Atrial Fibrillation and Aging: The Role of MicroRNA Networks Across Cellular, Structural, and Electrophysiological Remodeling

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting millions worldwide with an incidence that rises with age, and it carries a substantially increased risk of ischemic stroke, heart failure, and cognitive decline. Aging is its most important independent risk factor, yet biological rather than chronological age progressively alters the atrial substrate through interactions among cellular and tissue processes that increase susceptibility. Although the mechanisms linking biological aging to AF remain incompletely elucidated, microRNAs (miRNAs) have been implicated. Human studies show age-associated changes in atrial conduction, molecular regulation, and miRNA expression, while experimental models identify modifiable pathways contributing to structural or electrophysiological vulnerability. Within this architecture, miRNAs emerge as context-dependent regulatory and intercellular signaling nodes. Here we identify the missing-edge problem as a central limitation of the field, distinguishing mechanistic evidence from circulating-miRNA biomarker associations, and experimental targetability from clinical efficacy. We propose a model of networked atrial aging in which heterogeneous age-associated cellular states converge on structural and electrophysiological vulnerability. Further studies connecting aging state, miRNA targets, atrial phenotype, and AF within one biological framework are needed to establish causal pathways and enable biomarker and therapeutic translation.