Single nucleus transcriptomics reveals ITGA8-driven fibroblast remodeling in rheumatic valvular atrial fibrillation.

Atrial fibrillation (AF) associated with rheumatic valvular disease involves complex cellular remodeling of the atrial myocardium. Here, single-nucleus RNA sequencing of left atrial tissues from healthy donors and patients with persistent rheumatic valvular AF identified disease-associated transcriptional changes across major cardiac cell populations. Fibroblasts showed marked heterogeneity, with expansion of an ITGA8-enriched FB-C2-ELN state associated with extracellular matrix remodeling. Functional experiments demonstrated that ITGA8 promotes cardiac fibroblast proliferation, migration, and matrix production. In an ACh/CaCl2-induced rat model, fibroblast-targeted ITGA8 suppression reduced atrial fibrosis and AF susceptibility. These findings define cellular states associated with atrial remodeling and highlight fibroblast ITGA8 signaling as a regulator of fibrosis-related AF progression.