Background—Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD.

Methods and Results—We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow–mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B₁₂ (1 mg) daily (n=59) or (2) placebo (n=30). Total, protein-bound, and free plasma homocysteine, serum folate, and vitamin B₁₂ were measured at baseline and at 8 weeks. Flow-mediated dilatation improved after treatment with B vitamins (2.5±3.2% to 4.0±3.7%, P=0.002) but not placebo (2.3±2.6% to 1.9±2.6%, P=0.5). Vitamin therapy lowered plasma concentrations of total homocysteine (from 13.0±3.4 to 9.3±1.9 μmol/L, P<0.001), protein-bound homocysteine (from 8.7±2.8 to 6.2±1.4 μmol/L, P<0.001), and free homocysteine (from 4.3±1.2 to 3.0±0.6 μmol/L, P<0.001) and raised concentrations of serum folate (from 10.3±4.3 to 31.2±10.8 ng/mL, P<0.001) and vitamin B₁₂ (from 314±102 to 661±297 pg/mL, P<0.001). In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (r=−0.26, P=0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B₁₂. Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo.

Conclusions—Folic acid and vitamin B₁₂ supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.