Sex Differences in Circulating Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels and Adverse Outcomes in Coronary Artery Disease

Abstract

Background Women have higher circulating levels of soluble urokinase-type plasminogen activator receptor (suPAR), and elevated suPAR is associated with cardiovascular risk. The independent association of sex with suPAR and the impact of sex on its association with cardiovascular risk are unknown. Methods and Results Plasma suPAR was measured using ELISA in 2 cohorts of 666 asymptomatic individuals (49 years, 65% women) and 4184 patients with coronary artery disease (63 years, 37% women). Independent association of sex with suPAR was studied using linear regression models adjusted for demographics, risk factors, and visceral adiposity in asymptomatic participants. Impact of sex on association of suPAR with all-cause mortality was studied in patients with coronary artery disease using multivariable-adjusted Cox models. Sex-specific suPAR cutoffs for predicting all-cause mortality were calculated. Asymptomatic women had 10% higher suPAR compared with men after adjusting for confounders, and visceral adiposity partly accounted for this association. Over a median follow-up of 5.2 years, 795 deaths were recorded in patients with coronary artery disease. Log₂-transformed suPAR was independently associated with mortality (hazard ratio per 1-SD 1.72, 95% CI 1.60-1.85) and an interaction with sex was noted (P=0.005). Association of suPAR with mortality was slightly weaker in women (hazard ratio 1.61, 95% CI 1.41-1.83) compared with men (hazard ratio 1.83, 95% CI 1.67-2.00). However, using sex-specific suPAR cut-offs (4392 pg/mL for women and 3187 pg/mL for men), a similar mortality incidence was observed for both sexes (38.5% and 35.5%, respectively, P=0.3). Conclusions Women have 10% higher plasma suPAR levels compared with men. Elevated sex-specific plasma suPAR levels are equally predictive of risk of adverse events in both sexes.

Keywords: SuPAR; biomarkers; coronary artery disease; outcomes; sex differences.

Figure 1

Cumulative incidence of adverse outcomes across sex‐specific suPAR deciles. Sex‐specific cumulative incidence of all‐cause mortality (A) and cardiovascular death/nonfatal MI events (B) across deciles of plasma suPAR levels. The cumulative incidence of adverse outcomes across increased across sex‐specific suPAR deciles, but the progressive increase in women occurred in those above the fifth decile, whereas in men, the increase in risk began at levels above the sixth decile (>2918 pg/mL). The incidence of adverse outcomes among both men and women was similar at the highest sex‐specific suPAR levels (deciles 9 and 10). MI indicates myocardial infarction; suPAR, soluble urokinase‐type plasminogen activator receptor.

Figure 2

Kaplan–Meier survival among men and women above or below sex‐specific suPAR cutoffs. Kaplan–Meier curves for survival from all‐cause mortality (A) and cardiovascular death/nonfatal MI events (B) among men and women above or below the respective sex‐specific suPAR cutoffs. The sex‐specific suPAR cutoffs for all‐cause mortality were 4392 pg/mL for women (76th percentile) and 3187 pg/mL for men (64th percentile). The corresponding cutoffs for cardiovascular death/MI events were 3888 pg/mL for women (67th percentile) and 2941 pg/mL for men (56th percentile). MI indicates myocardial infarction; suPAR, soluble urokinase‐type plasminogen activator receptor.