Eating, vascular biology, and atherosclerosis: a lot to chew on.

Coronary risk factors, such as hypercholesterolaemia and hypertension, are primary causes of atherosclerosis, at least partly due to their adverse impact on vascular biology. Impaired vascular biological states, such as endothelial dysfunction and inflammation, however may be independently atherogenic. Three examples that suggest that vascular indexes need to be considered independent of risk factors are anti-inflammatory effects of statins, hormone replacement therapy (HRT), and post-prandial endothelial dysfunction and inflammation. The REVERSAL and PROVE IT-TIMI 22 trials demonstrated that changes in LDL cholesterol and C-reactive protein independently correlated with coronary atherosclerosis progression and coronary heart events. On-treatment C-reactive protein was as predictive of subsequent coronary events as was LDL cholesterol. Prior to the recent HRT trials, many clinicians routinely recommended HRT to post-menopausal women to lower their cardiovascular risk. This was not unreasonable because HRT increases HDL cholesterol and decreases LDL cholesterol and lipoprotein(a). At the same time, HRT increases inflammation (e.g. C-reactive protein) and coagulation, two key atherogenic factors. Estrogen and HRT improve endothelial function, but this improvement disappears within a few months for as yet unclear reasons. In light of these lipid-independent vascular biological effects, it is not surprising that the recent HRT trials did not find beneficial effects on cardiovascular risk. Esposito et al. review dietary effects on endothelial function and inflammation. In summary, both high-fat and high-sugar diets and single meals reduce endotheliumdependent vasodilation and increase inflammatory markers, such as C-reactive protein, interleukin-6, interleukin-8, interleukin-18, and tumour necrosis factor-a. The vascular effects of a high-fat meal last longer than those of a high-sugar meal, but the addition of a large sugar load to a high-fat meal increases the magnitude of the effects. A single high-fat meal also increases circulatingmicroparticles, another index of endothelial dysfunction, activates coagulation factor VII, and impairs vascular compliance. Several studies have shown that post-prandial vascular biological impairment is greater in subjects with diabetes mellitus. Considerable evidence suggests that high-fat and highsugar meals induce vascular dysfunction through increases in oxidative stress. Reactive oxygen species are increased following a high-fat meal, especially in diabetic subjects, and increased nitric oxide inactivation has been demonstrated. The addition of direct (e.g. vitamins C and E) and indirect (e.g. folic acid) antioxidants to single meals reduces post-prandial endothelial dysfunction. Increased oxidative stress reduces the activity of the redox sensitive enzyme, dimethylarginine dimethylaminohydrolase, increasing levels of asymmetric dimethylarginine (ADMA), which competes with L-arginine for nitric oxide synthase substrate availability. Post-prandial oxidative stress increases the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, at least partly due to increases in nuclear factor kB, a pro-inflammatory nuclear regulator.