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Integrated Genetic and Phenotypic Assessment of Dilated

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Integrated Genetic and Phenotypic Assessment of Dilated INTEGRATED GENETIC AND PHENOTYPIC ASSESSMENT OF DILATED CARDIOMYOPATHY This dissertation is submitted to Imperial College London for the degree of Doctor of Philosophy by Upasana Tayal MA(Oxon) BMBCh MRCP(UK) Royal Brompton Hospital Cardiovascular Research Centre Imperial College Faculty of Medicine August 2017 ABSTRACT Background: Dilated cardiomyopathy (DCM) affects up to 1 in 250 individuals and is the leading global indication for heart transplantation, though a subset of patients can recover myocardial function. Aim: To integrate clinical, genetic, and advanced imaging data to generate new insights into DCM pathobiology. Methods and Results 1) Evaluation of the genetic architecture of DCM in 647 unrelated Caucasian patients revealed that variants in only 5 of 57 putative DCM genes were significantly enriched compared to >30,000 reference samples. Truncating variants in the titin gene (TTNtv) accounted for the largest genetic contribution to DCM (excess burden 14.1%, p=6.4x10-82). 2) Cardiovascular magnetic resonance (CMR) phenotype study of 716 DCM patients demonstrated that TTNtv DCM was associated with a blunted hypertrophic response (mean 2 indexed left ventricular mass, g/m ; TTNtv-/+ 91.3 vs 83.5, padjusted=0.007). Moderate alcohol excess was an environmental modifier of the TTNtv phenotype (10.0% reduction in left ventricular ejection fraction, 95% CI -16.3 to -3.8%, p=0.002). 3) In 29 patients with recent onset DCM, myocardial contractile reserve during low-dose dobutamine stress CMR was an independent predictor of LV remodelling (p=0.007). Contractile reserve assessed by a novel cine-DENSE strain CMR sequence and relative RV contractile reserve were also predictive of LV remodeling. 4) Amongst 604 DCM patients, followed up for a median of 3.9 years for the primary composite endpoint of cardiovascular mortality, major arrhythmic events and major heart failure events, the presence of TTNtv did not influence the primary outcome (TTNtv unadjusted hazard ratio 0.81 [95% CI 0.41-1.63], p=0.56). Further analyses showed no evidence that gender or CMR mid-wall fibrosis status modified the effect of TTNtv. Conclusion These data improve our understanding of the genetic basis of DCM, provide mechanistic insight and inform risk stratification in DCM. 2 Template by Friedman & Morgan 2014 Word This thesis is dedicated to my parents and Mayank. Your unconditional love and support has made me everything I am today. 3 Template by Friedman & Morgan 2014 Word THESIS OVERVIEW DIAGRAM Research aim: Evaluate whether integrated assessment of genotype and phenotype data in DCM can improve understanding of DCM pathogenesis, inform patient stratification, and identify predictors of remodeling and outcome. INTRODUCTION Chapter 1: General Introduction Overview of background to research question Chapter 2: Evaluating the genetic architecture of DCM Burden of rare variants in DCM cohort compared to population genetic variation. Purpose of this chapter is to guide subsequent phenotype analysis. RESULTS Chapter 3: Clinical manifestations and phenotypic drivers of titin cardiomyopathy Evaluation of the phenotype and environmental modifiers of the commonest genetic contributor to Each chapter DCM using cardiovascular magnetic resonance contains: (CMR). • Introduction Chapter 4: Imaging predictors of cardiac • Methods remodeling • Results • Discussion Imaging sub-study to evaluate imaging predictors of • Outline of remodeling in patients with recent onset DCM, with a further work focus on contractile reserve, assessed through low- dose dobutamine CMR. Chapter 5: The role of clinical, imaging and genetic data in predicting clinical outcomes in dilated cardiomyopathy Final chapter brings together chapters 2 and 3, Chapter 6: Summary discussion evaluating the prognosis of titin cardiomyopathy. What this PhD adds to the field CONCLUSION Chapter 6: Summary overview What this PhD adds to the field and future work 4 Template by Friedman & Morgan 2014 Word DECLARATIONS Declaration of originality This thesis is the result of my own work other than where duly acknowledged or appropriately referenced. It has not been previously submitted, in part or whole, to any university of institution for any degree, diploma, or other qualification. Copyright declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. Upasana Tayal , BMBCh, MA (Oxon), MRCP (UK) Imperial College 5 Template by Friedman & Morgan 2014 Word ACKNOWLEDGEMENTS I am grateful to my supervisors for giving me the opportunity to undertake this PhD. I have learnt about science, innovation and resilience in equal measure. Sanjay, thank you for believing in me from the start and for your incredible support along the way. You gave me the academic freedom to explore and helped guide me through the more challenging moments. Stuart, thank you for taking a chance on me when I barely knew the difference between genes and jeans. Your academic guidance at every stage has been invaluable and I hope it is a resource I may draw upon for years to come. James, thank you for being so generous with your time, coming on board when I needed it the most. Thanks for your mentorship and scientific rigour. I am a better scientist and I now know how to use R (sort of). I am grateful to the MRC for funding this PhD, providing much needed peer approval of the work and setting the foundation for my academic career ahead. I am thankful to all the staff in the BRU, Genetics and Genomics Lab, and CMR department at the Royal Brompton Hospital. Particular thanks go to Gillian Rea and Rachel Buchan, my genetics guardian angels at the start of this PhD. The genetics group is the exemplar of team science and I have learnt an enormous amount from all who have been so generous with their knowledge, including (though by no means limited to) Nicky Whiffin, Liz Edwards, Roddy Walsh, Francesco Mazzarotto, and Paul Barton. Within the BRU, thanks to Prof Pennell for ongoing academic support, both personally and for the studies in this thesis. An enormous thank you to the wonderfully dedicated army of BRU research nurses, in particular Carmen Chan, Zohreh Farzad, Sally-Ann McRae, and Annashyl West for your help with my projects. Thanks also to Steve Collins and Yasin Karafil for keeping the BRU database alive and to Geraldine Sloane for your continuous project support. Thanks also to the research fellows (especially Brian, Amrit and Zohya) for your camaraderie and for making sure that coming to work was never a chore. Within CMR, an enormous debt of gratitude to Ric Wage for your support of the remodelling study and all round CMR wisdom. Thank you also to George Mathew and Karen Symmonds for teaching me how to scan. I am lucky to have had ready access to physics expertise and have found patient teachers in Peter Gatehouse, Jenny Keegan, Andy Scott, Iain Pierce, Pedro Ferreira, and Merlin Fair, thank you all. Last but not least, I thank Simon Newsome for his never-ending statistical mentorship and support. I hope the breadth and depth of what I have learnt from you is reflected in all my academic endeavours. A brief but heartfelt thanks must also go to my family and friends for keeping me sane over the last few years. And for the cocktails, holidays, and cuddles when said sanity was absent. Most importantly of all, I am of course indebted to the patients and volunteers who participated in this study. Clinical research is only possible thanks to the altruism and enthusiasm of these individuals. 6 Template by Friedman & Morgan 2014 Word CONTENTS Abstract .................................................................................................................................... 2 Thesis Overview Diagram ....................................................................................................... 4 Declarations .............................................................................................................................. 5 Acknowledgements .................................................................................................................. 6 Contents .................................................................................................................................... 7 List of Tables .......................................................................................................................... 13 List of Figures ........................................................................................................................ 15 List of Abbreviations and Acronyms ................................................................................... 17 Selected awards and publications ........................................................................................ 19 1 Introduction: Dilated Cardiomyopathy ........................................................................... 22 1.1 What is Dilated Cardiomyopathy? ............................................................................................. 22 1.1.1 Definition of Dilated Cardiomyopathy .............................................................................................. 22 1.1.2
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