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Myofilament Dynamics Modulate Cellular Drivers of Arrhythmogenesis in Human Cardiac Disease

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Myofilament Dynamics Modulate Cellular Drivers of Arrhythmogenesis in Human Cardiac Disease MYOFILAMENT DYNAMICS MODULATE CELLULAR DRIVERS OF ARRHYTHMOGENESIS IN HUMAN CARDIAC DISEASE by Melanie Anne Zile A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland October, 2017 © Melanie Anne Zile 2017 All rights reserved Abstract Cardiac arrhythmia is common in cardiac disease, but our understanding of the cellular mechanisms underlying arrhythmia is incomplete. Alternans, the beat-to-beat alteration in cardiac electrical or mechanical signals, has been linked to susceptibility to lethal arrhythmias in human heart failure (HF) as well as in human chronic atrial fibrillation (cAF). In addition, early afterdepolarizations (EADs), a type of aberrant cellular behavior that causes spontaneous slowing or reversal of normal repolarization, have been implicated as an arrhythmogenic trigger in human hypertrophic cardiomyopathy (HCM). Abnormal myofilament dynamics has been observed in human HF, HCM, and cAF, but whether this aberrant behavior alters the formation of alternans or EADs remains unknown. To address this gap in understanding, a computational modeling approach was taken. Three mechanistically-based bidirectionally coupled human electromechanical myocyte models were constructed, under the conditions of HF, HCM, or cAF. Our goal was to elucidate whether aberrant myofilament dynamics modulate the cellular drivers of arrhythmogenesis in human cardiac disease. In simulations with our human HF ventricular myocyte model, we found that the magnitudes of force, calcium, and action potential voltage alternans were modulated by heart failure induced-remodeling of mechanical parameters and sarcomere length due to the presence of myofilament feedback (MEF) at clinically-relevant pacing rates. In simulations with our human HCM ventricular myocyte model, we found that incorporating MEF diminished the degree of repolarization reserve reduction necessary for EADs to emerge and increased the frequency of EAD occurrence, especially at faster pacing rates. Longer sarcomere lengths and HCM-induced enhanced ii thin filament activation diminished the effects of MEF on EADs. Finally, in simulations with our human cAF atrial myocyte model, we found that MEF, via cooperativity in Troponin C buffering of cytoplasmic Ca2+, diminished the magnitude of action potential duration alternans. Also, enhanced thin filament activation, via either cAF-induced myofilament remodeling or longer sarcomere lengths, enhanced action potential duration alternans. Together, this thesis provides evidence that myofilament protein dynamics mechanisms play an important role in EAD and alternans formation, suggesting that targeting MEF or reversing disease induced myofilament remodeling may be alternative treatment approaches for prevention of arrhythmia in cAF patients. Advisor: Natalia A. Trayanova, Ph.D. Readers: Natalia A. Trayanova, Ph.D., Raimond L. Winslow, Ph.D. Thesis Committee: Feilim Mac Gabhann, Ph.D., Natalia A. Trayanova, Ph.D., Raimond L. Winslow, Ph.D. iii Acknowledgements The work presented here in my thesis would not have been possible with the support and mentorship of my advisor, Dr. Natalia Trayanova. I thank her for her guidance and for teaching me how to become a better scientist and writer. I would also like to thank the other members of my thesis committee, Dr. Raimond Winslow and Dr. Feilim Mac Gabhann, who have provided invaluable insight and guidance on my thesis work. I thank the Computational Cardiology Lab (Trayanova Lab) for their help over the years and for being a fantastically fun group of friends. I will miss the lab pushups, the “Crying Tom Brady” birthday cards, and the happy hours at Rocket to Venus. In particular, I would like to thank Dr. Patrick Boyle for his helpful critique of my papers, posters, and presentations, Robert Blake for creating and editing the “mech_bench” code, and Dr. Yasser Aboelkassem for his help brainstorming ideas and discussing the minutia of myofilament processes. Most importantly, I would like to thank my fantastic family, without whom I would have never had the confidence, support, nor opportunity to achieve all of the many successes in my life. Billy, Mom and Steve, Dad and Jill, Gram and Gramps, and GBob, to you I owe a lifetime of thanks. Thank you for your unconditional love and encouragement during the best and the worst of times, as well as all of the times in between. I am truly blessed to have such an amazing family. And finally, I would like to thank my wonderful friends who have turned Baltimore into my home. iv Contents Abstract .................................................................................................................. ii Acknowledgements .............................................................................................. iv Contents ................................................................................................................. v List of Tables ......................................................................................................... x List of Figures ....................................................................................................... xi Chapter 1 Introduction......................................................................................... 1 1.1 Organization and Summary of the Thesis ...................................................... 2 Chapter 2 Background: ........................................................................................ 4 Basic Cardiac Electrophysiology and Electromechanics .................................. 4 2.1 Blood Flow and the Healthy Human Heart.................................................... 5 2.2 Electrophysiology and Electromechanics of the Healthy Human Heart ....... 6 2.2.1 Normal Cardiac Rhythm 6 2.2.2 Cardiac Action Potential 7 2.2.3 Excitation-Contraction Coupling 9 2.2.4 Mechanoelectric Feedback 12 2.3 Electrophysiology and Electromechanics of the Diseased Human Heart .... 13 2.3.1 Arrhythmias 14 2.3.2 Cardiac Alternans 15 v 2.3.3 Afterdepolarizations 16 Chapter 3 Background: Computational Modeling .......................................... 18 3.1 Rationale for Computational Modeling of Cardiac Myocytes ..................... 19 3.2 Modeling Cell Membrane Kinetics .............................................................. 19 3.3 Modeling Calcium Handling........................................................................ 21 3.4 Modeling Cardiac Myofilament Dynamics ................................................. 21 Chapter 4 Study 1: .............................................................................................. 23 Rate-dependent force, intracellular calcium, and action potential voltage alternans are modulated by sarcomere length and heart failure induced-remodeling of thin filament regulation in human heart failure: A myocyte modeling study ........................................................................ 23 4.1 Introduction .................................................................................................. 24 4.2 Methods........................................................................................................ 27 4.2.1 Human Electromechanical Myocyte Model 27 4.2.2 Incorporating Heart Failure Remodeling 30 4.2.3 Alternans Protocol 33 4.2.4 Alternans Analysis 35 4.3 Results .......................................................................................................... 35 4.3.1 Abnormal Intracellular Calcium Handling Results in Force Alternans 35 4.3.2 Sensitivity of Alternans to Pacing Rate 38 4.3.3 Dependence of Force, Calcium and Voltage Alternans on Sarcomere Length 40 vi 4.3.4 Effect of Heart Failure Induced- Remodeling of Mechanical Parameters on Force, Calcium and Voltage Alternans 44 4.4 Discussion .................................................................................................... 47 4.4.1 Calcium Alternans Link Action Potential Voltage Alternans to Force Alternans 47 4.4.2 Force Alternans Are Large at Slow Pacing Rates and May Be Undetectable at Faster Pacing Rates 48 4.4.3 Implications of Heart Failure-Induced Mechanical Remodeling for Alternans Severity 49 4.5 Conclusions .................................................................................................. 50 Chapter 5 Study 2: .............................................................................................. 52 Myofilament Protein Dynamics Modulate EAD Formation in Human Hypertrophic Cardiomyopathy ................................................................ 52 5.1 Introduction .................................................................................................. 53 5.2 Methods........................................................................................................ 56 5.2.1 Human Electrophysiology-Force Myocyte Model 56 5.2.2 Incorporating HCM-Induced Remodeling 59 5.2.3 EAD Protocol 62 5.2.4 Analysis of EADs 64 5.3 Results .......................................................................................................... 64 5.3.1 MEF Alters EAD Emergence and Frequency of Occurrence 64 vii 5.3.2 Faster Pacing Enhances Effects of MEF on EAD Emergence and Frequency 70 5.3.3 Longer Sarcomere Length Diminishes MEF Effects on EAD Emergence and Frequency 73 5.3.4 Increased Severity of HCM-Induced Myofilament Remodeling Alters Effects of MEF on EAD Emergence and Frequency 76 5.4 Discussion ...................................................................................................
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