Cardiac Fibrosis in Dilated Cardiomyopathy: Transcriptomics Insights, Histological Correlations, and Organoid Model Verifications [RNA-seq II]

Dilated cardiomyopathy (DCM) represents a leading cause of heart failure among younger adults. Despite endomyocardial biopsy (EMB) transcriptome enriching our understanding of DCM, the link between its gene expression and phenotype remains unclear. RNA-seq analysis of 58 DCM samples and 12 publicly available control samples unveiled about 25,000 transcripts. A principal component analysis highlighted a distinct DCM-control separation. WGCNA revealed four transcriptome modules strongly associated with DCM. The purple module, which is the DCM-related module, was enriched with fibrosis-related genes and showed FSTL3 as a pivotal DCM-associated gene. , We further validated using cardiac fibrosis organoid models. Concurrently, FSTL3 expression reflected cardiac organoid fibrosis intensity. Furthermore, FGFR1 expression, along with its phosphorylation in DCM myocardial tissue, was correlated with fibrosis severity. Cardiac fibrosis organoid models treated with AZD4547, a selective FGFR1 inhibitor, suppressed fibrosis-related markers, underscoring its potential therapeutic efficacy against DCM-related cardiac fibrosis. Overall design: We established a cardiac organoid model using human induced pluripotent stem cell (hiPSC)-derived ventricular cardiomyocytes and epicardial cells. Three groups were compared: Control (n=3), Fibrotic condition (n=3), and Fibrotic condition treated with AZD4547 (n=3).