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Regulation of Cardiac Voltage Gated Potassium Currents in Health and Disease

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Regulation of Cardiac Voltage Gated Potassium Currents in Health and Disease REGULATION OF CARDIAC VOLTAGE GATED POTASSIUM CURRENTS IN HEALTH AND 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 Arun Sridhar, M.S. ****** The Ohio State University 2007 Dissertation Committee: Dr. Cynthia A. Carnes, Pharm.D, PhD Approved By: Dr. Robert L. Hamlin, DVM, PhD ______________________ Dr. Sandor Gyorke, PhD Advisor Dr. Mark T. Ziolo, PhD Graduate Program in Biophysics ABSTRACT Cardiovascular disease (CVD) is a major cause of mortality and morbidity worldwide. CVD accounts for more deaths than all forms of cancer in the United States. Hypertension, Heart Failure and Atrial Fibrillation are the most common diagnosis, hospitalization cause and the sustained cardiac arrhythmia respectively in the US. Sudden cardiac death is the one of the most common causes of cardiovascular mortality after myocardial infarction, and a common cause of death in heart failure patients. This has been attributed to the development of ventricular tachyarrhythmias. In addition, most forms of acquired CVD have been shown to produce electrophysiological changes due to very close interactions between structure, signaling pathways and ion channels. Due to the increased public heath burden caused by CVD, a high impetus has been placed on identifying novel therapeutic targets via translational research. Identification of novel therapeutic targets to treat heart failure and sudden death is underway and is still in a very nascent stage. In addition, ion channel blockers, more specifically “atrial-specific” ion channel blockers have proposed to be a major therapeutic target to treat atrial fibrillation without the risk of ventricular pro- arrhythmia. This dissertation addresses these important therapeutic issues from the standpoint of cellular electrophysiology. All experiments were amphotericin-B - ii - perforated whole cell patch-clamp experiments performed on isolated cardiac myocytes at 36 ± 0.5°C. Chapter 2 addresses a very important issue of identification of a purportedly “atrial-specific” ion current in the canine ventricle. The findings suggest that the current is not atrial-specific and has properties similar to the atrial ultra-rapid delayed rectifier current (IKur). This might have important implications for the use of IKur blockers for the treatment of atrial fibrillation. Hypertension leads to ventricular hypertrophy, and ionic and structural remodeling. Chronic hypertension leads to reduced ventricular compliance and if untreated can precipitate heart failure. Chapter 3 focuses on alterations in diastolic currents (IK1 and If) and their contribution to altered cardiac excitability in hypertensive heart failure. Chapter 4 is the first study to document ionic remodeling in a well characterized canine model of sudden cardiac death. Our findings suggest that + K current remodeling (predominantly a complete absence of IKr) causes prolongation and increased variability of the action potential duration and early after-depolarizations. This study provides a basis for examining the potential benefits of IKr activators as a therapeutic target to prevent arrhythmias and sudden death. Chapter 5 and Chapter 6 assess ventricular and atrial ionic remodeling in chronic heart failure. Chapter 5 presents some provocative preliminary data on - iii - the electrophysiologic reverse remodeling after cardiac resynchronization therapy. Chapter 6 focuses on atrial ionic remodeling in chronic heart failure. The results suggest that duration of heart failure is a very important predictor of persistence of atrial fibrillation in heart failure. In addition, preliminary data suggesting specific oxidative processes that regulate atrial K+ currents are presented. Some of these effects are reversible, while others are irreversible with acute myocyte anti-oxidant (glutathione) replenishment. These studies provide a foundation for examining a future research direction where the use of specific anti-oxidant interventions could be tested to assess prevention of atrial remodeling and therefore atrial fibrillation. We propose that these studies aid in understanding of important processes of K+ current remodeling in CVD. Understanding these mechanisms is important to devise new therapeutic targets for prevention/treatment of arrhythmias in CVD. - iv - Dedicated to Family, Friends and Gurus - v - ACKNOWLEDGMENTS As I start this section of my dissertation, I can only look back at gratitude at each and every person who has contributed to my education and well-being. A lot of wishes, blessings and good-will has gone into me becoming a Doctor of Philosophy. “For things to go the way we want it in life, there is only one primary requirement. Blessed to be at the right place, at the right time, to form the right association”. I have been blessed that way in a lot of ways during this lifetime. Call it luck, blessing or hardwork. I believe that its all due to one altruistic superpower called God (which I believe has no form, no religion but one that guides all that we do in a lifetime) for being extremely kind to me. I express my deepest gratitude to my advisor, Dr. Cynthia A. Carnes for her help and guidance throughout my graduate education. Her valuable insights and help, filled with her never ending enthusiasm, ever brimming confidence and careful attention to detail has been the guiding light behind this dissertation. I also thank my committee members, Dr. Robert L. Hamlin, Dr. Sandor Györke and Dr. Mark.T. Ziolo for sharing their opinions, and expressing unwavering support and guidance. I also thank my candidacy exam committee member, Dr. Peter J. Reiser. These wonderful scientists through their valuable interactions have shaped my thinking in the last 5 years. - vi - I would like to thank my colloborators – Dr.George E. Billman (Dept of Physiology and Cell Biology), Dr. Robert L. Hamlin and their laboratory members. All the data collected in this dissertation would not have been possible without the help of Drs. Yoshinori Nishijima, Adriana Pedraza-Toscano, Daise N.Q. da Cuñha, Anusak Kijtawornrat. My collaborative co-workers: Drs. Dmitry Terentyev, Andriy Belevych, Zuzana Kubalova, Serge Viatchenko-Karpinski and Ms. Inna Györke deserve special mention for their enthusiastic support and interaction. I also thank Ms. Ingrid Bonilla (an undergraduate summer student from University of Puerto Rico) for her help, enthusiasm and careful analysis of data. I also thank my lab mate, Dr. Veronique A. Lacombe for her input and thoughtful discussions throughout my graduate career. My special mention goes to Ms. Susan Hauser (Administrator – Biophysics Program) for her help even before I arrived here in the US. I will never be able to forget the wonderful interactions I had with Mr. Spencer J. Dech, Drs. Tomohiro Nakayama and Hitomi Nakayama in this laboratory. I also thank Dr. Thomas L. Clanton (Director, Biophysics Program) for his wonderful input throughout my graduate career. He has been a great source who helped me learn and understand science from life’s perspective. He has been a great teacher during my troubled times during the first year of my graduate school at OSU. I will remember his enthusiasm for science and his quote (“Keep on truckin’ ”) forever. - vii - I thank my teaching mentor Dr. James Coyle for his constant encouragement and guidance during my teaching assignment in the College of Pharmacy. My deep sense of gratitude goes to the wonderful physicians and surgeons at Madras Medical Mission (Chennai, India) for teaching me the nuances of cardiovascular medicine. It is here that I learnt so much about cardiovascular medicine, had great interactions with Mr. Gino Kurian, (Drs). Latchumana Dhas, KS Murthy, VM Kurian, G. Sumithran, Vijit Cherian and more importantly, Dr. KM Cherian. Thank you Dr.Cherian for providing with an excellent atmosphere and sharing your knowledge and ideas. It would be a sinful act, if I did not recognize my friends (past and present - in India and in the US) who have sharing the past 10 years with me. It has been one hell of a roller-coaster ride. I express my thanks for the emotional support that you all have provided me. Finally, my biggest eulogy and thanks to my family. I single out my grandmother, Mrs. Lakshmi Narasa and my sister, Aarthishree.S for their love and support. I am greatly indebted to my parents, Mr. S.V. Sridhar and Mrs. E.Mythreyi for their patience, courage and never-say-die attitude in life. I would not be at this stage in life and would not be able to attain success in the past 26 years, without their sacrifices for the sake of my education. They have been the primary reason for my drive and confidence to achieve “successive successes” - viii - (The term borrowed from my father’s dictionary of life). With their blessings and support, I hope to continue the good work in the future to benefit therapeutics and healthcare suffering from disease. - ix - VITA 11 January 1981…………………………..Born - Chidambaram, India 1998 -2002 …………………………BS (Physician Asst). BITS, Pilani 2002-2004……………………………………….MS (Biophysics) OSU Fall 2003…………………………..............................TA - Biology 113 Fall 2004, Fall 2005………………………………...TA, Pharmacy 777 PUBLICATIONS 1. Kubalova Z, Terentyev D, Viatchenko-Karpinski S, Nishijima Y, Gyorke I,Terentyeva R, da Cunha DN, Sridhar A, Feldman DS, Hamlin RL, Carnes CA, Gyorke S. Abnormal intrastore calcium signaling in chronic heart failure. Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14104-9.
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