CYTOKINE-INDUCED ARRHYTHMIAS IN CONGESTIVE HEART FAILURE

描述(申请者逐字描述)：心律失常是一种主要的 缺血性和非缺血性心肌病的健康问题。AS 多达50%的充血性心力衰竭患者死亡 突然间，每年造成超过25万人死亡。药理作用 心律失常的治疗经常失败，内部除颤器也很昂贵 并限制了生活质量。 炎性细胞因子，包括肿瘤坏死因子-α，在血清和 慢性心力衰竭患者的心脏。在以下情况下，肿瘤坏死因子-α也会一过性升高 心肌梗死，在脓毒症等炎症情况下会增加， 并随着年龄和肥大而增加。所有这些条件都是 特点是对室性心律失常的易感性增加。这个 细胞因子在心律失常发病机制中的潜在作用尚不清楚 经过广泛研究。我们最近改造出了过度表达的小鼠 心脏中的肿瘤坏死因子-α，并发展成一种以心房和心脏为特征的心肌病 心室扩张，射血分数降低，心力衰竭，并减少 生死存亡。对转基因小鼠的无线电遥测监测显示高级别的心房 以及室性心律失常。程序刺激的光学标测研究， 使用电压和钙敏感染料的朗宁多夫灌流心脏显示 诱发性室性心动过速(VT)，早搏慢传导， 舒张期升高和收缩期峰值钙离子降低，并延长 钙离子瞬变。这些小鼠与长QT转基因小鼠交配产生 突然死亡的后代，没有CHF的证据。 这个项目的目标是确定细胞因子(S)通过什么机制 可促进急性和慢性心脏疾病的心律失常和猝死 条件，并测试CHF的治疗是否逆转了这种效果。对这件事 最后，我们将研究动态遥测监测的小鼠，隔离 兰登多夫灌流的心脏对电压和钙离子敏感的染料染色，以及 分离对照组和转基因小鼠的心肌细胞。我们将：1)测试 假设急性暴露于肿瘤坏死因子-α、白介素1-β和/或内毒素可诱发 对心律失常，并确定责任机制(S)；2)确定 房性和室性心律失常的发病机制 肿瘤坏死因子-α致心衰小鼠模型。3)确定程度和程度 β-受体阻滞剂、血管紧张素转换酶抑制剂和可溶性药物治疗充血性心力衰竭的机制 肿瘤坏死因子受体减少心律失常；以及4)检查在多大程度上和以什么方式 复极异常加重心律失常和猝死的机制 在这个充血性心力衰竭的小鼠模型中。

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.