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: 2872953
• 负责人: Guy Salama
• 金额: $ 12.57万
• 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/2872953
• 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）：先天性患者 并获得了长QT综合征（LQTS）的扭转风险很高 （多态性心室心动过速，VT的变体）和猝死。 一个 LQT的标志是延长的QT间隔，是VT的前奏。 许多 电生理和细胞异常与 LQT。 增强复极化（DR）已被调用为 基于QT间隔的测量和T波的心律失常机制 更改。 电极记录表明，早期降极化 （EADS）随着时间的推移与启动的超音量反应相吻合 VT。 反过来，可以通过增加动作的干预措施来诱导EADS 电位（AP）持续时间（APD）和/或增加胞质（Ca+2），; CAI 引起细胞去极化。 所有这些问题的关键是 来自不同区域细胞的APD和CAI瞬变的异质性 心脏。 其他因素对于沉淀LQT的VT可能很重要， 例如CAI负载，血清K+和自主性失衡。 这些机制是 理解不足，并且仍然是猜想的问题。 目的是：1） 开发一个光学系统以同时映射AP，DR和CAI瞬变 通过用电压敏感和CAI指示染料染色心脏； 2）到 使用Anthopluerin A（AP-A）开发药物诱导的LQT模型 和D-氨基酚，并通过映射AP，CAI和 将EAD与CAI的变化相关联。来自不同区域的光学图 心脏（例如，心内膜，心外膜和 Midwall）将确定对EAD和/或倾向最大的地点 CAI异常。 3）确定沉淀LQT诱导的因素 通过改变心肌底物，干预措施（例如血清）来心律不齐 K+，CAI负载，α和/或β-激动剂）已知会增加的发生率 临床环境中的VT将通过 冠状动脉灌注酸盐或局部通过在选定位置进行的微型注射 引起VT的心脏。 该项目解决了重要的问题 LQT患者突然死亡的高风险。 它将测试基本 假设QT延长增强了a）DR，b） eads，c）传导EADS会激发VT和D）干预措施 需要在关键站点应用来触发EAD。