Abstract 15856: Genetics, Pathologic Characteristics, and Burden of Lethal Hypertrophic Cardiomyopathy Among Countywide Sudden Deaths

Abstract

Background: Annual incidence of sudden cardiac death (SCD) is reported at 1% in cohorts with known hypertrophic cardiomyopathy (HCM), but these estimates presume arrhythmic cause and miss occult cases dying before diagnosis. Hypothesis: Prospective surveillance and postmortem investigation of community sudden deaths will uncover the true burden of presumed SCD (pSCD) and arrhythmic death (SAD) attributable to HCM. Objectives: Determine characteristics and precise contribution of HCM to population pSCD and SAD. Methods: POST SCD (POstmortem SysTematic Investigation of Sudden Cardiac Death) is a prospective cohort study using autopsy, clinical records, and toxicology to adjudicate arrhythmic (potentially rescuable with implantable defibrillator) or non-arrhythmic (e.g., tamponade, overdose) causes among pSCDs 0-90 years in San Francisco County. We included all incident cases from 2/1/11-3/1/14 (n=525) and approximately every 3rd day from 3/1/14-9/1/22 (n=497). We identified HCM victims via 3 parallel approaches: 1) pathology criteria; 2) echocardiogram (TTE) review; 3) genetic analysis. Results: Of 1022 pSCDs in the 11-year study period, we identified 13 cases with HCM, yielding a 2% contribution to arrhythmic death burden: 10 met pathology criteria; 2 via review of 203 TTEs (missed on initial report); 1 with pathogenic ALPK3 mutation. Only 2 of 13 (15%) pSCDs with HCM had premortem diagnosis. A greater proportion of pSCDs with HCM had autopsy-confirmed arrhythmic cause than pSCDs without HCM (11/13 [85%] vs. 547/1009 [54%], p=0.03). HCM contribution to pSCD burden decreased with age (p=0.003), highest among victims <35 years, accounting for 7.1% (6/84) of pSCDs and 9.4% (3/32) of SADs. Genetic testing of 317 consented pSCDs (5/12 meeting pathologic or TTE HCM criteria) yielded pathogenic mutations in 40% (2/5), and identified 1 additional case without clinical phenotype. Conclusions: In this 11-year countywide postmortem study, HCM meeting pathologic, clinical, or genetic criteria was associated with autopsy-confirmed arrhythmic cause of sudden death, accounting for 2% of SADs, highest in cases <35 years. As 85% of cases were undiagnosed before pSCD, the true burden of HCM-related sudden death may be substantially underestimated.