Comprehensive autopsy characterization of sudden cardiac death

描述（由申请人提供）：心源性猝死（SCD）仍然是美国和发达国家的一个重大公共卫生问题。然而，SCD的真正负担仍然未知;在以前的研究中，可变的定义和不一致的确定方法导致其发病率的估计存在很大差异。通常引用的关于SCD风险的流行病学数据是一代人的历史，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的发病率和风险差异。金标准尸检研究定义的SCD的根本原因同样是过时的，并阻碍了只有一小部分SCD病例的转诊偏倚。因此，为了更精确地指导有效但昂贵的预防性治疗，例如植入式心律转复除颤器，迫切需要对SCD的当代流行病学和潜在原因以及迄今为止代表性不足的不同人群进行精确表征。 我们与县医学检查办公室开展了独特的合作，为旧金山弗朗西斯科的所有连续发生的SCD建立了一种强大的监测方法，旧金山是一个典型的多元化美国社区，预示着近期的全国人口变化。我们假设（1）广泛接受的SCD标准定义（WHO标准）对于真正的心脏非常不准确（2）与金标准尸检方法相比，在这个多样化的社区中，当代猝死（SD）的流行病学与来自同质人群的历史数据有很大不同，特别是反映了冠状动脉疾病（CAD）的贡献减少，（3）心脏质量是无CAD的患者中心肌SD的独立危险因素，和（4）间质性心肌纤维化是心肌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和血液动力学SD的发生率，以及这些SD病例中心脏疾病的患病率;（2）估计一般人群中心脏病理的患病率，并评估CAD、其他病理、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进行全面尸检评估，将心脏质量和心脏质量作为糖尿病SD的危险因素;以及（3）评价间质性心肌纤维化作为糖尿病性SD的危险因素，并通过比较糖尿病性SD亚组，探讨其作为CAD和其他心脏疾病影响的介导因素的作用。从目标1的病例到目标2的对照。我们将前瞻性地收集全面的表型、遗传、组织和心脏病理学数据。这些数据可能阐明一个更准确的定义SCD，新的独立的危险因素，在不同的人群中，糖尿病SD，并奠定了基础，为未来的遗传和分子研究。 公共卫生相关性：我们建议对所有连续发生的心源性猝死（SCD）进行全面的尸检评估，并在3年内对意外创伤对照的频率匹配样本进行评估，以确定SCD和心源性猝死的当代发生率及其危险因素。

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 Gold standard autopsy studies defining the underlying causes of SCD are similarly outdated and hindered by referral bias of only a small subset of SCD cases.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.