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Modulation of the Arrhythmia Substrate in Cardiovascular Disease

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Modulation of the Arrhythmia Substrate in Cardiovascular Disease Modulation of the Arrhythmia Substrate in Cardiovascular Disease DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Victor Paul Long III Graduate Program in Pharmaceutical Sciences The Ohio State University 2016 Dissertation Committee: Dr. Cynthia A. Carnes, Advisor Dr. Sandor Györke Dr. Kari Hoyt Dr. Peter J Mohler Copyright by Victor Paul Long III 2016 Abstract Heart failure remains a leading cause of morbidity and mortality in the United States. Many of the deaths attributed to heart failure are sudden, presumably due to lethal arrhythmia. It is a combination of structural and electrical remodeling within the failing heart that promotes the abnormalities of normal rhythm that lead to arrhythmia. This remodeling can occur in the ventricle, resulting in tachyarrhythmia or the sinus node, where it can cause either brady- or tachyarrhythmias. Potassium currents mediate the repolarization phase of ventricular action potential, as well as the diastolic phase of the sinoatrial node action potential. One of the purposes of the research described in this dissertation is to understand, from the standpoint of cellular electrophysiology, how alterations of potassium currents play a role in heart-failure induced arrhythmia. The second purpose is to determine if management of serum potassium levels by pharmacists is an effective strategy in patients to minimize proarrhythmia risk in patients taking antiarrhythmic medications. We found that heart failure duration is very important in the progressive reduction of the repolarization reserve of K+ currents in the ventricle. Our results differ from other models, as we were able to identify IKr reduction in chronic heart failure compared to short-term duration heart failure. As a consequence of depleted repolarization reserve, chronic heart failure resulted in a high frequency of early afterdepolarizations (cellular ii arrhythmia). We also found increased ventricular tissue fibrosis in chronic heart failure, a hallmark of human end stage heart failure which is often absent in short-term pacing models. Our chronic heart failure model was also used to investigate the role of adenosine- induced sinus node dysfunction in heart failure. Failing sinoatrial node cells had slower intrinsic firing rates versus normal control cells. We were able to demonstrate an increase in the sensitivity of the rate slowing effects of adenosine in failing sinoatrial node cells. These results are due to an increase in adenosine A1 receptor (A1R) and G-coupled inward rectifier (GIRK) signaling. The negative chronotropic effects of adenosine were abolished through the use of A1R and GIRK inhibitors. Finally, we tested the performance of an algorithm designed to allow pharmacists to manage patient serum potassium levels in patients taking antiarrhytmic medications. Due to the high risk of proarrhythmia among this population, we established a conservative range of serum potassium to prevent low potassium from affecting patient therapy. Patients undergoing the protocol reached desired potassium levels more quickly than standard of therapy, and were able to maintain these levels upon a follow up visit occurring months later. We propose that these studies provide insights into the cellular bases for the development of heart failure-induced arrhythmias, as well as optimizing management of arrhythmia in a clinical setting. iii Dedication This document is dedicated to my loving wife Tammy, and my two greatest achievements, Isaac and Zander. iv Acknowledgments The dissertation that follows is the combined product of caffeine-driven determination, all-nighters in the lab, and a little bit of luck. None of this would have been possible without the help of colleagues that helped and assisted me during my graduate school experience. I would like to foremost thank my advisor, Dr. Carnes for taking me into her laboratory in the first place. Her unwavering support kept me moving forward, especially during the frustrating period of starting sinoatrial cell isolation. She seemed to always make time for me if I needed anything at all. She was also very understanding of my unique circumstances (having two kids) and provided unbelievable flexibility when it was needed. I am forever grateful for her guidance and input into my work. Without her, I certainly would not have made it to this point. I also thank my committee members, Dr. Sandor Gyorke, Dr. Peter Mohler, and Dr. Kari Hoyt. In our committee meetings, their insights and suggestions really advanced my work and thinking. I’d like to thank our collaborators and their laboratory members for helping me and allowing me to work on their projects. These include Dr. Vadim Fedorov, Dr. Loren Wold, Dr. Sandor Gyorke, Dr. Thomas Hund, Dr. Melissa Snider, and Dr. Peter Mohler. v I’d also like to thank all of the present and past members of our laboratory: Jeanne Green, Jon Vecchiet, Jae Yoo, Stephen Baine, and Pedro-Vargas Pinto. I feel I need to give a special acknowledgment to Ingrid Bonilla, who really demonstrated a lot of patience in teaching me how to patch clamp, troubleshoot equipment, and perform data analysis. In addition, she is a good friend and helped keep the mood light during the many stressful times of this endeavor. Finally, I’d like to thank my wife for allowing me to jump into all this, especially when we had a comfortable life beforehand. This experience was something I had to do, and somehow she understood that. I acknowledge her sacrifice when I’m away for long hours (sometimes overnight) while she works full-time, goes to graduate school part- time, and raises two wonderful kids. She is the most exceptional person I’ve met in my life and I just want to say thank you for letting me do all this. vi Vita 1996................................................................West Chester East High School 2000................................................................B.S. Biochemistry, Virginia Tech 2007................................................................PharmD University of Maryland at Baltimore 2011 to present ..............................................Graduate Research Associate, Pharmaceutical Sciences, The Ohio State University Publications 1. Long VP, III, Carnes CA. Treating cocaine cardiotoxicity: Does receptor subtype matter (editorial)? Trends Cardiovasc.Med. 2015 Jan 12. 2. Smith SA, Sturm AC, Curran J, Kline CF, Little SC, Bonilla IM, Long VP, Makara M, Polina I, Hughes LD, et al. Dysfunction in the betaII spectrin- dependent cytoskeleton underlies human arrhythmia. Circulation 2015 Feb 24;131(8):695-708. 3. Long VP, III, Bonilla IM, Vargas-Pinto P, Nishijima Y, Sridhar A, Li C, Mowrey K, Wright P, Velayutham M, Kumar S, et al. Heart failure duration progressively vii modulates the arrhythmia substrate through structural and electrical remodeling. Life Sci. 2015 Feb 15;123:61-71. 4. Bonilla IM, Long VP, III, Vargas-Pinto P, Wright P, Belevych A, Lou Q, Mowrey K, Yoo J, Binkley PF, Fedorov VV, et al. Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure. PLoS.One. 2014;9(10):e108824. 5. Bonilla IM, Vargas-Pinto P, Nishijima Y, Pedraza-Toscano A, Ho HT, Long VP, III, Belevych AE, Glynn P, Houmsse M, Rhodes T, et al. Ibandronate and ventricular arrhythmia risk. J.Cardiovasc.Electrophysiol. 2014 Mar;25(3):299- 306. 6. Bonilla IM, Belevych AE, Sridhar A, Nishijima Y, Ho HT, He Q, Kukielka M, Terentyev D, Terentyeva R, Liu B, Long VP, et al. Endurance exercise training normalizes repolarization and calcium-handling abnormalities, preventing ventricular fibrillation in a model of sudden cardiac death. J.Appl.Physiol (1985.) 2012 Dec 1;113(11):1772-83. Fields of Study Major Field: Pharmaceutical Sciences Specialization: Translational Science viii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments............................................................................................................... v Vita .................................................................................................................................... vii List of Tables .................................................................................................................... xv List of Figures .................................................................................................................. xvi Chapter 1 : Introduction ...................................................................................................... 1 A Brief History of Cardiovascular Physiology and Electrophysiology .......................... 1 Early studies of the Heart ............................................................................................ 1 The Heart as an Electric Organ: The roots of electrophysiology .................................... 4 The Cardiac Conduction System ................................................................................. 6 The Study of Excitable Cells ....................................................................................... 8 Cardiac Action Potentials are Orchestrated by Ion Currents ........................................ 10 The Canine Action Potential.....................................................................................
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