Blood analysis of 15 valvular heart disease patients with atrial fibrillation revealed 3,308 altered genes compared to healthy controls, with 2,891 upregulated and 417 downregulated. Two key pathways emerged: intense systemic inflammation involving TNF signaling and cytokine interactions, plus widespread epigenetic remodeling centered on histone assembly genes like H4C6 and H3C13. This blood-based molecular signature offers significant clinical potential. Unlike traditional cardiac tissue studies requiring invasive procedures, peripheral blood sampling could enable routine monitoring of this specific atrial fibrillation subtype. The inflammatory findings suggest TNF inhibitors—already used for autoimmune conditions—might benefit these patients, while the histone changes point toward epigenetic therapies as novel treatment avenues. However, this preprint awaits peer review and has notable limitations: the small 15-patient cohort needs validation in larger populations, and the study establishes association rather than causation between these molecular changes and disease progression. The research represents an incremental but meaningful advance in personalizing atrial fibrillation treatment, potentially moving beyond one-size-fits-all approaches toward molecularly-guided therapy selection for valvular disease patients.