Mechanistic study of ECM phenotype switch in epicardial adipose tissue in atrial fibrillation: A bioinformatics study

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Epicardial adipose tissue (EAT) is closely associated with AF, but its molecular mechanisms remain incompletely understood. This study aimed to investigate the extracellular matrix (ECM) remodeling characteristics of AF-related EAT. Using the publicly available RNA-sequencing dataset GSE135445 (AF: n = 6, sinus rhythm: n = 6), we performed differential expression analysis (DESeq2) on gene-level counts regenerated from the raw sequencing reads, single-gene analysis focusing on ECM gene families, and gene set enrichment analysis. An "ECM phenotype switch" hypothesis was proposed based on the coordinated dysregulation of interstitial and basement membrane collagen genes. Differential expression analysis identified 610 differentially expressed genes. Notably, the basement membrane-specific collagen COL4A4 was significantly upregulated in AF (log2FC = 4.37, Padj = 2.7 × 10-9), accompanied by significant upregulation of COL4A3, whereas interstitial collagen repair genes (COL1A1, COL1A2, COL3A1, and FN1) showed consistent downregulation, defining an "ECM phenotype switch" characterized by suppressed interstitial repair coupled with independent basement membrane deposition; the fibrinolysis inhibitor SERPINE1 (plasminogen activator inhibitor-1) was also markedly upregulated (log2FC = 3.89, Padj = .026). Gene set enrichment analysis implicated ribosome biogenesis and translation dysregulation as a potential associated upstream program (normalized enrichment score = 2.26-3.03 and false discovery rate = 0.012-0.013). AF-related EAT exhibits an ECM phenotype switch characterized by suppressed interstitial collagen repair and independent basement membrane collagen deposition, potentially associated with ribosome biogenesis dysregulation. These hypothesis-generating findings provide a novel framework for understanding EAT-mediated atrial remodeling in AF.