Transmural heterogeneity in 3D fibrosis distribution is associated with endo‐epicardial electrical dyssynchrony in persistent atrial fibrillation

Despite the established role of endo-epicardial dissociation in the substrate of persistent atrial fibrillation (PsAF), the underlying mechanisms within the 3D atrial wall that lead to this phenomenon are not fully understood. Using personalized digital twin (DT) technology, we investigated the association between 3D transmurally heterogenous fibrosis architecture and endo-epicardial dissociation in PsAF. LGE-MRI scans from 21 PsAF patients were used to generate bi-atrial DTs. Following virtual induction of reentry using programmed stimulation, a comparative analysis of the electrophysiological and structural properties of reentry-sustaining regions (RRs, n = 91) against controls (non-RRs, n = 73) was performed. RRs exhibited significantly greater endo-epicardial dissociation compared to non-RRs, evidenced by larger differences in median transmembrane potential (60.1 vs. 4.1 mV, P < 0.001) and local activation times (55 vs. 14.9 ms, P < 0.001). Lower dice similarity coefficient (DSC) was observed in RRs compared with non-RRs (median 0.731 (IQR 0.660-0.812) versus 0.880 (IQR 0.642-0.971), respectively; P = 0.0009). In multivariable logistic regression, fibrosis percentage, transmembrane voltage difference, and DSC were independently associated with RR status, whereas LAT difference was not. Our findings reveal that 3D transmurally heterogeneous fibrosis architecture is associated with endo-epicardial electrical dissociation in PsAF, with increased dissociation observed in regions harbouring reentrant circuits. Our findings advance the mechanistic understanding of PsAF arrhythmogenesis and provide a rationale for developing novel mapping and ablation strategies that account for the transmural complexity of the atrial substrate. KEY POINTS: Persistent atrial fibrillation (PsAF) remains a significant clinical challenge, often marked by high rates of post-ablation recurrence. While endo-epicardial dissociation is a known factor in the PsAF substrate, the underlying mechanisms within the 3D atrial wall that lead to this phenomenon remain incompletely understood. In this study, we utilized personalized digital twin technology derived from LGE-MRI scans of 21 patients to investigate the association between transmurally heterogeneous fibrosis and endo-epi electrical dissociation. Our findings reveal that 3D transmurally heterogeneous fibrosis architecture is associated with endo-epicardial electrical dissociation in PsAF. In multivariable analysis, fibrosis percentage, transmembrane voltage difference, and DSC were independently associated with reentrant activity. This work not only advances the mechanistic understanding of PsAF arrhythmogenesis but also suggests that successful clinical ablation strategies must account for the full 3D complexity of the atrial wall to target hidden intramural and epicardial pathways.