Effect of Angiotensin Converting Enzyme Inhibitor on Plasma von Willebrand Factor Level in Patients with Coronary Artery Disease

Endothelial cells play important roles in maintaining normal vascular function and structure. Previous studies have revealed that patients with coronary artery disease show impaired endothelium-mediated function [1]. Restoration of endothelial function in those patients is extremely important to prevent disease progression. Treatment with angiotensin converting enzyme (ACE) inhibitors has been reported to improve endothelial function in both human and animal studies [2,3]. In those studies, improvement of endothelial function has been evaluated by vasodilator response of blood vessels or by morphological changes of coronary arteries observed by angiography. Increased levels of von Willebrand factor (vWf), a glycoprotein produced uniquely by endothelial cells and megakaryocytes, have been proposed to reflect generalized endothelial dysfunction [4]. Furthermore, high levels of vWf have been shown to predict cardiovascular mortality in patients with cardiovascular disease [5,6]. Previously, Hernandez et al. [7] measured plasma vWf levels in patients with immunoglobulin A nephropathy and found that ACE inhibitor treatment induced a significant decrease in both vWf levels and proteinuria. However, to date, there have been no studies that investigated the effects of ACE inhibitor treatment on endothelial function by measuring vWf in patients with coronary atherosclerosis. Therefore, we examined the effects of ACE inhibitor treatment on plasma levels of vWf antigen in these patients. Plasma levels of vWf antigen, angiotensin II and ACE activity were measured in 30 patients [25 males and 5 females, mean (SEM) age of 63.2 (1.7) years, ranging from 36 to 77 years] with stenotic coronary artery disease diagnosed by coronary angiography. Patients were divided into two groups: 15 patients with regular ACE inhibitor treatment (5–10 mg of enalapril) and 15 patients without ACE inhibitor treatment. ACE inhibitors had been administered longer than 6 months before the study. The plasma level of vWf was determined with an enzyme-linked immunosorbent assay kit (Diagnostica Stago, Asnieres, France) as reported previously [8]. Activity of ACE was measured by colorimetry with a commercially available kit (Fujirebio Inc., Tokyo, Japan) [8]. Levels of angiotensin II were determined by radioimmunoassay using specific anti-angiotensin II antibody (SRL Inc., Tokyo, Japan) [9]. There was no significant difference in clinical parameters between patients with and without regular ACE inhibitor treatment, except that plasma ACE activity and angiotensin II level were significantly lower in patients with ACE inhibitors than in those without ACE inhibitors (Table 1). As shown in Figure 1, mean plasma vWf antigen level was also significantly lower in patients with regular ACE inhibitor treatment than in those without ACE inhibitor treatment [93.3 (7.6) and 129 (7.8)%, p< 0.01]. However, no significant correlation was observed between plasma ACE activity or angiotensin II level and vWF antigen level in study subjects (r = − 0.10, p = 0.72 and r = + 0.11, p = 0.69, respectively). The present results suggest that ACE inhibitor treatment decreases vWf levels and thus restores endothelial dysfunction in patients with coronary artery sclerosis. Recently, Jager et al. [10] reported that increased level of vWf is a risk factor of cardiovascular mortality. The precise mechanism by which vWf increases cardiovascular risk is unclear. It has been suggested that vWf is a marker of generalized endothelial dysfunction [4], which is an important feature of atherothrombotic disease. Alternatively, it has been hypothesized that vWf, as an acute-phase reactant, reflects endothelial activation and stimulation and, as such, is a marker of more severe disease in general. Accordingly, the ECAT study showed that the risk of cardiovascular mortality predicted by vWf was explained by the risk predicted by CRP and/or fibrinogen [11]. Finally, vWf plays an important role not only in