Abstract / Summary
Abstract Background Sexual dimorphism in heart failure (HF) is well-recognized. Underlying transcriptomic mechanisms in prior studies that often-treated sex as a covariate, masking fundamental differences in cardiac remodeling. This study aimed to investigate sex-stratified RNA-seq analysis across HF subtypes to reveal distinct transcriptomic programs and provide a comprehensive, etiology-specific, sex-biased gene expression. Methods Left ventricular RNA-sequencing data from 366 samples — non-failing donors (NFD; n = 166), dilated cardiomyopathy (DCM; n = 166), hypertrophic cardiomyopathy (HCM; n = 28), and peripartum cardiomyopathy (PPCM; n = 6) were obtained from the MAGNet consortium (GSE141910), yielding expression data for 20781genes. Sex-stratified analyses integrated differential gene expression (DGE), age- and race-adjusted analysis of covariance (ANCOVA), upstream transcription factor (TF) enrichment, and functional pathway analysis. Results Median age was 55 years (53% male, 66% Caucasian). DCM exhibited greater DGE in males (2,438 upregulated/2,560 downregulated) than females (292/118), whereas HCM showed greater DGE in females (33/9) than males (19 upregulated only). Functional enrichment revealed distinct sex- and etiology-specific profiles: in males, immune/cytoskeletal processes in DCM and vascular/cytokine signaling in HCM; in females, immune regulation in DCM and Cell morphogenesis/post-translational protein modification in HCM. Upstream TF mapping revealed sex-divergent regulators—male networks anchored by SPI1/HIF1A and female networks by SP1, around a conserved, hormone-responsive STAT5/PGR core. SMOC2 (SPARC-related modular calcium-binding protein 2) was consistently upregulated as a sex- and etiology-independent marker of pathological remodeling (p = 2.2×10⁻¹⁶). Conclusions Although the transcriptomic architecture is substantially shared across sexes, HF exhibits etiology-specific sexual dimorphism and divergent biological programs. These sex-biased transcriptomic signatures may inform potential precision cardiovascular therapeutics.