Sex Differences in Circulating Biomarkers of Cardiovascular Disease

Abstract

Background: Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in cardiovascular disease (CVD).

Objectives: This study sought to investigate sex differences in circulating biomarkers representative of biological pathways implicated in the development of CVD among Framingham Heart Study participants.

Methods: The authors measured 71 circulating CVD protein biomarkers in 7,184 participants (54% women, mean age 49 years). Multivariable models were used to evaluate the associations of sex, menopause, and hormone status with biomarkers. Cox models were used to examine whether sex modified the association of biomarkers with incident CVD.

Results: Of 71 biomarkers examined, 61 (86%) differed significantly between men and women, of which 37 were higher in women (including adipokines and inflammatory markers such as leptin and C-reactive protein), and 24 were higher in men (including fibrosis and platelet markers such as MMP-8 (matrix metalloproteinase-8) and TIMP-1 (tissue inhibitor of metalloproteinases 1); false discovery rate q < 0.05 for all). Sex differences in biomarker profiles were most pronounced between pre-menopausal women versus men, with attenuated sex differences among post-menopausal women not taking hormone replacement therapy. Sex modified the association of specific biomarkers with incident CVD, including CD14 and apolipoprotein B (p_interaction <0.05 for all).

Conclusions: In a predominantly Caucasian population, the authors identified widespread sex differences in circulating biomarkers that reflect distinct pathways implicated in CVD, including inflammation, adiposity, fibrosis, and platelet homeostasis. Menopause and hormone status accounted for some, but not all, of the observed sex differences. Further investigation into factors underlying sex-based differences may provide mechanistic insight into CVD development.

Keywords: biomarkers; cardiovascular disease; female; sex.

Figure 1.. Multivariable-adjusted associations of single biomarkers with sex.

Volcano plot showing relative biomarker concentrations in men and women. Positive x-values (red) represent biomarkers that are higher in women and negative x-values (blue) represent biomarkers that are higher in men. Abbreviations: FDR = false discovery rate.

Figure 2.. Heatmap of sex differences in biomarkers by menopausal and hormonal status.

Heatmap displays relative sex differences in biomarker concentrations among (1) all women, (2) pre-menopausal women, (3) post-menopausal women, (4) post-menopausal women not on HRT, and (5) post-menopausal women on HRT compared with men. Positive ß-coefficients (red) represent biomarkers that are higher in women and negative ß (blue) represent biomarkers that are higher in men.

Figure 3.. Sex-specific multivariable-adjusted associations of single biomarkers with outcomes.

Association of biomarkers with CVD outcomes is modified by sex. Biomarkers presented here show sex*biomarker interaction P<0.05. All biomarkers are rank normalized. Original assay units are pg/mL. Abbreviations: HR = hazard ratio Central Illustration. Age-adjusted and multivariable-adjusted associations of single biomarkers with sex. Waterfall plot displays ß regression coefficients for individual biomarkers. ß-coefficients represent difference in biomarker concentration between women and men (referent), units expressed in standard deviations of rank-normalized biomarker. Positive ß-coefficient represents higher concentration in women and negative ß-coefficient represents higher biomarker concentration in men. Red bars represent age-adjusted model, blue bars represent multivariable-adjusted model. Multivariable model adjusts for age, sex, SBP, HTN treatment, HDL, total cholesterol, BMI, DM, and smoking. Abbreviations: MV = multivariable.

Central Illustration.. Sex Differences in Cardiovascular Biomarkers.

Multivariable-adjusted associations of single biomarkers with sex. Waterfall plot displays ß regression coefficients for individual biomarkers. ß-coefficients represent difference in biomarker concentration between women and men (referent), units expressed in standard deviations of rank-normalized biomarker. Positive ß-coefficient represents higher concentration in women and negative ß-coefficient represents higher biomarker concentration in men. Red bars represent higher concentrations in women, blue bars represent higher concentrations in men. Multivariable model adjusts for age, sex, SBP, HTN treatment, HDL, total cholesterol, BMI, DM, and smoking. Abbreviations: MV = multivariable..