Genetic Modulation of Left Ventricular Recovery

左心室恢复的基因调节

• 批准号: 6838152
• 负责人: DENNIS M. MCNAMARA
• 金额: $ 37.13万
• 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/6838152
• 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）：在出现新发作特发性扩张性心肌病后，三分之一的患者经历了左心室功能的急剧恢复，而对于大多数慢性心力衰竭和左心室功能障碍持续存在。 这种明显的临床结局变化部分取决于系统对心肌损伤的遗传异质性。 该人群已被排除在大多数临床试验之外，很少有研究检查了细胞因子和神经激素介质在调节早期心肌病中左心室恢复与重塑之间的平衡中的作用。 该提案将调查炎症和神经激素介质的遗传多态性是否会影响最近发作原发性（特发性）扩张性心肌病的患者随后的临床结局。 由于非缺血性原发性心肌病而导致的五百名患有左心室功能障碍（LVEF小于或相等0.40）的受试者将在七个中心招募，并随后评估随后的左心室恢复和免受临床事件的自由。 具体目标1将评估以下假设：促炎细胞因子TNF在介绍中的表达有助于恢复，并且更高的水平与LVEF的随后改善相关。 将研究TNF和IL-6启动子的遗传多态性对细胞因子反应和随后结果的影响。 具体目标2将评估ACE D等位基因将对左心室恢复的不利影响的假设，并通过增加基质金属蛋白酶的表达来起作用。 此外，增加受体下调或活性的β-肾上腺素能受体变异将影响LV恢复。 特定目标3将检查其他遗传基因座，这些基因座充当细胞因子和神经福音反应的修饰剂，尤其是NOS2，NOS3和醛固酮合酶。