Sex-based differences in bi-atrial mechanisms of atrial fibrillation and response to pulmonary vein isolation: a digital twin study
N Bodagh, V Vigneswaran, A Gharaviri, I Kotadia, M Klis, K Maciunas, A Von Kietzell, A Chiribiri, S Niederer, N Grubb, S Haldar, M O'Neill, S E WilliamsAbstract
Background
Sex-based differences have been reported in atrial fibrillation (AF) with an increased prevalence in men, yet a higher rate of arrhythmia recurrence following catheter ablation in women. The mechanisms responsible for this disparity remain unclear. Patient-specific computational digital twins enable controlled in silico interrogation of AF pathophysiology and can be utilised to explore sex-based differences in baseline AF mechanisms and response to pulmonary vein isolation.
Purpose
To explore sex-based differences in (1) baseline AF mechanisms and (2) mechanistic response to virtual pulmonary vein isolation.
Methods
Bi-atrial digital twins incorporating MRI-derived fibrosis distribution were constructed from atrial late gadolinium enhancement scans of 64 patients (36% female) undergoing first-time ablation (Figure 1). Simulations were conducted with the Courtemanche–Ramirez–Nattel human atrial cell model incorporating AF electrical remodelling. Incremental pacing from 20 predefined bi-atrial sites was performed under baseline conditions and repeated following virtual pulmonary vein isolation, yielding 40 simulations per patient (2,560 simulations total). Simulations were analysed to quantify AF initiation and termination rates as well as indices of activation complexity (wave count, phase singularity count, and wave coverage (wave area/bi-atrial area)).
Results
Under baseline conditions, female patients demonstrated a lower AF initiation rate compared with male patients (76±13% versus 85±12%; p=0.008) but no significant sex differences were observed in AF termination rate, bi-atrial wave count, phase singularity number, or wave coverage (Figure 2). Virtual pulmonary vein isolation significantly reduced the AF initiation rate and suppressed phase singularity burden in the entire cohort. The magnitude of AF initiation reduction was similar in female and male patients (Δ −8.9±8.3% versus −10.2±6.7; p=0.86), with no significant sex differences in changes in termination rate, wave count, phase singularity count, or wave coverage following virtual pulmonary vein isolation (p>0.05).
Conclusion
Male patients exhibit greater AF initiation propensity in bi-atrial digital twins which may contribute to the higher clinical prevalence of AF in men. However, once AF is established, activation complexity and mechanistic response to pulmonary vein isolation are comparable between sexes, suggesting that previously observed differences in clinical ablation outcomes may not be explained by sex-specific differences in bi-atrial AF mechanisms alone.