Genetic Modulation of Left Ventricular Recovery

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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.