Prolonged Ventricular Depolarization and Sudden Death in the Community

描述(由申请人提供)： 美国每年的心脏性猝死(SCD)发病率在20万至30万之间，其中绝大多数是由致命性心律失常引起的。在该领域已经形成了一种共识，即可以将多个预测因素结合起来作为风险评分，以加强SCD风险分层。在562例植入ICD的患者中，我们先前报道了12导联心电图上QRS间期延长(QRSd)延长的室性复极是复发性室性心律失常的预测指标，这与其他人的研究结果一致。现在，我们在普通人群中进行的一项单独研究的初步发现表明，QRSD可以在没有严重LVSD的情况下观察到，并且在更广泛的社区中是SCD的潜在预测因子。这项应用的目的是评估QRSD在普通人群中作为SCD风险预测因子的潜力。俄勒冈州猝死研究是一项在俄勒冈州波特兰市进行的基于人群的病例对照研究。大约。100万)。利用1100例SCD患者和1100例配对对照的临床信息和DNA样本，我们建议检验这样一种假设，即长时间的室性去极化独立地参与了CAD中性室性心律失常的底物，并且该底物受到中危表型特征(如2型糖尿病)以及个体基因组谱的调节。已确定的候选基因变异将在1200例SCD病例的单独人群中得到验证。我们的具体目标是：1.确定QRSD对SCD风险的独立贡献。2.确定QRSD的表型决定因素及其对SCD风险的贡献。3.探讨冠心病室壁除极基因变异与心源性心脏病易感性的关系。一项已建立和正在进行的基于人群的病例对照研究，以及临床电生理学、流行病学和基因组学方面的专业知识的现成可用，将有助于对QRSD如何增强SCD风险预测的详细评估。鉴于12导联心电图的广泛适用性和相对较低的成本，这项建议对SCD风险分层的任何加强都可能具有重要的临床意义。 公共卫生相关性： 项目简介心脏性猝死(SCD)是一个重大的公共卫生问题，在美国每年的发病率估计在20万至40万之间。在心电图上测量的心脏除极时间延长(QRS间期)似乎增加了SCD的风险，但这一临床发现目前不用于风险分层。阐明与QRS持续时间延长相关的SCD风险的决定因素具有快速临床和科学应用的潜力，从而提高普通人群中SCD的风险分层，以及针对心电图间期延长的患者亚组进行重点治疗，并有可能减轻SCD的人群负担。

DESCRIPTION (provided by applicant): ABSTRACT The annual incidence of sudden cardiac death (SCD) in the US ranges between 200,000 - 300,000 and the vast majority occur due to fatal arrhythmia. A consensus has emerged in the field for delineation of multiple predictors that could be combined as a risk score to enhance SCD risk stratification. In a population of 562 patients implanted with ICDs, we have previously reported that prolonged ventricular repolarization measured as increased duration of the QRS interval on the 12-lead ECG (?QRSd) was a predictor of recurrent ventricular arrhythmias, consistent with findings reported by others. Now our preliminary findings from a separate study in the general population indicate that ?QRSd can be observed in the absence of severe LVSD and is a potential predictor of SCD in the broader community. The goal of this application is to evaluate the potential of QRSd as a predictor of SCD risk in the general population. The Oregon Sudden Unexpected Death Study is an ongoing population-based case-control study in the Portland, Oregon metro area (pop. approx. 1,000,000). Using clinical information and DNA samples from 1100 SCD cases and 1100 matched controls, we propose to test the hypothesis that prolonged ventricular depolarization independently contributes to the ventricular arrhythmia substrate in CAD and that this substrate is modulated by intermediate risk phenotypic traits such as type 2 diabetes as well as the individual's genomic profile. Candidate gene variants identified will be validated in a separate population of 1200 SCD cases. Our specific aims are: 1. To determine the independent contribution of QRSd toward risk of SCD. 2. To identify phenotypic determinants of ?QRSd and their contribution to SCD risk. 3. To evaluate the role of ventricular depolarization-affecting gene variants in susceptibility to SCD among patients with CAD. An established and ongoing population-based case-control study and the ready availability of expertise in clinical electrophysiology, epidemiology and genomics will facilitate this detailed evaluation of how QRSd may enhance SCD risk prediction. Given the wide applicability and relatively low cost of the 12-lead ECG, any enhancement of risk stratification of SCD by this proposal is likely to have significant clinical relevance. PUBLIC HEALTH RELEVANCE: Project Narrative Sudden cardiac death (SCD) is a public health problem of significant magnitude, with an annual incidence estimated between 200,000 - 400,000 in the US. Prolongation of cardiac depolarization as measured on the electrocardiogram (QRS interval duration) appears to confer an increased risk of SCD, but this clinical finding is currently not used for risk stratification. Clarifying the determinants of SCD risk associated with prolonged QRS duration has the potential for rapid clinical and scientific application, leading to enhanced risk stratification for SCD in the general population, as well as focused therapy for patient subgroups with prolonged ECG intervals, and could potentially reduce the population burden of SCD.