Genetic Modulation of Left Ventricular Recovery

左心室恢复的基因调节

• 批准号: 6704336
• 负责人: DENNIS M. MCNAMARA
• 金额: $ 37.2万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704336
• 关键词: beta adrenergic receptor; clinical research; collagenase; cytokine; genetic polymorphism; heart ventricle; human subject; hypertrophic myocardiopathy; immunogenetics; interleukin 6; neuroendocrine system; nitric oxide synthase; peptidyl dipeptidase A; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): After presenting with new onset idiopathic dilated cardiomyopathy, one third of patients experience dramatic recovery of left ventricular function, while for the majority chronic heart failure and left ventricular dysfunction persist. This marked variation in clinical outcomes is determined in part by genetic heterogeneity of the systemic response to myocardial injury. This population has been excluded from most clinical trials and few studies have examined the role of cytokine and neurohormonal mediators in modulating the balance between left ventricular recovery and remodeling in early cardiomyopathy. This proposal will investigate whether genetic polymorphisms of inflammatory and neurohormonal mediators influence subsequent clinical outcomes for patients with recent onset primary (idiopathic) dilated cardiomyopathy. Five hundred subjects with recent onset left ventricular dysfunction (LVEF less than or equal too 0.40) due to non-ischemic primary cardiomyopathy will be enrolled at seven centers, and followed prospectively to evaluate subsequent left ventricular recovery and freedom from clinical events. Specific Aim 1 will evaluate the hypothesis that expression of the pro-inflammatory cytokine TNF at presentation facilitates recovery and that higher levels are associated with greater subsequent improvements in LVEF. The impact of genetic polymorphisms of the TNF and IL-6 promoters on the both the cytokine response and subsequent outcomes will be examined. Specific Aim 2 will evaluate the hypothesis that the ACE D allele will adversely affect left ventricular recovery and will act through increased expression of matrix metalloproteinases. In addition, beta-adrenergic receptor variants that increase receptor down-regulation or activity will influence LV recovery. Specific Aim 3 will examine other genetic loci which act as modifiers of the cytokine and neurohomonal response, in particular NOS2, NOS3 and aldosterone synthase.

描述（由申请人提供）：在出现新发特发性扩张型心肌病后，三分之一的患者左心室功能显着恢复，而大多数患者仍存在慢性心力衰竭和左心室功能障碍。 临床结果的这种显着差异部分是由心肌损伤全身反应的遗传异质性决定的。 该人群已被排除在大多数临床试验之外，并且很少有研究探讨细胞因子和神经激素介质在调节早期心肌病左心室恢复和重塑之间的平衡中的作用。 该提案将研究炎症和神经激素介质的遗传多态性是否影响近期发病的原发性（特发性）扩张型心肌病患者的后续临床结果。 七个中心将招募 500 名最近因非缺血性原发性心肌病而出现左心室功能障碍（LVEF 小于或等于 0.40）的受试者，并进行前瞻性随访，以评估随后的左心室恢复情况以及无临床事件的情况。 具体目标 1 将评估以下假设：促炎细胞因子 TNF 的表达有助于恢复，并且较高的水平与随后 LVEF 的较大改善相关。 将检查 TNF 和 IL-6 启动子的遗传多态性对细胞因子反应和后续结果的影响。 具体目标 2 将评估以下假设：ACE D 等位基因将对左心室恢复产生不利影响，并通过增加基质金属蛋白酶的表达来发挥作用。 此外，增加受体下调或活性的β-肾上腺素受体变异将影响左心室恢复。 具体目标 3 将检查充当细胞因子和神经激素反应调节剂的其他基因位点，特别是 NOS2、NOS3 和醛固酮合酶。