Atrial electrical remodeling spans molecular, electrical, and structural alterations that shorten refractoriness, facilitate reentry, and ultimately create the atrial substrate underlying atrial fibrillation. These changes include ion-channel dysfunction, calcium-handling abnormalities, oxidative injury, and deranged proteostasis that are tightly intertwined with atrial fibrosis and cardiomyopathy. High-density mapping and advanced imaging now allow in-vivo staging of this substrate: left atrial low-voltage areas and functional conduction phenomena identify regions of fibrosis and conduction slowing that are associated with post-ablation recurrence, although the benefit of LVA-targeted substrate ablation remains uncertain. Building on this pathophysiological framework, this review integrates experimental and clinical evidence to guide decision-making in atrial fibrillation therapy, emphasizing early rhythm-control strategies and careful substrate characterization in sinus rhythm. Pulmonary vein isolation is presented as the cornerstone of ablation, while adjunctive substrate-oriented strategies - including low-voltage modification, hybrid surgical-catheter approaches, and vein-of-Marshall-based techniques - are discussed as investigational options for selected high-risk patients. Finally, the review contrasts PV-dependent and non-PV-dependent forms of atrial fibrillation and appraises emerging AI-guided electrogram interpretation within a mechanism-driven framework for personalized management of atrial electrical remodeling.
Frontera et al. (2026) studied this question. Low-voltage areas identified by high-density mapping are associated with recurrence after ablation in atrial fibrillation, underscoring the need for careful substrate characterization.