CORRESPONDENCE: LETTERS TO THE EDITOR
Pregnancy-Associated Plasma Protein-A and Acute Coronary Syndromes: Cause or Consequence?
Elena Conti, MD, PhD*,
Massimo Volpe, MD, FAHA,
Cinzia Carrozza, MD, PhD,
Francesca Marzo, MD,
Cecilia Zuppi, MD,
Filippo Crea, MD, FACC and
Felicita Andreotti, MD, PhD, FESC
* Division of Cardiology, Second Faculty of Medicine, University "La Sapienza", Ospedale S. Andrea, Via di Grottarossa 1035-1039, 00100, Rome, Italy (Email: e_conti02{at}hotmail.com).
Heeschen et al. (1) report an approximately two-fold risk of death and myocardial infarction (MI) at 1 and 6 months linked with pregnancy-associated plasma protein-A (PAPP-A) >12.6 mIU/l among patients admitted for acute coronary syndromes (ACS), even with normal troponin levels. The investigators hypothesize plaque proteolysis by PAPP-A and harmful activation of insulin-like growth factor-1 (IGF-1) through PAPP-A’s lysis of IGF-binding proteins. We propose an alternative view.
Extracellular matrix degradation by PAPP-A, to our knowledge, has never been documented. Moreover, IGF-1 exerts broad cardiovascular protection, through insulin-sensitizing, nitric oxide–mediated, antiapoptotic, regenerative, preconditioning, and anti-inflammatory effects (2). How, then, can two apparently divergent properties (predictor of risk for PAPP-A and vasculoprotective for IGF-1) be reconciled?
Hypoxic/oxidative/inflammatory stress enhances PAPP-A’s bioactivity (2–4). Circulating PAPP-A levels are increased in ACS patients (1,4) and correlate (although not in all studies) with indices of inflammation and myocardial damage (1,2,4). Experimental damage raises local PAPP-A expression and IGF-1 bioactivity (2,4) with immunomodulatory and anti-inflammatory actions (4,5). During pregnancy, plasma PAPP-A is increased over 150-fold, with no parallel increase in ischemic risk; rather, reduced PAPP-A predicts adverse outcomes (6). These data suggest that PAPP-A is involved in physiological repair and replicative programs through its product, namely free IGF-1 (2–4).
Another circulating biomarker, B-type natriuretic peptide (BNP), is cardioprotective and secreted in proportion to the extent of ischemia. Elevated levels powerfully predict adverse events in patients with coronary syndromes (7). Intravenous BNP (nesiritide) is of proven benefit in managing cardiac patients.
Raised PAPP-A and BNP levels may be part of endogenous compensatory pathways aimed at tissue salvage and repair. We believe they strongly predict adverse outcomes because they are sensitive signals of damage, without necessarily causing it.
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References
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- Heeschen C, Dimmeler S, Hamm CW, Fichtlscherer S, Simoons ML, Zeiher AM. Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes J Am Coll Cardiol 2005;45:229-237.[Abstract/Free Full Text]
- Conti E, Carrozza C, Capoluongo E, Volpe M, Crea F, Andreotti F. Insulila-like growth factor-1 as a vascular protective factor Circulation 2004;110:2260-2265.[Free Full Text]
- Glerup S, Boldt HB, Overgaard MT, Sottrup-Jensen L, Giudice LC, Oxvig C. Proteinase inhibition by proform of eosinophil major basic protein (proMBP) is a multistep process of intra- and intermolecular disulfide rearrangements J Biol Chem 2005;280:9823-9832.[Abstract/Free Full Text]
- Conti E, Andreotti F, Zuppi C. Pregnancy-associated plasma protein-A as predictor of outcome in patients with suspected acute coronary syndromes Circulation 2004;109:e211-e212.[Free Full Text]
- Zhabin SG, Gorin VS, Judin NS. Reviewimmunomodulatory activity of pregnancy-associated plasma protein-A. J Clin Lab Immunol 2003;52:41-50.[Medline]
- Krantz D, Goetzl L, Simpson JL, et al. Association of extreme first-trimester free human chorionic gonadotropin-beta, pregnancy-associated plasma protein-A, and nuchal translucency with intrauterine growth retardation and other adverse pregnancy outcomes Am J Obstet Gynecol 2004;191:1452-1458.[CrossRef][ISI][Medline]
- Kragelund C, Gronning B, Kober L, Hildebrand P, Steffensen R. N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease N Engl J Med 2005;352:666-675.[Abstract/Free Full Text]
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