Invited critical reviewMeasurement and clinical significance of circulating PAPP-A in ACS patients
Introduction
Despite major progress in cardiovascular medicine, acute coronary syndromes (ACS), defined as unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI), remain the leading cause of mortality and morbidity globally. Many patients that suffer an ACS die without prior symptom [1]. On the other hand, there are reports showing that 2.1% to 3.8% of patients with MI are missed in the emergency department (ED) [2], [3] and 7.1% to 15.7% of patients with ACS suffer reinfarction or death within 30 days of presentation [4]. Thus, to be able to diagnose who is affected with ACS or to predict who is at risk of an acute thrombotic event in the near future is a major challenge to cardiovascular medicine.
There is growing interest in the search of novel circulating protein markers of ACS that increase before myocardial injury develops [5], [6]. Proteins that participate in the process of transforming a stable plaque to a vulnerable plaque are potential markers currently being investigated [5], [6]. One of these proteins is pregnancy-associated plasma protein A (PAPP-A) that has been regarded as a biomarker of plaque rupture [5], [7].
The aim of this review was to provide an overview of the clinical utility of PAPP-A in ACS patients and also to discuss the issues that may affect the measurement of circulating PAPP-A in ACS patients with immunoassays [8], [9], [10].
Section snippets
PAPP-A molecule
PAPP-A is a zinc-binding metalloproteinase and its known substrates in humans are insulin-like growth factor binding proteins (IGFBP)-4 and -5 [11], [12]. The biological activities of insulin-like growth factors (IGFs) are regulated by six IGFBPs [13]. The cleavage of IGFBP-4 and -5 by PAPP-A increases free bioactive IGFs for interactions with IGF receptors [14], [15].
The analysis of cloned cDNA has demonstrated that the PAPP-A subunit is a 1547-residue polypeptide [16]. It contains an
Cellular origin of PAPP-A in atherosclerotic plaques
There are data showing that ACS related PAPP-A could originate from atherosclerotic plaques. By immunohistochemical staining with antihuman PAPP-A antibodies, Bayes-Genis et al. demonstrated that PAPP-A was abundantly expressed in both eroded and ruptured coronary atherosclerotic plaques, but was only minimally expressed in stable plaques [7]. With quantitative RT-PCR, Sangiorgi et al. showed that PAPP-A mRNA was locally produced in carotid atherosclerotic plaques [26].
The cells responsible for
Diagnostic value
PAPP-A within a vulnerable coronary atherosclerotic plaque is thought to be released into the circulation when the plaque is disrupted through rupture or erosion. The disrupted plaque exposes prothrombotic material from its core to the blood, causing coronary thrombosis. If the resultant thrombus does not markedly affect coronary blood supply, no clinical symptom appears. If the thrombus blocks or reduces significantly the coronary blood flow, clinical manifestations of ACS occur [42]. As the
Factors that may affect PAPP-A measurement in ACS patients
PAPP-A levels vary markedly from one study to another (see Table 1). The same holds true for the cut-off levels used to determine the diagnostic and prognostic value of PAPP-A in ACS or chest pain patients. The difference in PAPP-A concentration may be relevant to different sampling time (kinetics reason), but may also be attributable to different antibody combination, methodology and standard material adopted. At the moment, there do exist some known factors that may affect PAPP-A measurement
Conclusions
Plaque rupture and subsequent thrombus formation are major events underlying ACS. The disruption of a plaque is believed to release PAPP-A to the circulation in the early phase of ACS, which may make PAPP-A a very early marker for the diagnosis of ACS. Until now, the published data on the diagnostic value of PAPP-A in ACS is still very limited because most studies have focused on the predictive value of PAPP-A in patients with ACS or suspected ACS. In such patients PAPP-A has been found to be a
References (59)
- et al.
Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room
Am J Cardiol
(1987) - et al.
Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A
FEBS Lett
(2001) - et al.
The Lin12-notch repeats of pregnancy-associated plasma protein-A bind calcium and determine its proteolytic specificity
J Biol Chem
(2004) - et al.
Circulating human pregnancy-associated plasma protein-A is disulfide-bridged to the proform of eosinophil major basic protein
J Biol Chem
(1993) - et al.
Pregnancy associated plasma protein-A: ultrasensitive immunoassay and determination in coronary heart disease
Clin Biochem
(2002) - 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) - et al.
Covalent interaction between proform of eosinophil major basic protein (proMBP) and pregnancy-associated plasma protein-A (PAPP-A) is a cell-mediated event and required for proMBP inhibition of the catalytic activity of PAPP-A
Arch Biochem Biophys
(2004) - et al.
Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor
J Biol Chem
(2000) - et al.
Proteinase inhibition by proform of eosinophil major basic protein (pro-MBP) is a multistep process of intra- and intermolecular disulfide rearrangements
J Biol Chem
(2005) - et al.
New insights on oxidative stress in the artery wall (Review)
J Thromb Haemost
(2005)