Inflammation, complement activation and endothelial function in stable and unstable coronary artery disease

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Abstract

Background

Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease (CAD). Apart from traditional risk factors complement activation and inflammation may trigger and sustain endothelial dysfunction. We sought to assess the association between endothelial function, high sensitivity C-reactive protein (hs-CRP) and markers of complement activation in patients with either stable or unstable coronary artery disease.

Methods

We prospectively recruited 78 patients, 35 patients with stable angina pectoris (SAP) and 43 patients with unstable angina pectoris (UAP). Endothelial function was assessed as brachial artery reactivity (BAR). Hs-CRP, C3a, C5a and C1-Inhibitor (C1 inh.) were measured enzymatically.

Results

Patients with UAP showed higher median levels of hs-CRP and C3a compared to patients with SAP, while BAR was not significantly different between patient groups. In UAP patients, hs-CRP was significantly correlated with cholesterol (r = 0.27, p < 0.02), C3a (r = 0.32, p < 0.001) and C1 INH.(r = 0.41, p < 0.003), but not with flow mediated dilatation (r = 0.09, P = 0.41). Hs-CRP and C1 INH.were found to be independant predictors of UAP in a backward stepwise logistic regression model.

Conclusions

We conclude that both hs-CRP, a marker of inflammation and C3a, a marker of complement activation are elevated in patients with UAP, but not in patients with SAP.

Introduction

Endothelial dysfunction plays an important role in the pathogenesis of coronary artery disease (CAD). Apart from traditional risk factors like cholesterol and smoking, complement activation and inflammation may trigger and sustain endothelial dysfunction. The complement cascade, activated during myocardial ischaemia, appears to mediate immune and inflammatory responses in ischaemic myocardium [1]. Complement activation contributes to myocardial necrosis through various pathways, including the activation of leukocytes and endothelial cells, increased apoptosis, upregulation of genes involved in cytokine production and by interfering with nitric oxide synthase activity [2]. Activation of the complement cascade in patients with MI is evidenced by elevated levels of activated complement byproducts, especially C3a, C5a and C5b-9 in patients' blood and atherosclerotic plaques [3]. The important role of complement activation in myocardial ischaemia has also been highlighted during cardiopulmonary bypass, whereby inflammation and tissue injury in these patients was inhibited with specific antibodies against complement in vivo [4]. Various intrinsic regulators exist that control unwanted complement activation. These include C1-inh., decay accelerating factor (DAF, CD 55), membrane cofactor protein (MCP), protectin (CD 59) and factor H. Factor H is a glycoprotein known to play a regulatory role in the activation of the alternative pathway of complement. This plasma protein prevents formation of the C3bBb convertase by competing with factor B and destabilizes the formed convertase by displacing factor B from C3b. It also functions as a cofactor for the proteolytic cleavage of C3b by factor I resulting in the formation of iC3b [5]. Complement activation can also be caused by mannan-binding lectin (MBL) a serum acute-phase protein secreted by the liver [2]. MBL deficiency has recently been associated with severe atherosclerosis [6].

Inflammation is closely linked to the pathogenesis of atherosclerosis. The acute phase reactant, C-reactive protein (CRP), is elevated in both patients with acute coronary syndromes [7] and those at risk of coronary artery disease [8]. Although CRP has known pro-inflammatory effects [9], the exact mechanism of its association with adverse events is uncertain. CRP reportedly activates the classical pathway of complement, whereas cholesterol and oxysterols activate the alternative pathway [10]. Furthermore, CRP frequently colocalizes with the terminal complement complex in early atherosclerotic lesions [11].

Endothelial dysfunction has been shown to have prognostic value in patients with chest pain [12]. We hypothesized that inflammation and complement activation are dominant determinants of endothelial function and anticipated that this relation would be stronger in UAP than SAP. We therefore measured endothelial dysfunction (as assessed by brachial artery reactivity [BAR]), inflammation (as assessed by hs-CRP) and complement activation (as assessed by C3a, C5a and C1 inh.) in patients with SAP and UAP.

Section snippets

Study design

This prospective, single-centre study was approved by the human ethics committee of the Princess Alexandra Hospital and was undertaken with the informed consent of all patients. The investigation conforms with the principles outlined in the declaration of Helsinki (Cardiovascular Research 1997; 35:2–4). Patients aged > 18 years were deemed eligible if they presented with either SAP or UAP. SAP was defined as a stable pattern of exertional chest discomfort over the preceding two months, that was

Results

Demographic data of the patients is shown in Table 1. The study groups comprised 35 patients with SAP (28 males, mean age 59 ± 9 years), and 43 patients with UAP (34 males, mean age 60 ± 13 years). Patients with UAP had a significantly higher heart rate, diastolic blood pressure, cholesterol and LDL cholesterol compared to those with SAP. Conversely, the SAP group was found to have a greater rate of prior myocardial infarction and coronary revascularization, as well as use of anti-platelet therapy,

Discussion

The results of this study indicate that both hs-CRP, a marker of inflammation and C3a, a marker of complement activation are elevated in patients with UAP, but not in patients with SAP. These data somehow confirm a recent study of Hoffmeister et. al [16], who found a strong correlation of significantly elevated CRP and the terminal complement complex (sC5b-9) in UAP patients, which they concluded may explain the prognostic value of CRP in acute coronary syndromes. The complement system

Acknowledgement

We would like to thank Michelle Kostner for correction of the manuscript.

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