Comprehensive autopsy characterization of sudden cardiac death

描述(由申请人提供)：在美国和发达国家，心脏性猝死(SCD)仍然是一个严重的公共卫生问题。然而，SCD的真正负担仍不清楚；先前研究中的可变定义和不一致的确定方法导致了对其发病率的巨大差异估计。通常引用的关于SCD风险的流行病学数据现在是一代人以前的数据，早于心脏护理的现代进步，并且来自同质人群。最近的数据，包括我们的初步研究，证实了少数民族人群中不同的发病率和风险。确定SCD潜在原因的黄金标准尸检研究也同样过时，并受到仅有一小部分SCD病例转诊偏见的阻碍。因此，为了更准确地指导有效但昂贵的预防性治疗，如植入型心脏复律除颤器，迫切需要准确描述SCD的当代流行病学和潜在原因，以及迄今未被充分代表的不同人群。我们与县法医办公室开展了独特的合作，为旧金山的所有连续事件SCD建立了强大的监控方法，旧金山是一个典型的多元化美国社区，预示着近期全国人口结构的变化。我们假设(1)被广泛接受的SCD(世界卫生组织标准)的标准定义在与黄金标准尸检方法相比时对真正的心脏(尤其是心律失常)原因的评估非常不准确，(2)在这个多样化的社区中，心律失常性猝死(SD)的当代流行病学与来自同种人群的历史数据有很大的不同，尤其是反映了冠心病(CAD)的减少，(3)在没有CAD的人中，心脏重量是心律失常SD的独立危险因素，(4)间质心肌纤维化是心律失常SD的独立危险因素。我们提出了三个具体目标：(1)通过对3年内所有连续发生的SCD进行全面的尸检评估，确定WHO SCD和心律失常SD的发生率，以及这些SD病例中心脏疾病的患病率；(2)通过对同一3年期间地理和人口统计学上相似的意外创伤死亡对照的频率匹配样本的综合尸检评估，估计普通人群中心脏病理的患病率，并评估CAD、其他病理和心脏质量作为心律失常SD的危险因素；(3)通过比较AIM 1和AIM 2的心律失常SD患者亚组，评价间质心肌纤维化是心律失常SD的危险因素，并探讨其作为冠心病和其他心脏疾病影响的中介因子的作用。我们将前瞻性地收集全面的表型、遗传、组织和心脏病理数据。这些数据可能会阐明SCD的更准确的定义，这是不同人群中心律失常SD的新的独立危险因素，并为未来的遗传学和分子研究奠定基础。 公共卫生相关性：我们建议对所有连续发生的心脏性猝死(SCD)进行全面的尸检评估，并在3年期间对意外创伤对照进行频率匹配的样本，以确定SCD和心律失常猝死的当代比率及其在不同社区的危险因素。

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) remains a significant public health problem in the United States and the developed world. The true burden of SCD, however, remains unknown; variable definitions and inconsistent ascertainment methods in previous studies have resulted in widely divergent estimates of its incidence. Commonly cited epidemiologic data on SCD risk are now a generation old, predate modern advancements in cardiac care, and were drawn from homogenous populations. More recent data, including our preliminary studies, confirm differential incidence and risk in minority populations. Gold standard autopsy studies defining the underlying causes of SCD are similarly outdated and hindered by referral bias of only a small subset of SCD cases. Thus, to more precisely direct effective but expensive preventive therapies, such as implantable cardioverter defibrillators, there is a critical need for a precise characterization of the contemporary epidemiology and underlying causes of SCD and in diverse populations heretofore underrepresented. We have developed a unique collaboration with the County Medical Examiner's Office to establish a robust surveillance method for all consecutive incident SCDs in San Francisco, a prototypic diverse U.S. community that presages near-term national demographic shifts. We hypothesize that (1) the widely accepted, standard definition of SCD (WHO criteria) is highly inaccurate for true cardiac (in particular arrhythmic) causes when evaluated in comparison to gold standard autopsy methods, (2) the contemporary epidemiology of arrhythmic sudden death (SD) in this diverse community differs substantially from historical data derived from homogenous populations, in particular reflecting a decreased contribution of coronary artery disease (CAD), (3) cardiac mass is an independent risk factor for arrhythmic SD in those without CAD, and (4) interstitial myocardial fibrosis is an independent risk factor for arrhythmic SD. We propose three specific aims: (1) To determine the rates of WHO SCD and arrhythmic SD, and the prevalence of cardiac conditions in these SD cases by performing a comprehensive autopsy evaluation of all consecutive incident SCDs over a 3-year period; (2) To estimate the prevalence of cardiac pathology in the general population and to evaluate CAD, other pathology, and cardiac mass as risk factors for arrhythmic SD by comprehensive autopsy evaluation of a frequency-matched sample of geographically and demographically similar accidental trauma death controls over the same 3-year period; and (3) To evaluate interstitial myocardial fibrosis as a risk factor for arrhythmic SD and to explore its role as a mediator of the effects of CAD and other cardiac conditions by comparing the subgroup of arrhythmic SD cases from Aim 1 to controls from Aim 2. We will prospectively collect comprehensive phenotypic, genetic, tissue, and cardiac pathologic data. These data may elucidate a more accurate definition of SCD, new independent risk factors for arrhythmic SD in diverse populations, and lay the groundwork for future genetic and molecular studies. PUBLIC HEALTH RELEVANCE: We propose the comprehensive autopsy evaluation of all consecutive incident sudden cardiac deaths (SCDs) and a frequency-matched sample of accidental trauma controls over a 3-year period to determine the contemporary rates of SCD and arrhythmic sudden death and its risk factors in a diverse community.