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An ICAM1⁺ inflammatory fibroblast state in atrial fibrillation and metabolic-stress-associated atrial remodeling
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DOI：10.1186/s13062-026-00932-y.png)
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Abstract
En 中文
Atrial fibrillation (AF) is associated with inflammatory and fibrotic atrial remodeling, but the fibroblast states connecting these processes remain incompletely defined. ICAM1 is a key inflammatory adhesion molecule, yet its cell-state context within atrial fibroblast heterogeneity remains unclear. Reanalysis of human left atrial single-cell RNA sequencing data identified an ICAM1⁺ inflammatory fibroblast state that was not detected among fibroblasts from sinus rhythm samples in this dataset and represented 17.3% of fibroblasts in AF samples. Trajectory inference, pathway enrichment, and co-expression network analysis associated this state with inflammatory and matrix-remodeling programs. In diet-induced obesity (DIO) mice, susceptibility to burst pacing–induced AF-like atrial tachyarrhythmia episodes was higher than in normal-diet controls (5/8 vs. 0/8 mice; Fisher’s exact P = 0.0256), accompanied by left atrial remodeling. RNA fluorescence in situ hybridization supported increased Icam1 expression in Tcf21⁺ fibroblast-associated stromal cells. ICAM1 protein was increased in CD140a-enriched atrial fibroblast fractions from DIO mice (relative ICAM1/β-actin: 2.70 ± 0.46 vs. 1.00 ± 0.15; P = 0.0001). In primary human cardiac fibroblasts, ICAM1 knockdown reduced migration under TGF-β1-stimulated conditions (49.90 ± 1.63% vs. 20.44 ± 1.51% wound closure; P < 0.0001), and reduced α-SMA and Collagen I fluorescence signals. Lentiviral TNXB overexpression partially restored Fibronectin and Collagen I expression under ICAM1-knockdown conditions (Fibronectin: 2.26 ± 0.21-fold vs. 4.11 ± 0.28-fold, P < 0.0001; Collagen I: 1.09 ± 0.06-fold vs. 1.54 ± 0.09-fold, P = 0.0004). This study identifies an AF-enriched ICAM1⁺ inflammatory fibroblast state associated with inflammatory–matrix remodeling programs. The findings support Icam1 upregulation in fibroblast-associated atrial stromal cells during DIO-associated remodeling and link ICAM1 perturbation to altered fibroblast migration and selected TNXB-associated matrix-protein readouts. Further fibroblast-specific and clinically annotated studies are needed to define causality and translational relevance.
Keywords:
Obesity
Atrial fibrillation
ICAM1
Inflammation
Fibroblast
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