Genetic Modulators of Sudden Death

猝死的基因调节剂

• 批准号: 7484265
• 负责人: Barry London
• 金额: $ 45.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484265
• 关键词: Accounting; Adrenergic Receptor; Affect; Arrhythmia; Biochemical; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Line; Cessation of life; Clinical; Code; Condition; Connexins; DNA Library; Databases; Defibrillators; Depressed mood; Development; Devices; Disease; EFRAC; End Point; Etiology; Event; Failure; Freedom; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Goals; Health; Heart failure; Implant; In Vitro; Individual; Inherited; Ion Channel; Ischemia; Lead; Left; Left Ventricular Dysfunction; Left Ventricular Function; Life; London; Long QT Syndrome; Malignant - descriptor; Measures; Modeling; Molecular Genetics; Mutation; Myocardial; Myocardial Infarction; Myocardial Ischemia; Neonatal; Numbers; Oryctolagus cuniculus; Outcome; Patients; Pharmacological Treatment; Phosphorylation; Placement; Play; Population; Populations at Risk; Potassium; Potassium Channel; Predisposition; Promoter Regions; Pump; Quality of life; Risk; Role; Shock; Sodium Channel; Structure; Sudden Death; Syndrome; Testing; Time; United States; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; base; beta-adrenergic receptor; clinically significant; cost; improved; in vivo; novel therapeutics; prophylactic; sudden cardiac death

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.

描述（由申请人提供）：心律不齐仍然是一个主要的健康问题，每年在美国每年至少造成25万人死亡。 药理学治疗通常弊大于利，并且设备疗法受到高成本和对生活质量影响的限制。 离子通道突变会引起罕见的遗传性心律失常，但仅占危及生命心律不齐和猝死的患者的一小部分。 大多数心律不齐发生在心肌缺血期间，心肌梗塞后以及任何病因的左心（LV）功能差的患者中发生。 除了射血分数（EF）外，已经确定了几乎没有临床上有用的指标分层猝死风险。 在易感患者心律不齐和调节猝死风险的离子通道表达和/或结构中微妙的差异的作用是未知的。 在缺血性的心肌病种群中，我们发现K+通道HERG（K897T）中的常见多态性会使生存率恶化并增加猝死。 Beta1-肾上腺素受体（S49G）的多态性还调节了泵衰竭与心律不齐死亡的风险。 在该提案中，我们将前瞻性测试离子通道和离子通道修饰基因中的多态性是否与具有内部心脏逆转表纤维剂（ICD）（ICD）和LV功能较差的人群中的心律失常有关。 我们将： 1）直接检验了HERG K897T多态性预测1700个EF低于30％和ICD植入物的人的心律失常敏感性。 这些受试者将在长达五年的时间内前瞻性遵循，并免于适当的ICD冲击作为主要终点。 2）检验以下假设：HERG K897T多态性通过改变通道周转和 /或磷酸化的改变在缺血的情况下选择性地促进心律不齐。 使用兔子MI模型，将使用细胞系和体内进行生化和电生理研究。 3）测试其他心脏基因的编码序列和启动子区域（例如离子通道，β-肾上腺素能受体，连接蛋白）中的功能多态性是否易于心律失常和/或心脏衰竭进展。 我们希望确定心脏猝死的常见形式的遗传预测因子。 这将允许鉴定心力衰竭患者的亚群，这将使ICD放置受益最大。

项目成果

Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function.

• DOI: 10.1161/jaha.114.001566
• 发表时间: 2015-07-31
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Aleong RG;Mulvahill MJ;Halder I;Carlson NE;Singh M;Bloom HL;Dudley SC;Ellinor PT;Shalaby A;Weiss R;Gutmann R;Sauer WH;Narayanan K;Chugh SS;Saba S;London B
• 通讯作者: London B