Genetic Modulators of Sudden Death

描述（由申请人提供）：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250,000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。

DESCRIPTION (provided by applicant): 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 beta1-adrenergic receptor (S49G) 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 percent 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 and or 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.