Comprehensive autopsy characterization of sudden cardiac death

描述（由申请人提供）：心源性猝死（SCD）在美国和发达国家仍然是一个重大的公共卫生问题。然而，SCD的真正负担仍然未知；在以往的研究中，不同的定义和不一致的确定方法导致对其发病率的估计大相径庭。通常引用的SCD风险的流行病学数据现在已经有一代人的历史了，早于现代心脏护理的进步，并且是从同质人群中提取的。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。定义SCD潜在原因的金标准尸检研究同样过时，并且仅受到一小部分SCD病例的转诊偏差的阻碍。因此，为了更精确地指导有效但昂贵的预防性治疗，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未被充分代表的不同人群进行精确描述。我们与县法医办公室开展了一项独特的合作，为旧金山所有连续发生的scd事件建立了强有力的监测方法。旧金山是美国一个典型的多元化社区，预示着近期全国人口结构的变化。我们假设：(1)与金标准尸检方法相比，广泛接受的SCD标准定义（WHO标准）对真正的心脏（特别是心律失常）原因的评估是高度不准确的；(2)在这个多样化的社区中，心律失常猝死（SD）的当代流行病学与来自同质人群的历史数据有很大不同，特别是反映出冠状动脉疾病（CAD）的贡献减少。(3)心肌质量是无冠心病患者发生心律失常的独立危险因素；(4)间质性心肌纤维化是发生心律失常的独立危险因素。我们提出了三个具体目标：(1)通过对3年期间所有连续发生的SCD进行全面的尸检评估，确定WHO SCD和心律失常性SD的发生率，以及这些SD病例中心脏疾病的患病率；(2)通过对相同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，估计心脏病理在普通人群中的患病率，并评估CAD、其他病理和心脏肿块作为心律失常SD的危险因素；(3)通过比较Aim 1的心律失常SD亚组与Aim 2的对照组，评估间质性心肌纤维化作为心律失常SD的危险因素，并探讨其作为CAD和其他心脏疾病影响的中介的作用。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。这些数据可能阐明更准确的SCD定义，不同人群中心律失常SD的新独立危险因素，并为未来的遗传和分子研究奠定基础。

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 Gold standard autopsy studies defining the underlying causes of SCD are similarly outdated and hindered by referral bias of only a small subset of SCD cases.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