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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes

Comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis

Christopher Heeschen, MD^*,*, Stefanie Dimmeler, PhD^*, Christian W. Hamm, MD, FACC, Stephan Fichtlscherer, MD^*, Maarten L. Simoons, MD, FACC, Andreas M. Zeiher, MD, FACC^* CAPTURE Study Investigators

^* Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany
Kerckhoff Heart Center, Bad Nauheim, Germany
Erasmus University, Thoraxcentre, Rotterdam, the Netherlands

Manuscript received July 9, 2004; accepted September 27, 2004.

^* Reprint requests and correspondence: Dr. Christopher Heeschen, Department of Internal Medicine III, Molecular Cardiology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany (Email: c.heeschen{at}em.uni-frankfurt.de).

OBJECTIVES: 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.

Abbreviations and Acronyms   ACS = acute coronary syndromes   CAPTURE c7E3 = Anti Platelet Therapy in Unstable Refractory Angina trial   CI = confidence interval   hsCRP = high-sensitivity C-reactive protein   IL = interleukin   PAPP-A = pregnancy-associated plasma protein A   ROC = receiver operating characteristic   sCD40L = soluble CD40 ligand   TnT = troponin T   VEGF = vascular endothelial growth factor

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