Genetic Modulators of Sudden Death

超出所提供的空间。心律失常仍然是一个主要的健康问题，在美国每年至少造成25万人死亡。药物治疗往往弊大于利，而且器械治疗由于成本高和对生活质量的影响而受到限制。离子通道突变引起罕见的遗传性心律失常，但仅占危及生命的心律失常和猝死患者的一小部分。大多数心律失常发生在心肌缺血，心肌梗死后，以及任何病因的左心室（LV）功能差的患者。除了射血分数（EF）外，很少有临床上有用的指标被确定为猝死风险分层。离子通道表达和/或结构的细微差异在诱发心律失常和调节猝死风险中的作用尚不清楚。在缺血性心肌病人群中，我们发现K+通道HERG （K897T）的常见多态性恶化了生存并增加了猝死。β -肾上腺素受体的多态性也调节泵衰竭与心律失常死亡的风险。在这项提议中，我们将前瞻性地测试离子通道和离子通道修饰基因的多态性是否与内部心脏转复除颤器（icd）和左室功能差的人群中的心律失常有关。我们将：1)直接验证1700例EF低于30%并植入ICD的患者HERG K897T多态性预测心律失常易感性的假设。受试者将被前瞻性随访长达5年，没有适当的ICD休克作为主要终点。2)验证HERG K897T多态性通过改变通道转换或磷酸化选择性地促进缺血情况下心律失常的假设。生化和电生理研究将在体外使用细胞系进行，在体内使用兔心肌梗死模型进行。3)检测其他心脏基因（如离子通道、β -肾上腺素能受体、连接蛋白）的编码序列和启动子区域的功能多态性是否使个体易患心律失常和/或心力衰竭。我们希望确定常见形式的心源性猝死的遗传预测因子。这将有助于确定从ICD安置中获益最多的心力衰竭患者亚群。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Arrhythmias remain a major health problem, causing at least 250,000 deaths annually in the United States. Pharmacological treatments often do more harm than good, and device therapies are limited by high cost and effects on quality of life. Ion channel mutations cause rare inherited arrhythmopathies, but account for only a small fraction of patients with life-threatening arrhythmias and sudden death. Most arrhythmias occur during myocardial ischemia, following myocardial infarction, and in patients with poor left ventricular (LV) function of any etiology. Aside from ejection fraction (EF), few clinically useful indicators to stratify the risk of sudden death have been identified. The role of subtle differences in ion channel expression and/or structure in predisposing patients to arrhythmias and modulating the risk of sudden death is unknown. In an ischemic cardiomyopathy population, we have found that a common polymorphism in the K+ channel HERG (K897T) worsens survival and increases sudden death. A polymorphism of the betal-adrenertic receptor ($49G) also modulates the risk of pump failure vs. arrhythmic death. In this proposal, we will prospectively test whether polymorphisms in ion channel and ion channel modifying genes are associated with arrhythmias in a population with internal cardioverter-defibrillators (ICDs) and poor LV function. We will: 1) Directly test the hypothesis that the HERG K897T polymorphism predicts arrhythmia susceptibility in 1700 individuals with an EF below 30% and ICD implants. The subjects will be followed prospectively for a period of up to five years with freedom from appropriate ICD shock as the primary endpoint. 2) Test the hypothesis that the HERG K897T polymorphism selectively promotes arrhythmias in the setting of ischemia via alterations in channel turnover andor phosphorylation. Biochemical and electrophysiological studies will be performed in-vitro using cell lines and in-vivo using a rabbit MI model. 3) Test whether functional polymorphisms in the coding sequences and promoter regions of other cardiac genes (e.g. ion channels, beta-adrenergic receptors, connexins) predispose individuals to arrhythmias and/or heart failure progression. We hope to identify genetic predictors for the common forms of sudden cardiac death. This would allow the identification of a subpopulation of heart failure patients that would benefit most from ICD placement. PERFORMANCE SITE ========================================Section End===========================================