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.
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 B
0.5 mg, and vitamin B
25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability.
At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high-sensitivity C-reactive protein [
=0.32]; soluble CD40L [
=0.33]; IL-6 [
=0.77]), endothelial dysfunction (vascular cell adhesion molecule-1 [
=0.27]; intercellular adhesion molecule-1 [
=0.08]; von Willebrand factor [
=0.92]), and hypercoagulability (P-selectin [
=0.33]; prothrombin fragment 1 and 2 [
=0.81]; D-dimer [
=0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7-μmol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy).
Lowering tHcy by 3.7 μmol/L with folic acid-based 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.