Determinants of Sudden Death Risk with Left Ventricular Hypertrophy

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DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) remains a major cause of mortality in the US. While the prophylactic implantable defibrillator has significantly reduced the incidence of SCD under the current eligibility criterion of severe left ventricular dysfunction (LVD), there is increasing recognition of the fact that a significant proportion of patients that suffer SCD may have risk predictors other than severe LVD. The overall goal of the research proposed in this application is to contribute to the further development of novel and effective SCD risk stratification methods. A prospective community-based case-control approach is proposed as a potentially useful step toward the identification of risk predictors for SCD. Concentric left ventricular hypertrophy (LVH), as defined by increased LV mass (LVM) without evidence of hypertrophic obstructive cardiomyopathy, is an independent predictor of increased SCD risk in human and experimental studies. LVH is a relatively common finding in patients with coronary artery disease (CAD), which, in turn, is the most common cardiac phenotype associated with SCD. Elucidation of risk predictors in patients with LVH and CAD, particularly in combination with severe LVD, may have significant implications for risk stratification of SCD. Our specific hypothesis is that (1) concentric LVH is an independent predictor of SCD in the general population; and that (2) abnormalities of cardiac repolarization and distinctive alterations in the myocardial interstitium are contributors to this risk. This hypothesis will be tested using data from the ongoing Oregon Sudden Unexpected Death Study (Ore-SUDS), established by the PI in 2002', which now has a clinical database of over 2000 SCD cases and controls and a DNA/tissue/blood sample archive (over 1000 patients) for the investigation of SCD among all residents of a large US community (Multnomah County OR, pop. 670,000). Our specific aims are: 1} To determine the contribution of LVH toward SCD risk in patients with CAD, as well as a potential synergistic effect in the presence of LVD. SCD cases with CAD and geographically matched controls will be ascertained prospectively, and the effect of LVH and LVD on SCD risk examined 2) To determine the contribution of abnormal ventricular repolarization toward occurrence of SCD in LVH. Indices of ventricular repolarization measured from the 12-lead EKG will be evaluated as potential independent predictors of SCD risk 3) To determine the nature and extent of interstitial remodeling in a separate subgroup of patients with isolated LVH and SCD. A postmortem, case control approach will be used to compare LV myocardial interstitial remodeling in a subgroup of SCD cases with isolated LVH, vs. controls with isolated LVH, vs. normal controls.