Molecular and Genomic Mechanisms Underlying the Pathophysiology of Atrial Fibrillation

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and a major cause of cardiovascular morbidity and mortality. Despite major therapeutic advances, the molecular determinants of AF initiation and persistence remain incompletely defined.  Methods: Current genomic and functional evidence were synthesised from large-scale genome-wide association studies (GWAS), transcriptomic, proteomic, and epigenomic investigations. Key molecular pathways implicated in calcium handling, fibrosis, and transcriptional regulation were reviewed with reference to translational models.  Results: Over one hundred AF-associated loci have been identified, most located within non-coding regulatory regions. The 4q25 locus near PITX2 shows the strongest and most reproducible association. Variants at this site influence calcium- handling proteins (SERCA2, RyR2) and modulate atrial electrophysiology. Integrative multi-omic analyses reveal disturbed Wnt, Notch, and BMP signalling, enhanced atrial fibrosis, and altered metabolic gene expression. Polygenic risk scores improve AF prediction beyond traditional risk factors.  Conclusions: AF results from the interaction of genetic predisposition and environmental stressors that converge on shared molecular pathways controlling calcium flux, structural remodelling, and inflammation. Translational integration of genomic and physiological data offers a pathway towards precision-based prevention and therapy.