Elsevier

Clinical Biochemistry

Volume 44, Issue 4, March 2011, Pages 312-318
Clinical Biochemistry

Pregnancy associated plasma protein-A (PAPP-A) is not a marker of the vulnerable atherosclerotic plaque

https://doi.org/10.1016/j.clinbiochem.2010.12.010Get rights and content

Abstract

Objective

To investigate if pregnancy associated plasma protein-A (PAPP-A) was present in the vulnerable plaque, and if not, to find alternative hypothesis for the release of PAPP-A.

Design and methods

Vulnerable plaques and control tissues were examined by immunohistochemistry. Volunteers and patients with non-atherosclerotic disease were examined for release of PAPP-A during ischemia and medical treatment. Non-atherosclerotic tissue samples were examined after incubation with heparins.

Results

We were not able to detect PAPP-A in vulnerable plaques. Patients and volunteers experiencing ischemic events without atherosclerotic lesions only had elevated PAPP-A when treated with heparin. When tissue from normal artery wall was incubated with heparin, PAPP-A was eluted. This was not the case for non-arterial tissue samples.

Conclusion

Elevation of PAPP-A in patients with acute coronary syndromes seems to be caused by heparin induced release of PAPP-A from the arterial wall and not due to excretion from vulnerable plaques.

Introduction

In 2001 Bayes-Genis et al. demonstrated that circulating pregnancy associated plasma protein-A (PAPP-A) was significantly higher in patients with both myocardial infarction and unstable angina pectoris than in patients with stable angina pectoris [1]. Since then numerous studies have examined the role of PAPP-A in coronary artery disease [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. These studies have demonstrated that circulating PAPP-A is elevated in patients with coronary artery disease and suggested a significant prognostic importance. Based on immunohistochemial analyses some research groups have suggested the site of PAPP-A synthesis to be vulnerable atherosclerotic plaques in the coronary arteries [1], [23]. However, in a recent study, we were unable to confirm these immunohistochemical findings using well characterized monoclonal anti PAPP-A antibodies on atherosclerotic plaques as well as on thrombus material isolated during percutaneous coronary intervention [24]. It has to be emphasized that during these experiments a strong and highly specific staining reaction of the cytoplasm of the syncytiotrophoblast in term placental tissue was seen [24]. Our findings led to the hypothesis: that PAPP-A in acute coronary syndrome may be derived from a site distant from the ischemic cardiac tissue.

The aim of the present study was to pursue this hypothesis by (i) expansion of our data on immunohistochemical analysis of atherosclerotic plaques and thrombi and to analyse serum concentrations of PAPP-A in vivo before, at and after the vulnerable plaque formation, (ii) analysis of circulating PAPP-A in patients with non-atherosclerotic myocardial infarction, (iii) examination of circulating PAPP-A in patients with extra-cardiac ischemia and (iv) analysis of whether the circulating PAPP-A in acute coronary syndromes is related to medical treatment.

Section snippets

Ethics

The trial complied with the Declaration of Helsinki. Ethical approval was given by the local ethics committee and The Danish Data Protection Agency.

Serum samples

Serum samples for PAPP-A quantification were obtained from the following groups of patients and volunteers:

Patients suspected for ST-segment elevation myocardial infarction

Of the 354 patients screened for this study 12 patients had normal smooth coronary arteries and one had atheromathosis. These patients had a median age of 66 years (range 44–81) and 8 were women. The final diagnoses of the patients were perimyocarditis (n = 8), cardiomyopathy (n = 2), ventricular tachycardia (n = 1), aortic dissection (n = 1) and pulmonary embolism (n = 1). Circulating PAPP-A was found to be elevated in all 13 patients. Median serum PAPP-A was 42 mIU/L ranging from 16.4 mIU/L to 88.2 mIU/L.

Patients treated with percutaneous transluminal septal myocardial ablation

Discussion

The present paper challenges the hypothesis that the site of origin and synthesis of circulating PAPP-A seen in patients with acute coronary syndromes is the atherosclerotic plaque. This study failed to demonstrate PAPP-A in the vulnerable plaque, but our data suggest the presence of PAPP-A in the arterial wall, and this PAPP-A can be released into the circulation triggered by administration of different types of heparin.

PAPP-A is a zinc-binding metalloproteinase first described in 1974 by Lin

Conclusion

The elevation of circulating PAPP-A seen in patients with acute coronary syndromes seems to be caused by heparin induced release of PAPP-A from the (non-atherosclerotic) arterial wall and not due to excretion from vulnerable plaques. The role of PAPP-A as a potential marker for the vulnerable plaque has to be reconsidered.

References (39)

  • G. Sangiorgi 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

    (2006)
  • M. Rossen et al.

    Optimisation of sandwich ELISA based on monoclonal antibodies for the specific measurement of pregnancy-associated plasma protein (PAPP-A) in acute coronary syndrome

    ClinBiochem

    (2007)
  • S. Dalager et al.

    Plaque in superficial femoral arteries indicates generalized atherosclerosis and vulnerability to coronary death: an autopsy study

    J Vasc Surg

    (2008)
  • C.J. Terkelsen et al.

    Temporal course of pregnancy-associated plasma protein-A in angioplasty-treated ST-elevation myocardial infarction patients and potential significance of concomitant heparin administration

    Am J Cardiol

    (2009)
  • T.M. Lin et al.

    Characterization of four human pregnancy-associated plasma proteins

    AmJObstetGynecol

    (1974)
  • D. Tornehave et al.

    Immunohistochemical demonstration of pregnancy-associated plasma protein A (PAPP-A) in the syncytiotrophoblast of the normal placenta at different gestational ages

    Placenta

    (1984)
  • T. Wahlstrom et al.

    Tissue localization of pregnancy-associated plasma protein-A (PAPP-A) in normal placenta

    Placenta

    (1981)
  • K.K. Iversen et al.

    Pregnancy-associated plasma protein-a, a marker for outcome in patients suspected for acute coronary syndrome

    Clin Biochem

    (2010)
  • A. Bayes-Genis et al.

    Pregnancy-associated plasma protein A as a marker of acute coronary syndromes

    NEnglJMed

    (2001)
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