Epigenetic Drivers of Atrial Fibrillation: Mechanisms, Biomarkers, and Therapeutic Targets

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia, associated with significant morbidity, mortality, and healthcare burdens. Despite therapeutic advances, recurrence rates remain high, particularly in persistent AF, underscoring the need for deeper mechanistic insight. Epigenetic regulation-comprising DNA methylation, histone modifications, chromatin remodeling, RNA methylation, and non-coding RNAs-has emerged as a key contributor to the structural, electrical, and inflammatory remodeling underlying AF. These mechanisms operate at the interface of genetic susceptibility and environmental exposure, offering a dynamic framework for understanding disease progression. Systemic stressors such as aging, obesity, diabetes, hypertension, hypoxia, and alcohol have been shown to induce epigenetic reprogramming in atrial tissue, further promoting atrial cardiomyopathy and arrhythmogenesis. Additionally, circulating epigenetic markers, particularly microRNAs, are being investigated for their potential in AF diagnosis, risk stratification, and therapeutic monitoring. Therapeutic strategies targeting epigenetic pathways-ranging from histone deacetylase inhibitors and miRNA-based therapeutics to CRISPR/dCas9-mediated epigenome editing-are under investigation. Additionally, sodium-glucose cotransporter 2 inhibitors may indirectly influence epigenetic programs and miRNA expression relevant to atrial remodeling. While promising, these approaches require further validation in terms of safety, delivery specificity, and long-term efficacy. High-resolution epigenomic mapping and integrative multi-omic approaches may enhance understanding of AF heterogeneity and enable personalized treatment strategies. This review provides an integrated appraisal of epigenetic mechanisms in AF and outlines their emerging diagnostic and therapeutic relevance.