The general aim of this application is to investigate mechanisms of reentrant arrhythmogenesis based on rate-dependent properties of cardiac depolarization and repolarization. The focus of this proposal is to test the hypothesis that rate dependent adaptation of cardiac wavelength is critically important to the mechanism of VT initiation. The applicant proposes to utilize an approach integrating high resolution cardiac optical mapping, a guinea pig model of reentrant VT, and computer simulations incorporating the most recent analytical formulations of single cell ionic currents and cardiac fiber structure, to investigate dynamic adaptation of cardiac wavelength as a mechanism of initiation of VT.
The specific aims i nclude: 1) to develop a generalized approach for measuring cardiac wavelength that accounts for electrical heterogeneities within a reentrant circuit; 2) to demonstrate how tissue anisotropy, the kinetics of membrane repolarization and conduction around pivot points influence wavelength; 3) to determine the ionic processes that determine cardiac wavelength; 4) to demonstrate that dynamic adaptation of wavelength is a requirement for the initiation of VT; and 5) to develop a new paradigm for antiarrhythmic or proarrhythmic actions based on a drugs influence on wavelength.
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