Ca Handling & Arrhythmias Associated with LQT Syndrome

描述（由申请人提供）：长QT综合征（LQTS）是一种遗传性 以QT间期延长和突发性心律失常发生率高为特征的疾病 心源性死亡（SCD）。尽管最近我们在理解上取得了进展， LQTS潜在的遗传和分子异常， 这些异常与SCD之间的关系尚不清楚。在 LQTS患者，晕厥发作和SCD是由扭转型室性心动过速引起的。 点（TdP），其中后去极化被认为是至关重要的 重要的作用细胞内钙的异常管理（即处理） 已被认为是后去极化的重要机制， 包括后去极化， 钙/钙调蛋白依赖性蛋白激酶II（CaM激酶）。我们假设 钙处理的不均匀性正常存在， 由LQTS中发生的电生理变化引起。因此，区域“热 出现“钙处理异常点”， 早期后除极（埃兹）和延迟后除极（DAD）。它 进一步假设后去极化的位置和时间 并且它们与跨壁复极梯度的相互作用 影响TdP的启动。他的建议的具体目标是：1） 确定细胞内的区域差异（即异质性） 心室钙处理和动作电位时程 正常发生的透壁和LQTS模型（即LOT 1，LQT 2， LQT 3）。2）：确定钙处理的细胞/分子机制 通常通过测量钙的水平来测量不均匀性 在对照条件下的调节蛋白表达。3)确定 增强异质性的细胞/分子机制（即异常） 获得性心肌缺血模型中细胞内钙处理和后去极化 LQTS，其中肌浆网和CaM激酶的钙释放是 重要机制。4)确定机械之间的关系， 埃兹的局部发生率、复极梯度和TdP发作， 获得性LQTS的所有三种模型，重点是 通过周期长度的暂停来启动。开发了新的光学测绘技术 并经PI验证，可测量跨膜电位和细胞内 将同时从完整心脏标本的256个部位采集钙， 采用该实验系统的一个主要优点是， 可以在心律失常启动期间测量参数， 能够将细胞和分子异常与心律失常联系起来， 是一个后果。本研究的长期目标是确定 细胞内钙处理异常与 与LQTS相关的心律失常（即TdP）。

DESCRIPTION (provided by applicant): Long QT syndrome (LQTS) is a genetic disease characterized by prolonged QT interval and a high incidence of sudden cardiac death (SCD). Despite recent advances in our understanding of the genetic and molecular abnormalities underlying LQTS, the mechanistic relationship between such abnormalities and SCD is not well understood. In patients with LQTS, episodes of syncope and SCD are caused by torsade de pointes (TdP), where afterdepolarizations are believed to play a critically important role. Abnormal management (i.e. handling) of intracellular calcium has been implicated as an important mechanism of afterdepolarizations, including afterdepolarizations that are enhanced by Calcium/calmodulin-dependent protein kinase II (CaM kinase). We hypothesize that heterogeneities of calcium handling are present normally and are enhanced by electrophysiological changes that occur in LQTS. As a result, regional "hot spots" of abnormal calcium handling develop that are prone to the formation of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). It is further hypothesized that the location and timing of afterdepolarizations and their interaction with transmural repolarization gradients can critically influence the initiation of TdP. The specific aims of his proposal are to: 1) Determine the regional differences (i.e. heterogeneities) of intracellular calcium handling and action potential duration across the ventricular transmural wall that occur normally and in models of LQTS (i.e. LOT1, LQT2, LQT3). 2): Determine the cellular/molecular mechanisms of calcium handling heterogeneities that occur normally by measuring the level of calcium regulatory protein expression under control conditions. 3) Determine the cellular/molecular mechanisms of enhanced heterogeneities of (i.e. abnormal) intracellular calcium handling and afterdepolarization in models of acquired LQTS, where calcium release from the sarcoplasmic reticulum and CaM klnase are important mechanisms. 4) Determine the mechanistic relationship between the regional occurrence of EADs, repolarization gradients, and episodes of TdP in all three models of acquired LQTS, with an emphasis on the mechanisms of initiation by pauses in cycle length. New optical mapping techniques developed and validated by the PI to measure transmembrane potential and intracellular calcium simultaneously from 256 sites across intact heart preparations will be used. A major advantage of this experimental system is that multiple cellular parameters can be measured during arrhythmia initiation, providing the unique ability to bridge cellular and molecular abnormalities with arrhythmias that are a consequence. The long term objectives of this study are to determine the mechanistic relationship between abnormal intracellular calcium handling and arrhythmias associated with LQTS (i.e. TdP).