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）：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，而大多数患者慢性心力衰竭和左心室功能障碍持续存在。 临床结果的这种显著变化部分取决于对心肌损伤的全身反应的遗传异质性。 这一人群已被排除在大多数临床试验之外，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。 本提案将研究炎症和神经激素介质的遗传多态性是否会影响近期原发性（特发性）扩张型心肌病患者的后续临床结局。 将在7家临床试验机构入组500例因非缺血性原发性心肌病近期发作左心室功能障碍（LVEF小于或等于0.40）的受试者，并进行前瞻性随访，以评价随后的左心室恢复和无临床事件。 具体目标1将评估以下假设：在出现时促炎细胞因子TNF的表达促进恢复，并且较高水平与LVEF的后续改善相关。 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将被检查。 具体目标2将评估ACE D等位基因将不利地影响左心室恢复并将通过增加基质金属蛋白酶的表达起作用的假设。 此外，增加受体下调或活性的β-肾上腺素能受体变体将影响LV恢复。 具体目标3将检查作为细胞因子和神经激素反应的修饰剂的其他遗传基因座，特别是NOS 2、NOS 3和醛固酮合酶。