Electrophysiological Effects of Neural Remodeling of the Ventricles

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DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) is the leading cause of death in the United States and accounts for almost 250,000 deaths/year. The vast majority of these deaths are thought to be due to ventricular tachyarrhythmias. Several cellular and molecular events that underlie sudden arrhythmic death have been well characterized. However, a major challenge in the field of cardiac electrophysiology is to understand how events at a cellular and molecular level translate into behavior of arrhythmias in the whole organ. The autonomic nervous system is a powerful regulator of arrhythmogenesis. Heightened sympathetic activity has well-known proarrhythmic consequences, including increased ventricular ectopy, decreased VF threshold, and increased inherent dynamic instability of cardiac wave propagation. However, the electrophysiological mechanisms that underlie such regulation are not well understood. The Neural Remodeling Hypothesis for SCD, states that in addition to electrical and structural remodeling of the ventricles, there is functional and structural remodeling of the cardiac neurons which directly leads to an increased susceptibility to SCD. This hypothesis will be tested in patients with ventricular dysfunction in this proposal. Specifically, we will determine whether electrophysiological heterogeneity (between normal and diseased myocardium) is enhanced to a greater extent by reflex-mediated sympathetic stimulation compared to direct simulation of sympathetic receptors in humans. We propose to study patients undergoing interventional electrophysiology procedures. In the long term, understanding the fundamental aspects of SCD is likely to result in the development of novel therapies for its prevention.