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

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. Log(2)-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.