Statins and the assessment of endothelial function

DEAR SIR We read with great interest the paper by Šebeštjen et al. [1], which showed that lipid-lowering with both cerivastatin and fenofibrate improved arterial vasoreactivity in patients with combined hyperlipidaemia, although the effects were greater in the patients receiving the statin. This small but well-designed study adds to the existing literature [2] that the statins have beneficial effects beyond lipid-lowering, such as improvement in peripheral endothelial function [as measured by flow-mediated dilation (FMD) of the brachial artery], antithrombotic or antiinflammatory effects and plaque stabilization, which may contribute to the beneficial effects in reducing cardiovascular events. Endothelial dysfunction has been regarded as an early event in atherosclerosis, preceding the formation of atherosclerotic plaques and evidence of endothelial damage/dysfunction has been clearly demonstrated in patients with vascular diseases, as well as in risk factors for coronary disease, such as hypertension, diabetes mellitus, hypercholesterolaemia and smoking [3]. However, the best way of assessing endothelial damage/dysfunction is still uncertain, and it is likely that a continuum exists between endothelial activation (likely to be related to early exposure to risk factors, such as smoking), endothelial dysfunction (leading to thrombogenesis and atherogenesis) and, finally, endothelial damage (leading to overt vascular damage and atherosclerosis) [4]. Noninvasive assessment of endothelial function usually relies on postischaemic dilation of forearm vessels, using plethysmography or by FMD of the brachial artery. However, these techniques have several disadvantages, as they are observer-dependent, require expensive specialized equipment, which require trained observer(s), and the possibility of inter- and intraobserver variability. Such techniques are also not practically possible to be used in large population-based epidemiological studies. Nevertheless, it is of note that almost all previous studies on the effect of statins on endothelial function have employed FMD of the brachial artery. An alternative assessment of endothelial damage/dysfunction is by measurement or plasma markers that are related to the endothelium, such as von Willebrand factor (vWf), soluble thrombomodulin or E-selectin [3]. For example, vWf has been widely accepted and well-established as a marker of endothelial damage. Raised levels of vWf been found in patients with all the major risk factors for atherosclerotic vascular disease and that treatment of these risk factors lowers vWf levels [3]. Goldsmith et al. [5] also reported a scanning electron microscopy study, which related the severity of atrial endothelial/endocardial damage to increasing plasma levels of vWf. Furthermore, we have pilot data in 89 hypertensive patients (78 men; mean age 64 years, SD 8.4; mean BP 167/91 mmHg) where plasma vWf levels significantly correlated with FMD (Spearman, r=−0.517, P < 0.001). Plasma markers such as vWf also have prognostic value in cardiovascular disease [3]. Indeed, prospective epidemiological studies have repeatedly shown vWf as an independent predictor of subsequent myocardial infarction or sudden death from coronary artery disease in patients with or without established coronary artery disease. Assessment of plasma markers is also relatively cheaper, more easily measured and readily available, with good reproducibility and low inter- and intraobserver variability, when compared with observer-dependent techniques such as FMD measurements. Plasma markers of endothelial damage/dysfunction can even be measured in thousands of patients – an essential feature for a potential screening tool in large population-based epidemiological studies. Do plasma markers `respond' to statins? We recently reported a 4-month randomized double-blind comparison of pravastatin and placebo in patients with vascular disease and hypercholesterolaemia; after 4 months of therapy, plasma vWf, total cholesterol and LDL-C levels were significantly reduced when compared with baseline (untreated) levels [6]. The greatest reduction was in levels of the inflammatory marker, CRP, which decreased by an average of 45%. Thus, in addition to cholesterol reduction, treatment with pravastatin also improved endothelial function and reduced inflammation. Thus, we would advocate that plasma markers would be an alternative assessment of endothelial damage/dysfunction, and we would be interested in whether Šebeštjen et al. [1] have such data to complement their excellent study.