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250，000例死亡。这些死亡中的绝大多数被认为是由于室性快速性心律失常。几个细胞和分子事件的基础上猝死已得到很好的表征。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。自主神经系统是一个强大的调节器的胚胎发生。交感神经活动增强具有众所周知的预防性后果，包括心室异位增加、VF阈值降低和心电波传播的固有动态不稳定性增加。然而，这种调节的电生理机制还不清楚。SCD的神经重塑假说指出，除了心室的电和结构重塑之外，还存在心脏神经元的功能和结构重塑，这直接导致对SCD的易感性增加。在本提案中，将在心室功能障碍患者中检验这一假设。具体来说，我们将确定是否电生理异质性（正常和患病心肌之间），以更大程度上增强反射介导的交感神经刺激相比，直接模拟人类的交感神经受体。我们建议研究接受介入电生理手术的患者。从长远来看，了解SCD的基本方面可能会导致开发新的预防治疗方法。

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.