title: Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis.
abstract: OBJECTIVE
  The goal of this study was to determine the predictive value of pregnancy-associated plasma protein-A (PAPP-A) in patients with acute coronary syndromes (ACS).
  
  
  BACKGROUND
  Pregnancy-associated plasma protein-A is a zinc-binding matrix metalloproteinase abundantly expressed in eroded and ruptured plaques and may serve as a marker of plaque destabilization.
  
  
  METHODS
  In 547 patients with angiographically validated ACS and in a heterogeneous emergency room population of 644 patients with acute chest pain, respectively, PAPP-A as well as markers of myocardial necrosis (troponin T [TnT]), ischemia (vascular endothelial growth factor [VEGF]), inflammation (high-sensitivity C-reactive protein [hsCRP]), anti-inflammatory activity (interleukin [IL]-10), and platelet activation (soluble CD40 ligand [sCD40L]) were determined. Patients were followed for the occurrence of death or myocardial infarction.
  
  
  RESULTS
  In patients with ACS, elevated PAPP-A levels (>12.6 mIU/l) indicated an increased risk (odds ratio 2.44 [95% confidence interval (CI) 1.43 to 4.15]; p = 0.001). When the analysis was restricted to TnT-negative patients, PAPP-A still identified a subgroup of high-risk patients (odds ratio [OR] 2.72 [95% confidence interval (CI) 1.25 to 5.89]; p = 0.009). In a multivariable model, PAPP-A (OR 2.01; p = 0.015), sCD40L (OR 2.37; p = 0.003), IL-10 (OR 0.43; p = 0.003), and VEGF (OR 2.19; p = 0.018) were independent predictors. Prospective validation in patients with chest pain confirmed that PAPP-A levels reliably identify high-risk patients (adjusted OR 2.32 [95% CI 1.32 to 4.26]; p = 0.008). Patients negative for all three markers (TnT, sCD40L, and PAPP-A) were at very low cardiac risk (30 days: 3.0% event rate; no death).
  
  
  CONCLUSIONS
  The PAPP-A level as a marker of plaque instability is a strong independent predictor of cardiovascular events in patients with ACS. Simultaneous determination of biomarkers with distinct pathophysiological profiles appears to remarkably improve risk stratification in patients with ACS.
authors.affiliation: Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. c.heeschen@em.uni-frankfurt.de
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Christian W
authors.initials: CW
authors.lastname: Hamm
authors.forename: Stephan
authors.initials: S
authors.lastname: Fichtlscherer
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Simoons
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000789:Angina, Unstable / Q000097:blood* / Q000150:complications / Q000401:mortality*; D002097:C-Reactive Protein / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood* / Q000150:complications / Q000401:mortality*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology*; D011237:Predictive Value of Tests; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D011379:Prognosis; D013577:Syndrome; D020107:Troponin T / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D020107:Troponin T; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D023201:CD40 Ligand; D002097:C-Reactive Protein; D011266:Pregnancy-Associated Plasma Protein-A