This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chambers, J. C. Articles by Kooner, J. S. Search for Related Content PubMed PubMed Citation Articles by Chambers, J. C. Articles by Kooner, J. S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL CYANOCOBALAMIN FOLIC ACID NITROGLYCERIN Related Collections Nutrition Secondary prevention Risk Factors Endothelium/vascular type/nitric oxide

(Circulation. 2000;102:2479.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Improved Vascular Endothelial Function After Oral B Vitamins

An Effect Mediated Through Reduced Concentrations of Free Plasma Homocysteine

John C. Chambers, MD; Per M. Ueland, MD; Omar A. Obeid, PhD; Jane Wrigley, RGN; Helga Refsum, MD; Jaspal S. Kooner, MD, FRCP

From the National Heart and Lung Institute (J.C.C., J.S.K.), Imperial College School of Medicine, Hammersmith Hospital, London, UK; the Department of Pharmacology (P.M.U., H.R.), University of Bergen, Armauer Hansen Hus, Bergen, Norway; Department of Human Nutrition (O.A.O.), St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London, UK; and the Department of Cardiology (J.W.), Ealing Hospital, Middlesex, UK.

Correspondence to Dr J.S. Kooner, MD, FRCP, Senior Lecturer and Consultant Cardiologist, National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail j.kooner{at}ic.ac.uk

Background—Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD.

Methods and Results—We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow–mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B₁₂ (1 mg) daily (n=59) or (2) placebo (n=30). Total, protein-bound, and free plasma homocysteine, serum folate, and vitamin B₁₂ were measured at baseline and at 8 weeks. Flow-mediated dilatation improved after treatment with B vitamins (2.5±3.2% to 4.0±3.7%, P=0.002) but not placebo (2.3±2.6% to 1.9±2.6%, P=0.5). Vitamin therapy lowered plasma concentrations of total homocysteine (from 13.0±3.4 to 9.3±1.9 µmol/L, P<0.001), protein-bound homocysteine (from 8.7±2.8 to 6.2±1.4 µmol/L, P<0.001), and free homocysteine (from 4.3±1.2 to 3.0±0.6 µmol/L, P<0.001) and raised concentrations of serum folate (from 10.3±4.3 to 31.2±10.8 ng/mL, P<0.001) and vitamin B₁₂ (from 314±102 to 661±297 pg/mL, P<0.001). In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (r=-0.26, P=0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B₁₂. Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo.

Conclusions—Folic acid and vitamin B₁₂ supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.

Key Words: endothelium • nutrition • arteriosclerosis

This article has been cited by other articles:

				A. L. Moens, C. J. Vrints, M. J. Claeys, J.-P. Timmermans, H. C. Champion, and D. A. Kass Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H1971 - H1977. [Abstract] [Full Text] [PDF]

				J. B Keogh, G. D Brinkworth, M. Noakes, D. P Belobrajdic, J. D Buckley, and P. M Clifton Effects of weight loss from a very-low-carbohydrate diet on endothelial function and markers of cardiovascular disease risk in subjects with abdominal obesity Am. J. Clinical Nutrition, March 1, 2008; 87(3): 567 - 576. [Abstract] [Full Text] [PDF]

				A. de Bree, L. A van Mierlo, and R. Draijer Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials Am. J. Clinical Nutrition, September 1, 2007; 86(3): 610 - 617. [Abstract] [Full Text] [PDF]

				C. J. Abularrage, A. N. Sidawy, P. W. White, G. Aidinian, K. J. DeZee, J. M. Weiswasser, and S. Arora Effect of Folic Acid and Vitamins B6 and B12 on Microcirculatory Vasoreactivity in Patients With Hyperhomocysteinemia Vascular and Endovascular Surgery, September 1, 2007; 41(4): 339 - 345. [Abstract] [PDF]

				L. M Title, E. Ur, K. Giddens, M. J McQueen, and B. A Nassar Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering Vascular Medicine, May 1, 2006; 11(2): 101 - 109. [Abstract] [PDF]

				J. D. Symons, U. B. Zaid, C. N. Athanassious, A. E. Mullick, S. R. Lentz, and J. C. Rutledge Influence of Folate on Arterial Permeability and Stiffness in the Absence or Presence of Hyperhomocysteinemia Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 814 - 818. [Abstract] [Full Text] [PDF]

				J. D. Symons, J. C. Rutledge, U. Simonsen, and R. A. Pattathu Vascular dysfunction produced by hyperhomocysteinemia is more severe in the presence of low folate Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H181 - H191. [Abstract] [Full Text] [PDF]

				X. Jiang, F. Yang, H. Tan, D. Liao, R. M. Bryan Jr, J. K. Randhawa, R. E. Rumbaut, W. Durante, A. I. Schafer, X. Yang, et al. Hyperhomocystinemia Impairs Endothelial Function and eNOS Activity via PKC Activation Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2515 - 2521. [Abstract] [Full Text] [PDF]

				H.-K. Kuo, F. A. Sorond, J.-H. Chen, A. Hashmi, W. P. Milberg, and L. A. Lipsitz The Role of Homocysteine in Multisystem Age-Related Problems: A Systematic Review J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2005; 60(9): 1190 - 1201. [Abstract] [Full Text] [PDF]

				A. T. Merchant, G. Msamanga, E. Villamor, E. Saathoff, M. O'Brien, E. Hertzmark, D. J. Hunter, and W. W. Fawzi Multivitamin Supplementation of HIV-Positive Women during Pregnancy Reduces Hypertension J. Nutr., July 1, 2005; 135(7): 1776 - 1781. [Abstract] [Full Text] [PDF]

				A. Tawakol, R. Q. Migrino, K. S. Aziz, J. Waitkowska, G. Holmvang, N. M. Alpert, J. E. Muller, A. J. Fischman, and H. Gewirtz High-Dose Folic Acid Acutely Improves Coronary Vasodilator Function in Patients With Coronary Artery Disease J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1580 - 1584. [Abstract] [Full Text] [PDF]

				S. J. Moat, S. N. Doshi, D. Lang, I. F. W. McDowell, M. J. Lewis, and J. Goodfellow Treatment of coronary heart disease with folic acid: is there a future? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H1 - H7. [Full Text] [PDF]

				A. Scholze, C. Rinder, J. Beige, R. Riezler, W. Zidek, and M. Tepel Acetylcysteine Reduces Plasma Homocysteine Concentration and Improves Pulse Pressure and Endothelial Function in Patients With End-Stage Renal Failure Circulation, January 27, 2004; 109(3): 369 - 374. [Abstract] [Full Text] [PDF]

				A. Hassan, B. J. Hunt, M. O'Sullivan, R. Bell, R. D'Souza, S. Jeffery, J. M. Bamford, and H. S. Markus Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction Brain, January 1, 2004; 127(1): 212 - 219. [Abstract] [Full Text] [PDF]

				L. M. Title, K. Giddens, M. M. McInerney, M. J. McQueen, and B. A. Nassar Effect of cyclooxygenase-2 inhibition with rofecoxib on endothelial dysfunction and inflammatory markers in patients with coronary artery disease J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1747 - 1753. [Abstract] [Full Text] [PDF]

				A. Liem, G. H. Reynierse-Buitenwerf, A. H. Zwinderman, J. W. Jukema, and D. J. van Veldhuisen Secondary prevention with folic acid: effects on clinical outcomes J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2105 - 2113. [Abstract] [Full Text] [PDF]

				A. De Bree, W. M. M. Verschuren, D. Kromhout, L. A. J. Kluijtmans, and H. J. Blom Homocysteine Determinants and the Evidence to What Extent Homocysteine Determines the Risk of Coronary Heart Disease Pharmacol. Rev., December 1, 2002; 54(4): 599 - 618. [Abstract] [Full Text] [PDF]

				G. Wang, C. W.H. Woo, F. L. Sung, Y. L. Siow, and K. O Increased Monocyte Adhesion to Aortic Endothelium in Rats With Hyperhomocysteinemia: Role of Chemokine and Adhesion Molecules Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1777 - 1783. [Abstract] [Full Text] [PDF]

				A. P. Burke, V. Fonseca, F. Kolodgie, A. Zieske, L. Fink, and R. Virmani Increased Serum Homocysteine and Sudden Death Resulting from Coronary Atherosclerosis With Fibrous Plaques Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1936 - 1941. [Abstract] [Full Text] [PDF]

				O. Stanger, H.-J. Semmelrock, W. Wonisch, U. Bos, E. Pabst, and T. C. Wascher Effects of Folate Treatment and Homocysteine Lowering on Resistance Vessel Reactivity in Atherosclerotic Subjects J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 158 - 162. [Abstract] [Full Text] [PDF]

				H. S. Randeva, K. C. Lewandowski, J. Drzewoski, K. Brooke-Wavell, C. O'Callaghan, L. Czupryniak, E. W. Hillhouse, and G. M. Prelevic Exercise Decreases Plasma Total Homocysteine in Overweight Young Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4496 - 4501. [Abstract] [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]

				J.D. Kark, R. Sinnreich, I.H. Rosenberg, P.F. Jacques, and J. Selhub Plasma Homocysteine and Parental Myocardial Infarction in Young Adults in Jerusalem Circulation, June 11, 2002; 105(23): 2725 - 2729. [Abstract] [Full Text] [PDF]

				M.C. Verhaar, E. Stroes, and T.J. Rabelink Folates and Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 6 - 13. [Abstract] [Full Text] [PDF]

				Z. Bagi, Z. Ungvari, and A. Koller Xanthine Oxidase-Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia: Possible Role of Peroxynitrite Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 28 - 33. [Abstract] [Full Text] [PDF]

				S. N. Doshi, I. F.W. McDowell, S. J. Moat, N. Payne, H. J. Durrant, M. J. Lewis, and J. Goodfellow Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering Circulation, January 1, 2002; 105(1): 22 - 26. [Abstract] [Full Text] [PDF]

				M. Cattaneo, D. N. Kiortsis, M. S. Elisaf, K.M. English, P.J. Pugh, K.S. Channer, S. C. Clarke, P. M. Schofield, A. A. Grace, J. C. Metcalfe, et al. Does Tamoxifen Enhance Endothelial Function by Lowering the Plasma Levels of Homocysteine? Effects of Tamoxifen on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis Effects of Tamoxifen on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis Response Circulation, December 11, 2001; 104 (24): e146 - e147. [Full Text] [PDF]

				J. T. Kuvin, A. R. Patel, K. A. Sliney, N. G. Pandian, W. M. Rand, J. E. Udelson, and R. H. Karas Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1843 - 1849. [Abstract] [Full Text] [PDF]

				J. C CHAMBERS and J. S KOONER Homocysteine: a novel risk factor for coronary heart disease in UK Indian Asians Heart, August 1, 2001; 86(2): 121 - 122. [Full Text] [PDF]

				S. N. Doshi, I. F. W. McDowell, S. J. Moat, D. Lang, R. G. Newcombe, M. B. Kredan, M. J. Lewis, and J. Goodfellow Folate Improves Endothelial Function in Coronary Artery Disease : An Effect Mediated by Reduction of Intracellular Superoxide? Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1196 - 1202. [Abstract] [Full Text] [PDF]

				J. Thambyrajah, M. J. Landray, H. J. Jones, F. J. McGlynn, D. C. Wheeler, and J. N. Townend A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1858 - 1863. [Abstract] [Full Text] [PDF]

				J. C. Chambers, L. Fusi, I. S. Malik, D. O. Haskard, M. De Swiet, and J. S. Kooner Association of Maternal Endothelial Dysfunction With Preeclampsia JAMA, March 28, 2001; 285(12): 1607 - 1612. [Abstract] [Full Text] [PDF]

				J. C. Chambers, P. M. Ueland, M. Wright, C. J. Dore, H. Refsum, and J. S. Kooner Investigation of Relationship Between Reduced, Oxidized, and Protein-Bound Homocysteine and Vascular Endothelial Function in Healthy Human Subjects Circ. Res., July 20, 2001; 89(2): 187 - 192. [Abstract] [Full Text] [PDF]