Genetic Modulation of Left Ventricular Recovery

描述(申请人提供)：在出现新的特发性扩张型心肌病后，三分之一的患者经历了左心功能的显著恢复，而对于大多数患者来说，慢性心力衰竭和左心功能障碍仍然存在。临床结果的这种显着差异部分是由对心肌损伤的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，很少有研究考察细胞因子和神经激素介质在调节早期心肌病左室恢复和重塑之间的平衡中的作用。这项建议将调查炎性和神经激素介质的基因多态性是否会影响新近发病的原发性(特发性)扩张型心肌病患者随后的临床结果。最近因非缺血性原发心肌病而出现左心功能不全(LVEF小于或等于0.40)的500名受试者将在7个中心登记，并进行前瞻性跟踪，以评估随后的左心功能恢复和免于临床事件。 具体目标1将评估这样一种假设，即在发病时表达促炎细胞因子肿瘤坏死因子有助于恢复，并且较高的水平与随后的左心室射血分数改善更大相关。我们将研究肿瘤坏死因子和白介素6启动子的遗传多态对细胞因子反应和后续结果的影响。具体目标2将评估ACE D等位基因将对左心室恢复产生不利影响的假设，并将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-肾上腺素能受体变异体将影响左心室的恢复。 具体目标3将检查作为细胞因子和神经原反应修饰物的其他遗传位点，特别是NOS2、NOS3和醛固酮合成酶。

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.