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Nassal M Thesis FINAL 4.1.16.pdf (15.54 MB)

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Identification of novel therapeutic targets for reentrant arrhythmias

Nassal, Michelle MJ
http://rave.ohiolink.edu/etdc/view?acc_num=case1459508947

Abstract Details

2016, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Cardiac reentrant arrhythmias are dependent upon two main components, slowed myocardial conduction and heterogeneous myocardial repolarization. Myocardial conduction is established by cellular excitability, primarily sodium current, and cell-to-cell communication, determined by gap junctions (GJ). Importantly, ischemia-induced cardiac GJ remodeling, mainly Cx43 the principal ventricular GJ protein, plays a causal role in determining myocardial conduction slowing and arrhythmogenesis. Ischemia induces Cx43 phosphorylation remodeling resulting in Cx43 lateralization away from the intercalated disc (ID), reduced conductance or increased degradation. Recently we found mild hypothermia (MH, 32°C) attenuates ischemia-induced conduction slowing and reduces arrhythmia susceptibility; however, the mechanism was unknown. MH may provide cardiac benefit by mitigating ischemia-induced Cx43 remodeling. The mechanisms by which MH may affect Cx43 remodeling to maintain GJ conductance and ultimately reduce arrhythmogenesis are unknown. Herein lies the rationale for the first part of this work. Specifically, determine the mechanistic role of Cx43 in determining MH preservation of conduction and potential ischemia-induced Cx43 phosphorylation remodeling. During ischemia, one of the most consistently altered Cx43 phosphorylation sites is serine 368 however the effects of S368 phosphorylation on myocardial conduction are conflicting. This work also investigated the role of S368 phosphorylation on myocardial conduction during metabolic stress. Finally, myocardial heterogeneous repolarization is a second prerequisite for reentrant arrhythmias. Action potential duration alternans (APD-ALT), where one beat has a long APD followed by a short APD, introduces repolarization heterogeneities in the ventricle and is a well-known mechanism of arrhythmias. APD-ALT is determined by calcium alternans (Ca-ALT) through Ca2+ sensitive repolarization currents. Importantly, APD-ALT is associated with the development of atrial fibrillation (AF). However the role of atrial APD-ALT and the mechanisms underlying the development of atrial Ca-ALT in AF remains unknown. Ventricular Ca-ALT is partially determined by sarcoplasmic reticular (SR) Ca2+ reuptake, which is largely determined by SERCA2a expression and function. If SERCA2a also governs atrial Ca-ALT, it may be a potential mechanism and therapeutic target for AF. This work investigated mechanisms of ventricular ischemia-induced arrhythmias with a focus on Cx43 remodeling and atrial arrhythmias focusing on SERCA2a in order to identify novel therapeutic targets for reentrant arrhythmias.
Lance Wilson (Advisor)
Joseph Piktel (Advisor)
Isabelle Deschenes (Advisor)
Corey Smith (Committee Chair)
George Dubyak (Committee Member)
Michiko Wantanabe (Committee Member)
154 p.
Physiology
Connexin43, ischemia, arrhythmias, SERCA2a, therapeutic hypothermia

Recommended Citations

Citations

  • Nassal, M. M. (2016). Identification of novel therapeutic targets for reentrant arrhythmias [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1459508947

    APA Style (7th edition)

  • Nassal, Michelle. Identification of novel therapeutic targets for reentrant arrhythmias . 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1459508947.

    MLA Style (8th edition)

  • Nassal, Michelle. "Identification of novel therapeutic targets for reentrant arrhythmias ." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1459508947

    Chicago Manual of Style (17th edition)

case1459508947
126
© 2016, some rights reserved.Creative Commons License Identification of novel therapeutic targets for reentrant arrhythmias by Michelle MJ Nassal is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.