Genetic Modulation of Left Ventricular Recovery

左心室恢复的基因调节

• 批准号: 7325703
• 负责人: DENNIS M. MCNAMARA
• 金额: $ 35.2万
• 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 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7325703
• 关键词: Acute; Acute Myocarditis; Affect; Aldosterone Synthase; Alleles; CCL26 gene; Cardiomyopathies; Chronic; Clinical; Clinical Trials; Cytokine Activation; DNA; Data; Dilated Cardiomyopathy; Disease-Free Survival; Echocardiography; Elevation; End Point; Enrollment; Equilibrium; Etiology; Event; Freedom; Genetic; Genetic Heterogeneity; Genetic Polymorphism; Genetic Variation; Genotype; Heart failure; Heterogeneity; Inflammatory; Injury; Interleukin-6; Intervention Trial; Left; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Left Ventricular Function; Left Ventricular Remodeling; Matrix Metalloproteinases; Measures; Mediator of activation protein; Modeling; Myocardial; Myocarditis; NOS2A gene; NOS3 gene; Nature; Other Genetics; Outcome; Patients; Peptidyl-Dipeptidase A; Plasma; Play; Population; Primary Myocardial Diseases; Primary idiopathic dilated cardiomyopathy; Probability; Rate; Receptor Down-Regulation; Recovery; Role; Time; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Variant; Ventricular; Viral; beta-adrenergic receptor; cytokine; experience; follow-up; genetic variant; human NOS2A protein; human NOS3 protein; human TNF protein; imidazole-4-acetic acid; promoter; response

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著恢复，而大多数慢性心力衰竭和左心室功能障碍持续存在。这种临床结果的显著差异部分是由心肌损伤全身反应的遗传异质性决定的。这一人群被排除在大多数临床试验之外，很少有研究检查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平衡中的作用。本研究将探讨炎症和神经激素介质的遗传多态性是否会影响新近发病的原发性（特发性）扩张型心肌病患者的后续临床结果。本研究将在7个中心招募500名因非缺血性原发性心肌病而出现近期左心室功能障碍（LVEF小于或等于过0.40）的受试者，并对其进行前瞻性随访，以评估随后的左心室恢复和免于临床事件的情况。