FACTORS THAT INITIATE ARRHYTHMIAS IN LONG QT SYNDROME

长 QT 综合征中引发心律失常的因素

• 批准号: 6351501
• 负责人: Guy Salama
• 金额: $ 13.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6351501
• 关键词: action potentials; alpha adrenergic agent; arrhythmia; beta adrenergic agent; calcium channel; calcium flux; calcium indicator; cytoplasm; disease /disorder model; electrophysiology; heart Purkinje's fiber; heart cell; heart innervation; heart ventricle; laboratory rabbit; long QT syndrome; microinjections; model design /development; potassium channel; sodium channel

DESCRIPTION (Adapted from applicant's abstract): Patients with congenital and acquired Long QT Syndrome (LQTS) have a high risk for Torsade de Pointe (a variant of polymorphic ventricular tachycardia, VT) and sudden death. A hallmark of LQTS is a prolonged QT interval, a prelude to VT. A number of electrophysiological and cellular abnormalities have been associated with LQTS. Enhanced Dispersion of Repolarization (DR) has been invoked as the arrhythmogenic mechanism based on measurements of QT intervals and T wave changes. Electrode recordings suggest that early after-depolarizations (EADs) are coincident in time with extra-systolic responses that initiate VT. In turn, EADS can be induced by interventions that increase action potential (AP) durations (APDS) and/or increase cytosolic (Ca+2),; Cai causing cell depolarization. Key to all these issues are the heterogeneities of APDs and Cai transients from cells in different regions of the heart. Other factors may be important to precipitate VT in LQTS, such as Cai load, serum K+, and autonomic imbalance. These mechanisms are poorly understood and remain a matter of conjecture. The aims are: 1) To develop an optical system to simultaneously map APs, DR, and Cai transients by staining hearts with voltage-sensitive and Cai indicator dyes; 2) To develop models of drug-induced LQTS in rabbits using Anthopluerin A (AP-A) and d-Sotasol and characterize the models by mapping APs, Cai and correlating EADS to changes in Cai. Optical maps from different regions of the heart (e.g., the Purkinje fibers on the endocardium, the epicardium and midwall) will identify the sites with the greatest propensity to EADs and/or Cai anomalies. 3) To determine the factors that precipitate LQT-induced arrhythmias by altering the myocardial substrate, interventions (e.g., serum K+, Cai load, alpha and/or beta-agonists) known to increase the incidence of VT in the clinical setting will be applied uniformly in the heart through the coronary perfusate or locally by micro-injections at selected sites on the heart to provoke VTs. The project addresses important questions given the high risk of sudden death in patients with LQTS. It will test basic hypothesis that QT prolongation enhances a) the DR, b) the incidence of EADs, c) that the conduction of EADS provokes VT and d) that intervention(s) applied at key sites are needed to trigger EADs.

描述（改编自申请人的摘要）：患有先天性疾病的患者 和获得性长 QT 综合征 (LQTS) 患尖端扭转型室性心动过速的风险很高 （多形性室性心动过速的一种变体，VT）和猝死。 一个 LQTS 的标志是 QT 间期延长，这是 VT 的前奏。 一些 电生理和细胞异常与 LQTS。 增强复极色散 (DR) 已被称为 基于 QT 间期和 T 波测量的心律失常机制 变化。 电极记录表明早期后除极 (EAD) 与启动的期外收缩反应在时间上一致 VT。 反过来，可以通过增加行动的干预措施来诱发 EADS 潜在（AP）持续时间（APDS）和/或增加胞质（Ca+2）；蔡 引起细胞去极化。 所有这些问题的关键是 不同区域细胞的 APD 和 Cai 瞬变的异质性 的心。 其他因素可能对 LQTS 中 VT 的发生也很重要， 如蔡负荷、血清K+、植物神经失衡等。 这些机制是 知之甚少，仍然是一个猜想。 目标是： 1) 开发光学系统以同时映射 AP、DR 和 Cai 瞬变 用电压敏感染料和 Cai 指示剂染料对心脏进行染色； 2) 至 使用 Anthopluerin A (AP-A) 开发药物诱导的兔 LQTS 模型 和 d-Sotasol 并通过映射 AP、Cai 和 来表征模型 将 EADS 与 Cai 的变化相关联。不同地区的光学地图 心脏（例如心内膜、心外膜和心外膜上的浦肯野纤维） midwall）将识别最有可能发生 EAD 的地点和/或 蔡异常。 3) 确定促成LQT诱导的因素 通过改变心肌底物、干预措施（例如血清 K+、Cai 负荷、α 和/或 β 激动剂）已知会增加以下疾病的发生率 临床环境中的 VT 将通过以下方式均匀应用于心脏： 冠状动脉灌注液或通过在选定部位进行局部微注射 激发 VT 的心脏。 该项目解决了给出的重要问题 LQTS 患者猝死的风险很高。 它将测试基本 假设 QT 延长会增强 a) DR，b) 的发生率 EAD，c) EADS 的传导会引发 VT，并且 d) 干预 需要在关键地点应用才能触发 EAD。