Sex differences in proteomics of cardiovascular disease: results from the Yale-CMD registry

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Abstract Background Cardiovascular disease is the leading cause of death globally, with notable sex differences in its presentation, mechanisms, and outcomes. Purpose We investigated the serum proteomic profiles of coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) patients to uncover sex-specific biological pathways and their roles in disease development. Methods Using the Yale-CMD registry's biobank, we performed a secondary analysis on adults with ischemic symptoms who underwent cardiac PET/CT and were not experiencing myocardial infarction, hemodynamic instability, acute heart failure, febrile illness, dialysis, or consent incapacity. Using PET/CT, we classified participants as controls (normal coronary flow reserve [CFR], no perfusion defect or coronary calcification), CAD (if new perfusion defect or known revascularization), or CMD (CFR <2 without defect or calcification). Using proximity extension assays (Olink® Explore 3072) in high-throughput proteomic analysis, we examined 2944 plasma proteins. Differential protein abundance analysis was performed using linear regression models adjusting for age, race, body mass index, history of diabetes, dyslipidemia, hypertension, and smoking to detect significant changes in protein abundance, with false discovery rate (FDR) control. Functional pathway analyses were conducted to identify the biological functions of the sex-differentially expressed proteins. Results Between 2014-2020, 91 patients of 190 in the registry provided blood samples for this analysis. Participants had median age 56.0 (50.0 - 62.0) years with 66% females. Among these, 48% were controls, 24% had CAD and 27% had CMD. Using linear regression adjusting for confounders, we identified significant sex differences in protein levels related to reproductive functions across all 3 cohorts (Fig. 1). In the CAD cohort, FSHB was upregulated in females, while INSL3 and EDDM3B were upregulated in males (FDR < 0.05). In the CMD cohorts, 6 proteins were differentially expressed (FDR < 0.05), with SCGB3A1 and HGFAC higher in females, and INSL3, SPINT3, EDDM3B, and KLK3 higher in males. Pathway analysis revealed that among patients with CAD, females had upregulation in immune system processes (Fig. 2A), while males showed upregulation of proteins related to endothelial regulation of blood flow (Fig. 2B). Among patients with CMD, females showed upregulation of lipid and glucose metabolism (Fig. 2C), while males showed upregulation of angiogenesis-related proteins (Fig. 2D). Conclusion We demonstrated significant sex differences in proteomic profiles among patients with CAD and CMD, underscoring the potential importance of sex-specific pathways in the pathophysiology of CVD. Our finding supports a need for large-scale validation studies to develop sex-tailored therapeutic strategies and advance precision medicine in cardiovascular health.Differential protein expression by sexPathway overrepresentation