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Advisory Committee Chair

Vladimir G Fast

Advisory Committee Members

Steven M Pogwizd

Jack Rogers

Document Type

Thesis

Date of Award

2011

Degree Name by School

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

Abstract

Background: Defibrillation shocks are commonly used to interrupt life-threatening cardiac arrhythmias, but these strong electrical shocks may cause post-shock arrhythmias, the ionic mechanism of which is not well known. Strong shocks cause electroporation and diastolic Cai2+ increase, which may possibly lead to focal arrhythmias via spontaneous Cai2+ rise (SCR), activation of inward Na+-Ca2+ exchange current (INCX), and rise in membrane potential (Vm). The objective of this study was to examine the role of intracellular calcium and the Cai2+-dependent ionic mechanism in post-shock arrhythmias. Methods: Experiments were performed in patterned cultures of neonatal rat myocytes. Fluorescent dyes and two 16x16 photodiode arrays were utilized to perform simultaneous optical mapping of Vm and Cai2+ to assess the occurrence of SCRs. To elucidate the ionic mechanism of post-shock arrhythmias, drugs were applied including a Cai2+ chelator BAPTA, an INCX inhibitor KB-R7943, and an inhibitor of the inward rectifier current (IK1) BaCl2. Results: Optical mapping at the arrhythmia source demonstrated that Vm upstrokes always preceded Cai2+ transients, and the Vm-Cai2+ delay during arrhythmic beats did not differ from the delay during paced beats. Analysis of the diastolic Cai2+ changes revealed a slow gradual rise of diastolic Cai2+ consistent with membrane electroporation, but no significant Cai2+ rises preceding Vm upstrokes were observed. Application of BAPTA-AM decreased the duration of post-shock arrhythmias whereas application of KB-R7943 increased the arrhythmia duration. These findings indicate that, despite the absence of SCRs, changes in Cai2+ did affect post-shock arrhythmias. This effect could potentially be mediated by Cai2+ inhibition of the outward component of the IK1 current and destabilization of resting Vm. This hypothesis was supported by results of BaCl2 application, which increased the arrhythmia duration. Conclusions. Post-shock arrhythmias are not caused by spontaneous Cai2+ rises and the inward NCX current. However, these arrhythmias are dependent on Cai2+ changes, probably via Cai2+-dependent modulation of the outward IK1 current.

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