Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death

Abstract

Background Inflammation, coagulation, and cell stress contribute to atherosclerosis and its adverse events. A biomarker risk score (BRS) based on the circulating levels of biomarkers C-reactive protein, fibrin degradation products, and heat shock protein-70 representing these 3 pathways was a strong predictor of future outcomes. We investigated whether soluble urokinase plasminogen activator receptor (suPAR), a marker of immune activation, is predictive of outcomes independent of the aforementioned markers and whether its addition to a 3-BRS improves risk reclassification. Methods and Results C-reactive protein, fibrin degradation product, heat shock protein-70, and suPAR were measured in 3278 patients undergoing coronary angiography. The BRS was calculated by counting the number of biomarkers above a cutoff determined using the Youden’s index. Survival analyses were performed using models adjusted for traditional risk factors. A high suPAR level ≥3.5 ng/mL was associated with all-cause death and myocardial infarction (hazard ratio, 1.83; 95% confidence interval, 1.43–2.35) after adjustment for risk factors, C-reactive protein, fibrin degradation product, and heat shock protein-70. Addition of suPAR to the 3-BRS significantly improved the C statistic, integrated discrimination improvement, and net reclassification index for the primary outcome. A BRS of 1, 2, 3, or 4 was associated with a 1.81-, 2.59-, 6.17-, and 8.80-fold increase, respectively, in the risk of death and myocardial infarction. The 4-BRS was also associated with severity of coronary artery disease and composite end points. Conclusions SuPAR is independently predictive of adverse outcomes, and its addition to a 3-BRS comprising C-reactive protein, fibrin degradation product, and heat shock protein-70 improved risk reclassification. The clinical utility of using a 4-BRS for risk prediction and management of patients with coronary artery disease warrants further study.

Soluble Urokinase-Type Plasminogen Activator Receptor in Black Americans with CKD

“…The association between higher baseline suPAR and allcause mortality is consistent with other studies in select patient populations, including those with cancer, infection, cardiovascular diseases, and patients with diabetes and ESKD (23)(24)(25)(26)(27). The mechanism underlying the association between suPAR and mortality requires additional study, but it does not appear to be mediated solely by classic inflammation, as associations were robust after adjustment for CRP in our study as well as others (24,27,28).…”

Soluble Urokinase Plasminogen Activator Receptor and the Risk of Coronary Artery Disease in Young Chinese Patients

“…However, the association between suPAR and the risk of CAD in young Chinese patients is independent of hs-CRP levels. This is in agreement with a previous report by Ghasemzedah et al who showed that suPAR, hs-CRP, fibrin degradation product, and heat shock protein-70 are independent risk factors for CAD [ 25 ]. Lyngbaek et al have shown that CRP is positively associated with anthropometric measures, such as BMI and waist circumference, whereas suPAR is linked to endothelial dysfunction and atherosclerosis [ 26 ].…”

Predicting Mortality in African Americans With Type 2 Diabetes Mellitus: Soluble Urokinase Plasminogen Activator Receptor, Coronary Artery Calcium, and High‐Sensitivity C‐Reactive Protein

“…This is the first study of which we are aware comparing suPAR with CAC for association with all‐cause mortality. We and others have previously reported that suPAR levels are predictive of outcomes independent from traditional risk factors and add incremental benefit to models adjusted for biomarkers including hs‐CRP, raising the C‐statistic by 0.050 . Conversely, addition of hs‐CRP to fully‐adjusted models led to a change in C‐statistic in the range of 0.004 .…”

“…We and others have previously reported that suPAR levels are predictive of outcomes independent from traditional risk factors and add incremental benefit to models adjusted for biomarkers including hs-CRP, raising the C-statistic by 0.050. [11][12][13]17,31 Conversely, addition of hs-CRP to fullyadjusted models led to a change in C-statistic in the range of 0.004. 32 In the present AA-DHS analysis, neither hs-CRP or CAC were independent predictors of all-cause mortality or improved risk discrimination after adjusting for known clinical characteristics such as smoking, insulin use, and kidney function, findings that contrast with previously reported associations.…”