Invited critical review
Measurement and clinical significance of circulating PAPP-A in ACS patients

https://doi.org/10.1016/j.cca.2007.02.036Get rights and content

Abstract

Background

The rupture of coronary atherosclerotic plaque and subsequent thrombus formation are major events underlying acute coronary syndromes (ACS). Pregnancy associated plasma protein A (PAPP-A), a biomarker of plaque rupture, has been studied in patients with ACS. This review aimed to provide an overview of clinical utility of PAPP-A in ACS patients and analytical issues adhering to immunological PAPP-A measurement.

Methods

The literature relating to PAPP-A in ACS, the molecular structure and immunodetection of PAPP-A was reviewed. PubMed was used to search the relevant articles published from 1974 to 2006.

Results

Higher PAPP-A concentrations have been found in patients with ACS than in patients with stable angina and subjects without coronary artery disease. Elevated PAPP-A concentrations have also been shown to associate with adverse cardiac events in ACS patients. The prognostic value of PAPP-A appears to be independent of cardiac troponins. Noteworthy, the PAPP-A form that accounts for increase in ACS is uncomplexed with the proform of eosinophil major basic protein (proMBP). However, PAPP-A assays applied in clinical studies published thus far detect total PAPP-A. Consequently, the clinical value may be non-optimal when total PAPP-A is measured in ACS patients. In addition, the clinical value can also be affected by the analytical factors that exert an effect on the performance of PAPP-A assays.

Conclusions

PAPP-A appears to be a very promising biomarker useful in the clinical management of ACS patients. However, more prospective and interventional studies with carefully established immunoassays are required to validate its clinical utility.

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

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