Arhythmogenic Mechanisms

心源性猝死（SCD）可发生在年轻的，否则健康的个体患有 遗传性基因突变儿茶酚胺能多形性室性心动过速（CPVT）是一种 以肾上腺素能介导的多轮双向 （biVT）和多形性（PVT）室性心动过速，导致晕厥和/或SCD， 无结构性心脏病; 40岁时死亡率约为30%。多达40点 人心肌肌浆网（SR）钙释放通道（ryanodine）突变 2型受体[RyR 2]），与SR Ca 2+通道功能缺陷有关，已在 受CPVT和致心律失常性右心室心肌病2型（ARVC 2）影响的个体。 我们的中心目标是确定CPVT的电生理机制。我们采取 这是一种独特的敲入小鼠模型（RyR 2 +/RyR 2 R4496 C）的优势，该模型携带鼠 相当于RyR 2中导致CPVT的人类错义突变（R4497 C）。最近的数据 表明给予咖啡因和肾上腺素能激动剂使RyR 2 +/RyR 2 R4496 c 小鼠心脏biVT，PVT和VF，这表明Ca 2+释放增加的参与 通过有缺陷的RyR 2通道我们的假设是，该模型中的心律失常， 在CPVT患者中，延迟后除极（DAD）是由发生在 特殊心室传导系统的左、右支浦肯野纤维。我们 将使用从分子到器官水平的综合方法来验证这一假设。我们 具体目标是：1。探讨SR-Ca ~（2+）渗漏的发生机制。 RyR 2 +/RyR 2 R4496 C小鼠心脏的心脏浦肯野纤维和心室肌细胞。2.到 确定从RyR 2 +/RyR 2 R4496 C心脏获得的心室肌细胞和浦肯野细胞是否 在细胞外Ca 2+增加的情况下或在 用咖啡因和/或异丙肾上腺素灌注。3.为了确定电生理 RyR 2 +/RyR 2 R4496 C小鼠心脏中biVT和PVT的机制。结果来自 建议的研究应该提供对CPVT表型的基本理解， 深入了解心力衰竭等疾病的机制， 由于异常SR Ca 2 * 释放而增加对心律失常的脆弱性。

Sudden cardiac death (SCD) can occur in young, otherwise healthy individuals suffering from inherited gene mutations. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated rounds of bidirectional (biVT) and polymorphic (PVT)ventricular tachycardias, leading to syncope and/or SCD in the absence of structural heart disease; mortality is ~30% by the age of 40 years. As many as 40 point mutations in the human cardiac sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor type 2 [RyR2]), linked to defective SR Ca2+ channel function, have been reported in individuals affected by CPVT and arrhythmogenic right ventricular cardiomyopathy type 2(ARVC2). Our central objective is to determine the electrophysiological mechanisms of CPVT. We take advantage of a unique knock-in mouse model (RyR2+/RyR2R4496C), which carries the murine equivalent of a human missense mutation (R4497C) in RyR2 that results in CPVT. Recent data show that administration of caffeine and of adrenergic agonists predisposes the RyR2+/RyR2R4496c mouse heart to biVT, PVT and VF, which suggests the involvement of increased Ca2+ release through the defective RyR2 channels. It is our hypothesis that arrhythmias in this 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. We will test this hypothesis using an integrative approach from the molecule to the organ level. Our Specific Aims are:1. To investigate the mechanisms underlying the occurrence of SR-Ca2+ leak in cardiac Purkinje fibers and ventricular myocytes of the RyR2+/RyR2R4496C mouse heart. 2. To determine whether ventricular myocytes and Purkinje cells obtained from RyR2+/RyR2R4496C heart undergo DADs and triggered activity in the presence of increased extracellular Ca2+ or during superfusion with caffeine and/or isoproterenol. 3. To determine the electrophysiological mechanisms of biVT and PVT in the RyR2+/RyR2R4496C mouse heart. The results derived from the proposed studies should provide fundamental understanding to the CPVT phenotype and give insight into mechanisms in conditions such as heart failure and others in which there is an increased vulnerability to arrhythmias due to abnormal SR Ca2* release.