Towards mechanisms-driven strategy for persistent atrial fibrillation ablation: Leveraging digital twins.

Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting 1-2% of the global population, and is a major cause of stroke and heart failure. With the population aging, its prevalence is expected to increase further, imposing a growing burden on healthcare systems. However, the gold standard treatment-pulmonary vein isolation with catheter ablation that primarily prevents pulmonary vein triggers from initiating fibrillatory conduction-has limited efficacy in the persistent form of AF (PsAF), which is characterized by atrial fibrotic remodeling. Thus far, numerous intra-atrial electrogram-based mapping approaches have been developed to identify PsAF arrhythmogenic substrate locations capable of attracting reentries (LRs) and guide substrate modification in clinical practice; however, their clinical effectiveness remains controversial and the optimal ablation strategy remains unclear. Furthermore, extensive substrate ablation may adversely affect patients post-ablation due to scar-related atrial tachycardia or impaired atrial function despite successful AF control. Recently, personalized heart digital twins (DTs) have emerged as a promising technology for precision medicine, enabling non-invasive patient-specific reconstruction of cardiac electrical activity using clinical imaging and electrophysiological data. Personalized DTs allow investigation of patient-specific electrophysiological behavior, prediction of arrhythmia inducibility, and identification of arrhythmogenic substrates pre-procedurally. In this review, we summarize the mechanisms underlying PsAF maintenance, current limitations of PsAF ablation therapy, and recent advances in DT technology, highlighting its potential to facilitate mechanism-driven, personalized ablation planning and improve PsAF patient care.