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.
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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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30(12):
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G. Onder, E. Capoluongo, M. Cesari, P. Lulli, R. Liperoti, B. Giardina, A. Russo, R. Bernabei, and F. Landi
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|
|
|
|
|
|
|
S. C. Harrington, R. D. Simari, and C. A. Conover
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June 22, 2007;
100(12):
1696 - 1702.
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|
|
|
|
|
|
|
W. Koenig and N. Khuseyinova
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27(1):
15 - 26.
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|
|
|
|
|
|
|
E. Capoluongo, F. Ameglio, P. Lulli, A. Minucci, C. Santonocito, P. Concolino, E. Di Stasio, S. Boccacci, V. Vendettuoli, G. Giuratrabocchetta, et al.
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January 1, 2007;
292(1):
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|
|
|
|
|
|
|
R. Body and C. Ferguson
Pregnancy-associated plasma protein A: a novel cardiac marker with promise.
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November 1, 2006;
23(11):
875 - 877.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Wittfooth, Q.-P. Qin, J. Lund, I. Tierala, K. Pulkki, H. Takalo, and K. Pettersson
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September 1, 2006;
52(9):
1794 - 1801.
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|
|
|
|
|
|
|
R. P. Giugliano and E. Braunwald
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July 18, 2006;
48(2):
386 - 395.
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|
|
|
|
|
|
|
A. A. Elesber, C. A. Conover, A. E. Denktas, R. J. Lennon, D. R. Holmes Jr, M. T. Overgaard, M. Christiansen, C. Oxvig, L. O. Lerman, and A. Lerman
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July 2, 2006;
27(14):
1678 - 1684.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Kaski and D. W. Holt
Pregnancy-associated plasma protein-A and cardiovascular risk
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July 2, 2006;
27(14):
1637 - 1639.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Sangiorgi, A. Mauriello, E. Bonanno, C. Oxvig, C. A. Conover, M. Christiansen, S. Trimarchi, V. Rampoldi, D. R. Holmes Jr, R. S. Schwartz, et al.
Pregnancy-Associated Plasma Protein-A Is Markedly Expressed by Monocyte-Macrophage Cells in Vulnerable and Ruptured Carotid Atherosclerotic Plaques: A Link Between Inflammation and Cerebrovascular Events
J. Am. Coll. Cardiol.,
June 6, 2006;
47(11):
2201 - 2211.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Biasucci and V. Rizzello
Pregnancy-associated plasma protein-a: do specific markers of vascular or plaque activation exist, and do we really need them?
Clin. Chem.,
June 1, 2006;
52(6):
913 - 914.
[Full Text]
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|
|
|
|
|
|
|
T. Mueller, B. Dieplinger, W. Poelz, and M. Haltmayer
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Clin. Chem.,
June 1, 2006;
52(6):
1096 - 1103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. S. Vasan
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May 16, 2006;
113(19):
2335 - 2362.
[Full Text]
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|
|
|
|
|
|
|
R. Tabibiazar, R. A. Wagner, A. Deng, P. S. Tsao, and T. Quertermous
Proteomic profiles of serum inflammatory markers accurately predict atherosclerosis in mice
Physiol Genomics,
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25(2):
194 - 202.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. J. Armstrong, D. A. Morrow, and M. S. Sabatine
Inflammatory Biomarkers in Acute Coronary Syndromes: Part IV: Matrix Metalloproteinases and Biomarkers of Platelet Activation
Circulation,
March 7, 2006;
113(9):
e382 - e385.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q.-P. Qin, S. Kokkala, J. Lund, N. Tamm, X. Qin, M. Lepantalo, and K. Pettersson
Immunoassays Developed for Pregnancy-Associated Plasma Protein-A (PAPP-A) in Pregnancy May Not Recognize PAPP-A in Acute Coronary Syndromes
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March 1, 2006;
52(3):
398 - 404.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Conover, L. K. Bale, S. C. Harrington, Z. T. Resch, M. T. Overgaard, and C. Oxvig
Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells: inhibition by resveratrol
Am J Physiol Cell Physiol,
January 1, 2006;
290(1):
C183 - C188.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. S. Ginsburg, M. P. Donahue, and L. K. Newby
Prospects for Personalized Cardiovascular Medicine: The Impact of Genomics
J. Am. Coll. Cardiol.,
November 1, 2005;
46(9):
1615 - 1627.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Mitchell, M. D. Brown, I. B.A. Menown, and J. A. Kline
Novel Protein Markers of Acute Coronary Syndrome Complications in Low-Risk Outpatients: A Systematic Review of Potential Use in the Emergency Department
Clin. Chem.,
November 1, 2005;
51(11):
2005 - 2012.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Conti, M. Volpe, C. Carrozza, F. Marzo, C. Zuppi, F. Crea, and F. Andreotti
Pregnancy-Associated Plasma Protein-A and Acute Coronary Syndromes: Cause or Consequence?
J. Am. Coll. Cardiol.,
October 18, 2005;
46(8):
1583 - 1584.
[Full Text]
[PDF]
|
|
|
|
|
|
|
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J. Am. Coll. Cardiol.,
October 18, 2005;
46(8):
1584 - 1585.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Crea and F. Andreotti
Pregnancy associated plasma protein-A and coronary atherosclerosis: marker, friend, or foe?
Eur. Heart J.,
October 2, 2005;
26(20):
2075 - 2076.
[Full Text]
[PDF]
|
|
|
|
