This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thambyrajah, J. Articles by Townend, J. N. Search for Related Content PubMed PubMed Citation Articles by Thambyrajah, J. Articles by Townend, J. N.

CLINICAL STUDY: CORONARY ARTERY DISEASE

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

Jeetendra Thambyrajah, BMedSci, MRCP^*, Martin J. Landray, MRCP^*, Heather J. Jones, RGN^*, Fiona J. McGlynn, RGN, David C. Wheeler, MD, FRCP and Jonathan N. Townend, MD, MRCP^*

^* Division of Medical Sciences (Cardiology), University of Birmingham, Birmingham, United Kingdom
Department of Nephrology, Queen Elizabeth Hospital, Birmingham, United Kingdom

Manuscript received May 11, 2000; revised manuscript received February 1, 2001, accepted February 15, 2001.

Reprint requests and correspondence: Dr. J. Thambyrajah, Department of Cardiovascular Medicine, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, United Kingdom.
jeet{at}thambyrajah.freeserve.co.uk

OBJECTIVES

This study was designed to determine the effects of folic acid therapy on endothelial function in patients with coronary artery disease (CAD).

BACKGROUND

Hyperhomocysteinemia, a risk factor for CAD, may cause atherosclerosis by oxidative endothelial injury. Folic acid reduces plasma homocysteine, but the effect on adverse vascular events is unknown.

METHODS

In a double-blind placebo-controlled trial, 90 patients (mean age [range] 63 [46 to 79] years, 79 men) with CAD were randomized to either folic acid 5 mg or placebo daily for 12 weeks. Endothelial function was assessed by measuring: 1) flow-mediated endothelium-dependent dilation (EDD) of the brachial artery; 2) combined serum nitrite/nitrate (NO_X) concentrations and; 3) plasma von Willebrand factor (vWF) concentration.

RESULTS

At the end of the study, plasma homocysteine was lower in the folic acid group compared with the placebo group (mean [95% confidence interval] 9.3 (8.5 to 10.1) vs. 12.3 [11.3 to 13.4] µmol/l, p < 0.001). Although there were no significant differences in EDD, serum NO_X or plasma vWF between the two groups, there was a greater increase in EDD from baseline in the folic acid group compared to placebo (1.2 [0.7 to 1.8] vs. 0.4 [–0.3 to 1.1] %, p = 0.07).

CONCLUSIONS

Folic acid reduced plasma homocysteine and was associated with a trend toward improved endothelial function in patients with CAD. The absence of an unequivocally positive result may have been due to inadequate sample size or chance. This reinforces the need for the results of large randomized controlled trials before the implementation of routine folic acid supplementation.

Abbreviations and Acronyms   CAD = coronary artery disease   vWF = von Willebrand factor

This article has been cited by other articles:

				C. Antoniades, A. S. Antonopoulos, D. Tousoulis, K. Marinou, and C. Stefanadis Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials Eur. Heart J., January 1, 2009; 30(1): 6 - 15. [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]

				A. S. Pena, E. Wiltshire, R. Gent, L. Piotto, C. Hirte, and J. Couper Folic Acid Does Not Improve Endothelial Function in Obese Children and Adolescents Diabetes Care, August 1, 2007; 30(8): 2122 - 2127. [Abstract] [Full Text] [PDF]

				K. E. MacKenzie, E. J. Wiltshire, R. Gent, C. Hirte, L. Piotto, and J. J. Couper Folate and Vitamin B6 Rapidly Normalize Endothelial Dysfunction In Children With Type 1 Diabetes Mellitus Pediatrics, July 1, 2006; 118(1): 242 - 253. [Abstract] [Full Text] [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]

				K. H. Bonaa, I. Njolstad, P. M. Ueland, H. Schirmer, A. Tverdal, T. Steigen, H. Wang, J. E. Nordrehaug, E. Arnesen, K. Rasmussen, et al. Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction N. Engl. J. Med., April 13, 2006; 354(15): 1578 - 1588. [Abstract] [Full Text] [PDF]

				Homocysteine Lowering Trialists' Collaboration Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials Am. J. Clinical Nutrition, October 1, 2005; 82(4): 806 - 812. [Abstract] [Full Text] [PDF]

				H.-J. Priebe Perioperative myocardial infarction--aetiology and prevention Br. J. Anaesth., July 1, 2005; 95(1): 3 - 19. [Abstract] [Full Text] [PDF]

				G. Landesberg, M. Mosseri, V. Shatz, I. Akopnik, M. Bocher, M. Mayer, H. Anner, Y. Berlatzky, and C. Weissman Cardiac troponin after major vascular surgery: The role of perioperative ischemia, preoperative thallium scanning, and coronary revascularization J. Am. Coll. Cardiol., August 4, 2004; 44(3): 569 - 575. [Abstract] [Full Text] [PDF]

				G. Landesberg, V. Shatz, I. Akopnik, Y. G. Wolf, M. Mayer, Y. Berlatzky, C. Weissman, and M. Mosseri Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1547 - 1554. [Abstract] [Full Text] [PDF]

				G. Landesberg, M. Mosseri, Y. G. Wolf, M. Bocher, A. Basevitch, E. Rudis, U. Izhar, H. Anner, C. Weissman, and Y. Berlatzky Preoperative Thallium Scanning, Selective Coronary Revascularization, and Long-Term Survival After Major Vascular Surgery Circulation, July 15, 2003; 108(2): 177 - 183. [Abstract] [Full Text] [PDF]

				F. F. Willems, W. R. M. Aengevaeren, G. H. J. Boers, H. J. Blom, and F. W. A. Verheugt Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease J. Am. Coll. Cardiol., August 21, 2002; 40(4): 766 - 772. [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]

				G. Buccianti, S. Raselli, I. Baragetti, F. Bamonti, E. Corghi, C. Novembrino, C. Patrosso, F. M. Maggi, and A. L. Catapano 5-methyltetrahydrofolate restores endothelial function in uraemic patients on convective haemodialysis Nephrol. Dial. Transplant., May 1, 2002; 17(5): 857 - 864. [Abstract] [Full Text] [PDF]