Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects.
OBJECTIVE
An elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases. In this study, we tested the hypothesis that hyperhomocysteinemia induces endothelial dysfunction mediated, at least in part, through nitric oxide-dependent mechanisms and that folic acid supplementation improves endothelial function in hyperhomocysteinemic subjects.


METHODS
Endothelial function was evaluated in healthy controls and hyperhomocysteinemic subjects by measuring plasma levels of the nitric oxide-derived end products nitrite and nitrate and by assessing vasodilatory 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 products (12.1 microM [range 4.4 to 41.8] versus 24.6 microM [13.6 to 53.2]; P <0.001), a significantly lower endothelium-dependent vasodilatory response to acetylcholine (P <0.01), hyperemic response in the microcirculation (P <0.01), and total forearm blood flow during reactive hyperemia (P = 0.01). There was no significant difference in the endothelium-independent response. Folic acid treatment for 12 months increased the plasma level of nitric oxide-derived end products by 121% (95% confidence interval [CI], 72% to 170%), the vasodilatory response to acetylcholine by 124% (95% CI, 36% to 212%), and the 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 least in part, by depressing endothelial function, possibly through nitric oxide-dependent mechanisms. This effect can be reversed by folic acid supplementation.
Holven
K B
KB
Lipid Clinic, University Hospital, Rikshospitalet, Oslo, Norway.
Holm
T
T
Aukrust
P
P
Christensen
B
B
Kjekshus
J
J
Andreassen
A K
AK
Gullestad
L
L
Hagve
T A
TA
Svilaas
A
A
Ose
L
L
Nenseter
M S
MS
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D006397:Hematinics / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000188:drug therapy*; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D012867:Skin / Q000098:blood supply; D014664:Vasodilation / Q000187:drug effects*
D006397:Hematinics; D009569:Nitric Oxide; D005492:Folic Acid; D002784:Cholesterol