doi: 10.1161/hc0102.101388
(Circulation. 2002;105:22.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering
From the Cardiovascular Sciences Research Group, Wales Heart Research Institute, Departments of Pharmacology (S.N.D., M.J.L.), Biochemistry (I.F.W.M., S.J.M.), and Cardiology (J.G.), and the Department of Medical Computing and Statistics (N.P.), University of Wales College of Medicine, Heath Park, Cardiff, UK.
Correspondence to Dr J. Goodfellow, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. E-mail GoodfellowJ{at}cardiff.ac.uk
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.
Methods and 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 µm; P<0.001) and was largely complete by 4 hours (101 compared with 51 µm; P<0.001). tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79 µmol/L; P=NS). fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55 compared with 1.78 µmol/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.
Key Words: risk factors • plasma • coronary disease • endothelium
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|
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|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
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|
|
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 C. Shirodaria, C. Antoniades, J. Lee, C. E. Jackson, M. D. Robson, J. M. Francis, S. J. Moat, C. Ratnatunga, R. Pillai, H. Refsum, et al. Global Improvement of Vascular Function and Redox State With Low-Dose Folic Acid: Implications for Folate Therapy in Patients With Coronary Artery Disease Circulation, May 1, 2007; 115(17): 2262 - 2270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 A. J.M. de Craen, D. J. Stott, R. G.J. Westendorp, A. Khare, M. Lopez, J. Gogtay, E. P. Quinlivan, J. F. Gregory III, H. Refsum, A. D. Smith, et al. Homocysteine, B vitamins, and cardiovascular disease. N. Engl. J. Med., July 13, 2006; 355(2): 205 - 206. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
B. J Venn, T. J Green, R. Moser, and J. I Mann Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study Am. J. Clinical Nutrition, March 1, 2003; 77(3): 658 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 K. Robinson Homocysteine and vascular disease Eur. Heart J., October 1, 2002; 23(19): 1482 - 1484. [Full Text] [PDF]
|
|
|
|
|
|
B. Marasini, M. Massarotti, and M. L. Biondi Homocysteine and Vascular Diseases Circulation, August 13, 2002; 106 (7): e33 - e33. [Full Text] [PDF]
|
|
|
|
|
|
N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]
|
|