Ca Handling & Arrhythmias Associated with LQT Syndrome

描述(申请人提供)：QT间期延长综合征(LQTS)是一种遗传性疾病 以QT间期延长和突发事件发生率高为特征的疾病 心源性死亡(SCD)。尽管最近我们对 LQTS的遗传和分子异常，发病机制 这种异常与SCD之间的关系尚不清楚。在……里面 LQTS、晕厥和SCD的发作是由扭转性脑缺血引起的 尖端(TDP)，其中后除极被认为起关键作用 重要的角色。细胞内钙的异常管理(即处理) 被认为是后去极化的一种重要机制， 包括通过以下方式增强的后去极化 钙/钙调蛋白依赖性蛋白激酶II(CaM激酶)。我们假设 钙处理的异质性正常存在并得到加强 通过LQTS中发生的电生理变化。因此，地区性的“火爆” 钙处理异常的斑点形成，容易形成 早期后除极(EAD)和延迟后除极(DAD)。它 进一步假设后去极化的位置和时间 它们与跨壁复极梯度的相互作用 影响TDP的启动。他的建议的具体目的是：1) 确定细胞内的区域差异(即异质性) 跨脑室的钙处理和动作电位时程 正常和LQTS模型(即LOT1，LQT2， LQT3)。2)：确定钙处理的细胞/分子机制 通过测量钙的水平正常出现的不均一性 在对照条件下的调节蛋白表达。3)确定 异质性增强的细胞/分子机制(即异常) 获得性心肌梗死模型的细胞内钙处理和后除极 LQTS，其中从肌浆网和CaM Klnase释放的钙是 重要的机制。4)确定两者之间的机械关系 年EADS、复极梯度和TDP事件的区域出现 所有三种获得性LQTS模型，重点介绍了 通过在周期长度中暂停来启动。开发了新的光学测绘技术 并通过PI验证了跨膜电位和细胞内电位的测量 将同时从完整的心脏制剂中的256个部位提取钙 使用。这个实验系统的一个主要优点是多个细胞 可在心律失常启动期间测量参数，提供独特的 将细胞和分子异常与心律失常连接起来的能力 是一种后果。这项研究的长期目标是确定 细胞内钙调节异常与细胞内钙离子异常的机制关系 与LQTS(即TDP)相关的心律失常。

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).