Cardiometabolic Substrate Modification in Atrial Fibrillation: Obesity and Epicardial Adipose Tissue in the Era of Incretin-Based Therapies and Catheter Ablation

Atrial fibrillation (AF) is increasingly understood as the electrical expression of a systemic and atrial cardiometabolic disease rather than an isolated disorder of pulmonary-vein triggers. Obesity, insulin resistance, hypertension, sleep-disordered breathing, heart failure with preserved ejection fraction, and visceral adiposity promote atrial stretch, inflammation, fibrosis, autonomic imbalance, and conduction heterogeneity. Epicardial adipose tissue (EAT), particularly the peri-left-atrial depot, may provide a local mechanistic bridge between systemic metabolic dysfunction and atrial cardiomyopathy through paracrine, inflammatory, fibrotic, and infiltrative pathways. This framework has direct therapeutic implications. Structured weight loss, cardiorespiratory fitness, alcohol reduction, and comprehensive risk-factor management can reduce AF burden and improve rhythm-control outcomes, although the magnitude of benefit varies across populations and trial designs. Incretin-based therapies have introduced a potentially important pharmacologic route to substrate modification. Semaglutide and tirzepatide produce substantial weight loss and favorable cardiovascular and heart-failure effects, while emerging observational and prospective data suggest lower AF incidence and post-ablation recurrence. However, evidence for reduced post-ablation recurrence remains predominantly non-randomized and is susceptible to residual confounding, treatment-selection effects, and healthy-user bias. Causality, weight-independent antiarrhythmic effects, optimal timing relative to ablation, and durability after treatment withdrawal remain unresolved. Observational sodium-glucose cotransporter-2 (SGLT2) inhibitor data support further investigation of cardiometabolic approaches to rhythm control, although randomized evidence has not consistently demonstrated benefit. Our review integrates mechanistic, imaging, lifestyle, pharmacologic, and electrophysiological evidence and proposes a practical model in which catheter ablation and cardiometabolic substrate modification are complementary strategies.