Sex-based differences in bi-atrial voltage in atrial fibrillation: a multimodal and digital twin approach to distinguish physiological variation from pathological remodelling

BACKGROUND: Sex-based differences in atrial voltage have been reported in atrial fibrillation (AF), but it is unclear whether these differences reflect pathological remodelling or physiological variation. OBJECTIVE: To assess sex-based differences in voltage, contextualised by complementary measures of substrate remodelling and AF mechanisms. METHODS: A multicentre, prospective study was conducted in patients scheduled for AF ablation. Bi-atrial voltage mapping was combined with electrophysiological assessment, structural and functional assessment using cardiac MRI, and mechanistic interrogation using patient-specific digital twins. Propensity score matching was used to account for baseline differences between sexes. Exploratory receiver operating characteristic analysis was conducted to estimate sex-specific mean left atrial voltage cutoffs based on 12-month arrhythmia recurrence status. RESULTS: Seventy patients (62±12 years; 31% female) were included. Women demonstrated lower mean bipolar voltages than men, with this difference persisting after 1:1 propensity score matching (n=44) in both left (1.66±0.71mV versus 2.12±0.55mV, p=0.028) and right atria (1.79±0.49mV versus 2.20±0.59mV, p=0.025). Propensity score-matched analyses revealed no significant differences in other structural, functional, or electrophysiological parameters, with digital twin analyses demonstrating no significant differences in AF termination, phase singularity count, wave dynamics, or response to virtual ablation. Women had lower mean left atrial voltage cutoffs calibrated to 12-month arrhythmia recurrence status than men (1.74mV versus 2.26mV). CONCLUSIONS: Women with AF exhibit lower bi-atrial voltages despite comparable substrate characteristics and AF mechanisms, suggesting that observed voltage differences may reflect physiological variation rather than pathological remodelling. Sex-specific voltage thresholds may improve the accuracy of substrate assessment and facilitate personalised treatment.