Determinants of Sudden Death Risk with Left Ventricular Hypertrophy

描述（由申请人提供）：心源性猝死（SCD）仍然是美国死亡的主要原因。虽然预防性植入式除颤器在目前严重左心室功能障碍（LVD）的资格标准下显著降低了SCD的发病率，但越来越多的人认识到，很大一部分SCD患者可能存在严重左心室功能障碍以外的风险预测因素。本申请中提出的研究的总体目标是为进一步开发新颖有效的SCD风险分层方法做出贡献。提出了一种前瞻性社区病例对照方法，作为识别SCD风险预测因素的潜在有用步骤。同心性左室肥厚（LVH），定义为无肥厚性阻塞性心肌病证据的左室质量（LVM）增加，在人类和实验研究中是SCD风险增加的独立预测因子。LVH是冠状动脉疾病（CAD）患者中相对常见的发现，而冠心病又是与SCD相关的最常见的心脏表型。阐明LVH和CAD患者的风险预测因素，特别是合并严重LVD的患者，可能对SCD的风险分层具有重要意义。我们的具体假设是：(1)同心LVH是普通人群中SCD的独立预测因子；(2)心脏复极异常和心肌间质明显改变是导致这种风险的因素。这一假设将使用正在进行的俄勒冈意外猝死研究（Ore-SUDS）的数据进行验证，该研究由PI于2002年建立，目前拥有超过2000例SCD病例和对照的临床数据库，以及DNA/组织/血液样本档案（超过1000例患者），用于调查美国大型社区（摩特诺玛县，俄勒冈州，流行）所有居民的SCD。670000)。我们的具体目标是：1}确定LVH对冠心病患者SCD风险的贡献，以及LVD存在时的潜在协同效应。我们将前瞻性地确定伴有CAD的SCD病例和地理匹配的对照组，并检查LVH和LVD对SCD风险的影响2)确定心室异常复极对LVH中SCD发生的贡献。12导联心电图测量的心室复极指数将被评估为SCD风险的潜在独立预测因子3)确定孤立性LVH和SCD患者的间质重构的性质和程度。将采用尸检、病例对照的方法，比较孤立LVH的SCD亚组、孤立LVH的对照组和正常对照组的左室心肌间质重构。

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.