Does sex modify an association of electrophysiological substrate with sudden cardiac death? The Atherosclerosis Risk in Communities (ARIC) study

BACKGROUND: Sex is a well-recognized risk factor for sudden cardiac death (SCD). We hypothesized that sex modifies the association of electrophysiological (EP) substrate with SCD. OBJECTIVE: The purpose of this study was to determine whether there are sex differences in electrocardiographic (ECG) measures and whether sex modifies the association of ECG measures of EP substrate with SCD. METHODS: Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n = 14,725; age 54.2 ± 5.8 years; 55% female; 74% white) were included. EP substrate was characterized by heart rate, QRS, QTc, Cornell voltage, spatial ventricular gradient (SVG), and sum absolute QRST integral (SAI QRST) ECG metrics. Two competing outcomes were adjudicated: SCD and non-SCD. Interaction of ECG metrics with sex was studied in Cox proportional hazards and Fine-Gray competing risk models. Model 1 was adjusted for prevalent cardiovascular disease (CVD) and risk factors. Time-updated model 2 was additionally adjusted for incident nonfatal CVD. Relative hazard ratio (RHR) and relative subhazard ratio with 95% confidence interval (CI) for SCD and non-SCD risk for women relative to men were calculated. Model 1 was adjusted for prevalent CVD and risk factors. Time-updated model 2 was additionally adjusted for incident nonfatal CVD. RESULTS: Over median follow-up of 24.4 years, there were 530 SCDs (incidence 1.72; 95% CI 1.58–1.88 per 1000 person-years). Women compared to men experienced a greater risk of SCD associated with Cornell voltage (RHR 1.18; 95% CI 1.06–1.32; P = .003), SAI QRST (RHR 1.16; 95% CI 1.04–1.30; P = .007), and SVG magnitude (RHR 1.24; 95% CI 1.05–1.45; P = .009), independently from incident CVD. CONCLUSION: In women, the global EP substrate is associated with up to 24% greater risk of SCD than in men, suggesting differences in underlying mechanisms and the need for sex-specific SCD risk stratification.