Integrated Inflammatory and Epigenetic Signatures in Peripheral Blood Mononuclear Cells Reveal Novel Mechanisms of Valvular Heart Disease-Associated Atrial Fibrillation

BackgroundThe molecular drivers distinguishing valvular heart disease-associated atrial fibrillation (VHD-AF) from other AF etiologies remain poorly defined, with prior transcriptomic studies largely focused on non-valvular AF. MethodsWe performed RNA sequencing on peripheral blood mononuclear cells (PBMCs) from 15 patients with VHD-AF and 15 age- and sex-matched healthy controls. Bioinformatic analyses identified differentially expressed genes (DEGs), enriched pathways, and protein-protein interaction (PPI) networks. ResultsWe identified 3,308 DEGs (2,891 upregulated, 417 downregulated) in VHD-AF patients. Functional enrichment revealed two dominant mechanisms: (i) a pronounced systemic inflammatory response, with significant enrichment in cytokine-cytokine receptor interaction (P=1.2e-15) and TNF signaling pathways (P=3.4e-08); and (ii) a core epigenetic module centered on nucleosome assembly (P=8.9e-12) and histone-related genes. PPI network analysis identified a high-confidence hub module (Cluster 1) overwhelmingly composed of histone genes (e.g., H4C6, H3C13). ConclusionThis first PBMC transcriptomic map of VHD-AF reveals a convergent pathology of chronic inflammation and widespread epigenetic remodeling. The findings nominate TNF inhibition and histone-modifying agents as potential therapeutic strategies and position PBMC-derived signatures as minimally invasive biomarkers for this specific AF population.