title: Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering.
abstract: BACKGROUND
  Homocysteine is a risk factor for coronary artery disease (CAD), although a causal relation remains to be proven. The importance of determining direct causality rests in the fact that plasma homocysteine can be safely and inexpensively reduced by 25% with folic acid. This reduction is maximally achieved by doses of 0.4 mg/d. High-dose folic acid (5 mg/d) improves endothelial function in CAD, although the mechanism is controversial. It has been proposed that improvement occurs through reduction in total (tHcy) or free (non-protein bound) homocysteine (fHcy). We investigated the effects of folic acid on endothelial function before a change in homocysteine in patients with CAD.
  
  
  RESULTS
  A randomized, placebo-controlled study of folic acid (5 mg/d) for 6 weeks was undertaken in 33 patients. Endothelial function, assessed by flow-mediated dilatation (FMD), was measured before, at 2 and 4 hours after the first dose of folic acid, and after 6 weeks of treatment. Plasma folate increased markedly by 1 hour (200 compared with 25.8 nmol/L; P<0.001). FMD improved at 2 hours (83 compared with 47 microm; P<0.001) and was largely complete by 4 hours (101 compared with 51 microm; P<0.001). tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79 micromol/L; P=NS). fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55 compared with 1.78 micromol/L; P=0.02). FMD improvement did not correlate with reductions in either fHcy or tHcy at any time.
  
  
  CONCLUSIONS
  These data suggest that folic acid improves endothelial function in CAD acutely by a mechanism largely independent of homocysteine.
authors.affiliation: Cardiovascular Sciences Research Group, Wales Heart Research Institute, Department of Pharmacology, University of Wales College of Medicine, Heath Park, Cardiff, UK.
authors.forename: Sagar N
authors.initials: SN
authors.lastname: Doshi
authors.forename: Ian F W
authors.initials: IF
authors.lastname: McDowell
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Moat
authors.forename: Nicola
authors.initials: N
authors.lastname: Payne
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Durrant
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Lewis
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goodfellow
mesh_terms: D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D006397:Hematinics / Q000097:blood / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013763:Tetrahydrofolates / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome; D014664:Vasodilation / Q000502:physiology
chemical_list: D006397:Hematinics; D013763:Tetrahydrofolates; D006710:Homocysteine; D005492:Folic Acid; C005984:5-methyltetrahydrofolate