Distinct Sex-Associated Phenotypes of Sudden Cardiac Arrest Across Clinical, ECG, and Echocardiographic Domains: Replication in Two Communities and Comparison with the Framingham Heart Study

Background: Sex differences in sudden cardiac arrest (SCA) incidence and outcomes are well established, but risk stratification underperforms in women. It is important to delineate sex-specific patterns in SCA across clinical, electrocardiographic, and echocardiographic domains. Methods: We studied out-of-hospital SCA cases from the Oregon Sudden Unexpected Death Study (ORSUDS; Portland, 2002-2020; discovery) and Prediction of Sudden Death in Multi-Ethnic Communities (PRESTO; Ventura County, 2015-2024; external replication). Sex differences in 38 comorbidities, 19 ECG and 12 echocardiographic measures were estimated using multivariable-adjusted logistic regression. Female sex was the modeled dependent measure (male as reference). ORSUDS estimates were compared with those in the Framingham Heart Study (FHS), a community-based reference cohort, using FDR-adjusted Cochran Q tests. Results: Among 5130 ORSUDS cases, 1715 (33.4%) were women (median age, 70.4 years [IQR, 58.7-81.8]) and 3415 (66.6%) were men (65.6 [55.0-76.8]). Compared with men, women had higher BMI (per 5 kg/m2, 1.11 [1.08-1.15]) and higher odds of thyroid disease (2.56 [2.17-3.13]), asthma (2.33 [1.92-2.86]), mood disorder (2.17 [1.85-2.50]), dementia (1.27 [1.02-1.56]), and left ventricular hypertrophy (LVH, 3.13 [2.44-4.00]). Women also had lower odds of coronary artery disease (0.61 [0.52-0.71]), atrial fibrillation (0.67 [0.56-0.79]), prolonged QTc (0.45 [0.35-0.57]), prolonged PR (0.53 [0.41-0.68]), premature contractions (0.77 [0.60-0.98]), sleep apnea (0.53 [0.43-0.65]), and reduced LVEF (0.40 [0.29-0.54]). Most findings were replicated in PRESTO (n=2719). In contrast, several of these differences were reversed in the community (FHS, n=3539;FDR-significant): prolonged QTc was more common in women, whereas LVH, dementia, heart failure, and higher BMI were more common in men. Conclusions: Sex differences among SCA cases were mostly reproducible in SCA cohorts, and distinct from sex-related patterns in the community. These results have implications for development of sex-specific SCA risk assessment and prevention strategies.