Improving endothelial vasomotor function

The vascular endothelium is a confluent, cellular monolayer that lines the entire vascular compartment at the interface between blood and the vessel wall. This “organ” possesses complex endocrine and paracrine functions and is intimately concerned in controlling vasomotor tone and preventing atherosclerosis and thrombosis.¹ Indeed, endothelial dysfunction plays a key part in the pathogenesis and progression of atherosclerosis.²

An important and relatively recently discovered endothelial product is nitric oxide, a simple, highly reactive gas previously known as endothelium-derived relaxing factor. Endothelial nitric oxide itself possesses potent antiatherogenic properties, inhibits platelet aggregation, and regulates vascular tone.¹ Bioavailable nitric oxide may be increased either by enhancing its production or by reducing its inactivation—for example, by reactive oxygen species, which are thought to damage the endothelium and promote atherosclerosis. Indirect measurement of bioavailable nitric oxide, through its vasodilating properties, is an extensively investigated surrogate of endothelial (vasomotor) function in clinical and experimental studies. In this context, endothelial vasomotor dysfunction occurs in the coronary arteries of patients with coronary atherosclerosis³ and with standard risk factors for atherosclerosis,⁴ and more recently it has been associated with the novel risk factors hyperhomocysteinaemia and low birth weight.⁵

Coronary endothelial vasomotor function may be assessed using quantitative angiography to measure vasodilatation induced by agonists (such as acetylcholine) or mechanical stimuli (increased flow) that stimulate the endothelium to produce nitric oxide; impaired function is associated with reduced dilatation. This assessment, although informative, is invasive and potentially hazardous and so not applicable to routine clinical practice. However, coronary endothelial vasomotor dysfunction has been shown to correlate closely with endothelial function measured in large peripheral arteries.⁶ Measurement of endothelial function in accessible peripheral vessels, such as the brachial artery, is therefore a useful surrogate of coronary endothelial vasomotor function and can be measured by changes in forearm blood flow induced by nitric oxide releasing agonists (using venous plethysmography) or by flow mediated dilatation (using high resolution ultrasound).

Many studies have shown that endothelial vasomotor dysfunction is reversible with risk factor intervention (such as smoking cessation, physical exercise) and drugs (angiotensin converting enzyme inhibitors, statins, vitamin C, folic acid, fish oils, and spironolactone).^7–10 Until recently, however, we lacked clear evidence of a prognostic link between coronary endothelial vasomotor dysfunction and cardiovascular events. Two recent prospective studies have, for the first time, shown that coronary endothelial vasomotor dysfunction predicts cardiovascular events.¹¹,¹²

Thus, if endothelial vasomotor dysfunction is associated with standard risk factors, can its measurement further improve risk stratification? This question has not been conclusively answered, though data from these prospective studies suggest that it may be more predictive of cardiovascular events than standard risk factors.¹¹ Furthermore, in people with mild coronary atheroma those with the greatest endothelial vasomotor dysfunction had a worse prognosis than those with mild dysfunction, there being no significant difference in risk factors or disease severity between the groups.¹² The observation that standard risk factor scoring in general practice in the United Kingdom will identify only 59% of men at risk of myocardial infarction or sudden death over a five year period is further evidence that standard risk factor detection will not reveal all those at risk of cardiac events.¹³

At present, clear prospective evidence for benefit, in terms of decreased cardiovascular events, after improving endothelial vasomotor function does not exist, although there is circumstantial evidence to support this link. Several large secondary prevention studies (4S, HOPE, RALES, GISSI Prevenzione study) have shown clear benefit in patients treated with different drugs which in separate studies have been shown to improve endothelial vasomotor function experimentally.⁸,⁹ None of these prevention studies prospectively measured endothelial function, so attributing the improved outcome to enhanced endothelial function is speculative.

Assuming that measurement of endothelial vasomotor function adds usefully to current methods of risk stratification, do we have a test that may be applied to the general population? At present we do not. Though widely used in research, flow mediated dilatation and venous plethysmography are not useful for population screening. Both require specialised equipment and skilled operators, and venous plethysmography requires insertion of an intra-arterial needle. A more widely applicable tool for assessing endothelial vasomotor function is needed, and methods such as pulse wave velocity analysis are currently under investigation.¹⁴

The drugs that improve endothelial vasomotor function are already available.^8–10 If further studies show clinical benefit after enhancing endothelial vasomotor function the race to find a clinically useful tool to measure it will begin. This will allow more accurate targeting and monitoring of therapy to reduce cardiovascular risk in the individual.