Relationship among pregnancy associated plasma protein-A levels, clinical characteristics, and coronary artery disease extent in patients with chronic stable angina pectoris
Juan Cosin-Sales1,
Juan Carlos Kaski1,*,
Michael Christiansen2,3,
Paul Kaminski1,
Claus Oxvig4,
Michael T. Overgaard4,
Della Cole1 and
David W. Holt1
1Department of Cardiac and Vascular Sciences, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
2Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark
3Copenhagen Heart Arrhythmia Research Center, Copenhagen, Denmark
4Department of Molecular Biology, Science Park, University of Aarhus, Aarhus, Denmark
Received 21 September 2004; revised 21 June 2005; accepted 30 June 2005; online publish-ahead-of-print 29 July 2005.
* Corresponding author. Tel: +44 020 87255901; fax: +44 020 87253328. E-mail address: jkaski{at}sghms.ac.uk
See page 2075 for the editorial comment on this article (doi:10.1093/eurheartj/ehi475)
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Abstract
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Aims To assess, in chronic stable angina (CSA) patients, the relationship among clinical characteristics and cardiovascular risk factors, extent of coronary artery disease (CAD), and pregnancy-associated plasma protein-A (PAPP-A) levels.
Methods and results We studied 643 CSA patients (63±10 years, 482 men) undergoing diagnostic coronary angiography; 97 with angiographically normal coronary arteries or <50% stenosis, 127 with single vessel disease (VD), and 419 with multi-VD. Patients' age, gender, cardiovascular risk factors, body mass index, history of previous myocardial infarction, angina class, left ventricular ejection fraction (LVEF), and treatment were assessed at study entry. PAPP-A levels (mIU/L) were higher in men than in women (6.2±2.4 vs. 5.2±1.8; P<0.001) and in hypertensive vs. normotensive patients (6.4±2.8 vs. 5.8±2.1; P=0.01). PAPP-A correlated directly with age (r=0.19, P<0.001) and inversely with LVEF (r=0.11, P=0.01). Patients with multivessel disease (VD) had higher PAPP-A levels (6.45±2.58) than those with single-VD (5.49±1.54, P<0.001) or normal coronaries (4.62±1.17, P<0.001). Male gender, age, history of a previous MI, hypercholesterolaemia, and PAPP-A levels were independent predictors for the presence of CAD.
Conclusion In CSA patients PAPP-A levels correlate with age, male gender, hypertension, and CAD extent. In the present study, PAPP-A was an independent predictor for the presence and extent of CAD.
Key Words: Chronic stable angina PAPP-A Inflammation Coronary artery disease extent
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Introduction
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Circulating levels of pregnancy-associated plasma protein-A (PAPP-A), a zinc binding metalloproteinase, have been shown to be elevated in patients with acute coronary syndromes (ACS) compared with patients with chronic stable angina (CSA) and healthy subjects.13 In ACS patients, PAPP-A was abundantly expressed in vulnerable atheromatous plaques suggesting a role in plaque disruption.1 PAPP-A has also been associated with carotid atherosclerosis. Beaudeux et al.4 showed that increased PAPP-A levels represent a potential marker of echogenic carotid atherosclerotic lesions in asymptomatic hyperlipidaemic patients. In CSA patients, we have recently shown that PAPP-A and its endogenous inhibitor, proMBP, were related to the presence of complex coronary stenosis.5 The metalloproteolytic activity of PAPP-A is known to be directed towards insulin-like growth factor (IGF) binding proteins, causing the release of protein-bound IGF and thereby promoting the possible pro-atherogenic effects of IGF-I.68
Only few, if any, data exist regarding the effect of age, gender, and cardiovascular risk factors on PAPP-A levels. Similarly, little is known regarding the association between PAPP-A levels and coronary artery disease (CAD) extent in patients with CSA.
In this study, we sought to assess the relationship between PAPP-A and the presence and extent of coronary atherosclerosis in patients with CSA and positive exercise stress testing. We also studied the effects of several clinical variables, i.e. age, gender, body mass index (BMI), angina grade, conventional cardiovascular risk factors, and C-reactive protein levels on PAPP-A levels in patients with CSA.
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Methods
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Patients
We assessed 674 consecutive patients with CSA who underwent routine diagnostic coronary angiography in our institution. CSA was diagnosed in the presence of typical chest pain during exercise, relieved by rest and/or sublingual nitrates, with symptoms unchanged for at least 6 months before study entry. All patients had >0.1 mV ST-segment depression during exercise stress testing. We did not include patients with the following: recent (<12 weeks) acute coronary syndromes, life threatening arrhythmias, valve heart disease, acute or chronic liver disease, renal failure, connective tissue or rheumatic disorders, and immunological conditions. Thirty one patients were excluded, 12 because of consistently higher high sensitivity C-reactive protein (hs-C-reactive protein) levels (>10 mg/L) and 19 in whom PAPP-A could not be measured for technical reasons.
Age, gender, height, weight, BMI, blood pressure levels, Canadian Cardiovascular Society (CCS) angina class, history of previous myocardial infarction (MI), cardiovascular risk factors including systemic hypertension, diabetes mellitus, smoking, hyperlipidaemia, and family history of CAD as well as cardiac medications were assessed and recorded at study entry.
All patients gave written informed consent before study entry and the study was approved by the Local Research Ethics Committee.
Angiographic analyses
As described in previous studies from our group,9,10 coronary angiography was carried out according to the Judkins technique and images of the coronary tree were obtained in routine standardized projections with the digital Philips Integris 3000 system (Philips, Holland). Two experienced cardiologists, unaware of the patients' clinical history and biochemical results, reviewed all angiographic images. In every coronary angiogram, we assessed the number of major coronary arteries showing
50% reductions in lumen diameter and patients were subdivided into those without CAD if no coronary artery showed a
50% reduction in lumen diameter, those with single-VD if only one coronary stenosis was detectable, and those with multi-VD if two or more coronary artery stenoses were present.
Blood sampling, PAPP-A, and hs-C-reactive protein measurement
Fasting blood samples were obtained from every patient just before diagnostic coronary angiography. Blood was drawn and centrifuged immediately and the serum was then aliquoted and stored at 80°C.
Hs-C-reactive protein measurements were performed on the COBAS Integra (Roche Diagnostics Limited, Lewes, East Sussex, UK) using the C-reactive protein-Latex assay in both the high sensitivity application (analytical range 0.212 mg/L) and the normal application (analytical range 2160 mg/L). Analytical precision of the hs-C-reactive protein-Latex assay was 7.6% at a level of 1.02 mg/L, 3.3 at 1.79 mg/L, and 1.3% at a level of 4.36 mg/L. Samples outside the analytical range of the hs-C-reactive protein-Latex assay were analysed by the C-reactive protein-Latex assay in the normal application. The analytical precision of the normal C-reactive protein-Latex assay was 2.4% at a level of 29.5 mg/L and 1.3% at a level of 113 mg/L.
PAPP-A levels were determined by means of a biotintyramide-amplified enzyme immunoassay with a limit of detection of 0.03 mIU/L and intra-assay and inter-assay coefficients of variation of 10 and 15%, respectively. PAPP-A polyclonal antibodies were used for capture and a combination of monoclonal antibodies was used for detection. The assay was calibrated against the World Health Organization's international reference standard 78/610, which is the standard for pregnancy-associated proteins.
Statistical analysis
The sample size was based on preliminary data obtained in our laboratory and was determined on the basis of the following assumptions: Type I error of 0.05 (two-sided), power of 80%, difference on PAPP-A levels between non-CAD and single-VD patients of 0.5 mIU/L, standard deviation of 1.7, and also assuming that one out of six patients would not have coronary stenoses >50% diameter reduction, the calculated study population was 639. However, 674 patients were recruited to allow for possible analytic problems while processing the samples or other eventualities potentially leading to patient attrition. Twelve patients with >10 mg/L C-reactive protein levels (median 25 mg/L) were not included for analysis, as these high levels were likely to indicate the presence of inflammatory processes other than atherosclerosis. Results for normally distributed continuous variables are expressed as the mean±SD, and continuous variables with non-normal distribution are presented as the median value (interquartile interval). All P-values are two-tailed and confidence intervals (CIs) have been calculated at the 95% level. Comparisons of continuous variables were analysed using one-way analysis of variance (post hoc Bonferroni test) and unpaired t-tests. The KruskalWallis and MannWhitney U-tests were used when variables were not normally distributed. Proportions were compared using two-way cross tabulation and the
2 test. The Spearman two-way test was used to assess the relation between two quantitative variables and non-normal distribution. The Pearson two-way test was used to assess the relationship between two quantitative variables normally distributed. Multivariable analysis used linear regression analysis to assess the influence of age, gender, cardiovascular risk factors, and different medications on PAPP-A levels, and binary logistic regression analysis was used to assess independent predictors of the presence of CAD. Backward stepwise selection was used to derive the final model for which significance levels of 0.1 and 0.05 were chosen to exclude and include terms, respectively. Variables included in multivariable analysis were those that showed a correlation in univariable analysis, which was significant at the 20% level. The Bonferroni adjustment procedure was used to avoid inflation of Type I error due to multiple testing.
Receiver operating characteristic (ROC) analysis regarding levels of PAPP-A that identify the presence of CAD was also carried out. The SPSS 10.0 statistical package (SPSS Inc., Chicago, IL, USA) was used for analysis.
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Results
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A total of 643 patients (63±10 years, 482 men) were included. Of these, 97 (15%) had angiographically normal (or near normal coronary arteries, i.e. <50% stenosis), 127 (20%) had single-VD, and 419 (65%) had
2-VD. Baseline clinical characteristics, cardiovascular risk factors, medical treatments, and biochemical results in these patients at study entry are shown in Table 1. Mean left ventricular ejection fraction (LVEF) was 64.9±11.9%.
PAPP-A levels (mIU/L) ranged from 1.9 to 28 with a mean value of 6.0±2.3. In the whole group, PAPP-A levels were significantly higher in men compared with women (6.2±2.4 vs. 5.2±1.8; P<0.001) and in hypertensive vs. normotensive patients (6.4±2.8 vs. 5.8±2.1; P=0.01). PAPP-A levels were weakly correlated with patients' age (r=0.19, P<0.001), and a weak inverse correlation was also found between PAPP-A and LVEF (r=0.11, P=0.01). PAPP-A levels did not correlate with cholesterol (P=0.9) or hs-C-reactive protein (P=0.6) levels, BMI (P=0.09), CCS class (P=0.4), smoking status (P=0.11), diabetes (P=0.4), or previous MI (P=0.5). Regarding cardiovascular drugs, PAPP-A levels were lower in patients taking statins (6.1±2.4 vs. 5.5±1.5; P=0.02). Using linear regression, only differences in PAPP-A levels between males and females, hypertensive and normotensive patients, and the PAPP-A correlation with age remained significant after multivariable adjustment for variables showing a significant relationship or a trend (P<0.20) with PAPP-A levels. These included BMI, smoking status, and treatment with statins and ACE-inhibitors. Other existing differences were no longer significant after multivariable adjustment.
Hs-C-reactive protein levels (mg/L) ranged from 0.1 to 28.9 with a median value of 2.2. Hs-C-reactive protein levels were significantly higher in women [2.9 (4.2)] compared with men [2.1 (3.2)]; (P=0.001), smokers [3.0 (4.9)] vs. non-smokers [2.0 (2.9)]; (P<0.001), and hypertensive [2.7 (3.7)] vs. normotensive [2.0 (3.3)] patients; (P=0.002).
Hs-C-reactive protein levels showed a weak correlation with age (r=0.12, P=0.001) and BMI (r=0.18, P<0.001). After multivariable adjustment following previously mentioned criteria, differences between hypertensive and normotensive patients were no longer significant.
PAPP-A and hs-C-reactive protein levels and CAD extent
PAPP-A levels were related to CAD extent. CSA patients with multi-VD had significantly higher PAPP-A levels (6.45±2.58 mIU/L) than those with single-VD (5.49±1.54 mIU/L, P<0.001) and patients without CAD (4.62±1.17 mIU/L, P<0.001). PAPP-A levels were significantly higher in single-VD patients compared with patients without CAD (P=0.012) (Figure 1). A comparison between patients without CAD and those with single-VD and multi-VD combined, yielded even more striking differences regarding PAPP-A levels. These differences remained statistically significant after multivariable adjustment for confounding factors such age, gender, hypertension, smoking status, BMI, previous MI, LVEF, statin and ACE-inhibitor treatments, as assessed by linear regression analysis. In contrast, hs-C-reactive protein levels did not differ significantly (P=0.29) among patients with single [2.0 (3.2) mg/L] or multi vessel [2.2 (3.7) mg/L] disease compared with those without coronary artery stenoses [2.7 (2.4) mg/L].

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Figure 1 Error bars showing mean (95% CI) PAPP-A levels in patients without coronary disease (no CAD), patients with single-vessel CAD (single-VD) and those with multi-VD.
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PAPP-A and hs-C-reactive protein levels as markers of the presence of CAD
Multivariable logistic regression analysis was performed to assess predictors of the presence or absence of CAD in these patients. Age, gender, BMI, history of previous MI, CCS angina class, cardiovascular risk factors, cardiovascular treatments, hs-C-reactive protein and PAPP-A levels were included as independent variables. Of these variables, male gender, age, history of a previous MI, hypercholesterolaemia, and PAPP-A levels were independent predictors for the presence of CAD (Table 2).
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Table 2 Independent variables predicting the presence of CAD in the study population (logistic regression analysis)
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ROC curve analysis was carried out to assess the diagnostic ability of both PAPP-A and hs-C-reactive protein levels, regarding the presence of CAD. In patients with CAD, the mean area (95% CI) under the ROC curve for PAPP-A was 0.75 (0.720.78) and for hs-C-reactive protein, 0.45 (0.410.49). Patients with normal coronary arteriograms or <50% coronary stenosis were considered to represent the control group. A PAPP-A threshold level of 4.5 mIU/L had the highest combined sensitivity (45%) and specificity (84%) for the identification of CAD (Figure 2).

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Figure 2 ROC curves for PAPP-A and hs-C-reactive protein levels in patients with and without CAD. The mean area under the ROC curve was 0.75 for PAPP-A and 0·45 for hs-C-reactive protein in patients with CAD.
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Discussion
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The present study reports for the first time a significant relationship between circulating PAPP-A levels and the number of diseased coronary arteries in patients with stable angina pectoris. In contrast, hs-C-reactive protein levels in our study did not correlate with the number of affected coronary vessels. Our results suggest that high PAPP-A levels may be a marker for the presence of CAD in patients with CSA.
The role of PAPP-A in coronary atherosclerosis
The association found in the present study between PAPP-A levels and CAD extent suggests that PAPP-A may be both a marker of atherosclerotic CAD and a pathogenic agent in coronary atherosclerosis. PAPP-A has been shown to enzymatically release IGF from its binding protein.6 Unbound IGF induces vascular smooth muscle growth and migration as well as extracellular matrix synthesis in the atherosclerotic plaque.8,1115 IGF-I also promotes macrophage activation, chemotaxis, LDL cholesterol uptake by macrophages, and the release of proinflammatory cytokines by these cells,16,17 which are known to play a role in the development of atherosclerotic lesions. However, this might not be the only link between PAPP-A and atherogenesis. PAPP-A is a member of the metzincin family of metalloproteinases,18 which are secreted by activated macrophages participating in coronary local inflammatory processes, and have been involved in coronary atherosclerosis and atheromatous plaque disruption.1922 In concordance with these findings, in a previous study in stable angina patients we observed that the ratio between PAPP-A and its endogenous inhibitor proMBP significantly correlated with the presence of complex (vulnerable) coronary stenoses.5
Bayes-Genis et al.23 showed that PAPP-A was associated with the development of neointimal hyperplasia after coronary angioplasty. Later, this same group1 of investigators showed that PAPP-A levels were higher in patients admitted to hospital with MI and unstable angina, compared with stable angina patients and healthy controls. Our observations in the present study significantly expand those of Bayes-Genis et al.1,23 and suggest a role for PAPP-A as a marker for the presence of obstructive CAD in patients with CSA.
Interestingly, we also observed that PAPP-A levels were higher in men compared with women, in hypertensive vs. normotensives, and in older compared with younger CAD patients. In agreement with our findings, Khosravi et al.2 previously reported that PAPP-A levels were higher in healthy men than women, but the reason for this difference remains speculative. In relation to conventional risk factors and PAPP-A levels, the lack of correlation between PAPP-A and hypercholesterolaemia in our study agrees with previous findings by Beaudeux et al.4 In a small group of patients Ceska et al.24 reported that atorvastatin treatment decreased PAPP-A levels even though the change was not statistically significant.
Inflammatory markers and extent of CAD
The relation between biochemical markers of inflammation and the presence and extent of CAD in chronic stable patients is controversial. Mori et al.25 reported that baseline C-reactive protein levels were associated with the severity of coronary atherosclerosis. Subsequently, Tataru et al.26 found a correlation between C-reactive protein levels and the number of vessels diseased in patients with a previous history of MI, whereas Zebrack et al.27 observed only a weak correlation between C-reactive protein levels and CAD extent in patients without MI. In contrast, Azar et al.28 and Hoffmeister et al.29 reported a lack of correlation between C-reactive protein levels and CAD. In agreement with the latter studies, we did not find a significant difference between patients with and without CAD and C-reactive protein levels. Our findings regarding C-reactive protein are endorsed by a recent consensus statement30 that inflammatory markers do not appear to be good predictors of atherosclerotic disease extent. Contrary to findings with C-reactive protein in the present study, we found that PAPP-A levels were significantly higher in patients with multivessel CAD than in those with single-VD or without CAD. ROC analysis indicated that PAPP-A could be a useful clinical tool for the detection of obstructive CAD in stable angina patients. This potential role of PAPP-A in the clinical setting deserves investigation in large prospective trials.
Study limitations
We have used model building procedures to assess the prognostic value of the variables of interest. Although these are frequently used in these kind of studies, concern may exist from a statistical point of view that chance predictors could be included in the final model, and the strength of the associations found between true predictors and outcome could vary at each step depending on which (true and chance) predictors are included at a particular step.
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Conclusion
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A significant association was found between PAPP-A levels and the extent of CAD in stable angina patients. PAPP-A was also found to be an independent predictor of CAD, and a concentration >4.5 mIU/L may be clinically useful to identify patients with obstructive CAD.
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Acknowledgements
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M.C. was supported by a grant from the Birthe and John Meyer Foundation. J.C.S. was the recipient of a research scholarship from the Spanish Society of Cardiology.
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