TGF-β-Driven Atrial Fibrosis in Atrial Fibrillation: From Mechanistic Insights to Targeted Therapies

Abstract

The prevalence of atrial fibrillation (AF), one of the most common cardiac arrhythmias, has significantly increased, especially within the aging population. Atrial fibrosis, a hallmark of the structural changes seen in AF, is characterized by abnormal activation and proliferation of atrial fibroblasts accompanied by excessive deposition of extracellular matrix. The initiation and progression of fibrosis are regulated by multiple profibrotic cytokines, with transforming growth factor-beta (TGF-β) serving as the primary mediator. Elevated expression and activation of TGF-β are frequently observed in myocardial diseases, where it drives myofibroblast differentiation, migration, and collagen production via the Smad-dependent and Smad-independent pathways. These fibrotic alterations disrupt normal atrial electrical conduction, thereby facilitating the onset and progression of AF. This review summarizes the role of TGF-β-mediated fibrotic remodeling in AF pathogenesis and treatment. We explored the molecular mechanisms underlying TGF-β signaling in atrial fibrosis, evaluated its potential as a predictive biomarker for AF and recurrence after ablation, and discussed therapeutic strategies targeting this pathway. Increasing evidence from studies on natural and synthetic TGF-β inhibitors highlights the potential of modulating this signaling cascade to attenuate fibrosis and enhance clinical outcomes. Our review underscores the pivotal role of TGF-β signaling in AF development and supports its potential as a promising target for therapeutic intervention capable of improving the efficacy of antiarrhythmic treatments.