Divergent Atrial Transcriptomic Signatures in Diabetic and Nondiabetic Atrial Fibrillation

ABSTRACT Background Diabetes mellitus (DM) increases the risk of atrial fibrillation (AF), but the molecular mechanisms underlying DM‐related atrial remodeling remain unclear. This study aimed to characterize transcriptomic differences, including microRNA (miRNA) profiles, between atrial tissue from AF patients with and without DM. Methods Right atrial appendage samples were collected from 12 patients with AF undergoing cardiac surgery (six with DM and six without DM). Total RNA was analyzed by high‐throughput RNA sequencing. Differentially expressed genes (DEGs) and miRNAs were identified using Welch's t ‐test ( p < 0.05), and pathway analyses were performed using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA). Results Forty‐six protein‐coding genes and nine miRNAs were differentially expressed between the two groups. Upregulated genes in the DM group, including MYH6 and SLN , were related to contractile and calcium‐handling functions, while downregulated genes, such as ADAMTS4 , CP , and histone family members, were linked to extracellular matrix and chromatin regulation. GO and GSEA analyses revealed activation of mitochondrial ATP synthesis pathways and suppression of immune and inflammatory signaling. Additionally, distinct miRNA expression changes—such as upregulation of miR‐3120 and downregulation of miR‐4524B and miR‐6503 —suggested potential epigenetic regulation mechanisms. Conclusions Transcriptomic profiling revealed that AF with DM is characterized by enhanced mitochondrial metabolism, suppressed immune pathways, and altered miRNA expression. These findings suggest that DM modifies the atrial substrate through metabolic and epigenetic mechanisms, providing novel insights into AF pathogenesis in diabetic patients.