Arrhythmia Mechanisms in Two Inherited Cardiac Diseases

描述（由申请人提供）： 心律失常引起的心脏性猝死（SCD）是美国的主要死因。近年来，在遗传性心律失常疾病中形成肌膜离子通道的蛋白质突变的鉴定极大地促进了对危及生命的心律失常的底物的理解。但许多问题仍然没有答案。这项新项目的资助申请概述了对两种不同遗传性疾病致心律失常性右室心肌病（ARVC）和儿茶酚胺能多态性室性心动过速（CPVT）的致心律失常基础的多学科研究。总体目标是确定结构或Ca 2+调节蛋白的改变如何转化为最终导致危及生命的心律失常和SCD的电异常。实验和数值方法将被用来比较和对比基本的细胞和生物物理学的变化，潜在的致癌机制，在患者患有这些毁灭性的疾病。我们提出的策略源于这样一种想法，即理解遗传性心律失常机制中涉及的因素需要一种综合方法。因此，我们已经组装了一组三个实验和理论研究项目，解决ARVC和CPVT心律失常的机制的基本问题。在项目1和3下提出的合作工作旨在证明破坏桥粒完整性的ARVC相关突变导致差距连接斑块的破坏;并且差距连接斑块的破坏损害心脏动作电位的传播，从而为心律紊乱的产生创造底物。为了解决CPVT的问题，项目2和3将利用一种独特的敲入小鼠模型，该模型重现了CPVT的表型，其特征在于肾上腺素能介导的多轮双向（biVT）和多态性（PVT）室性心动过速，导致SCD。这两个项目中的互补工作将检验以下假设：小鼠模型中的biVT和PVT以及CPVT患者中的推断，是由专门心室传导系统的右支和左支浦肯野纤维处发生的延迟后去极化（DAD）触发的。在ARVC和CPVT中，项目3提出的数值和生物实验应该在高阶和低阶积分之间提供坚实的联系。完成所提出的工作应该提供新的见解，导致复杂的心律和SCD的基本机制。

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) caused by arrhythmias is a major cause of death in the United States. In recent years the identification of mutations in proteins that form sarcolemmal ion channels in inherited arrhythmic diseases has greatly contributed to the understanding of the substrate for life-threatening arrhythmias. But many questions remain unanswered. This application for funding of a new program project outlines multidisciplinary research on the arrhythmogenic bases of two different inherited diseases, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The general objective is to determine how alterations of either structural or Ca2+ regulatory proteins translate into electrical abnormalities that ultimately result in life-threatening arrhythmias and SCD. Experimental and numerical approaches will be used to compare and contrast basic cellular and biophysical alterations underlying the possible arrhythmogenic mechanisms in patients suffering from these devastating diseases. Our proposed strategy derives from the idea that understanding the factors involved in the mechanisms of inherited arrhythmias requires an integrative approach. We have therefore assembled a group of three experimental and theoretical research projects that address fundamental questions on the mechanisms of arrhythmias in ARVC and CPVT. Collaborative work proposed under Projects 1 and 3 seeks to demonstrate that ARVC-relevant mutations that disrupt the integrity of the desmosome carry as a consequence the disruption of the gap junction plaque; and that the disruption of the gap junction plaque impairs the propagation of the cardiac action potential, thus creating a substrate for the generation of cardiac rhythm disturbances. To address the problem of CPVT, Projects 2 and 3 will utilize a unique knock in mouse model that recapitulates the phenotype of CPVT, which is characterized by adrenergically mediated rounds of bidirectional (biVT) and polymorphic (PVT) ventricular tachycardias leading to SCD. Mutually complementary work in both projects will test the hypothesis that biVT and PVT in the mouse model, and by inference in CPVT patients, are triggered by delayed afterdepolarizations (DADs) occurring at Purkinje fibers on the right and left branches of the specialized ventricular conducting system. In both ARVC and CPVT, numerical and biological experiments proposed by Project 3 should provide a solid link between the higher and the lower orders of integration. Accomplishing the work being proposed should provide new insight into fundamental mechanisms leading to complex cardiac rhythms and SCD.