Traditional risk factors for coronary artery disease (CAD) can only explain 
approximately two thirds of the observed clinical events. This has maintained 
interest in other nutritional and biochemical factors that might contribute to 
the underlying pathophysiology of vascular disease. Two such factors are dietary 
antioxidants and plasma homocysteine. Established risk factors such as 
hypertension, smoking and diabetes mellitus are all associated with increased 
oxidative stresses due to excess free radical activity in the vascular wall. 
This may facilitate the development of vascular disease because of (i) increased 
oxidation of low-density lipoprotein (LDL) particles which increases their 
propensity to deposition in the vascular wall, (ii) inactivation of 
endothelium-derived nitric oxide, and (iii) direct cytotoxicity to endothelial 
cells. Protective antioxidant molecules include vitamin C and vitamin E of which 
the latter is lipid soluble and is the primary antioxidant defence in 
circulating LDL particles. Epidemiological studies have suggested strongly that 
individuals who have high circulating concentrations or dietary intake of 
natural antioxidant vitamins are protected against vascular disease events (18). 
Furthermore, many studies have demonstrated a beneficial effect of natural and 
synthetic antioxidants on surrogate markers of vascular disease such as 
endothelial function and lipoprotein oxidation. However, large prospective 
randomized controlled intervention trials, mostly involving vitamin E (e.g. 
CHAOS, HOPE (22)), have failed to demonstrate any beneficial effect upon 
vascular mortality in high risk individuals. Possible reasons for these 
disappointing results include the pro-oxidant effects of high dose antioxidant 
supplements, particularly in patients with established vascular disease. 
Homocysteine is a sulphydryl-containing amino acid derived from the 
demethylation of dietary methionine. Epidemiological studies over 30 years have 
shown that increased concentrations of homocysteine are associated with vascular 
disease. This link is independent of other risk factors, is consistent across 
many studies and is strongly dose-related. Recently, evidence has accumulated to 
suggest that this link is also biologically plausible because homocysteine 
promotes oxidant injury to the vascular endothelium, impairs 
endothelium-dependent vasomotor regulation and may also alter the coagulant 
properties of the blood. Plasma homocysteine levels can be reduced by dietary 
supplements of folic acid and B vitamins. Studies are currently being undertaken 
to examine the impact of these vitamins in high risk patients and, thereby, 
establish a causative role for homocysteine in promoting vascular events.