Sex differences in molecular pathways underlying cardiovascular health in Black Americans.

Black Americans face a high burden of cardiovascular disease (CVD), with more than 60% of Black adult women affected. However, sex-specific molecular mechanisms underlying poor cardiovascular health (CVH) in this population remain largely unknown. In this study, we examined sex-specific transcriptomics signatures associated with CVH among Black adult men and women. Whole blood RNA-sequencing was performed on 373 Black adults. CVH was assessed using the American Heart Association Life's Simple 7 (LS7) score. Differential gene expression (DGE) analysis comparing participants with poor-to-intermediate CVH (LS7 < 10) versus ideal CVH (LS7 scores ≥ 10) was conducted using LIMMA. Sex-stratified functional enrichment analysis was conducted using FGSEA and ClueGo. Shared differentially expressed genes (DEGs) were evaluated using fixed-effects meta-analysis. Upstream transcription factor, cytokine, and kinase activities were inferred using DoRothEA and OmniPath to assess sex-specific gene expression regulation at the transcriptional, and post-transcription level. Among females, 430 DEGs were identified and indicated activation of RUNX2, PBX3, TFAP4 and enrichment of actin cytoskeletal pathways, consistent with vascular remodeling. In males with poor-to-intermediate CVH, 344 DEGs were detected and indicated inferred activation of GATA4, MAZ, and SOX10 and enrichment of pathways related to cardiac conduction and cellular metabolism. Thirteen DEGs were shared across sexes, including upregulation of DNAJC6, KANK2, SPTB, and MSTRG.22508, reflecting conserved stress response programs involving cytoskeletal remodeling and membrane stabilization. Although both sexes with poor-to-intermediate CVH exhibited suppression of adaptive immune effectors, in females the downregulation of KIR2DL4, KLRF1, and SH2D1B occurred alongside inhibition of RFX1/5, transcription factors essential for MHC class II expression and antigen presentation. In males, immune suppression was instead associated with inhibition of STAT1, indicating a shift away from cytokine-driven signaling. We identified distinct sex-specific molecular differences underlying CVH in a cohort of Black adults. Females with poor-to-intermediate CVH activate cytoskeletal and vascular remodeling pathways, consistent with structural reshaping. In contrast, males activate cardiac conduction and metabolic signaling programs, reflecting functional and bioenergetic compensation. Although both sexes exhibit immune repression in poor-to-intermediate CVH compared to ideal CVH, the mechanisms diverge, underscoring distinct sex-specific biological trajectories that may contribute to differential CVD risk and therapeutic effectiveness.