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

Abstract

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.

Keywords: atrial cardiomyopathy; atrial fibrillation; epicardial adipose tissue; fibrosis; inflammation; metabolic dysfunction; rhythm control; substrate modification.

Figure 1

Pathophysiological drivers of atrial cardiomyopathy in atrial fibrillation. Atrial cardiomyopathy (AtCM) arises from a convergence of diverse upstream mechanisms, including inflammasome activation, gut dysbiosis, lipid dicarbonyl stress, epicardial adipose tissue dysfunction, metabolic derangements, ageing, sex-specific remodeling, and genetic predisposition. These processes contribute to the structural, electrical, and thromboembolic remodeling of the atrial myocardium, fostering the initiation and perpetuation of atrial fibrillation (AF).

Figure 2

Pathophysiological continuum linking risk factors, atrial cardiomyopathy, atrial fibrillation, and adverse outcomes: therapeutic targets and interventional strategies. Atrial cardiomyopathy arises from the convergence of diverse risk factors—ageing, systemic inflammation, metabolic dysfunction, oxidative stress, and epicardial adipose tissue accumulation—which collectively drive maladaptive atrial remodeling. This remodeling manifests as progressive structural, electrical, and molecular alterations, creating a vulnerable substrate predisposed to the initiation and maintenance of atrial fibrillation. Once established, AF accelerates the underlying myocardial pathology, establishing a self-perpetuating cycle that amplifies thromboembolic risk and contributes to heart failure progression and mortality. Therapeutic strategies span the continuum from upstream prevention to disease modification and downstream rhythm stabilization. Lifestyle interventions, including sustained weight loss and management of sleep-disordered breathing, represent critical upstream targets. Pharmacologic modulation of neurohormonal and metabolic pathways—through RAAS inhibition, SGLT2 inhibitors, and GLP-1 receptor agonists—addresses the core mechanisms of remodeling. Targeted approaches aimed at inflammasome activation, oxidative injury, and fibro-inflammatory signaling offer mechanistically precise avenues for intervention. Rhythm control strategies, particularly early catheter ablation, and structural therapies such as cardiac resynchronization or mitral valve repair, hold promise for reversing remodeling and modifying clinical trajectory. This integrated framework reflects a paradigm shift toward substrate-directed, disease-modifying approaches in the management of atrial fibrillation.