Genetic Modulators of Sudden Death

描述(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，设备治疗因成本高和对生活质量的影响而受到限制。离子通道突变导致罕见的遗传性心律失常，但只占威胁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，以及任何原因的左心功能低下的患者。除了射血分数(EF)，几乎没有临床上有用的指标来分层猝死的风险。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方面的作用尚不清楚。 在缺血性心肌病人群中，我们发现K+通道HERG(K897T)的一个常见的多态性会恶化存活率并增加猝死。β1-肾上腺素能受体(S49G)的多态性也调节泵衰竭与心律失常死亡的风险。在这项建议中，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是否与存在内部心脏转复除颤器(ICD)和左心功能低下的人群的心律失常有关。我们会： 1)直接验证HERG K897T基因多态性预测1700例EF低于30%且植入ICD的个体的心律失常易感性的假设。受试者将以免于适当的ICD休克为主要终点进行长达五年的前瞻性追踪。 2)验证HERG K897T多态通过改变通道翻转和/或磷酸化，选择性地促进缺血时心律失常的假设。生化和电生理学研究将在体外使用细胞系进行，并在体内使用兔MI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是否使个体易患心律失常和/或心力衰竭进展。 我们希望找出常见形式的心脏性猝死的遗传预测因子。这将允许确定将从ICD放置中受益最大的心力衰竭患者的亚群。

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.