CORRESPONDENCE: LETTERS TO THE EDITOR
Reply
Christopher Heeschen, MD*,
Stefanie Dimmeler, PhD,
Stephan Fichtlscherer, MD and
Andreas M. Zeiher, MD, FACC
* J.W. Goethe University, Department of Medicine III, Molecular Cardiology, Theodor-Stern-Kai 7, Frankfurt 60590, Germany (Email: c.heeschen{at}em.uni-frankfurt.de).
We thank Dr. Conti and colleagues for their interesting contribution regarding our recent study on the predictive value of pregnancy-associated plasma protein-A (PAPP-A) in patients with acute coronary syndromes (ACS) (1). As stated in the discussion section of our report, the exact role of PAPP-A in the pathophysiology in ACS still remains illusive. In this context, we could only speculate about the putative role of the metalloproteinase (MMP) PAPP-A in the setting of atherosclerotic plaque destabilization, which may lead to clinical manifestation as an ACS. We completely agree with Dr. Conti and colleagues that no data are currently available directly demonstrating that PAPP-A per se leads to degradation of extracellular matrix. However, because matrix degradation has been shown for other MMPs, it is quite reasonable to assume that PAPP-A may also act at least in part through a similar mechanism.
Of note, release and subsequent activation of insulin-like growth factor-1 (IGF-1), a potential protective factor in the cardiovascular system, through PAPP-A activation may indeed represent an alternative mechanism as suggested by Conti et al. (2). Although this potential mechanism proposed by Dr. Conti and co-workers is similarly reasonable and appealing, there is also no definitive evidence that this is the most relevant mechanism of action of PAPP-A in the setting of an ACS. Unfortunately, we can neither support nor disprove the researchers’ hypothesis as we did not have a chance to measure IGF-1 levels in our study populations. Actually, it would not seem to be appropriate to draw mechanistic conclusions from this kind of clinical study. Circulating levels of biomarkers such as PAPP-A only represent the integral of PAPP-A generation as well as degradation in patients with ACS, but these studies alone cannot provide any hint on the source and the mode of action of PAPP-A in unstable atherosclerotic plaques, respectively. Thus, one should be very cautious in drawing any definite mechanistic conclusions from the levels of circulating biomarkers in any disease. Apparently, further experimental studies are truly needed to prove the exact role and mechanism of PAPP-A in atherosclerosis and its complications.
In summary, we aimed in our study to place the biomarker PAPP-A into the context of inflammation and matrix degradation as this view is supported by the current literature (3–5). Independent of the actual mechanism by which PAPP-A may contribute to plaque destabilization and/or plaque healing, however, PAPP-A remains an independent and powerful predictor for adverse events in patients with ACS and, thus, deserves further investigation regarding its clinical utility as a diagnostic biomarker.
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References
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1. Heeschen C, Dimmeler S, Hamm CW, Fichtlscherer S, Simoons ML, Zeiher AM. Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromescomparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. J Am Coll Cardiol 2005;45:229-237.[Abstract/Free Full Text]
2. Conti E, Carrozza C, Capoluongo E, Volpe M, Crea F, Andreotti F. Insulin-like growth factor-1 as a vascular protective factor Circulation 2004;110:2260-2265.[Free Full Text]
3. Bayes-Genis A, Conover CA, Overgaard MT, et al. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes N Engl J Med 2001;345:1022-1029.[Abstract/Free Full Text]
4. Beaudeux JL, Burc L, Imbert-Bismut F, et al. Serum plasma pregnancy-associated protein Aa potential marker of echogenic carotid atherosclerotic plaques in asymptomatic hyperlipidemic subjects at high cardiovascular risk. Arterioscler Thromb Vasc Biol 2003;23:e7-e10.[Abstract/Free Full Text]
5. Lund J, Qin QP, Ilva T, et al. Circulating pregnancy-associated plasma protein A predicts outcome in patients with acute coronary syndrome but no troponin I elevation Circulation 2003;108:1924-1926.[Abstract/Free Full Text]
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