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
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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.
Clinical Perspective
What is new?
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This study is the first community-based analysis to comprehensively characterize pre-arrest sex-associated profiles across clinical, ECG, and echocardiographic domains, externally validate them, and compare them with a community reference population.
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Women with SCA were more strongly associated with non-cardiac comorbidities, LVH, preserved LVEF, and mitral valve abnormalities, whereas male cases were characterized by coronary and peripheral vascular disease, atrial fibrillation, prolonged PR and QTc intervals, premature contractions, and reduced LVEF.
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Several sex associations, including QTc prolongation, LVH, body mass index, heart failure, and dementia, differed in magnitude or direction from patterns in the community reference population.
What are the clinical implications?
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Our findings suggest candidate features for future sex specific risk factor analyses and potential components for sex-specific risk models for SCA.
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Clinicians may need to recognize the critical need to extend beyond dependence on just the value of the left ventricular ejection fraction for SCA risk prediction, especially in women.
