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Acquired Electrophysiological Remodeling and Cardiac Arrhythmias

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Acquired Electrophysiological Remodeling and Cardiac Arrhythmias DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ingrid M. Bonilla Mercado Graduate Program in: Pharmaceutical Sciences The Ohio State University 2014 Dissertation Committee: Dr. Cynthia A. Carnes, Advisor Dr. Peter J. Mohler Dr. Kari Hoyt Dr. Sandor Györke Abstract Heart disease is the number one killer in the U.S. Some of the most common heart diseases are myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). Due to the high mortality and morbidity caused by heart disease, it is important to improve our understanding of the pathophysiology to identify new therapeutic targets with the ultimate goal of developing new drug therapies. Each type of heart disease has to be treated differently since differences in structural and electrophysiological remodeling occurs. The purpose of the research described in this dissertation is to provide a more in depth understanding of acquired electrophysiological remodeling in specific diseases to provide a basis for improved therapeutic approaches. Diseases studied include: post- MI animals susceptible to ventricular fibrillation, chronic HF, and chronic HF with AF superimposed. Additionally since acquired electrophysiological remodeling can also result as an adverse drug effect, a study of drug-induced arrhythmia mechanisms is included. We found that exercise training protects against lethal arrhythmias in the post- MI setting, through normalization of ventricular repolarization and restoration of the repolarizing current, IKr. IKr block is a common cause of drug-induced cardiac arrhythmia, and we evaluated a drug suspected of causing drug-induced arrhythmias. Surprisingly, ii rather than IKr block, a synergistic combination of decreased transient outward current and abnormal myocyte calcium were the basis of this form of drug-induced arrhythmia. The potential role of reactive species in the pathogenesis of arrhythmias was examined using SIN-1(a peroxynitrite donor) in atrial and ventricular myocytes. While repolarization is longer during SIN-1 exposure in both chambers, effects on repolarization stability were chamber-dependent and effects in the ventricle were arrhythmic. In chronic HF we found that IKCa contributes to ventricular but not atrial repolarization, and that IKCa blockade in ventricular cells is arrhythmogenic. We also found that AF superimposed on chronic HF does not further change atrial cellular repolarization, but it increases fibrosis, a possible mechanism for AF perpetuation. The main conclusion of this body of work is that it is important to study both chambers (atria and ventricle) when considering possible antiarrhythmic targets or new drugs, and that disease-specific remodeling is an important contributor to abnormal electrical function and arrhythmogenesis. iii Dedication To my Family and Friends iv Acknowledgments Contrary to many people that know what they want to be when they grow up, I can say, that having a PhD was not on my list. Where I come from there are no big universities that offer PhD programs thus, my lack of information about graduate school. The most I knew of was to get a masters and then you don’t find a job. Even though my dream wasn’t always being a scientist while doing my bachelor’s degree I always knew that I wanted something more and somehow I knew that if I stayed in Puerto Rico I wasn’t going to find that thing that make me happy. That’s the reason why I applied to the summer research opportunity here in Ohio State at the College of Pharmacy (without even knowing where Ohio was on the map and without an idea what I was going to do during that summer). I had no idea of what summer research was, and therefore I had no expectations. But I have to say that to my surprise once I started working I realized that I just found what I was looking for. I had found a profession that makes me happy and that I wanted to do for the rest of my life. Now the hard part was to be able to get into the graduate school in OSU. This was no easy task and took a lot of effort not only on my part but from my mentor also. v I can’t say that it was an easy task to finish my graduate degree. There were many times where I thought it was the end and if not because of my hard work and the help of many people (I would say an army of people) that stood there for me, helped me and guided me I would not be writing this today. Every day I thank God for putting the right people in my way and for giving me the strength to keep going even when the road seemed very rocky. I am extremely thankful and forever in debt with my advisor Dr. Carnes. I know it was not an easy task to deal with me and I have to say that she had a lot of patience in order to deal with me. Also I want to thank her for believing in me, giving me the confidence that I was capable of doing this and for treating me as more than a student, rather as a family member. Without her help and guidance I would not be here. I will also like to express my deepest and sincere thanks to all the past and present members of the laboratory: Arun Sridhar, Yoshinori Nishijima, Chun Li, Pedro Vargas- Pinto, Jeanne Green and last but not least Victor Long, for their constant help even if they are not in the lab anymore and for putting up with me. Additionally I will like to thanks our collaborators and their respective laboratory members for helping me: Dr. Gyorke, Dr. Billman, Dr. Hamlin and Dr. Mohler. I thank my committee members: Dr. Sandor Gyorke, Dr. Peter J. Mohler and Dr. Kari Hoyt for making this experience a memorable one and for sharing your opinion and guidance during this process. Thanks to the pharmacology division members for guiding me and for making sure that I was progressing adequately. vi All this work wouldn’t have been possible without the help of NHLBI supplement for minorities who supported me and part of my investigations for the past 4 years. I would also like to thank my past and present friends for giving me the support necessary to keep going. They were the ones that were there on every step of my way and always motivated me to keep going. Last but not least I will like to express my deepest and sincere thanks to my family. For their constant support, taking care of me, loving me no matter what and being there for me unconditionally. My sister, who was always one phone call away and has always been there for me and my husband for making my goals part of his goals and riding along with me on this roller coaster. I know this is not the end, this is just the beginning of a very long road. I hope I can continue doing research and helping to contribute to the improvement of cardiac disease and one day being able to have my own laboratory, do my own research and teach other students all my acquired knowledge. I will also like to return the favor of being supported and helped by so many wonderful people by helping new students find and pursue their passion as I am doing. vii Vita March 2004 ....................................................Colegio San Benito 2008................................................................B.S. Industrial Microbiology, University of Puerto Rico, Mayagüez Campus 2008-2009 ......................................................Laboratory technician, The Ohio State University 2009 - Present ...............................................Graduate Research Associate, Department of Pharmacology, The Ohio State University Publications 1. Sridhar A, Nishijima Y, Terentyev D, Terentyeva R, Uelmen R, Kukielka M, Bonilla IM, Robertson GA, Györke S, Billman GE, Carnes CA. Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death. Am J Physiol Regul Integr Comp Physiol. 2008 Nov;295(5):R1463-72. 2. Nishijima Y, Sridhar A, Bonilla I, Velayutham M, Khan M, Terentyeva R, Li C, Kuppusamy P, Elton TS, Terentyev D, Györke S, Zweier JL, Cardounel AJ, Carnes CA. Tetrahydrobiopterin depletion and NOS2 uncoupling contribute to heart failure-induced alterations in atrial electrophysiology. Cardiovasc Res. 2011 Jul ;91(1):71-9. viii 3. Belevych AE, Terentyev D, Terentyeva R, Ho HT, Gyorke I, Bonilla IM, Carnes CA, Billman GE, Györke S. Shortened Ca2+ signaling refractoriness underlies cellular arrhythmogenesis in a postinfarction model of sudden cardiac death. Circ Res. 2012 Feb 17;110(4):569-77. 4. Gudmundsson H, Curran J, Kashef F, Snyder JS, Smith SA, Vargas-Pinto P, Bonilla IM, Weiss RM, Anderson ME, Binkley P, Felder RB, Carnes CA, Band H, Hund TJ, Mohler PJ. Differential regulation of EHD3 in human and mammalian heart failure. J Mol Cell Cardiol. 2012 May;52(5):1183-90. 5. Bonilla IM, Sridhar A, Györke S, Cardounel AJ, Carnes CA. Nitric oxide synthases and atrial fibrillation. Front Physiol. 2012 Apr 23;3:105. 6. Wang H, Bonilla IM, Huang X, He Q, Kohr MJ, Carnes CA, Ziolo MT. Prolonged Action Potential and After depolarizations Are Not due to Changes in Potassium Currents in NOS3 Knockout Ventricular Myocytes. J Signal Transduct. 2012 Aug;2012:645721. 7. Bonilla IM, Belevych AE, Sridhar A, Nishijima Y, Ho HT, He Q, Kukielka M, Terentyev D, Terentyeva R, Liu B, Long VP, Györke S, Carnes CA, Billman GE. Endurance exercise training normalizes repolarization and calcium-handling abnormalities, preventing ventricular fibrillation in a model of sudden cardiac death. J Appl Physiol. 2012 Dec;113(11):1772-83. 8. Bonilla IM, Sridhar A, Nishijima Y, Györke S, Cardounel AJ, Carnes CA.
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