Electrophysiological Effects of Neural Remodeling of the Ventricles

描述（由申请人提供）：心源性猝死（SCD）是美国的主要死亡原因，每年约有25万人死亡。绝大多数死亡被认为是由于室性心动过速。导致突发性心律失常死亡的几个细胞和分子事件已被很好地描述。然而，心脏电生理学领域的一个主要挑战是了解细胞和分子水平上的事件如何转化为整个器官的心律失常行为。自主神经系统是心律失常发生的有力调节者。交感神经活动增强具有众所周知的心律失常后果，包括心室异位增加、VF阈值降低和心波传播固有的动态不稳定性增加。然而，这种调节背后的电生理机制还没有得到很好的理解。SCD的神经重构假说指出，除了心室的电和结构重构外，心脏神经元的功能和结构重构直接导致SCD易感性增加。本研究将在脑室功能障碍患者中验证这一假设。具体来说，我们将确定与直接模拟人类交感受体相比，反射介导的交感刺激是否在更大程度上增强了电生理异质性（正常和病变心肌之间）。我们建议对接受介入性电生理手术的患者进行研究。从长远来看，了解SCD的基本方面可能会导致开发新的预防方法。

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.