CYTOKINE-INDUCED ARRHYTHMIAS IN CONGESTIVE HEART FAILURE

描述（申请人的描述逐字）：心律失常是一个主要的 缺血性和非缺血性心肌病健康问题。作为 多达50%的充血性心力衰竭（CHF）患者死亡 突然之间，每年有超过25万人死亡。药理 心律失常的治疗经常失败，并且内部除颤器昂贵 并限制生活质量。 包括TNF-α在内的炎性细胞因子在血清中增加， CHF患者的心脏。TNF-α也短暂增加， 心肌梗死，在炎症性疾病如败血症中升高， 并且随着年龄和肥大而增加。所有这些条件都是 以增加的对室性心律失常的敏感性为特征。的 细胞因子在心律失常发病机制中的潜在作用尚未被 广泛研究。我们最近设计了一种小鼠， TNF-α在心脏和发展心肌病的特点是心房和 心室扩张，射血分数降低，CHF， 生存对转基因小鼠的无线电遥测监测显示， 和室性心律失常。程序刺激的光学映射研究， Langendorff灌注心脏使用电压和Ca 2+敏感染料显示， 诱发性室性心动过速（VT），早搏传导缓慢， 舒张期Ca 2+升高，收缩期峰值Ca 2+降低， Ca 2+瞬变。这些小鼠与长QT转基因小鼠交配产生 后代突然死亡，没有CHF的证据。 本项目的目标是确定细胞因子 可促进急性和慢性心脏病患者的心律失常和猝死 条件下，并测试是否治疗CHF逆转的影响。本 最后，我们将研究流动遥测监测小鼠，隔离， Langendorff灌注的心脏用电压和Ca 2+敏感染料染色，和 从对照和转基因小鼠分离肌细胞。我们将：1）测试 假设急性暴露于TNF-α、IL-1 β和/或LPS容易导致 心律失常，并确定负责的机制; 2）识别 在老年人中引起房性和室性心律失常的机制 CHF的TNF-α小鼠模型。3)确定在何种程度上和通过何种方式 β受体阻滞剂、ACE抑制剂和可溶性 TNF受体减少心律失常;和4）检查在何种程度上和通过何种方式 机制复极异常加剧心律失常和猝死 在这个CHF小鼠模型中。

DESCRIPTION (the applicant's description verbatim): Arrhythmias are a major health problem in cardiomyopathies of both ischemic and non-ischemic origin. As many as 50 percent of patients with congestive heart failure (CHF) die suddenly, accounting for more than 250,000 annual deaths. Pharmacological treatments of arrhythmias often fail, and internal defibrillators are expensive and limit quality of life. Inflammatory cytokines, including TNF-alpha, are increased in the serum and hearts of patients with CHF. TNF-alpha is also transiently increased following myocardial infarction, is elevated in inflammatory conditions such as sepsis, and increases with age and hypertrophy. All of these conditions are characterized by increased susceptibility to ventricular arrhythmias. The potential role of cytokines in the pathogenesis of arrhythmias has not been extensively studied. We have recently engineered mice that overexpress TNF-alpha in the heart and develop a cardiomyopathy characterized by atrial and ventricular dilatation, decreased ejection fraction, CHF, and decreased survival. Radio-telemetry monitoring of transgenic mice shows high-grade atrial and ventricular arrhythmias. Optical mapping studies of program-stimulated, Langendorff-perfused hearts using voltage- and Ca2+-sensitive dyes show inducible ventricular tachycardia (VT), slow conduction of premature beats, elevated diastolic and decreased peak systolic Ca2+, and prolongation of the Ca2+ transient. Mating of these mice to long QT transgenic mice yields offspring that die suddenly, without evidence of CHF. The goals of this project are to determine the mechanism(s) by which cytokines may promote arrhythmias and sudden death in acute and chronic cardiac conditions, and to test whether treatments for CHF reverse the effects. To this end, we will study ambulatory telemetry-monitored mice, isolated Langendorff-perfused hearts stained with voltage- and Ca2+-sensitive dyes, and isolated myocytes from control and transgenic mice. We will: 1) Test the hypothesis that acute exposure to TNF-alpha, IL-1 beta, and/or LPS predisposes to cardiac arrhythmias, and determine the mechanism(s) responsible; 2) Identify the mechanisms responsible for atrial and ventricular arrhythmias in the TNF-alpha mouse model of CHF. 3) Determine to what extent and by what mechanisms treatments of CHF with beta-blockers, ACE inhibitors, and soluble TNF receptors decrease arrhythmias; and 4) Examine to what extent and by what mechanisms repolarization abnormalities exacerbate arrhythmias and sudden death in this mouse model of CHF.