title: 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: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Nima
authors.initials: N
authors.lastname: Ghasemzedah
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Salim S
authors.initials: SS
authors.lastname: Hayek
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Ko
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Eapen
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Riyaz S
authors.initials: RS
authors.lastname: Patel
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Pankaj
authors.initials: P
authors.lastname: Manocha
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Hatem
authors.initials: H
authors.lastname: Al Kassem
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Mohamed
authors.initials: M
authors.lastname: Khayata
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Emir
authors.initials: E
authors.lastname: Veledar
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kremastinos
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Christian W
authors.initials: CW
authors.lastname: Thorball
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Tomasz
authors.initials: T
authors.lastname: Pielak
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Sergey
authors.initials: S
authors.lastname: Sikora
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: A Maziar
authors.initials: AM
authors.lastname: Zafari
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Stamatios
authors.initials: S
authors.lastname: Lerakis
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Laurence
authors.initials: L
authors.lastname: Sperling
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Viola
authors.initials: V
authors.lastname: Vaccarino
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.).
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Epstein
authors.affiliation: From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.); Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.); Department of Biostatistics, Florida International University, Miami (E.V.); Department of Cardiology, University of Athens School of Medicine, Greece (D.K.); Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.); Stemedica Cell Technologies, Inc., San Diego, CA (S.S.); Department of Epidemiology, Emory University, Atlanta, GA (V.V.); and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.). aquyyum@emory.edu.
authors.forename: Arshed A
authors.initials: AA
authors.lastname: Quyyumi
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis*; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood / Q000150:complications / Q000000981:diagnostic imaging* / Q000401:mortality; D018450:Disease Progression; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis*; D018840:HSP70 Heat-Shock Proteins / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood*; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D018840:HSP70 Heat-Shock Proteins; D055293:Receptors, Urokinase Plasminogen Activator; D002097:C-Reactive Protein
keywords: biomarker; cardiovascular outcomes; coronary artery disease; prognosis; risk score