Comprehensive autopsy characterization of sudden cardiac death

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 Gold standard autopsy studies defining the underlying causes of SCD are similarly outdated and hindered by referral bias of only a small subset of SCD cases.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