctor, a family member, or close friend. Background and Purpose of the Research: Coronary artery disease (CAD) is related to changes in the blood vessels, specifically, increased stiffness and a reduced ability to accommodate increases in blood flow. This may contribute to poor heart and blood vessel health. Aerobic exercise programs have shown to improve blood vessel health in both healthy and diseased populations. Moderate intensity continuous exercise (MICE) training is standard of care for many cardiac rehab programs, but data suggest that high-intensity interval training may provide larger and quicker improvements in aerobic fitness and blood vessel health. MICE involves exercising an intensity that can be sustained for a long duration (i.e., 30 mins), whereas high-intensity interval exercise (HIIE) involves exercising at intensities near your maximum for a short period of time (i.e., 1 min), separated by periods of
73
recovery at a lower intensity. However, limited information is available on blood vessel function and the effects of exercise. No study has determined the optimal HIIE protocol in females with CAD. You are invited to participate in a research study, a part of a Master’s thesis, being conducted at the Toronto Rehabilitation Institute (TRI), the Toronto Western Hospital (TWH), and the University of Toronto. This study compares the effects of different aerobic exercise protocols, particularly ones that include HIIE. You are being asked to participate because you have CAD and are currently taking part in or have completed a cardiac rehab program. Assessments before and after HIIE or MICE will be compared to determine the effects of each exercise protocol and find out which one is most effective.
Study Eligibility:
The following are the main eligibility criteria for the study:
• Documented CAD (i.e. myocardial infarction, coronary artery surgery, percutaneous coronary intervention)
• No history of heart failure, unstable angina, or significant arrhythmia
• Currently participating in or have completed a cardiac rehab program
If you have given your consent to be screened for possible participation in research studies, your patient file will be reviewed to confirm that you are eligible to participate. If you have not given your consent to be screened, review of your patient file will not be done until your consent to participate in this study has been received. Your date of birth, contact information, and health history will be retrieved from your patient file. The study coordinator, along with the study doctor and your cardiac rehab supervisor, will determine if you have any condition that would increase your risk of injury or cardiovascular event during HIIE.
Study Design:
If you choose to participate in this study, you will be asked to complete five study visits. The first visit is a familiarization session at the TR Rumsey Centre or TWH, and the other four will take place at the University of Toronto’s Goldring Centre for High Performance Sport (100 Devonshire Place, Toronto ON, M5S 2C9). Each session will occur at the same time of day, scheduled approximately one week between visits.
Study Visits and Procedures:
Table 1. Summary of study visits
STUDY
VISIT
TIME
COMMITMENT
LOCATION OF
VISIT ASSESSMENTS
1 1 hour
TR – Rumsey
or TWH
1. Consent 2. Medical history
questionnaire 3. Heart rate 4. Rating of perceived exertion
2-5 2.5 hours
UofT - Goldring 1. Height and weight (Visit 2) Each of the following done during Visits 2-5:
74
2. Blood pressure 3. Heart rate 4. Rating of perceived exertion 5. Blood vessel stiffness 6. Blood vessel function 7. In-task preference and
enjoyment
Preference and enjoyment of each exercise will be assessed at the end of Visit 5
It is important to remember the following things during this study:
• Each study visit should be completed at the same time of day (i.e., morning or afternoon)
• Avoid planned exercise 24h before your study visit
• Avoid caffeine or alcohol consumption 12h before your study visit
• Avoid tobacco use 6h before your study visit
• Eat no less than 3h before your study visit. These meals should be similar.
• Tell a member of the study team about any change in your health
• Tell a member of the study team if you no longer wish to be in the study
Visit 1
This visit will involve the following:
a) Consent b) Medical history questionnaire will ask about your heart health history and lifestyle
behaviours (i.e., smoking, alcohol, etc). c) Heart rate will be measured throughout the visit using a heart rate monitor. d) Treadmill familiarization: You will complete an exercise session on a treadmill. Throughout
the session, heart rate and rating of perceived exertion will be monitored. Treadmill speed and incline combinations will be determined in order to achieve target heart rates determined from your exercise test. You will be exercising at light, moderate, and high intensities for various interval durations (i.e., 30s, 1 mins, 4 mins).
Visits 2-5
During Visits 2-5, you will be asked to complete an exercise session lasting 25-35 mins. This will consist of a warm-up period, followed by HIIE or MICE. Measurements will be taken before, during, and for 60 mins after exercise. The effects of 4 different treadmill exercise protocols will be examined, and the order you complete them will be randomized: Protocol #1 – Four 4-min intervals at high-intensity (close to your max) with 3-min moderate-intensity recovery (what you would typically do during your cardiac rehab class) between intervals. Protocol #2 – Ten 1-min intervals at high-intensity with 1-min low-intensity recovery (very slow walking pace) between intervals. Protocol #3– 30s of high-intensity with 30s low-intensity recovery for 4 minutes, followed by 3 mins of moderate-intensity exercise. This bout will be repeated 4 times.
75
Protocol #4 – 30 mins of moderate-intensity continuous exercise (what you would typically do during your cardiac rehab class). Visits 2-5 will involve the following assessments: a) Height and weight will be measured once at Visit 2. b) Blood pressure will be measured at 8 time points throughout
the visit using an inflatable cuff on your arm. c) Heart rate will be measured throughout the visit using a Polar
heart rate monitor chest strap and wrist watch, as well as with electrodes on your chest (i.e., electrocardiogram (ECG)). An ECG measures the electrical activity of the heart. Patches (electrodes) attached by wires to a machine will be put on your chest so that the machine can record the pattern of your heart beats. We will prepare your skin for the electrodes by cleaning it with alcohol and lighly abrading it with sandpaper-like material.
d) Blood vessel (Arterial) Stiffness: During this test, you will be lying on a testing table. Your blood vessel (i.e., artery) stiffness will be measured using a pen-like device called a tonometer. The tonometer will be applied using light pressure on your right neck and right groin (see Figure 1). At each of these sites, we will be able to measure your pulse, and from this information can determine how stiff your blood vessels are. We will also measure the distance between each of these sites using a measuring tape. This will be measured before and after exercise.
e) Blood vessel (Endothelial) Function: The endothelium is a thin layer of cells that lines the inside of your blood vessels. To assess its function, we will use an ultrasound to take pictures of the blood vessel in your right arm (i.e., brachial artery) at rest. A blood pressure cuff on your right forearm will then be inflated for five minutes. When we release the cuff, we will take more pictures of your brachial artery for three minutes. We are interested in seeing how big the brachial artery gets after the cuff is released. This will be assessed before and twice after exercise.
f) Participant exercise preference and enjoyment will be assessed during each exercise, and at the end of Visit 5. You will be asked how you feel and your enjoyment for each exercise protocol.
Potential Risks (Injury, Discomfort, Inconvenience):
Risk of HIIE: Performing exercise carries risk, although minimal, even with HIIE (1 heart attack leading to death during 130,000 hours of MICE and 2 nonfatal heart attacks during 46,000 hours of HIIE). Your cardiac rehab supervisor and the study coordinator have reviewed your file to check for anything that might increase your risk for a cardiovascular event while performing HIIE. Your vitals will be monitored carefully and you can stop at any point during testing. There will be a physician on-site during all study visits. You may develop muscle soreness 24-48 hours after completion of the exercise session, but this should go away in 2-3 days. With treadmill exercise, there is a risk that you may fall. This risk will be minimized during Visit 1, where you will become familiar with starting/stopping, and slowing down/speeding up on the treadmill. You can press the emergency stop button on the treadmill to bring the treadmill to a
76
stop. A clip will be attached to you and will halt the treadmill in the event that you close to the end of the treadmill belt. Risk of heart rate and blood pressure assessment: There are no known risks associated with using a heart rate monitor or blood pressure cuff. The electrocardiogram (ECG) to also assess heart rate is painless and you should not feel anything while the ECG is done. The electrodes (the stickers placed on your chest) may cause a small amount of redness, or in rare cases a rash which should disappear within a few days. Risk of blood vessel stiffness assessment: There are no known risks associated with the use of a tonometer to measure your pulse. During blood vessel stiffness assessment, a small area of your leg/groin will be exposed in order to access to your femoral artery. Measures will be taken to ensure privacy during this assessment. Risk of blood vessel function assessment: There are no known risks associated with the use of ultrasound to look at the blood vessel in your arm. Inflation of the blood pressure cuff on your arm during the blood vessel function assessment may cause some discomfort and/or a “pins and needles” sensation. However, these feelings should resolve when the cuff is deflated or shortly after (i.e. within 15 mins). If you have any questions or concerns about the risks mentioned above, please discuss them with the study coordinator or study doctor.
Potential Benefits:
While you may not receive direct benefits from participation in the study, you will receive information on the health of your arteries. This study will help to determine the most effective and time-efficient exercise protocol for patients with CAD. The results from this study will help inform exercise prescription in cardiac rehab, and will potentially result in changes to improve current practices.
Confidentiality and Privacy:
If you agree to participate in this study, the study coordinator will look at your patient file and collect only the information needed for the study. Personal health information is any information that could identify you and includes:
• name
• contact information (phone number, email)
• date of birth (month, year)
• new or existing medical records (types, dates, and results of medical tests or procedures) Other than members of the study team, representatives of the University Health Network (UHN) including the UHN Research Ethics Board (REB) may look at the study records and your personal health information to check that the information collected for the study is correct and to make sure that the proper laws and guidelines are being followed. If you participate in this study, information about you from this study may be stored in your patient file and in the UHN computer system. The UHN shares the patient information stored on its computers with other hospitals and health care providers in Ontario so they can access the information if it is needed for your clinical care. The study team can tell you what information
77
about you will be stored electronically and may be shared outside of the UHN. If you have any concerns about this, or have any questions, please contact the UHN Privacy Office at 416-340-4800, x6937 (or by email at [email protected]). Any personal health information or personal information collected about you will be ‘de-identified’ by replacing your personal identifying information with a ‘study ID’. The principal and study investigators are in control of the study ID key, which is needed to connect your personal health information to you. All electronic files will be protected and stored on UHN’s
secure network, accessible only by the study investigators. The link between the study ID and your personal identity will be stored separately from all other study data. No information that identifies you will be sent elsewhere without your explicit consent for this (i.e., to notify your cardiac rehab supervisor, study doctor, or family physician of adverse events). The study investigators will keep your study records securely stored for up to 10 years after the study has been completed, and then the study records will be securely destroyed. It is important to understand that despite these protections being in place, there continues to be the risk of unintentional release of information. The principal and study investigators will protect your records and keep all the information in your study file confidential to the greatest extent possible. The chance that this information will accidentally be given to someone else is small.
New Findings or Information:
We may learn new things during the study that you may need to know. We can also learn about things that might make you want to stop participating in the study. If so, you will be notified about any new information in a timely manner.
Study Results:
The results of this study may be presented at conferences, published in scientific journals, and shared with health care professionals. Your identity will remain confidential (i.e., you will not be personally identified in any presentation or publication of the study results). If you are interested in getting a copy of the published study results, you should contact the study coordinator. A copy of your personal results will be made available to you upon request.
Costs and Reimbursement:
You will be reimbursed $25 for Visits 2-5, for a total of $100, to compensate you for any study-related expenses you may incur (i.e., travel, meals).
Rights as a Participant:
If you are harmed as a direct result of taking part in this study, all necessary medical treatment will be made available to you at no cost. By signing this form, you do not give up any of your legal rights against the investigators or involved institutions for compensation, nor does this form relieve the investigators, sponsor or involved institutions of their legal and professional responsibilities.
Voluntary Participation and Withdrawal:
Your participation in this study is completely voluntary. You may decide to not take part in this study, and this will not affect your health care at any UHN centre or any future interactions/relationships with the investigators of the study. By signing this form, you are
78
agreeing to participate in the study. If you choose to participate, you can withdraw at any time, even after you have given consent. You will not be asked to do any aspect of the study that you are not comfortable with. The study personnel may discontinue your participation in the study for various reasons, including:
• It is not in your best interest to continue in the study.
• You become injured or your health status deteriorates, making you ineligible for study participation.
• You fail to follow study instructions.
• The study is cancelled.
If you withdraw or are withdrawn from the study, data collected by the study investigators up until your withdrawal may be included in the research results. However, at the time of
withdrawal, you may also request retraction/withdrawal of any of your data collected up to
that point.
Alternatives to being in the study:
If you choose not to participate in this study, you will continue your participation in your cardiac rehab program. This includes the standard aerobic and resistance training program, education, counseling, and exercise testing. If you are a graduate of the cardiac rehab program, you will continue your current participation. Your decision to participate in the study will not affect your medical care.
Conflict of Interest:
There are no conflicts of interest to report.
Questions about the Study:
If you have any questions, concerns, or would like to speak to the study team for any reason, please call: Paul Oh (principal investigator) at 416-597-3422 x5263 or Vanessa Dizonno (study coordinator) at 416-946-5487 during business hours or email at [email protected]. Contact by email is preferred. However, please note that communication via e-mail is not absolutely secure. Thus, please do not communicate personal health or sensitive information via e-mail.
If you have any questions about your rights as a research participant or have concerns about this study, call the Chair of the University Health Network Research Ethics Board (UHN REB) or the Research Ethics office number at 416-581-7849. The REB is a group of people who oversee the ethical conduct of research studies. The UHN REB is not part of the study team. Everything that you discuss will be kept confidential.
79
Consent:
This study has been explained to me and any questions I had have been answered. I know that I may leave the study at any time. I agree to the use of my information as described in this form. I agree to take part in this study. By providing my email address and/or phone number, I agree to be contacted through the below method(s) of communication. Email address: ______________________________________ Phone Number: _____________________________________ I consent to participate in this study. I will be given a signed copy of this consent form. Print Study Participant’s Name Signature Date In the event of an adverse event, I agree for my cardiac rehab supervisor, medical director, and family physician to be notified. Print Study Participant’s Name Signature Date My signature means that I have explained the study to the participant named above. I have answered all questions. Print Name of Person Signature Date Obtaining Consent
80
Appendix E: Borg Rating of Perceived Exertion
81
Appendix F: Medical History Questionnaire
Have you, or a family member, been
diagnosed with and/or are you currently
receiving treatment for any of the following:
If yes, please specify:
Personal Family
Arrhythmia
Atrial Fibrillation or Flutter
Coronary Artery Disease or Cardiomyopathy
Significant Valvular Disease
Heart Disease (<65 years old in family)
Hypertension
Syncope (fainting, passing out)
Palpitations
Heart Failure
Diabetes
Asthma
History of Thyroid Disorder
Sleep Apnea or any Sleep-Disordered Breathing
Current/Recent Viral or Chronic Illness
Chronic Inflammatory Disease
Use of Cardioactive Drugs including SSRI's
82
Family History of:
-Sudden Cardiac Death
Lifestyle
Current alcohol consumption (drinks per week)
Recreational Drug Use
Current prescription drugs (List all)
Current non-prescription drugs
(Including supplements; List all)
Current or Previous smoking status (Yes or No)
83
Appendix G: Extended Technical Protocols
Visit 1 Description: Consent and treadmill familiarization session taking place at TR-Rumsey in patients with coronary artery disease.
Intervention: Intervals of various intensities and durations performed on a treadmill, with continuous HR and RPE assessment.
Purpose: To 1) obtain consent, and 2) accustom participants to treadmill exercise (ie. start/stop, speed up/slow down, straddle), and 3) determine treadmill speeds corresponding to the target intensities through %HRR and RPE.
Preparation:
- Review patient file to determine eligibility and target HR - Print: Consent form (x2), Visit checklist form, Visit 1 data collection form
Equipment:
- Treadmill - Polar HR chest strap and wristwatch - Clipboard
- Borg RPE
Procedure:
1. Participant arrives to TR-Rumsey and meets with V.D. before or after education session 2. V.D. goes over consent form and participant gives informed consent 3. Put Polar HR chest strap on participant and wear wristwatch 4. Notify CRS that participant is beginning exercise 5. Give an overview of the exercise session 6. Attach safety clip when participant is on treadmill
7. Begin familiarization protocol 8. Conclude familiarization protocol 9. Remove Polar HR chest strap 10. Schedule Visit 2 11. Discharge participant
Responsibilities:
VD
• Consent process
• Manage treadmill speed/inclines
• Record HR, RPE, speed, incline CRS
• Assist in the event of an adverse event
84
Detailed Research Protocol – Familiarization:
TIME (min:sec) ACTION
0:00 Begin warm-up
2:00 Adjust speed and incline if necessary
4:45 VD
1. Record HR and RPE 2. Record speed and incline
5:00 Begin 3-min moderate-intensity
7:00 Adjust speed and incline if necessary
7:45 VD
1. Record HR and RPE 2. Record speed and incline
8:00 Begin 3-min low-intensity
10:00 Adjust speed and incline if necessary
10:45 VD
1. Record HR and RPE 2. Record speed and incline
11:00 Begin 3-min high-intensity
13:00 Adjust speed and incline if necessary
13:45 VD
1. Record HR and RPE 2. Record speed and incline
14:00 Begin passive rest
19:00 Begin warm-up
21:00 Adjust speed and incline if necessary
21:45 VD
1. Record HR and RPE 2. Record speed and incline
22:00 Begin 1-min high-intensity interval
22:45 VD
1. Record HR and RPE 2. Record speed and incline
23:00 Begin 1-min low-intensity recovery
23:45 VD
1. Record HR and RPE 2. Record speed and incline
24:00 Begin 1-min high-intensity interval
24:45 VD
1. Record HR and RPE 2. Record speed and incline
25:00 Begin 1-min low-intensity recovery
25:45 VD
1. Record HR and RPE
85
2. Record speed and incline
26:00 Begin 4-min high-intensity interval
29:45 VD
1. Record HR and RPE 2. Record speed and incline
30:00 Begin 3-min moderate-intensity recovery
32:45 VD
1. Record HR and RPE 2. Record speed and incline
33:00 Begin 30-sec low-intensity recovery
33:15 VD
1. Record HR and RPE 2. Record speed and incline
33:30 Begin 30-sec high-intensity interval
33:45 VD
1. Record HR and RPE 2. Record speed and incline
34:00 Begin 30-sec low-intensity recovery
34:15 VD
1. Record HR and RPE 2. Record speed and incline
34:30 Begin 30-sec high-intensity interval
34:45 VD
1. Record HR and RPE 2. Record speed and incline
35:00 Begin 3-min cool-down
38:00 END EXERCISE
EXAMPLE of Visits 2-5 – 4x4 protocol Description: Interval exercise session with physiological assessment at UofT’s Heart Health Laboratory in patients with coronary artery disease.
Intervention: Four 4-min high-intensity intervals, interspersed with 3-min of moderate-intensity recovery performed on a treadmill, with assessment of hemodynamic and vascular health measures.
Purpose: To determine the physiologic response to interval exercise with hemodynamic and gas analysis during exercise, and pre- and post-exercise assessment of vascular health.
Preparation:
- Use HRs and speed/incline combinations from familiarization session - Print: 4x4 data collection form, Visit checklist form, Post-exercise data collection form,
Preference and enjoyment questionnaires - Remind participant to abstain from: alcohol, caffeine, exercise, tobacco, and to eat a
similar meal before visit
86
- Ask participant to bring their exercise diary
Equipment:
- Motorized treadmill - Automated BP monitor (BPTru) - Motion-tolerant BP monitor (Tango) - Vivid E90 cardiovascular ultrasound system
- Manual blood pressure cuff - Sphygmomanometer - Vmax metabolic cart - Polar HR chest strap and wristwatch - 3x 3M ECG electrodes
- 5cm abrasive tape
- 1x alcohol pad
- electrical simulation box
- Clipboard
- Towel - 1x Cavi wipe
- 1x facemask or mouthpiece
- 1x noseclip
- 1x gauze pad
- cleaning solution
- stadiometer and weight scale
- measuring tape
- waterproof eyeliner
Procedure:
1. Participant arrives to Goldring Centre for High Performance and Sport and is escorted to Heart Health Lab
2. Complete visit checklist
3. Begin baseline assessments protocol
4. Conclude baseline assessments protocol
5. Give overview of the exercise session
6. Begin exercise protocol
7. Conclude exercise protocol
8. Begin post-exercise assessments protocol
9. Conclude post-exercise assessments protocol
10. Allow participant to change/shower 11. Schedule Visit 3
12. Discharge participant 13. Clean equipment/lab space
Responsibilities:
VD
• Complete pre-visit checklist and anthropometric measurements
• Perform pre- and post-exercise assessments
• Monitor exercise intensity (HR, RPE) and gait stability during exercise
• Manage treadmill speed/inclines during exercise
87
• Record HR, RPE, BP, speed, incline during exercise
• First responder for adverse events RA
• Assist in exercise BP measurements
• Obtain RPE Sport medicine physician
• Assist in the case of an adverse event
Detailed Research Protocol – Baseline assessments:
TIME (min:sec) ACTION
0:00 Height and weight measurements
1:00 VD
1. Record height 2. Record weight
2:00 Participant brought to back room to lay supine
3:00 VD
1. Palpate brachial artery and mark 2. Put on BPTru cuff
3:30 Rest
13:30 Resting HR and BP measurements
17:30 VD
1. Record last 3 HR and BP values
18:00 Electrode placement
18:00 VD
1. Landmark
2. Abrade and clean areas for electrode application 3. Apply electrodes
BEGIN cfPWV assessment
19:00 VD
1. Palpate carotid artery and mark 2. Palpate femoral artery and mark 3. Measure from carotid to sternal notch 4. Measure from sternal notch to femoral 5. Input data in program 6. Attach electrode wires
Begin first PWV assessment
21:00 VD
1. Record PW at carotid site 2. Record PW at femoral site 3. Record cf-PWV (m/s)
Conclude first PWV assessment
Begin second PWV assessment
31:00 VD
1. Record PW at carotid site
88
2. Record PWV at femoral site 3. Record cf-PWV (m/s)
Conclude second PWV assessment *If measurements differ by >0.5m/s, complete a third PWV assessment
CONCLUDE cfPWV assessment
Begin bFMD assessment
36:00 VD
1. Attach electrode wires 2. Place blood pressure cuff on right forearm 3. Acquire longitudinal image of brachial artery
42:00 Record 30 seconds baseline
42:30 VD
1. Inflate cuff 20-30mmHg above systolic BP 2. Occlude artery for 5 minutes
46:30 Record 30 seconds at low-flow occlusion
47:30 VD
1. Deflate cuff
47:30 Record 3 minutes post-occlusion
50:30 VD
1. Mark probe application with waterproof eyeliner 2. Remove BP cuff
Conclude bFMD assessment
50:30 VD
1. Polar HR monitor fitting 2. Mouthpiece for gas analysis 3. Tango BP cuff 4. Review exercise protocol
60:00 BEGIN EXERCISE
Detailed Research Protocol – 4x4 exercise protocol:
TIME (min:sec) ACTION
0:00 Begin warm-up
2:00 Adjust speed and incline if necessary
4:30 RA
1. Obtain RPE VD
1. Record HR and RPE 2. Record speed and incline
5:00 Begin 4-min high-intensity interval
7:00 Adjust speed and incline if necessary
8:30 RA
1. Hold arm for BP 2. Obtain RPE
VD
1. Record BP, HR and RPE 2. Record speed and incline
9:00 Begin 3-min moderate-intensity recovery
89
11:00 Adjust speed and incline if necessary
11:30 RA
1. Hold arm for BP 2. Obtain RPE
VD
3. Record BP, HR and RPE
4. Record speed and incline
12:00 Begin 4-min high-intensity interval
14:00 Adjust speed and incline if necessary
15:30 RA
1. Hold arm for BP 2. Obtain RPE
VD
3. Record BP, HR and RPE
4. Record speed and incline
16:00 Begin 3-min moderate-intensity recovery
18:00 Adjust speed and incline if necessary
18:30 RA
3. Obtain RPE VD
1. Record HR and RPE 2. Record speed and incline
19:00 Begin 4-min high-intensity interval
21:00 Adjust speed and incline if necessary
22:30 RA
1. Obtain RPE VD
3. Record HR and RPE 4. Record speed and incline
23:00 Begin 3-min moderate-intensity recovery
25:00 Adjust speed and incline if necessary
25:30 RA
1. Hold arm for BP 2. Obtain RPE
VD
3. Record BP, HR and RPE 4. Record speed and incline
26:00 Begin 4-min high-intensity interval
28:00 Adjust speed and incline if necessary
29:30 RA
1. Hold arm for BP 2. Obtain RPE
VD
3. Record BP, HR and RPE 4. Record speed and incline
30:00 Begin 3-min moderate-intensity recovery
32:00 Adjust speed and incline if necessary
32:30 RA
1. Obtain RPE VD
1. Record HR and RPE 2. Record speed and incline
33:00 Begin 3-min cool-down
35:00 Adjust speed and incline if necessary
35:30 RA
1. Obtain RPE VD
1. Record HR and RPE 2. Record speed and incline
36:00 END EXERCISE
90
Detailed Research Protocol – Post-exercise assessments:
TIME (min:sec) ACTION
0:00 Post 1-min BP
1:00 VD
1. Record BP using Tango (on treadmill)
1:00 Participant brought to back room to lay supine
Begin bFMD assessment
2:00 VD
1. Place blood pressure cuff on right forearm 2. Acquire longitudinal image of brachial artery
7:00 Record 30 seconds baseline
10:00
HARD 10
VD
1. Inflate cuff 20-30mmHg above systolic BP 2. Occlude artery for 5 minutes
14:00 Record 30 seconds at low-flow occlusion
15:00 VD
1. Deflate cuff
15:00 Record 3 minutes post-occlusion
18:00 Conclude bFMD assessment
Post 20-min BP assessment
18:00 VD
1. Place BPTru on right arm
2. Record 2 BP measures
Post 30-min PWV assessment
20:00 VD
1. Palpate carotid artery and mark 2. Palpate femoral artery and mark 3. Measure from carotid to sternal notch 4. Measure from sternal notch to femoral 5. Attach electrode wires 6. Measure BP 7. Remove BPTru BP cuff 8. Input data in program
Begin first PWV asessment
22:00 VD
1. Record PWV at carotid site 2. Record PWV at femoral site 3. Record cf-PWV (m/s)
Begin second PWV assessment
30:00 VD
1. Record PW at carotid site 2. Record PWV at femoral site 3. Record cf-PWV (m/s)
91
35:00 Conclude second PWV assessment *If measurements differ by >0.5m/s, complete a third PWV assessment
Post 40-min BP assessment
35:00 VD
1. Place BPTru on right arm
2. Record 2 BP measures
Begin post 60-min FMD
37:00 VD
1. Place blood pressure cuff on right forearm 2. Acquire longitudinal image of brachial artery
54:30 Record 30 seconds baseline
55:00
HARD 55
VD
1. Inflate cuff 20-30mmHg above systolic BP 2. Occlude artery for 5 minutes
59:00 Record 30 seconds at low-flow occlusion
60:00 VD
1. Deflate cuff
60:00 Record 3 minutes post-occlusion
63:00 Conclude bFMD assessment
CONCLUDE POST-EXERCISE ASSESSMENTS
92
Appendix H: Pre-visit checklist
Pre-visit Checklist
Planned exercise <24h prior?
Caffeine <12h prior?
Alcohol <12h prior?
Tobacco <6h prior?
Meal <3h prior? Similar to last meal?
Change in health?
Change in medications (ie. beta-blockers)? - time taken
Hydration status (≥8oz)?
Baseline Assessment
__:__ 1 2 3 4
Height (cm)
Weight (kg)
Blood Pressure
Heart Rate
cfPWV *third if 1&2 differ >0.5m/s
bFMD
Notes
cfPWV bFMD
Carotid position –
Femoral position –
Pressure applied –
Brachial position –
Probe angle –
Pressure applied –
93
Appendix I: Data collection sheets
Visit 1 – Consent and Familiarization
☐ Consent form complete
☐ Medical history questionnaire complete
☐ Pre-visit checklist complete
3-month CPA:
Description HR range RPE Speed Incline
Resting HR
Peak HR
20%HRR L.I. recovery/cool-down
≤11
30-40%HRR Warm-up 11-12
60-70%HRR M.I. recovery/MICE 14-15
85-95%HRR H.I. interval 17-19
Time Description Duration
(min)
Achieved speed Achieved incline Achieved HR Achieved RPE
00:00 Warm-up 5
05:00 M.I. 3
08:00 L.I. 3
11:00 H.I. 3
14:00 Passive rest 5
19:00 Warm-up 3
22:00 H.I. 1
94
23:00 L.I. 1
24:00 H.I. 1
25:00 L.I. 1
26:00 H.I. 4
30:00 M.I. 3
33:00 L.I. 0.5
33:30 H.I. 0.5
34:00 L.I. 0.5
34:30 H.I 0.5
35:00 Cool down 3
38:00 END
Notes
95
Visit 2-5 – 4x4 HIIE protocol
Cool-down Warm-up M.I. recovery H.I. interval
%HRR 20 30-40 60-70 85-95
RPE ≤11 11-12 14-15 17-19
Target HR
Target Speed
Target Incline
Time Description Duration
(min)
Achieved
Speed
(mph)
Achieved
Incline
(%)
Achieved
HR
Achieved
RPE
Blood
Pressure
Enjoyment Feeling
00:00 Standing ‘Pretest’
2
00:00 Warm-up ‘Exercise
5
05:00 (1) H.I. 4 8:15 5:45
09:00 M.I. 3 10:15 9:45
12:00 (2) H.I. 4 15:15 14:45
16:00 M.I. 3 16:45
19:00 (3) H.I. 4
23:00 M.I. 3 25:15
26:00 (4) H.I. 4 29:15 28:45
30:00 M.I. 3 32:45
33:00 Cool-down 3
36:00 END
96
Visit 2-5 – 10x1 HIIE protocol
Cool-down/L.I. recovery Warm-up H.I. interval
%HRR 20 30-40 85-95
RPE ≤11 11-12 17-19
Target HR
Target Speed
Target Incline
Time Descriptio
n
Duration
(min)
Achieved Speed
(mph)
Achieved
Incline (%)
Achieved
HR
Achieved
RPE
Blood
Pressure
Enjoyment Feeling
00:00 ‘Pretest’
Standing 2
00:00 ‘Exercise’
Warm-up 5
05:00 (1) H.I. 1 5:45
06:00 L.I. 1
07:00 (2) H.I. 1 7:15
08:00 L.I. 1 8:45
09:00 (3) H.I. 1
10:00 L.I. recovery
1 10:15
11:00 (4) H.I. 1 11:45
97
12:00 L.I. 1 12:45
13:00 (5) H.I. 1 13:15
14:00 L.I. 1
15:00 (6) H.I. 1
16:00 L.I. 1
17:00 (7) H.I. 1
18:00 L.I. 1
19:00 (8) H.I. 1
20:00 L.I. 1 20:15
21:00 (9) H.I. 1 21:45
22:00 L.I. 1
23:00 (10) H.I. 1 23:15
24:00 L.I. 1 24:45
25:00 Cool-down
3
28:00 END
98
Visit 2-5 – TRI.P.
L.I. recovery/Cool-down Warm-up M.I. interval H.I. interval
%HRR 20 30-40 60-70 85-95
RPE ≤11 11-12 14-15 17-19
Target HR
Target Speed
Target Incline
Time Description Duration
(min)
Achieved Speed
(mph)
Achieved
Incline
Achieved
HR
Achieved
RPE
Blood
Pressure
Enjoyment Feeling
00:00 Standing ‘Pretest’
2
00:00 Warm-up ‘Exercise’
5
05:00 (1) H.I. 0.5 5:15
05:30 L.I. 0.5
06:00 (2) H.I. 0.5
06:30 L.I. 0.5
07:00 (3) H.I. 0.5
07:30 L.I. 0.5
08:00 (4) H.I. 0.5 8:00
08:30 L.I. 0.5 8:45
09:00 M.I. 3 11:15 11:45
12:00 (1) H.I. 0.5
12:30 L.I. 0.5
13:00 (2) H.I. 0.5
13:30 L.I. 0.5
14:00 (3) H.I. 0.5
14:30 L.I 0.5
15:00 (4) H.I. 0.5 15:00 15:15
99
15:30 L.I. 0.5 15:45
16:00 M.I. 3 16:00
19:00 (1) H.I. 0.5
19:30 L.I. 0.5
20:00 (2) H.I. 0.5
20:30 L.I. 0.5
21:00 (3) H.I. 0.5
21:30 L.I. 0.5
22:00 (4) H.I. 0.5
22:30 L.I. 0.5
23:00 M.I. 3 25:15
26:00 (1) H.I. 0.5
26:30 L.I. 0.5
27:00 (2) H.I. 0.5
27:30 L.I. 0.5
28:00 (3) H.I. 0.5
28:30 L.I. 0.5
29:00 (4) H.I. 0.5 29:00 29:15
29:30 L.I. 0.5
30:00 M.I. 3 32:45
33:00 Cool-down 3
36:00 END
Notes
100
Visit 2-5 – MICE protocol
Cool-down Warm-up M.I.
%HRR 20 30-40 60-70
RPE ≤11 11-12 14-15
Target HR
Target Speed
Target Incline
Time Description Duration
(min)
Achieved Speed
(mph)
Achieved
Incline (%)
Achieved
HR
Achieved
RPE
Blood
Pressure
Enjoyment Feeling
00:00 Standing ‘Pretest’
2
00:00 Warm-up ‘Exercise
5
05:00
M.I.
30
5:45
10:45
12:00 11:15 15:00
16:45
20:00 19:15 31:00
33:45
35:00 34:15
35:00 Cool-down 3
38:00 END
101
Appendix J: HIIE Questionnaire
Date: _______________ RA: _______________ Participant ID: ____________________
Intentions
1. How likely is it that you will engage in high-intensity interval exercise at least once in the next four (4) weeks?
1 2 3 4 5 6 7 8 9
Not likely at
all
Not likely
Neutral Somewhat likely
Very likely
Preference
Please answer the following questions based on your experience from this study. Select only one answer for each question.
1. Please indicate how much you liked or disliked each exercise protocol you performed in this study:
4x4 1 2 3 4 5 6 7
Very much
disliked
Somewhat disliked
Neutral Liked somewhat
Extremely liked
10x1 1 2 3 4 5 6 7
Very much
disliked
Somewhat disliked
Neutral Liked somewhat
Extremely liked
TRI.P. 1 2 3 4 5 6 7
Very much
disliked
Somewhat disliked
Neutral Liked somewhat
Extremely liked
4x4 – 4-min intervals of high-intensity, 3-min recovery of moderate-intensity,
repeated 4 times. Total time = 28 mins
10x1 – 1-min intervals of high-intensity, 1-min recovery of low-intensity, repeated 10
times. Total time = 20 mins
102
30 1 2 3 4 5 6 7
Very much
disliked
Somewhat disliked
Neutral Liked somewhat
Extremely liked
2. Please rank the exercise protocols (4x4, 10x1, TRI.P., 30) in order of preference. Most preferred 1) ___________________ 2) ___________________ 3) ___________________ Least preferred 4) ___________________ 3. For the exercise protocol you preferred the most (as indicated in question 2), how likely are you to perform it at least once in the next four (4) weeks?
1 2 3 4 5 6 7 8 9
Not likely at
all
Not likely
Neutral Somewhat likely
Very likely
4. For the exercise protocol you preferred the most (as indicated in question 2), how likely are you to perform it at least once per week in the next four (4) weeks?
1 2 3 4 5 6 7 8 9
Not likely at
all
Not likely
Neutral Somewhat likely
Very likely
5. For the exercise protocol you preferred the most (as indicated in question 2), how likely are you to perform it more than once per week in the next four (4) weeks?
1 2 3 4 5 6 7 8 9
Not likely at
all
Not likely
Neutral Somewhat likely
Very likely
6. For the exercise protocol you preferred the most (as indicated in question 2), indicate how much you would like or dislike if it were to be incorporated into your cardiac rehabilitation exercise program.
1 2 3 4 5 6 7
Very much
disliked
Somewhat disliked
Neutral Liked somewhat
Extremely liked
103
7. Assume each exercise protocol provided you with the exact same health benefits, which one would you choose to do regularly over the next four (4) weeks?
a) 4x4 b) 10x1 c) TRI.P. d) 30
Thank you for completing this survey and for your participation in the study!
104
Appendix K: Additional Results
Table 6. Additional results.
Figure 11. Group average SBP and DBP response to the exercise protocols.
0 50 100100
150
200
% of session
SB
P (
mm
Hg
)
4x4
10x1
TRIP
MICE
0 50 10050
60
70
80
90
100
% of session
DB
P (
mm
Hg
)
4x4
10x1
TRIP
MICE
Variable PROTOCOL
P value 4x4 10x1 TRIP MICE
Time of peak (% of session)
HR VO2
Standing
HR (bpm) VO2 (ml·kg-1·min-1) Exercise protocol preference
72 ± 29% 62 ± 20%
63 ± 9
4.0 ± 0.9 39
89 ± 12% 81 ± 14%
65 ± 10
3.6 ± 0.9 24
81 ± 15% 66 ± 23%
66 ± 11
3.8 ± 1.1 36
86 ± 18% 60 ± 35%
67 ± 10
3.7 ± 1.0 41
p=0.028 p=0.152
p=0.262 p=0.769
Data presented as mean ± standard deviation. bpm, beats per minute, HR, heart rate, VO2, oxygen uptake