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