Relationship between mitochondrial membrane potential collapse and electrical failure in a globally ischemic heart

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Publication Type dissertation
School or College College of Engineering
Department Bioengineering
Author Venable, Paul W.
Title Relationship between mitochondrial membrane potential collapse and electrical failure in a globally ischemic heart
Date 2015-05
Description Sudden Cardiac Arrest (SCA) remains one of the leading causes of death in the United States. During SCA, the inability of the heart to pump blood causes progressive metabolic and functional derangements in the heart itself. In the majority of SCA cases, the defining event of death is the failure of defibrillation shocks and cardio-pulmonary resuscitation (CPR) procedures to restore circulation within the first 10 minutes. Resuscitation failure is often due to either asystole (the lack of activation in the heart) or recurrent ventricular fibrillation following defibrillation. The exact physiological mechanisms determining the occurrence of these phenomena within the clinically relevant time frame remain largely unknown. One postulated mechanism linking metabolic stress and electrical abnormalities during SCA is the loss of mitochondrial inner membrane potential (delta epsilon m) and the consequent activation of the adenosine triphosphate (ATP)-sensitive potassium channel (KATP) when cellular ATP is critically depleted. The goal of this dissertation was to investigate the relationship between delta epsilon m depolarization, electrical failure, and arrhythmias in a model of SCA. The work consisted of three projects. In the first, I characterized the spatiotemporal dynamics of electrical failure in a whole-heart model of VF-induced SCA. I demonstrated that the electrical depression develops in a heterogeneous fashion across the heart and is partially dependent on KATP activation. In the second project, I developed a method to detect delta epsilon m depolarization during global ischemia using spectral analysis of confocally recorded delta epsilon m-sensitive fluorescence. The method is based on the spatial periodicity of mitochondrial packaging in ventricular myocytes and the preferential accumulation of cationic fluorophores in well-polarized mitochondria and addresses the limitations of the traditional mean fluorescence approach during ischemia. Using this method, in the third project, I determined the temporal relationship between ischemic delta epsilon m depolarization and myocardial inexcitability. Additionally, I modulated the energy balance in ischemic hearts using rapid pacing, the inhibitor of myosin II ATPase, blebbistatin, and the inhibitor of anaerobic glycolysis, sodium iodoacetate. This study showed a strong correlation between the onset of asystole and the time of delta epsilon m loss under all tested conditions, and revealed a strong protective effect of Blebbistatin against asystole, delta epsilon m loss, and postreperfusion arrhythmias.
Type Text
Publisher University of Utah
Subject Arrhythmias; Cardiac; Confocal imaging; Electrophysiology; Mitochondria; Optical mapping
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Rights Management Copyright © Paul W. Venable 2015
Format Medium application/pdf
Format Extent 3,533,965 Bytes
Identifier etd3/id/3774
ARK ark:/87278/s6b88hff
Setname ir_etd
Date Created 2016-02-29
Date Modified 2021-05-06
ID 197325
Reference URL https://collections.lib.utah.edu/ark:/87278/s6b88hff
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