Cardiac Biomarkers of Damage and Dysfunction

THE EFFECTS OF PROLONGED BOUTS OF EXERCISE AND ACUTE ISCHEMIC PRECONDITIONING ON CARDIAC BIOMARKER RELEASE Mark Anthony Benson A thesis submitted in partial fulfilment of the requirements of Liverpool John Moores University for the degree of Doctor of Philosophy August 2017 i Page i Page i Abstract Although habitual exercise can have profound beneficial effects on the cardiovascular system, there is a growing evidence base to suggest that single acute bouts of endurance exercise can lead to the release of cardiac biomarkers of damage and dysfunction. Whether this cardiac biomarker release is indicative of reversible or irreversible cardiomyocyte damage is not clear. The first study in this thesis employed a new high sensitivity assay to assess cardiac troponin (cTnI) as well as N terminal pro-brain natriuretic peptide (NT-proBNP) before, during and after 2 hr of treadmill exercise in young, healthy but non-athletic participants. No cTnI samples were elevated above the detection limit of the assay during exercise and only one participant had a detectable cTnI value post-exercise (22 ng/L). NT-proBNP levels were elevated more consistently during exercise and recovery. In the second study, the repeatability of cardiac biomarker responses to 2 hr of treadmill exercise was assessed 1 and 12 weeks after an initial trial (Study 1). The same participant had an elevated cTnI value post-exercise in week 0 (22ng/L) and week 1 (30 ng/L). All other participants had no detectable cTn in trials in week 0 and 1. At week 12 one participant (different to the person in week 0 and 1) had elevated cTnI post-exercise (25 and 38 ng/l). NT-proBNP levels rose with exercise in all trials but peaked earlier in trial 1 and demonstrated great individual variability. Study 3 and 4 investigated the role that ischemia may play in cardiac biomarker release and cardiac functional changes after endurance exercise. Ischemia was studied indirectly by employing remote ischemic preconditioning (RIPC) in a single-blind crossover research design. In study 3 trained cyclists completed 2 one hour time trials in a controlled laboratory environment with trials preceded immediately RIPC or a SHAM protocol. cTnI values were reduced after the RIPC trial compared to the SHAM during recovery from exercise (significant main effect for trial). NT-proBNP and indices of cardiac function were not mediated by RIPC. Using the same RIPC intervention in study 4 we employed a longer exercise task (160 km cycle) in trained cyclists. We confirmed a partial attenuation of cTnI appearance post-exercise following the RIPC intervention compared to the SHAM. In addition NT-proBNP was lower after the RIPC trial but RIPC did not mediate any change in cardiac function post-exercise. These data reflect the first tentative evidence that ischaemia could be implicated in post-exercise cardiac biomarker release. Although exercise can lead to cardiac biomarker appearance, and ischaemia may be implicated mechanistically, the rapid appearance and removal of these biomarkers as well as the limited impact on cardiac function still supports a reversible insult to the cardiomyocytes. ii Page ii Acknowledgement When I started planning for this PhD I contacted an old lecturer of mine (Professor Tom Reilly). He wrote a lovely email on all the different projects that were available and who to contact. It was a long detailed email. When I was an undergraduate student I remember Tom’s professionalism, fair play, always willing to help students, never seemed to be too busy. I got to know Professor Reilly on a professional level when he supervised my undergraduate dissertation and on a more personal level when I ran for the university running club and the long trips to Hollymount’s international road race. Tom I thank you. I would like to thank Professor Adrian Lees. Adrian in many ways was very similar to Tom. Very thoughtful, very knowledgeable, professional, always willing to help. He had a deep love of sport & exercise science. Adrian was one of those people that had the ability to give without directly giving. Adrian, like Tom, was softly spoken, had time for everybody, was another true professional, and he did make a difference. I thank Adrian for just being himself. I am lucky to have been taught by him. Thanking my postgraduate supervisor third is not the traditional way and I hope it does not offend. I would like to thank my supervisor Professor Keith George for his contribution and professionalism, for all the support and encouragement he has gave me during the long months and years I have spent undertaking my PhD. Without his guidance and constant feedback this would have been a very different experience. The iii Page iii university is very lucky to have staff like Professor Keith George. Thank you for your patience, understanding, guidance and professionalism, I have learned so much. During my research studies I have been very lucky to have my own daughter on the research team. She was part of the RIPC team. Jemima is just finishing off her A- level exams and has been accepted to read Sport & Exercise Science for the 2017 academic year. A very big thank you to Beth McCarthy, a friend of my daughters, she was also part of the RIPC team. Thank you to Dr. Helen Jones the phlebotomist at LJMU and a big thank you to Dr. Neil Chester for his patience and professional attitude. Nothing was too small or too stupid for Neil. I am lucky to have had the opportunity to work with Neil, Thanks Neil. To the many more people I met at the university I thank you all. Lastly, I would like to thank my family for all their love and encouragement. To my wife (Anne), I am sorry you had to spend all those lonely hours watching TV by yourself whilst I ran to the study to work on my PhD. At times, you must have thought it was never going to end. Anne thank-you for supporting me throughout this PhD project. It would not have happened without your support. Lastly, I could have spent more time with my other daughter Siobhan, I hope I was not hiding in the study too much. Siobhan has one more year before she starts her university journey reading Psychology. iv Page iv Table of contents Page Chapter 1: _________________________________________________________________________ 1 Introduction _______________________________________________________________________ 1 1.1. Background Context __________________________________________________________ 1 1.2. Thesis Overview _____________________________________________________________ 5 Chapter 2: _________________________________________________________________________ 7 Review of the literature ______________________________________________________________ 7 2.1. Definition and History of Cardiac Biomarkers ______________________________________ 7 2.2. Cardiac Troponin (cTn) and Exercise ____________________________________________ 11 2.3. NT-proBNP and Exercise ______________________________________________________ 18 2.4. Repeatability of Cardiac Biomarker Response to Exercise ___________________________ 21 2.5. Clinical Consequences and Potential Mechanisms of Cardiac Biomarker Release _________ 24 2.5.1. Ischaemia and Cardiac Biomarker Appearance __________________________________ 26 2.6. The Link between Cardiac Biomarker Appearance and Cardiac Functional Changes Post- exercise. ______________________________________________________________________ 32 2.7. Summary __________________________________________________________________ 34 2.8. Study Hypotheses ___________________________________________________________ 36 Chapter 3: ________________________________________________________________________ 37 Study 1: Is there a rapid turnover of hs-cTnI and NT-proBNP during and after 2 h of prolonged moderate intensity exercise in healthy active individuals? __________________________________ 37 3.1. Introduction _______________________________________________________________ 37 3.2. Methods __________________________________________________________________ 39 Participants _________________________________________________________________ 39 Protocol ____________________________________________________________________ 40 Blood Sampling and Analysis ____________________________________________________ 41 Statistical Analyses ___________________________________________________________ 43 3.3. Results ____________________________________________________________________ 43 3.4. Discussion _________________________________________________________________ 45 Limitations __________________________________________________________________ 49 3.5. Conclusion _________________________________________________________________ 49 v Page v Chapter 4: ________________________________________________________________________ 50 Study 2: The short and long-term repeatability of the hs-cTnI and NT-proBNP response to a 2 h bout of prolonged moderate intensity running in healthy active individuals. _______________________ 50 4.1. Introduction _______________________________________________________________ 50 STUDY 2: Hypothesis 2a: _______________________________________________________ 51 4.2. Methods __________________________________________________________________ 52 Participants _________________________________________________________________ 52 Protocol ____________________________________________________________________ 53 Statistical Analyses ___________________________________________________________ 53 4.3. Results ____________________________________________________________________ 54 4.4. Discussion

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