Determinants of Sudden Death Risk with Left Ventricular Hypertrophy

描述（由申请方提供）：心源性猝死（SCD）仍然是美国的主要死亡原因。虽然预防性植入式除颤器在当前严重左心室功能障碍（LVD）的合格性标准下显著降低了SCD的发生率，但人们越来越认识到，相当一部分患有SCD的患者可能具有除严重LVD以外的风险预测因子。本申请中提出的研究的总体目标是有助于进一步开发新颖有效的SCD风险分层方法。一个前瞻性的以社区为基础的病例对照方法提出了一个潜在的有用的一步，确定SCD的风险预测因子。在人体和实验研究中，同心性左心室肥大（LVH）是SCD风险增加的独立预测因子，定义为LV质量（LVM）增加，无肥厚性梗阻性心肌病证据。LVH是冠状动脉疾病（CAD）患者中相对常见的发现，而CAD又是与SCD相关的最常见心脏表型。在LVH和CAD患者中，特别是合并严重LVD的患者中，阐明风险预测因子可能对SCD的风险分层有重要意义。我们的具体假设是：（1）向心性LVH是一般人群中SCD的独立预测因子;（2）心脏复极异常和心肌肥厚的独特改变是该风险的贡献者。将使用PI于2002年建立的正在进行的俄勒冈州意外猝死研究（Ore-SUDS）的数据对该假设进行检验，该研究目前拥有超过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），用于在美国大型社区（Multnomah县OR，人口670，000）的所有居民中调查SCD。我们的具体目标是：1}确定CAD患者中LVH对SCD风险的贡献，以及存在LVD时的潜在协同效应。将前瞻性地确定患有CAD的SCD病例和地理上匹配的对照，并检查LVH和LVD对SCD风险的影响。2）确定异常心室复极对LVH中SCD发生的贡献。12导联EKG测量的心室复极指数将作为SCD风险的潜在独立预测因子进行评价3）确定单独LVH和SCD患者亚组中间质重塑的性质和程度。将采用尸检、病例对照方法比较SCD病例亚组（伴孤立性LVH）与对照组（伴孤立性LVH）与正常对照组的LV心肌间质重塑。

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.