The Genetic Mechanisms and Pathology of Atrial Fibrillation: A Narrative Review

Atrial fibrillation (AF), the most prevalent tachyarrhythmia worldwide, is a complex condition influenced by genetic, structural, and environmental factors. While AF in the elderly is often associated with underlying cardiac disease, early-onset or “lone” AF (LAF) exhibits a stronger genetic predisposition. Studies have identified both monogenic and polygenic contributors to AF risk. Monogenic mutations, inherited in Mendelian patterns, often affect ion channels and regulatory proteins, while polygenic variants modulate susceptibility and interact with environmental factors. Genome-wide association studies (GWAS) and exosome-wide association studies (ExWAS) have expanded our understanding of AF genetics, identifying numerous susceptibility loci, though challenges remain in linking these variants to specific molecular mechanisms. Pathophysiologically, AF results from a balance of triggers, drivers, and substrates. Triggers, such as ectopic foci in the pulmonary veins, initiate AF episodes, while structural and electrical remodeling perpetuates the arrhythmia. Fibrosis, atrial dilation, and tachycardia-induced remodeling promote reentry circuits and irregular conduction, increasing AF vulnerability. The interplay between genetic predisposition and remodeling processes underscores the complexity of AF maintenance, particularly in persistent AF forms. Emerging insights into AF genetics and pathophysiology highlight the need for personalized approaches to its prevention and management. Understanding genetic risk, combined with targeted therapies addressing structural and electrical remodeling, holds promise for improved patient outcomes. Future research into AF’s molecular and genetic mechanisms will be key to advancing precision medicine in this field.