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，在美国每年造成至少25万人死亡。 药物治疗往往弊大于利，器械治疗受到高成本和对生活质量影响的限制。 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期间、心肌梗死后以及任何病因导致的左心室（LV）功能不良的患者中。 除了射血分数（EF），很少有临床上有用的指标来分层猝死的风险已被确定。 离子通道表达和/或结构的细微差异在诱发患者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（K897 T）的一种常见多态性降低了生存率并增加了猝死。 β 1-肾上腺素能受体（S49 G）的多态性也可调节泵衰竭相对于药物性死亡的风险。 在本研究中，我们将前瞻性地检测离子通道和离子通道修饰基因的多态性是否与内心律转复除颤器（ICD）和左室功能不良人群的心律失常相关。 我们将： 1)直接检验HERG K897 T多态性预测1700名EF低于30%且植入ICD的个体的心律失常易感性的假设。 受试者将接受长达5年的前瞻性随访，无适当ICD电击作为主要终点。 2)检验HERG K897 T多态性通过改变通道转换和/或磷酸化选择性促进缺血性心律失常的假设。 将使用细胞系在体外和使用兔MI模型在体内进行生物化学和电生理学研究。 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的功能多态性是否使个体易患心律失常和/或心力衰竭进展。 我们希望能找出常见心脏性猝死的遗传预测因子。 这将允许识别将从ICD放置中获益最多的心力衰竭患者亚群。

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.