Effects of folate treatment and homocysteine lowering on resistance vessel reactivity in atherosclerotic subjects

Hyperhomocysteinemia is associated with arterial hypertension and endothelial dysfunction in healthy humans. Placebo-controlled vitamin intervention studies cannot distinguish intrinsic actions of homocysteine (tHcy) and folate concentrations on the endothelium. The present two-period crossover study investigates the effects of tHcy lowering through oral folic acid on antioxidant status and resistance vessel reactivity in patients with established coronary artery disease (CAD). We investigated 27 male patients with angiographically documented multivessel CAD aged 50 (range 46-56) years. Resistance vessel reactivity was assessed by measurement of postischemic reactive hyperemia (RH) in the forearm using venous occlusion plethysmography at baseline, after 6 weeks of treatment with 5 mg of oral folic acid, and after a washout period of another 6 weeks. Plasma folate increased 3.49-fold with a mean tHcy reduction of 21.3%. Peak reactivity of resistance vessels improved significantly (18.97-23.60 ml/min(-1) per 100 ml; P = 0.01) with unchanged total antioxidant status (TAS; 0.912-0.944 muM; P = 0.4). This effect was limited to subjects (n = 14) with a tHcy reduction >2 muM (median reduction, 14.4-9.6 muM, P < 0.001). In the 13 subjects with a below-median reduction, tHcy remained unaltered (9.7-9.6 μM, P = 0.88) and TAS increased significantly (.923-1.055 μM, P = 0.006), whereas RH peak flow was not affected (20.22-22.99 ml/min(-1) per 100 ml, P = 0.28). Homocysteine lowering >2 muM through folic acid supplementation improves resistance vessel reactivity in patients with CAD. Our data support the hypothesis that homocysteine lowering may have intrinsic vasoprotective effects largely independent of folate.