Background and Purpose - Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine (total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. Methods - We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B12 0.5 mg, and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. Results - At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high- sensitivity C- reactive protein [P=0.32]; soluble CD40L [P=0.33]; IL- 6 [P=0.77]), endothelial dysfunction (vascular cell adhesion molecule- 1 [P=0.27]; intercellular adhesion molecule- 1 [P=0.08]; von Willebrand factor [P=0.92]), and hypercoagulability (P- selectin [P=0.33]; prothrombin fragment 1 and 2 [P=0.81]; D- dimer [P=0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7- μ mol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). Conclusions - Lowering tHcy by 3.7 μ mol/L with folic acidbased multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation, endothelial dysfunction, or hypercoagulability measured in our study. The possible explanations for our findings are: (1) these biomarkers are not sensitive to the effects of lowering tHcy (eg, multiple risk factor interventions may be required); (2) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured; or (3) elevated tHcy is a noncausal marker of increased vascular risk.
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