No significant effect on C-reactive protein, sICAM-1, oxidized LDL and autoantibodies against oxidized LDL

FA = Folic acid; B6 = vitamin B6; B12 = vitamin B12; F.u. = follow-up.

vention studies (table 2), only the VISP trial has been published so far [66], In this study, 3,680 stroke patients with a baseline plasma homocysteine of 13.4 ^mol/l were randomized to a high- or low-dose multivitamin B treatment. After 2 years, the primary end-point, recurrent ischemic stroke, was reached in 9.2% in the high-dose vitamin group and in 8.8% in the low-dose group. There was also no significant difference in a composite end-point consisting of stroke, coronary artery disease or death between the two groups (risk ratio 1.0, 95% CI 0.8-1.1). The disappointing results may have been related to the small difference in plasma homocysteine that was achieved. Plasma homo-cysteine was about 13 ^mol/l in the low-dose group and 11 ^mol/l in the highdose group. The small difference was probably due to the dietary folic acid fortification that was instituted in North America in 1998 in order to reduce the risk of neural tube defects in newborns. Inclusion of patients took place from 1997 to 2001 and those who had been randomized to the control group exhibited lower plasma homocysteine levels during follow-up than expected. However, a small beneficial effect of active homocysteine-lowering treatment could not be excluded in this trial. Results of other trials are awaited eagerly, but due to the folic acid fortification, studies taking place in North America may suffer from a similar power shortage.

Pathophysiological Considerations

Several animal models of hyperhomocysteinemia have been used to elucidate the mechanisms behind the atherogenic properties of homocysteine. Hyperhomocysteinemia has been induced in animals by supplementation of methionine or homocysteine, by dietary restriction of folate, choline, cobala-min, and/or pyridoxine, and by disrupting genes encoding for enzymes involved in homocysteine metabolism, such as CBS, MTHFR and MS.

Genetically induced hyperhomocysteinemia does not seem to cause atherosclerosis in animal models [68, 69], whereas dietary-induced hyperhomo-cysteinemia was shown to be associated with the development and acceleration of atherosclerotic lesions, especially in susceptible animal models, such as the apolipoprotein E (apoE)-deficient mouse [70, 71], Mice lacking the gene for apoE develop hypercholesterolemia and spontaneous atherosclerotic lesions in the aortic root and branch points, which resemble human atherosclerosis. Interestingly, apoE knockout mice which were also made deficient for CBS (double knockout mice), exhibited larger atherosclerotic lesions than apoE control mice [72].

Endothelial Dysfunction

Normal endothelium is a highly active organ with many vascular functions. These include the regulation of vascular tone, the composition of suben-

Table 2. Randomized, controlled homocysteine-lowering trials with clinical end-points






Liem et al. [65]

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