Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects

PURPOSE: An elevated plasma homocysteine concentration is an independent ri sk factor for cardiovascular diseases, In this study, we tested the hypothe sis that hyperhomocyteinemia induces endothelial dysfunction mediated, at l east in part, through nitric oxide-dependent mechanisms and that folic acid supplementation improves endothelial function in hyperhomocysteinemic subj ects. SUBJECTS AND METHODS: Endothelial function was evaluated in healthy control s and hyperhomocysteinemic subjects by measuring plasma levels of the nitri c oxide-derived end products nitrite and nitrate and by assessing vasodilat ory responses in the skin microcirculation and forearm vasculature. in the subjects with hyperhomocysteinemia, these measurements were repeated after 6 weeks and 12 months of folic acid supplementation. RESULTS: Compared with healthy controls, hyperhomocysteinemic subjects had significantly lower median plasma levels of nitric oxide-derived end produc ts (12.1 muM [range 4.4 to 41.8] versus 24.6 muM [13.6 to 53.2]; P <0.001), a significantly lower endothelium-dependent vasodilatory response to acety lcholine (P <0.01), hyperemic response in the microcirculation (P <0.01), a nd total forearm blood flow during reactive hyperemia (P = 0.01). There was no significant difference in the endothelium-independent response, Folic a cid treatment for 12 months increased the plasma level of nitric oxide-deri ved end products by 121% (95% confidence interval [CI], 72% to 170%), the v asodilatory response to acetylcholine by 124% (95% CI, 36% to 212%), and th e ischemia-mediated hyperemic responses in the microcirculation by 60% (95% CI, 25% to 96%) and in the forearm vasculature by 47% (95% CI, 21% to 73%) CONCLUSIONS: Homocysteine appears to induce its atherogenic effect, at leas t in part, by depressing endothelial function, possibly through nitric oxid e-dependent mechanisms. This effect call be reversed by folic acid suppleme ntation. (C) 2001 by Excerpta Medica, Inc.