The objective of this research is to bring a new level of understanding of the electrical events in the process of defibrillation by employing realistic 3D simulations of ventricular defibrillation in close conjunction with experimental observations. Specifically, we focus on unraveling the mechanisms that underlie the initiation and the subsequent propagation of post-shock activations within the complex 3D structure of the ventricles. We postulate that the propagation pattern of the early global post-shock activations is determined by differences in shock-induced virtual electrode polarization between a) ventricular surfaces and tissue depth, and b) left and right ventricles, while subsequent transition to ventricular fibrillation results from scroll-wave filament instability specific to the left ventricle. We further propose that the mechanisms of initiation of the early global post-shock activations are shock-waveform specific: make/break excitation mechanisms underlie activations following monophasic shocks, while virtual electrode-induced graded response mechanisms give rise to the global activations that follow biphasic shocks, with afterdepolarization and/or small-scale tissue heterogeneities as alternative mechanisms. To test these hypotheses, we will conduct computer simulations of electrical induction of arrhythmia and defibrillation. We propose to integrate into our basic bidomain model of the rabbit ventricles, among other features, 1) realistic rabbit ventricular membrane kinetics applicable to defibrillation, 2) regional electrophysiological heterogeneities in the ventricles, and 3) the ability to simulate """"""""experimental optical maps"""""""" through depth averaging. This new powerful simulation tool will then be used, in conjunction with surface optical recordings, to provide mechanistic insight into 3D post-shock behavior that is currently outside the reach of experimental measurement alone. The proposed research is expected to guide experimental design and interpretation of experimental findings, and ultimately, to lead to rational rather than trial-and-error advancements in defibrillation procedure.
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