High- but not low-dose folic acid improves endothelial function in coronary artery disease

European Journal of Clinical Investigation

Volumn 36, Issue 12, 2006, Pages 850-859

  Moat, S J ^a   Madhavan, A ^b   Taylor, S Y ^b   Payne, N ^b   Allen, R H ^c   Stabler, S P ^c   Goodfellow, J ^b   McDowell, I F W ^b   Lewis, M J ^b   Lang, D ^b  

^a UNIVERSITY HOSPITAL OF WALES   (United Kingdom)

^b CARDIFF UNIVERSITY   (United Kingdom)

^c UNIVERSITY OF COLORADO   (United States)

Author keywords

Coronary disease; Endothelial function; Folic acid; Nitric oxide synthase; Risk factors

Indexed keywords

BETAINE; ENDOTHELIAL NITRIC OXIDE SYNTHASE; FOLIC ACID; HOMOCYSTEINE; METHIONINE; PLACEBO;

ADULT; AGED; ANIMAL TISSUE; ARTERY ENDOTHELIUM; ARTICLE; CELL CULTURE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CORONARY ARTERY DISEASE; CORRELATION ANALYSIS; DIMERIZATION; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG MEGADOSE; ENDOTHELIUM CELL; FOLIC ACID BLOOD LEVEL; HUMAN; ISOMETRICS; LOW DRUG DOSE; MAJOR CLINICAL STUDY; NONHUMAN; PRIORITY JOURNAL; RABBIT; RANDOMIZATION; RANDOMIZED CONTROLLED TRIAL; STATISTICAL SIGNIFICANCE; VASCULAR RING; WESTERN BLOTTING;

AGED; BETAINE; CARDIOTONIC AGENTS; CORONARY ARTERIOSCLEROSIS; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; ENDOTHELIUM, VASCULAR; FEMALE; FOLIC ACID; HEMATINICS; HUMANS; MALE; MIDDLE AGED;

EID: 33750728400     PISSN: 00142972     EISSN: 13652362     Source Type: Journal    
DOI: 10.1111/j.1365-2362.2006.01739.x     Document Type: Article

References (43)

1. Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO et al. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003;41:1769-75.
2. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101:1899-06.
3. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101:948-54.
4. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002;106:653-8.
5. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57.
6. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202.
7. Lobo A, Naso A, Arheart K, Kruger WD, Abou-Ghazala T, Alsous F et al. Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12. Am J Cardiol 1999;83:821-5.
8. Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998;316:894-8.
9. Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Newcombe RG, Lewis MJ. Oral folate enhances endothelial function in hyperhomocysteinaemic subjects. Eur J Clin Invest 1999;29:659-62.
10. Chambers JC, Ueland PM, Obeid OA, Wrigley J, Refsum H, Kooner JS. Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine. Circulation 2000;102:2479-83.
11. Doshi SN, McDowell IF, Moat SJ, Lang D, Newcombe RG, Kredan MB et al. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular super-oxide? Arterioscler Thromb Vasc Biol 2001;21:1196-202.
12. Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ et al. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation 2002;105:22-6.
13. Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 2000;36:758-65.
14. Woo KS, Chook P, Chan LL, Cheung AS, Fung WH, Qiao M et al. Long-term improvement in homocysteine levels and arterial endothelial function after 1-year folic acid supplementation. Am J Med 2002;112:535-9.
15. Guo H, Lee JD, Xing Y, Cheng J, Ueda T, Toyoda K et al. Changes of homocysteine levels and arterial endothelial function in patients with high risk of coronary artery disease after 6-month folic acid supplementation. Acta Cardiol 2004;59:503-6.
16. Lekakis JP, Papamichael CM, Papaioannou TG, Dagre AG, Stamatelopoulos KS, Tryfonopoulos D et al. Oral folic acid enhances endothelial function in patients with hypercholesterolaemia receiving statins. Eur J Cardiovasc Prev Rehabil 2004;11:416-20.
17. Mangoni AA, Sherwood RA, Asonganyi B, Swift CG, Thomas S, Jackson SH. Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes. Am J Hypertens 2005;18:220-6.
18. Tawakol A, Migrino RQ, Aziz KS, Waitkowska J, Holmvang G, Alpert NM et al. High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. J Am Coll Cardiol 2005;45:1580-4.
19. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578-88.
20. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567-77.
21. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.
22. Cai S, Khoo J, Channon KM. Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycaemic human endothelial cells. Cardiovasc Res 2005;65:823-31.
23. Ravi K, Brennan LA, Levic S, Ross PA, Black SM. S-nitrosylation of endothelial nitric oxide synthase is associated with monomerization and decreased enzyme activity. Proc Natl Acad Sci USA 2004;101:2619-24.
24. Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest 2002;109:817-26.
25. Brouwer IA, Verhoef P, Urgert R. Betaine supplementation and plasma homocysteine in healthy volunteers. Arch Intern Med 2000;160:2546-7.
26. Matthews A, Johnson TN, Rostami-Hodjegan A, Chakrapani A, Wraith JE, Moat SJ et al. An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria. Br J Clin Pharmacol 2002;54:140-6.
27. Doshi SN, Naka KK, Payne N, Jones CJ, Ashton M, Lewis MJ et al. Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide. Clin Sci (Lond) 2001;101:629-35.
28. Allen RH, Stabler SP, Lindenbaum J. Serum betaine, N,N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism 1993;42:1448-60.
29. Lang D, Kredan MB, Moat SJ, Hussain SA, Powell CA, Bellamy MF et al. Homocysteine-induced inhibition of endothelium-dependent relaxation in rabbit aorta: role for super-oxide anions. Arterioscler Thromb Vasc Biol 2000;20:422-7.
30. Cai S, Alp NJ, McDonald D, Smith I, Kay J, Canevari L et al. GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerisation. Cardiovasc Res 2002;55:838-49.
31. Pullin CH, Ashfield-Watt PA, Burr ML, Clark ZE, Lewis MJ, Moat SJ et al. Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype. J Am Coll Cardiol 2001;38:1799-805.
32. Olthof MR, van Vliet T, Boelsma E, Verhoef P. Low-dose betaine supplementation leads to immediate and long-term lowering of plasma homocysteine in healthy men and women. J Nutr 2003;133:4135-8.
33. Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Med, 2005:2:e135.
34. Yap S, Boers GH, Wilcken B, Wilcken DE, Brenton DP, Lee PJ et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol 2001;21:2080-5.
35. Carlsson CM, Pharo LM, Aeschlimann SE, Mitchell C, Underbakke G, Stein JH. Effects of multivitamins and low-dose folic acid supplements on flow-mediated vasodilation and plasma homocysteine levels in older adults. Am Heart J 2004;148:E11.
36. Durga J, van Tits LJ, Schouten EG, Kok FJ, Verhoef P. Effect of lowering of homocysteine levels on inflammatory markers: a randomized controlled trial. Arch Intern Med 2005;165:1388-94.
37. Dusitanond P, Eikelboom JW, Hankey GJ, Thom J, Gilmore G, Loh K et al. Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial. Stroke 2005;36:144-6.
38. Klerk M, Durga J, Schouten EG, Kluft C, Kok FJ, Verhoef P. No effect of folic acid supplementation in the course of 1 year on haemostasis markers and C-reactive protein in older adults. Thromb Haemost 2005;94:96-100.
39. Verhaar MC, Wever RM, Kastelein JJ, van Dam T, Koomans HA, Rabelink TJ. 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 1998;97:237-41.
40. Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Endothelial dysfunction by acute hyperhomocyst (e) anaemia: restoration by folic acid. Clin Sci (Lond) 1999;96:235-9.
41. Stroes ES, van Faassen EE, Yo M, Martasek P, Boer P, Govers R et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 2000;86:1129-34.
42. Moat SJ, Clarke ZL, Madhavan AK, Lewis MJ, Lang D. Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis. Eur J Pharmacol 2006;530:250-8.
43. Hyndman ME, Verma S, Rosenfeld RJ, Anderson TJ, Parsons HG. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 2002;282:H2167-72.