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

Circ Cardiovasc Qual Outcomes. 2017 Mar;10(3):e001493. doi: 10.1161/CIRCOUTCOMES.115.001493.


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.

Keywords: biomarker; cardiovascular outcomes; coronary artery disease; prognosis; risk score.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / blood
  • C-Reactive Protein / analysis*
  • Coronary Angiography
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / complications
  • Coronary Artery Disease / diagnostic imaging*
  • Coronary Artery Disease / mortality
  • Disease Progression
  • Female
  • Fibrin Fibrinogen Degradation Products / analysis*
  • HSP70 Heat-Shock Proteins / blood*
  • Humans
  • Male
  • Middle Aged
  • Myocardial Infarction / diagnosis
  • Myocardial Infarction / etiology*
  • Myocardial Infarction / mortality
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Receptors, Urokinase Plasminogen Activator / blood*
  • Risk Assessment
  • Risk Factors
  • Severity of Illness Index


  • Biomarkers
  • Fibrin Fibrinogen Degradation Products
  • HSP70 Heat-Shock Proteins
  • Receptors, Urokinase Plasminogen Activator
  • C-Reactive Protein