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European Heart Journal Advance Access originally published online on January 18, 2006
European Heart Journal 2006 27(7):802-807; doi:10.1093/eurheartj/ehi730
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Prognostic significance of plasma osteopontin levels in patients with chronic stable angina

Piercarlo Minoretti1,2, Colomba Falcone2,3, Margherita Calcagnino3, Enzo Emanuele2, Maria P. Buzzi3, Enrico Coen2 and Diego Geroldi2,*

1Department of Cardiology, Alessandro Manzoni Hospital of Lecco, Lecco, Italy
2Interdepartmental Center for Research in Molecular Medicine (CIRMC), University of Pavia, Viale Taramelli 24, I-27100 Pavia, Italy
3Department of Cardiology, IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy

Received 20 September 2005; revised 16 December 2005; accepted 23 December 2005; online publish-ahead-of-print 18 January 2006.

* Corresponding author. Tel: +39 0382 528 341; fax: +39 0382 526 259. E-mail address: ccirmc{at}unipv.it

See page 766 for the editorial comment on this article (doi:10.1093/eurheartj/ehi743)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Aims Levels of the secreted glycophosphoprotein osteopontin (OPN) have been associated with the presence and extent of coronary artery disease (CAD). The present study assessed the relationship between plasma OPN concentrations and prognosis in patients with chronic stable angina (CSA).

Methods and results OPN was measured in baseline plasma samples from 799 patients with stable angina pectoris and angiographically documented CAD. Participants were prospectively followed-up for a median of 2.7 years (maximum 4.1 years). The primary study endpoint was the composite of non-fatal myocardial infarction and death from cardiovascular causes. In the univariate Cox proportional hazard analysis, the log-transformed OPN level [hazard ratio (HR) 1.79, 95% CI 1.35–2.36, P<0.001] was significantly related to adverse outcome. In addition, hypertension, levels of C-reactive protein, and statin use were associated with future adverse events. Levels of OPN (HR, 1.88; P<0.001) and C-reactive protein (HR, 1.42; P=0.003), as well as the presence of hypertension (HR, 2.39; P=0.008) remained statistically significant, independent predictors of adverse cardiovascular outcome in a multivariable Cox proportional hazard analysis.

Conclusion Baseline levels of OPN are an independent predictor of future adverse cardiac events in patients with CSA and may be useful for risk stratification.

Key Words: Osteopontin • Stable angina • Prognosis • Risk stratification


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgement
 References
 
Osteopontin (OPN) is a secreted calcium-binding glycophosphoprotein that has been implicated in numerous physiological and pathological events including cell-mediated immunity, inflammation, tumour progression, and cell survival.1,2 Although originally viewed as a mediator involved mainly in bone remodelling and tissue debridement,3 in recent years it has become apparent that OPN may exert important cardiovascular effects.

Consistent with its role in atherogenesis, OPN has been identified as a prominent component of human atherosclerotic lesions where it is synthesized by cells of the monocyte/macrophage lineage and to a lesser extent by endothelial and vascular smooth muscle cells.4,5 Specifically, OPN was found to be highly upregulated in symptomatic human carotid atherosclerosis,6 in arteries of diabetic patients,7 and in calcified coronary plaques.8 Further evidence for a role of this molecule in atherosclerotic vascular disease came from studies in animal models. In fact, genetic knockout of OPN attenuated the extent of angiotensin II-accelerated atherosclerosis in ApoE–null mice.9 In addition, it has been recently reported that OPN deficiency resulted in reduced atherogenesis in ApoE/LDL receptor double knockout mice.10 On the contrary, OPN transgenic mice have been shown to develop larger atherosclerotic lesions by an atherogenic diet when compared with non-transgenic littermates.11

In the clinical setting, the results of a recent investigation in a Japanese population undergoing coronary angiography have shown a positive relation between the circulating OPN levels and the presence and extent of coronary artery disease (CAD).12 However, data are lacking concerning the impact of OPN on future cardiovascular prognosis in patients with angiographically established CAD.

Working from the assumption of a substantial contribution of OPN in vascular homeostasis, we hypothesized that plasma OPN levels could affect prognosis in patients with stable CAD, with possible implications for risk stratification and secondary prevention. Therefore, we prospectively investigated the prognostic significance of circulating OPN levels in a large Italian cohort of patients with chronic stable angina (CSA). The second aim of our study was to investigate the association between OPN concentrations and clinical, biochemical, and therapeutic features in these patients. We focused our attention on chronic CAD patients as these subjects are poorly characterized in terms of biochemical markers in the assessment of prognosis,13,14 and there is a growing need of biomarkers to better characterize this patient group.15,16


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgement
 References
 
Patient selection
From a larger cohort of patients (n=1103) undergoing coronary angiography for the assessment of chronic stable chest pain, we prospectively investigated 799 patients (595 males and 204 females; mean age: 64.9±9.6). Two hundred and fifty-four patients were not included as they presented with acute coronary syndrome (ACS) and 50 patients did not give their consent for participation in the study. CSA was defined as typical chest pain brought on by exertion and relieved by rest or sublingual nitrates or both, a positive ECG exercise test (>1 mm ST-segment depression), and/or reversible perfusion defects on myocardial radionuclide imaging. In all study patients, symptoms were stable for at least 3 months before study entry. All participants showed at least one stenosis (>50%) diagnosed in a major coronary artery. Patients were recruited consecutively at two hospitals in Northern Italy (Alessandro Manzoni Hospital of Lecco and IRCCS San Matteo Hospital of Pavia) from 1 February 2000 to 30 November 2002.

Patients with significant valvular heart disease, cardiomyopathy, prior coronary revascularization, history of organ transplantation, autoimmune or malignant disease, acute or chronic liver disease, chronic renal insufficiency, and human immunodeficiency virus were not included in the study.

At study entry, all patients underwent a comprehensive clinical examination and biochemical evaluation. In addition, patients completed a questionnaire that provided information about any history of hypertension, diabetes mellitus, family history of CAD, smoking status, and current medication use. Hypertension was defined as a history of hypertension for >1 year requiring the initiation of antihypertensive therapy by the primary physician. Diabetes mellitus was diagnosed in patients who had previously undergone dietary treatment, had received additional oral antidiabetic or insulin medication, or had a current fasting blood sugar level of >126 mg/dL. A family history of CAD was defined as documented evidence of pre-mature CAD in a close relative (men <55 and women <65 years of age). Subjects were classified as currently smoking, as having smoked in the past (if they had stopped >4 weeks and <40 years earlier), or as never having smoked (if they had never smoked or had stopped ≥40 years later).17

The patients were followed-up for a median of 2.7 years (maximum 4.1 years). Composite outcome of non-fatal myocardial infarction defined according to the World Health Organization criteria (i.e. raised cardiac enzymes, characteristic ECG changes, and prolonged typical chest pain) and death from cardiovascular causes represented the study endpoint. As done previously in other prospective cohorts of stable CAD patients,18,19 revascularization procedures during follow-up were not considered as ‘new events’ and did not count as adverse outcome as they were mainly dictated by the results of the index angiography. After the follow-up, the clinical outcome of the study participants was assessed by reviewing their medical records supplemented by an interview of the patient or a family member to make sure that the patient was alive. In the case of death, the hospital records and death certificates were reviewed to verify death. No patients were lost at follow-up.

Study participants were Italian nationality. The local Ethics Committee approved the study, and the written informed consent was obtained from all subjects.

Biochemical measurements
In the morning of the day that angiography was performed, fasting blood samples were drawn by venipuncture into a vacutainer coated with EDTA. The samples were centrifuged at 3000 r.p.m. at 4°C for 10 min within 30 min of collection. Plasma aliquots were stored at –80°C until analysis, which was performed between January and March 2005. Levels of OPN in plasma samples were measured with a sandwich enzyme-linked immunosorbent assay using a commercially available kit (IBL, Hokkaido, Japan), which detects human OPN when present at ≥5 ng/mL, according to the manufacturer's protocol. Briefly, 1:5 diluted testing samples were incubated in the OPN antibody-pre-coated wells at 37°C for 1 h. Following washing, 100 µL of labelled OPN antibody solution was added into each well and incubated for 30 min at 4°C. After washing, tetramethyl benzidine was used as a colouring agent, and the absorbance at 450 nm was measured by an automatic ELISA reader (Bio-Rad, Segrate, Italy). The intra- and inter-assay coefficients of variations were <5 and <8%, respectively.

All other biochemical parameters were measured immediately. The lipid profile including total cholesterol, HDL cholesterol, triglyceride, and other biochemical parameters was measured using a Hitachi 7600–310 autoanalyzer (Hitachi, Tokyo, Japan). The LDL cholesterol concentration was calculated using the Friedewald equation. Lipoprotein(a) was determined using an ELISA method (Dunton Green, Kent, UK). C-reactive protein was measured by a highly sensitive diagnostic assay (Dade Behring, Marburg, Germany). All samples were analysed in triplicate by the laboratory personnel blinded to the clinical outcome of the patients.

Statistical analysis
Statistical analyses were performed using SPSS 11.0 (SPSS Inc., Chicago, IL, USA). The Kolmogorov–Smirnov test was used to verify the normality of distribution of continuous variables. Data are presented as mean values (SD), medians (interquartile range), or as count and percentages, as appropriate. Variables with a non-Gaussian distribution were logarithmically transformed for further analyses. Correlations among variables were computed using the Spearman rank-correlation coefficients. We assessed independent predictors of plasma OPN concentrations by using the multiple regression analysis. Predictors included were all the demographical, clinical, and biochemical characteristics of the study subjects.

For all survival analyses, the endpoint was death from cardiovascular causes or non-fatal myocardial infarction. Non-cardiac mortality was treated as a right-censored event time (n=11). Cumulative survival plots according to the quartiles of OPN levels were univariately evaluated by the Kaplan–Meier analysis (log-rank test). Because the Kaplan–Meier method cannot adjust for the effects of other factors, univariate and multivariable Cox proportional hazards models were used to identify independent predictors of adverse cardiac outcome at follow-up. The multivariable Cox model included all the demographical, clinical, and biochemical characteristics of the study participants. The appropriateness of the proportional hazards assumption was verified using graphical methods and tested as per Grambsch and Therneau.21 The assumption of linearity for the Cox models was examined through visual inspection, and no violation was found. Hazard ratios (HRs) and their 95% CIs were calculated with the estimated regression coefficients and their standard errors in the Cox models. A value of P<0.01 (two-sided) was considered as statistically significant to reduce the likelihood of type I error.22


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgement
 References
 
Baseline characteristics of the study patients and predictors of plasma OPN levels
The main clinical, biochemical, and therapeutic characteristics of the study group at baseline are detailed in Table 1. Plasma OPN concentration in the study cohort was significantly skewed, ranging from 5 to 841 ng/mL with a median of 270 ng/mL and an interquartile range from 79 to 443 ng/mL. Baseline OPN levels were significantly correlated with age (r=0.14, P<0.001), C-reactive protein levels (r=0.10, P=0.005), triglyceride concentrations (r=0.09, P=0.02), and the number of significantly diseased vessels (r=0.18, P<0.001). Notably, patients receiving statins had lower levels of OPN when compared with those who did not take these drugs (median 251 vs. 329 ng/mL, respectively, P<0.001). Multiple linear regression analysis was performed to investigate the independent predictors of OPN levels. Predictors included in the model were all the variables listed in Table 1. The results suggested that treatment with statins (ß=–0.15, P<0.001), the number of diseased vessels (ß=0.16, P<0.001), and age (ß=0.13, P<0.001) were independent predictors of baseline plasma OPN levels.


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  		Table 1 Baseline characteristics of the 799 consecutive patients with CSA
 
OPN and adverse cardiac events during follow-up
During a median follow-up period of 2.7 years, the study endpoint was reached by 69 of the 799 patients (8.6%). Categorization of the patient population according to OPN quartiles revealed a statistically significant trend towards higher event rates through increasing OPN quartiles (log rank=19.68, P<0.001, Figure 1).


Figure 7301
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  		Figure 1 Kaplan–Meier survival plots for adverse cardiovascular events according to the quartiles of OPN concentrations. The OPN levels were as follows: first quartile, <79 ng/mL; second quartile, 79–270 ng/mL; third quartile, 270–443 ng/mL; and fourth quartile, >443 ng/mL. Note the truncated ordinate axis.

 
As shown in Table 2, in the univariate Cox proportional hazard analysis, the log-transformed OPN level (HR, 1.79, 95% CI 1.35–2.36, P<0.001) was significantly related to adverse cardiac outcome. In addition, hypertension, levels of C-reactive protein, and statin use were associated with future adverse cardiovascular events. In a multivariable Cox proportional hazard analysis, levels of OPN (HR, 1.88; P<0.001) and C-reactive protein (HR, 1.42; P=0.003), as well as the presence of hypertension (HR, 2.39; P=0.008) remained statistically significant, independent predictors of adverse cardiovascular outcome (Table 2).


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  		Table 2 Univariate and multivariable Cox regression analysis of future adverse cardiovascular events
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgement
 References
 
The significance of OPN for coronary atherosclerosis has recently been given its first epidemiological support. A cross-sectional evaluation in a patient group at high-vascular risk (subjects undergoing coronary angiography) has indeed revealed a strong positive association between the OPN plasma level and the presence and extent of coronary vessel stenosis.12

The present study is the first prospective survey addressing the association between OPN and future cardiovascular events in a large cohort of patients with stable coronary disease. Besides identifying the main correlates of OPN levels such as age, the number of significantly diseased vessels, and statin therapy, our results showed a strong association between baseline OPN concentrations and risk of future ‘hard’ events in CSA patients. Although the pathophysiological mechanisms underlying the predictive value of OPN are probably multifactorial and cannot be directly inferred from our present study, it is worth noting that the adverse prognostic effect of elevated OPN levels was independent of traditional vascular risk factors as well as high-sensitive C-reactive protein, a highly relevant biomarker during the assessment of prognosis in this patient group.14

As also suggested for C-reactive protein previously,23 it is feasible that the predictive ability of OPN as observed in our study may indicate that this molecule is not only involved in plaque formation, but could also be a marker of CAD activity. OPN is an arginine–glycine–aspartate-containing acidic glycoprotein that is known to induce chemotactic movement of several cells involved in the atherosclerotic process such as vascular smooth muscle cells and macrophages.2,24 In addition, a growing body of experimental evidence has now accrued that OPN has the capacity to induce the proliferation of vascular smooth muscle cells25 and may inhibit nitric oxide synthase expression in macrophages and endothelial cells.26,27 Taken together, these findings suggest that OPN may be critically involved in the inflammatory processes that take place within the arterial wall in atherogenesis and atheromatous plaque disruption. Alternatively, another potential explanation for the association between elevated OPN levels and adverse outcome may involve coronary calcifications. Indeed, as coronary calcium could provide useful prognostic information in patients with CAD,28,29 it would be tempting to speculate that circulating OPN may be linked to cardiovascular prognosis by influencing coronary calcium scores. Although in our present report coronary calcium scoring was not assessed with computed tomography, further studies aiming to untangle the relationship among OPN, coronary calcium, and cardiac prognosis are warranted. Additionally, as recent findings suggest that there may be a link between the inflammation and the propensity to calcification,30,31 further research is also required to investigate the possible interactions between OPN and coronary plaque instability.

An intriguing finding of our study is that the use of statins was associated with lower plasma OPN concentrations in patients with CSA, even after adjustment for potential confounders. It should be noted that a previous report has demonstrated that NK-104, a potent synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, reduced OPN expression both at protein and mRNA levels in cultured rat aortic smooth muscle cells.32 These findings are consistent with the established anti-inflammatory properties of statins33 and may also indicate that reduced OPN levels in patients receiving statins could be a marker of the beneficial effects of these drugs on vascular smooth muscle cells function.

Besides the observed correlation of OPN levels with statin use, we have also observed correlations of OPN with age, C-reactive protein levels, and the number of diseased coronary vessels. The latter finding is in agreement with the results of Ohmori et al.12 that OPN may be a biochemical marker of the anatomical extent of the coronary atheromatous process. However, it is important to note that at multivariable analysis, the prognostic significance of OPN in assessing future events was independent of all predictors of plasma OPN concentrations.

Some limitations of our study merit consideration. First, our population consisted exclusively of Caucasian Italian subjects without ethnical diversity. Therefore, extrapolation of any conclusions from the present investigation may be incorrect and future studies in different clinical cohorts are needed to confirm and expand our findings. Secondly, the measurement of OPN was performed on samples that were stored at –80°C. We therefore cannot exclude the possibility of protein degradation. However, the samples for this study were only thawed once, and we have noted measured OPN values to be similar in fresh and frozen aliquots. Thirdly, it should be kept in mind that we limited our investigation to a clinical cohort of stable patients referred for coronary angiography and with evidence of significant CAD. We nonetheless deliberately focused our attention on this patient group because, in contrast to ACSs, there is a paucity of biomarkers that can be used in clinical practice to characterize CSA patients.14 Notably, the growing need to better characterize these subjects is further emphasized by the substantial proportion of chronic CAD patients who fail to receive adequate treatment.16

In summary, our findings provide evidence that circulating OPN levels are an independent prognostic biomarker for patients with CSA. Further studies are required to elucidate whether OPN could be predictive of adverse cardiac outcome in ACS patients, as well as in initially healthy subjects.


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
References
 
This work was supported partly by a grant from the IRCCS San Matteo Hospital (Ricerca Corrente 2004), Pavia, Italy.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 

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