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Advisory Committee Chair

Steven M Pogwizd

Advisory Committee Members

Xun Ai

Raymond E Ideker

Andrew E Pollard

Document Type

Thesis

Date of Award

2013

Degree Name by School

Master of Science in Biomedical Engineering (MSBME) School of Engineering

Abstract

Ventricular fibrillation is a lethal cardiac arrhythmia which alters electrophysiological properties of the myocardium while concurrently inducing global ischemia and is associated with high mortality rates. Studies on the organization of long-duration ventricular fibrillation (LDVF) have shown that an endocardial to epicardial (i.e. transmural) activation rate gradient exists during ventricular fibrillation in canine and human myocardium; however, the underlying mechanism is unknown. This study tested the hypothesis that the activation rate gradient reflects heterogeneous changes in tissue electrical resistivity resulting in differential transmural electrical uncoupling of the ventricular myocardium. LDVF (>5min) was electrically induced in anesthetized, open-chest rabbits using an AC stimulus. Intramural electrograms for activation mapping were recorded using bipolar plunge needle electrodes throughout the left and right ventricles. Intramural resistivity was measured in the sub-endocardial (Endo), midmyocardial (Mid), and sub-epicardial (Epi) layers of the basal anterior left ventricular wall using a novel, modified four-electrode resistivity technique. Activation mapping and resistivity were assessed concurrently in each study. An activation rate gradient developed during LDVF in the left ventricle where the Epi developed a significantly slower activation rate compared to more endocardial levels of myocardium soon after fibrillation onset. This gradient occurred with spatiotemporal heterogeneity. LDVF induced immediate steep increases in Epi resistivity with Mid and then Endo increases developing subsequently. Steep resistivity increase consistent with electrical uncoupling proceeded transmurally in the left ventricle with earliest rise developing in the Epi. The onset of Epi steep resistivity rise was closely associated with the development of the Endo-Epi activation rate gradient. Steep resistivity increases developed much more quickly during LDVF than during global myocardial ischemia. Our novel resistivity measurement system enabled us to observe a mechanism of ventricular fibrillation which had not previously been described. Steep resistivity increases indicating differential transmural electrical uncoupling occur with similar time course as the LDVF activation rate gradient and is most marked in the epicardium during early stages of ventricular fibrillation. Gap junction proteins such as Connexin43 may play a role. These findings suggest pharmacologic modulation of electrical coupling as a potential therapeutic approach to improve treatment for LDVF.

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