Arrhythmia mechanisms in Long QT Syndrome

标题：长QT综合征的心律失常机制 摘要 长QT综合征（LQTS）是一种以QT间期为特征的遗传性或获得性疾病 延长并与危及生命的心律失常和突发性心律失常的高发生率有关 年轻人的心源性死亡在先天性LQTS的已知变体中，大多数是 由心脏复极钾电流相关基因突变引起。 实验研究表明，心脏传导系统在启动中起着积极的作用 并维持LQTS观察到的心律失常。然而，缺乏直接证据， 心律失常的机制还不清楚。在这个提议中， 使用表达hERG突变的成年兔心肌细胞和先进的多尺度 计算机模拟将被用来研究心脏浦肯野系统在 遗传性和药物诱导的LQTS，特别是LQT 2的促发作用。建议书提交人 假设存在时浦肯野细胞复极储备显著减少 LQTS条件增加了他们早期后去极化和触发活动的倾向。 此外，His-PS内的区域对hERG突变表现出强的差异敏感性 导致心室中的不均匀激活模式，从而引发心律失常。两 HERG通道（LQT 2）中的新型显性负突变P632 L和S428 P将被发现， 在转染的心肌细胞中进行实验研究。实验表征将是 在多个整合水平-分子， 单细胞和三维-以获得进一步的机制见解。的有害影响 浦肯野系统内的区域电不均匀性及其对 LQTS突变以及药物诱导的长QT效应将使用三维 计算机建模和并行实验。将进行系统研究， 研究浦肯野系统网络在启动EAD诱导的异位活动和 心动过缓依赖性触发的多形性室性心动过速发作。拟议的研究具有 有可能提供关于疾病的宝贵见解，并可能揭示疾病的机制。 在遗传和获得性疾病中的肿瘤发生。 关键词：长QT综合征，浦肯野系统，心律失常，计算机建模。

TITLE: Arrhythmia mechanisms in Long QT Syndrome ABSTRACT The long QT syndrome (LQTS) is an inherited or acquired disease characterized by QT interval prolongation and is associated with life threatening arrhythmias and high incidences of sudden cardiac deaths in young adults. Among the known variants of congenital LQTS, majority are caused by mutations in genes associated with cardiac repolarizing potassium currents. Experimental studies have suggested an active role of the cardiac conduction system in initiation and maintenance of arrhythmia observed in LQTS. However direct evidence is lacking and the arrhythmia mechanisms are not well understood. In this proposal, a combination of experiments using adult rabbit cardiomyocytes expressing hERG mutations and advanced multiscale computer modeling will be utilized to study the role of cardiac Purkinje system in arrhythmogenesis in inherited as well as drug-induced LQTS, specifically LQT2. The proposers hypothesize that significant reduction of the repolarization reserve in Purkinje cells in presence of LQTS conditions increases their propensity to early afterdepolarizations and triggered activity. Furthermore, the regions within the His-PS exhibit strong differential sensitivity to hERG mutations resulting into heterogeneous activation patterns in the ventricles, thus initiating arrhythmia. Two novel dominant negative mutations, P632L and S428P, in HERG channels (LQT2) will be experimentally studied in transfected cardiomyocytes. The experimental characterizations will be incorporated into human biophysical computer models at multiple levels of integration– molecular, single cell and three dimensional– to obtain further mechanistic insights. The detrimental effects of regional electrical heterogeneity within the Purkinje system and its differential sensitivity to LQTS mutations as well as drug-induced long QT effects will be studied using three dimensional computer modeling and concurrent experiments. Systematic study will be conducted to investigate the role of Purkinje system network in initiating EAD-induced ectopic activity and in bradycardia-dependent triggered episodes of polymorphic VT. The proposed research has the potential to provide invaluable insights about the disease and may reveal mechanisms of arrhythmogenesis in inherited as well as acquired forms of the disease. Keywords: Long QT syndrome, Purkinje system, arrhythmia, and computer modeling.