Atrial Cardiomyopathy in Atrial Fibrillation: Mechanistic Pathways and Emerging Treatment Concepts

Atrial fibrillation (AF) is increasingly recognized not merely as an arrhythmia, but as a clinical manifestation of atrial cardiomyopathy (AtCM)-a progressive, multifaceted disease of the atrial myocardium involving structural, electrical, mechanical, and molecular remodeling. AtCM often precedes AF onset, sustains its perpetuation, and contributes to thromboembolic risk independently of rhythm status. Emerging evidence implicates diverse pathophysiological drivers of AtCM, including inflammation, epicardial adipose tissue, metabolic dysfunction, oxidative stress, ageing, and sex-specific remodeling. The NLRP3 inflammasome has emerged as a central effector in atrial inflammation and remodeling. Gut microbial dysbiosis, lipid dicarbonyl stress, and fibro-fatty infiltration are also increasingly recognized as contributors to arrhythmogenesis. AtCM is further linked to atrial functional valve regurgitation and adverse outcomes in AF. Therapeutically, substrate-directed strategies-ranging from metabolic modulation and immunomodulation to early rhythm control-offer promise for altering the disease trajectory. This review synthesizes mechanistic insights into AtCM and discusses emerging therapeutic paradigms that aim not merely to suppress arrhythmia but to modify the underlying substrate. Recognizing AF as a syndrome of atrial disease reframes management strategies and highlights the urgent need for precision medicine approaches targeting the atrial substrate.