All ETDs from UAB

Advisory Committee Chair

Steven M Pogwizd

Advisory Committee Members

Vladimir G Fast

Rodolphe P Katra

Jack M Rogers

Rosa Serra

Document Type

Thesis

Date of Award

2017

Degree Name by School

Master of Biomedical Engineering (MBE) School of Engineering

Abstract

Sudden cardiac death claims more than 300,000 lives per year in the US alone. Because it frequently goes unwitnessed, the underlying ventricular fibrillation (VF) may persist for well over 5 minutes (long duration VF, or LDVF) before attempts at defibrillation, and successful defibrillation is often followed by post-shock arrhythmias and refibrillation. The development of novel and effective therapies for LDVF, which represents a significant unmet medical need, remains largely hindered by a relatively poor understanding of the arrhythmogenic onset and maintenance of LDVF, as well as its deleterious sequelae in the context of the whole heart. Prolonged VF has been associated with development of a transmural activation gradient, with marked slowing of epicardial activation, the basis of which remains undetermined. Dysregulation of intracellular calcium per se may contribute to persistence of LDVF and increased post-shock arrhythmias -- whether through enhanced triggered activity or altered conduction – as well as altered contractile dysfunction post defibrillation. In these studies, we explored changes in epicardial activation and intracellular calcium, and their relationship to each other during LDVF. We hypothesized that LDVF is associated with slow epicardial activation that is related to altered electrical and intracellular calcium dynamics. A stable model of LDVF was developed in the rabbit heart, since most studies of LDVF have been limited to large animal (canine and porcine) models. Epicardial action potentials and intracellular calcium transients were optically mapped simultaneously, and complementary intramural plunge electrodes were incorporated for recording transmural activation. At 4 min of VF, a transmural activation gradient developed with significant increases in cycle length (CL), diastolic interval (DI), calcium transient (CaT) duration (CaD), and CaT recovery time. The results of these studies suggest that impaired calcium handling does not play a major role in the initial slowing of epicardial activation during LDVF, but may contribute to prolonged VF maintenance and post-shock arrhythmias. These studies provide important insights into the biochemical mechanisms underlying LDVF and the foundation for developing and testing of novel therapeutic approaches to the treatment of LDVF.

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