Elevated levels of neopterin are associated with carotid plaques with complex morphology in patients with stable angina pectoris
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.
References (29)
- et al.
Serum neopterin in acute coronary syndromes
Lancet
(1997) - et al.
Increased neopterin in patients with chronic and acute coronary syndromes
J Am Coll Cardiol
(1997) - et al.
Serum neopterin and complex stenosis morphology in patients with unstable angina
J Am Coll Cardiol
(2000) - et al.
Modification of the Modified Diet Renal Disease (MDRD) study equation for Japan
Am J Kidney Dis
(2007) - et al.
Analysis of reduced forms of biopterin in biological tissues and fluids
Anal Biochem
(1980) - et al.
Increased concentrations of neopterin in carotid atherosclerosis
Atherosclerosis
(1994) - et al.
Inflammation and hemostasis biomarkers for predicting stroke in postmenopausal women: the Women's Health Initiative Observational Study
J Stroke Cerebrovasc Dis
(2008) - et al.
Ischemic stroke events and carotid atherosclerosis. Results of the Osaka follow-up Study for ultrasonographic Assessment of Carotid Atherosclerosis (the OSACA study)
Stroke
(1995) - et al.
Carotid intima-media thickness and plaque characteristics as a risk factor for stroke in Japanese elderly men
Stroke
(2004) - et al.
Carotid plaque surface irregularity predicts ischemic stroke. The Northern Manhattan Study
Stroke
(2006)