The role of lipid-lowering therapy in multiple risk factor management.

Epidemiological studies have demonstrated that the risk of death from coronary heart disease (CHD) increases in parallel with increasing serum cholesterol levels. The risk is highest in patients with severely elevated cholesterol levels [i.e. > 6.2 mmol/L(240 mg/dl)]. However, even in patients with serum cholesterol levels of 4.7 to 5.7 mmol/L (180 to 220 mg/dl), mortality from CHD is 30 to 70% higher than in patients with cholesterol levels < 4.7 mmol/L (180 mg/dl). A number of factors other than serum total cholesterol levels affect CHD risk. It is increasingly accepted that dysfunction of the vascular endothelium contributes to the pathogenesis of atherosclerosis. Experimental evidence and clinical studies suggest that endothelium-derived nitric oxide (NO) plays an important role as an endogenous antiatherogenic molecule, and that reduced levels of NO may promote progression of atherosclerosis. Hypercholesterolaemia can hasten atherogenesis in part by reducing levels of NO. In humans, it is possible to evaluate the effects of hypercholesterolaemia by measuring the vasodilator response to pharmacological or physical stimuli that increase the synthesis and release of endothelium-derived NO. The use of high resolution external ultrasound to assess post-ischaemic brachial artery vasodilation in patients with cardiovascular risk factors has demonstrated that endothelial dysfunction exists, even in the absence of overt atherosclerotic plaques. Impaired endothelium-dependent vasodilation has been observed in asymptomatic individuals with hypercholesterolaemia, as well as in patients with other recognised risk factors. Dietary and pharmacological lipid lowering has been shown to produce improvements in endothelial-dependent vasodilation. Among normocholesterolaemic healthy young individuals without cardiac risk factors, endothelium-dependent vasodilation was more likely to be impaired in those with relatively higher total and low density lipoprotein-cholesterol levels (i.e. above versus below the 25th percentile). This suggests that an inverse and continuous relationship exists between the prevailing cholesterol level and endothelial function. The implication of these findings is that the treatment of hypercholesterolaemia remains, at present, an underutilised means of reducing CHD.