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Targeting Gap Junctions as a Mechanism and Potential Treatment of Cardiac Arrhythmias

Strom, Maria
http://rave.ohiolink.edu/etdc/view?acc_num=case1262100592

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Cardiac gap junctions play a critical role in intercellular communication, impulse conduction and propagation. Gap junction remodeling and under expression are increasingly implicated in playing a role in cardiac disease and arrhythmogenesis. In fact, the principle ventricular gap junction protein, connexin43 (Cx43), is reduced in disease states such as heart failure (HF). Recently, we used high-resolution optical mapping to demonstrate that transmural gradients of repolarization was responsible for reentrant ventricular tachycardia in the canine model of pacing induced heart failure. Localized uncoupling at the epicardial-midmyocardial (Epi-Mid) interface provides a mechanistic link between specific changes in intercellular coupling by gap junctions to the change in spatial gradients of repolarization across the ventricular wall. While it is well established that slow conduction and increased gradients of repolarization are important to the initiation of reentrant arrhythmias, the precise role of reduced intercellular communication in arrhythmogenesis remains unresolved. Furthermore, it is unclear whether localized restoration of coupling (by gene transfer) can eradicate the substrate for arrhythmias. Herein lies the rationale for this work. Cx43 is proposed to be the mechanism and potential therapeutic target of cardiac arrhythmia mechanisms. Specifically, computer modeling, optical mapping and targeted gene transfer to enhance cellular communication are used in the investigation of the following paradigms. 1) Mechanisms of Arrhythmogenesis: Establish the proof of concept that localized uncoupling across the Epi-Mid interface is a mechanism in the maintenance of electrophysiological heterogeneity. 2) Enhancement of Cellular Communication: Target gene transfer to enhance cellular communication by increasing expression of Cx43 in-vivo 3) Inhibition of Arrhythmogenic Substrate: Determine the phenotypic consequence of increased Cx43 expression by measuring functional indices of cell to cell coupling in intact normal and diseased tissue. 4) Arrhythmia Suppression: Determine if targeted gene expression to restore intercellular coupling can suppress ventricular arrhythmias in failing myocardium, while not enhancing susceptibility to arrhythmias in normal myocardium (i.e. no proarrhythmic effect). The results of these studies draw a mechanistic link between altered gap junction expression and arrhythmogenic substrates, and provide an entirely novel paradigm for arrhythmia therapy based on improvement of cell to cell communication.
David Rosenbaum, MD (Advisor)
J. Kevin Donahue, MD (Committee Member)
Kenneth Gustafson, PhD (Committee Chair)
Andrew Rollins, PhD (Committee Member)
Mark Dunlap, MD (Committee Member)
168 p.
Biomedical Research
gap junctions; mapping; arrhythmias; gene therapy

Recommended Citations

Citations

  • Strom, M. (2010). Targeting Gap Junctions as a Mechanism and Potential Treatment of Cardiac Arrhythmias [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1262100592

    APA Style (7th edition)

  • Strom, Maria. Targeting Gap Junctions as a Mechanism and Potential Treatment of Cardiac Arrhythmias. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1262100592.

    MLA Style (8th edition)

  • Strom, Maria. "Targeting Gap Junctions as a Mechanism and Potential Treatment of Cardiac Arrhythmias." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1262100592

    Chicago Manual of Style (17th edition)

case1262100592
586
© 2009, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.