Elsevier

Atherosclerosis

Volume 208, Issue 2, February 2010, Pages 524-530
Atherosclerosis

Elevated levels of neopterin are associated with carotid plaques with complex morphology in patients with stable angina pectoris

https://doi.org/10.1016/j.atherosclerosis.2009.07.054Get rights and content

Abstract

Objective

Neopterin is an activation marker for monocytes/macrophages, and circulating levels of neopterin are elevated in patients with coronary complex lesions in unstable angina pectoris. We investigated the possible association between neopterin and complex carotid plaques which may be associated with the risk of ischemic stroke in patients with stable angina pectoris (SAP).

Methods

We measured plasma levels of neopterin in 102 patients with SAP and carotid ultrasound was performed for evaluation of the presence of carotid plaques and plaque surface characteristics categorized as complex or noncomplex. In addition, endarterectomy specimens of extracranial high-grade carotid stenosis with complex plaques from five patients with SAP were immunohistochemically examined with antibodies to smooth muscle cells, endothelial cells, platelets, macrophages, and T cells.

Results

Plasma neopterin levels were significantly higher in patients with complex carotid plaques than in those with noncomplex plaques (median [interquartile range]: 24.2 [19.2–39.3] nmol/L vs. 19.4 [11.9–25.1] nmol/L; P = 0.01) or without any plaques (18.8 [14.9–23.6] nmol/L; P = 0.001). On multivariate logistic analyses after adjustment for traditional atherosclerotic risk factors, multi-vessel coronary disease and high sensitivity C-reactive protein, neopterin levels were independently associated with the presence of complex carotid plaques (adjusted OR 2.21 per SD increase, 95%CI 1.13–4.33, P = 0.02). Immunohistochemical staining revealed abundant neopterin-positive macrophages in carotid complex lesions.

Conclusion

These findings demonstrate that carotid plaques with complex morphology have increased circulating neopterin levels and immunohistochemical localization of neopterin in patients with SAP. Neopterin can be considered an important biomarker of plaque destabilization in carotid artery atherosclerotic lesions in this population.

Introduction

Recent studies have shown that complex plaques in the carotid arteries, such as lesions exhibiting irregularity or ulcerated surface morphology, detected on carotid ultrasound independently predict ischemic stroke [1], [2], [3], [4]. Although the reason for the relationship between complex carotid plaques and ischemic stroke is unclear in detail, complex carotid plaques may be not only a potential source of emboli but also a marker of generalized atherosclerosis and indicate systemic atherosclerotic instability [3], [4]. Detection of carotid complex lesions by carotid ultrasound might thus help identify patients at high risk for ischemic stroke [3], [4].

Inflammatory processes play roles in the pathogenesis of atherosclerotic plaque and its thrombotic complications. Monocyte/macrophage activation plays a significant role in the inflammatory process associated with atherosclerosis and plaque vulnerability [5]. Neopterin, a by-product of the guanosine triphosphate pathway, is produced by activated macrophages after stimulation by interferon-γ released by T cells, and is an activation marker for monocytes/macrophages [6], [7]. The previous studies have reported that serum levels of neopterin are elevated in patients with unstable angina pectoris (UAP) compared with control subjects and patients with stable angina pectoris (SAP) [8], [9]. Furthermore, several coronary angiographic studies have shown a relationship between increased neopterin levels and coronary complex lesions in patients with UAP [10], [11]. Recently, our immunohistochemical study using coronary atherectomy specimens confirmed a significantly higher prevalence of neopterin-positive macrophages in culprit lesions in patients with UAP than in those with SAP [12].

On the other hand, even in patients with SAP, mean levels of serum neopterin have been shown to be higher than in healthy volunteers [9]. In this context, Schumacher et al. speculated that pronounced atherosclerosis in large vessels like the carotid artery might induce higher mean levels of neopterin in SAP patients [9]. We hypothesized that increased plasma neopterin levels in patients with SAP may be related to carotid plaque instability such as characteristic of complex plaques. In this study, we measured circulating plasma neopterin levels in patients with SAP and evaluated the relationship between plasma neopterin levels and carotid plaque surface morphology assessed by carotid ultrasound (group I). Additionally, we immunohistochemically examined the expression of neopterin in specimens of carotid plaque complex lesions obtained from SAP patients undergoing carotid endarterectomy (CEA) (group II).

Section snippets

Study patients: group I (plasma neopterin)

We enrolled 106 patients (81 men, mean age, 68 ± 10 years) with SAP who were admitted to Osaka City General Hospital to undergo coronary angiography. SAP was defined as effort-related angina without any change in clinical pattern in the preceding 2 months. All patients in the study had angiographically documented coronary disease and underwent carotid ultrasound. Patients were excluded from the study if they had previous carotid endarterectomy/angioplasty, or intercurrent inflammatory, infectious

Plasma levels of neopterin and carotid plaque characteristics: group I

The study population consisted of 102 patients with SAP; 62 patients with 1-vessel coronary disease (61%) and 40 with multi-vessel coronary disease (39%). There were no differences in plasma neopterin levels (20.4 [14.9–29.0] nmol/L vs. 20.6 [14.7–29.1] nmol/L; P = 0.89) and hs-CRP levels (0.63 [0.34–1.4] mg/L vs. 0.87 [0.45–2.7] mg/L; P = 0.13) between patients with 1-vessel coronary disease and those with multi-vessel coronary disease.

On carotid ultrasound examination, at least one atherosclerotic

Discussion

The present study has demonstrated that increased plasma neopterin levels in patients with SAP were independently associated with the presence of complex carotid plaques after adjustment for multi-vessel coronary disease and hs-CRP. Furthermore, immunohistochemical examination revealed the presence of abundant neopterin-positive macrophages in carotid complex lesions in SAP patients.

Previously, Weiss et al. [24] reported an association between increased serum concentrations of neopterin and

Conclusions

Carotid plaques with complex morphology have increased plasma neopterin levels and immunohistochemical localization of neopterin in patients with SAP. Neopterin can be considered an important biomarker of plaque destabilization in carotid artery atherosclerotic lesions in this population.

Conflicts of interests

None.

Acknowledgement

This study was supported by Grants-in-Aid for Scientific Research (No. 18590339) from the Japan Society for the Promotion of the Science, Tokyo, Japan.

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