Effects of High-Intensity Aerobic Interval Training on Cardiovascular Disease Risk and Health

393 Pages·2017·5.71 MB·English

by  Scott Adams

Effects of High-Intensity Aerobic Interval Training on Cardiovascular Disease Risk and Health-
related Quality of Life in Testicular Cancer Survivors: The HIITTS Trial

By
Scott C. Adams

A thesis submitted in partial fulfillment of the requirement for the degree of

Doctor of Philosophy

Faculty of Physical Education and Recreation
University of Alberta

© Scott C. Adams, 2017
Abstract
Background
Testicular cancer (TC) survivors (TCS) are an understudied, high-risk group susceptible
to late-onset treatment-related cardiovascular disease (CVD), psychosocial, and health-related
quality of life (HRQoL) deficits in the years following treatment. Importantly, despite having the
second highest cure rate of all solid tumors, improvements in overall survival from testicular
cancer are being off-set by treatment-related CVD. Aerobic exercise training prevents the
development and mitigates the severity of cardiovascular and psychosocial deficits, similar to
those experienced by TCS, in healthy and clinical populations including some cancer survivor
groups. However, no studies to date have assessed the effects of aerobic exercise training on
cardiovascular, psychosocial, and HRQoL deficits in TCS. High-intensity aerobic interval
training (HIIT) is a modality of aerobic exercise training which involves alternating periods of
vigorous- and light-intensity aerobic exercise; and, compared to moderate-intensity continuous
aerobic exercise training (MCT), evidence suggests that HIIT may cause greater improvements in
exercise capacity, cardiac and vascular health, metabolic and lipid-profile changes, antioxidant
defenses, and possibly even HRQoL.

Purpose
The purpose of my dissertation was to evaluate the effects of a 12-week aerobic HIIT
program on traditional and novel CVD risk factors, surrogate markers of cardiovascular and
overall mortality, psychosocial function, and HRQoL in a population-based sample of TCS.

Methods
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© Scott C. Adams, 2017
The High-Intensity Interval Training in Testicular cancer Survivors (HIITTS) trial was a
randomized controlled trial. Recruited through the Alberta Cancer Registry and the surveillance
clinic at the Cross Cancer Institute, 63 TCS were randomly allocated to either HIIT or a wait-list
control usual care (UC) group. All HIIT and the UC participants were asked to maintain the low-
to-moderate intensity physical activity they were performing at baseline throughout the duration
of the 12-week intervention/observation period. Participants in the HIIT group were asked to
attend thrice-weekly supervised exercise sessions for 12 weeks. The HIIT intervention consisted
of four 4-minute work periods involving uphill walking/jogging on a treadmill between 75% and
95% of VO which were separated by three 3-minute active recovery periods performed at a
2peak
lower intensity, for a total of 35 minutes per session (including a 5-minute warm-up and 5-minute
cool-down). Participants in the UC group were invited to participate in a 6-week condensed
version of the HIIT protocol after the 3-month follow-up period. Assessments were made at
baseline, immediately postintervention, and at 3-month follow-up [patient-reported outcomes
(PROs) only]. Participants’ general and cardiovascular health were assessed using a maximal
exercise protocol, non-invasive measures of vascular structure and function, resting and post
exercise autonomic nervous system function, blood-based biomarkers, as well as self-report
questionnaires (i.e., PROs) pertaining to physical activity, HRQoL, cancer-related fatigue (CRF),
sleep quality, depression, anxiety, stress, and self-esteem.

Results
Postintervention data were available in ≥97% of participants for our primary outcome
(VO ) and 37 out of 45 (82%) secondary cardiovascular and PROs. HIIT participants
2peak
completed 99% of all exercise sessions and achieved 98% of their target exercise intensity.
Analysis of covariance (ANCOVA) revealed that, compared to UC, HIIT caused improvements
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© Scott C. Adams, 2017
in the primary outcome of VO (3.7 mL O /kg/min; 95% CI: 2.4 to 5.1; p<0.001) and
2peak 2
numerous secondary outcomes including Framingham CVD Risk Score (FRS) (p=0.011),
arterial-thickness (p<0.001), arterial-distensibility (p=0.049), arterial-stiffness (p<0.001),
microvascular reactivity (p=0.039), resting heart rate (p=0.012), parasympathetic reactivity
(p=0.033); post-exercise parasympathetic reactivation (p<0.001), inflammation (p=0.045), low-
density lipoprotein (p=0.014), CRF (p=0.003), self-esteem (p=0.029), the mental component
score (p=0.034), role-physical (p=0.048), general health (p=0.016), vitality (p=0.001), and social
functioning (p=0.011). Moreover, the effects of HIIT on CRF (p=0.031) and vitality (p=0.015)
persisted at 3-month follow-up. Exploratory analyses also provided preliminary evidence that
changes in VO may have partially mediated the postintervention improvements in the mental
2peak
component score, vitality, and mental health; and the 3-month follow-up improvements in CRF
and vitality. There were no HIIT-related adverse events.

Conclusions
The HIITTS trial provides the first randomized evidence that 12 weeks of supervised
HIIT causes significant and potentially clinically meaningful improvements in traditional and
novel CVD risk factors, surrogate markers of cardiovascular and overall mortality, and patient-
reported CRF, self-esteem, and HRQoL in TCS. If confirmed, the HIIT-related mitigation of
treatment-related sequalae may lead to subsequent improvements in the quality and length of life
in TCS. Further investigation of HIIT to reduce cardiovascular morbidity/mortality and improve
both psychosocial function and HRQoL in TCS is warranted.
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© Scott C. Adams, 2017
Preface

This doctoral dissertation is the original work of myself, Scott C. Adams. The HIITTS
trial received research ethics approval from the Health Research Ethics Board of Alberta –
Cancer Committee (Trial ID# 14-0183) and the University of Alberta. The introduction (Chapter
1), discussion (Chapter 5), and Appendices B – F are my original work.
Chapters 2 (primary paper) and 3 (online supplement) of this dissertation are in press as
Scott C. Adams, MSc, Darren S. DeLorey, PhD, Margie H. Davenport, PhD, Michael K.
Stickland, PhD, Adrian S. Fairey, MD, MSc, Scott North, MD, Alexander Szczotka, and Kerry S.
Courneya, PhD. (2017 – in press), Effects of high-intensity aerobic interval training on
cardiovascular disease risk in testicular cancer survivors: a phase II randomized controlled
trial, Cancer, pp. XXX-XX. I was responsible for the trial conception, design, intervention and
control group supervision, data collection, data analyses and interpretation, and wrote the first
draft of the manuscript. Drs. Courneya, DeLorey, and Davenport made important contributions to
the study conception, design, and data analyses. Drs. Courneya and DeLorey provided equipment
for and supervised the data collection. All coauthors provided important feedback on aspects of
data interpretation and provided critical appraisals of the manuscript content.
Chapter 4 (secondary paper) of this dissertation is under review as Scott C. Adams,
Darren S. DeLorey, Margie H. Davenport, Adrian S. Fairey, Scott North, and Kerry S. Courneya,
Effects of high-intensity aerobic interval training on fatigue, psychosocial function and
health-related quality of life in testicular cancer survivors: a phase II randomized
controlled trial, submitted. I was responsible for the trial conception, design, intervention and
control group supervision, data collection, data analyses and interpretation, and wrote the first
draft of the manuscript. Drs. Courneya, DeLorey, and Davenport made important contributions to
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© Scott C. Adams, 2017
the study conception, design, and data analyses. Drs. Courneya and DeLorey provided the
equipment for and supervised the data collection. All coauthors provided important feedback on
aspects of data interpretation and provided critical appraisals of the manuscript content.
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© Scott C. Adams, 2017
Acknowledgements

I would like to offer my heartfelt thanks to my supervisor and mentor, Dr. Kerry
Courneya. Your passion and drive are apparent in all that you do, and this has been an
exceptional training experience for me. My time in your lab has been rich with opportunities for
professional development and collaboration, as well as introspection and personal growth. I will
forever be appreciative of your guidance, support, and belief in me. I wish to extend my sincere
gratitude to my committee members Drs. Darren DeLorey and Margie Davenport. Darren, you
have been an incredible mentor and source of support throughout my time in your laboratory and
classroom – our time together has been truly memorable! Margie, thank you for all of the time
and energy you dedicated to training me and supporting me throughout this trial. I wish to thank
Drs. Michael Stickland, Scott North, and Adrian Fairey. Mike, thank you for your selfless
support of my technical training, professional development, and my project! Scott and Adrian,
thank you for your guidance, commitment to this project, and for being advocates of our work
and field. Many thanks to my colleagues within the Behavioural Medicine Laboratory including
Andria, Cindy, Ciara, and Dong-Woo. Your benevolence, integrity, and support have been
unwavering and deeply appreciated. I look forward to our ongoing collaboration in the years to
come! To my students and volunteers (especially Sydney, Brittany, Misha and Alexander),
thank you for your tireless efforts in collecting and analyzing our data. To the incredible HIITTS
trial participants, thank you for your dedication and commitment to this trial. Together we have
created something truly special! To my friends throughout the faculty and extended community,
thank you for all of the laughter, libations, and leisure-time pursuits which helped me maintain a
modicum of sanity and a smile on my face. To my amazing family (on both sides of the aisle),
thank you for the endless love and physical/financial support you have extended me over these
many years. From forcing me to stay seated at the homework table to expressing genuine interest
in my work, you have always been there for me when I needed you most! To my wife Rhiannon,
I cannot imagine being on this wild ride with anyone else! You are my champion and my shelter.
You are my inspiration and my foundation. Thank you for believing in me, pushing me to pursue
my dreams, and holding me up along the way! I love you. To my son Avery, thank you for
sleeping well, eating well, and letting daddy get his work done.

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Table of Contents
Abstract .......................................................................................................................................... ii
Preface ............................................................................................................................................ v
Acknowledgements ...................................................................................................................... vii
Table of Contents ....................................................................................................................... viii
List of Tables ................................................................................................................................ xii
List of Figures ............................................................................................................................. xiii
Key Dissertation Abbreviations ................................................................................................ xiv
Chapter I – Introduction .............................................................................................................. 1
1.1 Testicular Cancer ................................................................................................................ 2
1.2 Treatment-Related Risks in Testicular Cancer Survivors .............................................. 3
1.2.1 Treatment-Related Risks: Cardiovascular Disease ................................................... 4
1.2.2 Treatment-Related Risks: Psychosocial and HRQoL Impairments ......................... 6
1.2.3 Summary: Testicular Cancer and Related Risks ....................................................... 8
1.3 Exercise Benefits in Healthy and Other Clinical Populations......................................... 9
1.4 Exercise Benefits and Testicular Cancer Survivorship ................................................... 9
1.4.1 Exercise Benefits: Cardiovascular ............................................................................... 9
1.4.2 Exercise Benefits: Psychosocial & HRQoL ............................................................... 11
1.4.3 Summary: Testicular Cancer and Aerobic Exercise ............................................... 13
1.5 Overview of the Dissertation ............................................................................................ 14
1.6 References .......................................................................................................................... 16
Chapter II – Primary Manuscript ............................................................................................. 30
2.1 Abstract .............................................................................................................................. 33
2.2 Introduction ....................................................................................................................... 35
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2.3 Methods .............................................................................................................................. 36
2.4 Results ................................................................................................................................ 40
2.5 Discussion ........................................................................................................................... 42
2.6 References .......................................................................................................................... 45
Chapter III – Online Supplement for the Primary Manuscript ............................................. 57
3.1 Participants ........................................................................................................................ 58
3.2 Randomization and Blinding............................................................................................ 58
3.3 Exercise Training and Usual Care Conditions ............................................................... 59
3.4 Assessment of Primary and Secondary Endpoints......................................................... 60
3.4.1 Exercise Assessments .................................................................................................. 60
3.4.2 Resting Hemodynamic, Vascular, and Nervous System Assessments .................... 61
3.4.3 Carotid Plaque ............................................................................................................. 63
3.4.4 Carotid Intima-Media Thickness ............................................................................... 63
3.4.5 Carotid Distensibility .................................................................................................. 64
3.4.6 Flow-Mediated Dilation and Microvascular Function ............................................ 64
3.4.7 Respiratory Sinus Arrhythmia .................................................................................. 66
3.4.8 Pulse Wave Velocity .................................................................................................... 67
3.4.9 Blood-based Biomarker Assessments ........................................................................ 68
3.4.10 Cardiovascular Disease Risk Assessments .............................................................. 68
3.5 Statistical Analyses and Sample Size Calculation .......................................................... 69
3.6 References .......................................................................................................................... 70
Chapter IV – Secondary Manuscript ........................................................................................ 77
4.1 Abstract .............................................................................................................................. 79
4.2 Introduction ....................................................................................................................... 81
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4.3 Methods .............................................................................................................................. 83
4.4 Results ................................................................................................................................ 87
4.5 Discussion ........................................................................................................................... 89
4.6 References .......................................................................................................................... 94
4.7 Online Supplement .......................................................................................................... 109
Chapter V - Discussion ............................................................................................................. 110
5.1 Overview .......................................................................................................................... 111
5.2 Summary of Findings ...................................................................................................... 111
5.3 Future Research Directions ............................................................................................ 115
5.4 Practical Implications ..................................................................................................... 122
5.5 Strengths and Limitations .............................................................................................. 125
5.6 Conclusions ...................................................................................................................... 129
5.7 References ........................................................................................................................ 131
Bibliography .............................................................................................................................. 139
Appendix A: TC Diagnostic and Prognostic Information ..................................................... 193
Appendix B: Methods of Cardiovascular Health Assessment .............................................. 196
Appendix C: Methods of Psychosocial and HRQoL Health Assessment ............................. 222
Appendix D: CVD Risk Screening & Treatment-Related CVD Risks in TCS ................... 228
Appendix E: The Role of Aerobic Exercise Training in TC Survivorship .......................... 252
Appendix F: Exercise Prescription Considerations for TCS ................................................ 274
Appendix G: HIITTS Trial Cover Letter ............................................................................... 281
Appendix H: Alberta Cancer Registry Cover Letter ............................................................. 283
Appendix I: Participant Screening Sheet ................................................................................ 285
Appendix J: Informed Consent ................................................................................................ 288
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