Determinants of Sudden Death Risk with Left Ventricular Hypertrophy

描述(由申请人提供)：在美国，心脏性猝死(SCD)仍然是主要的死亡原因。虽然根据目前严重左心功能不全(LVD)的资格标准，预防性植入式除颤器显著降低了SCD的发生率，但越来越多的人认识到这样一个事实，即相当大比例的SCD患者可能有严重LVD以外的危险预测因素。本申请中提出的研究的总体目标是为进一步开发新的、有效的SCD风险分层方法做出贡献。提出了一种基于社区的前瞻性病例对照方法，作为识别SCD风险预测因素的潜在有用步骤。在人类和实验研究中，向心性左室肥厚(LVH)是SCD风险增加的独立预测因子，其定义为无肥厚性梗阻性心肌病证据的左心室质量(LVM)增加。左心室肥厚是冠状动脉疾病(CAD)患者中比较常见的发现，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)在普通人群中，向心性LVH是SCD的独立预测因子；(2)心脏复极异常和心肌间质的独特改变是这种风险的贡献者。这一假设将使用正在进行的俄勒冈州猝死研究(Ore-SUDS)的数据进行验证，该研究由PI于2002年建立，目前拥有一个包含2000多个SCD病例和对照的临床数据库和一个DNA/组织/血液样本档案(超过1000名患者)，用于在美国一个大型社区(马尔特诺马县或POP)的所有居民中调查SCD。67万人)。我们的具体目标是：1)确定左心室肥厚对冠心病患者SCD风险的贡献，以及LVD存在时的潜在协同效应。前瞻性确定有冠心病和地理位置匹配的对照组的SCD病例，研究LVH和LVD对SCD危险性的影响。2)确定左心室异常复极在LVH SCD发生中的作用。12导联EKG测量的心室复极指数将被评估为SCD风险的潜在独立预测指标3)以确定单独的LVH和SCD患者亚组的间质重构的性质和程度。我们将采用死后病例对照的方法，比较单纯性左心室肥厚的SCD患者、单纯左室肥厚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.