Jinjin Wu, Yuliang Wang, Weizhuo Liu, Zhengjie Wang, Jingjing Liu, Zikun Wang, Lei Yang, Lin Sun, Yilin Pan, Yangyang Sun, Li Zhang, Yongjun Qian, Yangyang Zhang
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.