Clinical Science (2004) 106, 353–358 (Printed in Great Britain) 353 Folic acid does not improve endothelial function in healthy hyperhomocysteinaemic subjects Richard J. WOODMAN * †, David E. CELERMAJER‡, Peter L. THOMPSON * † and Joseph HUNG * † ∗ School of Medicine and Pharmacology, University of Western Australia, West Australian Institute of Medical Research, GPO Box X2213, Perth, WA 6847, Australia, †Sir Charles Gardiner Hospital Campus of the Heart Research Institute of Western Australia, Sir Charles Gardiner Hospital, Nedlands, Perth, WA 6909, Australia, and ‡Department of Cardiology, Royal Prince Alfred Hospital and The Heart Research Institute, Sydney, NSW 2050, Australia A B S T R A C T Folic acid supplementation lowers total plasma homocysteine (tHcy) and improves endothelial function in individuals with coronary artery disease (CAD) and in those with additional CAD risk factors. In the present study, we assessed whether endothelial function is impaired in healthy subjects with hyperhomocysteinaemia but without other CAD risk factors and whether folic acid supplementation improves endothelial function in these subjects. Flow-mediated dilatation (FMD) of the brachial artery was performed on 26 healthy subjects, age 49 + − 2 years (mean + − S.E.M.), with high tHcy (15.6 + − 1.5 µmol/l) and 16 healthy age-matched subjects with low tHcy (7.9 + − 0.6 µmol/l; P < 0.001). Subjects with high tHcy were then randomized to receive 5 mg/ day of folic acid or placebo for 8 weeks in a double-blind cross-over trial with a 4-week washout. FMD was not associated with tHcy and was not different between high and low tHcy groups (7.0 + − 0.6 % compared with 6.6 + − 1.2 %, P = 0.76). Treatment with folic acid decreased tHcy by 34 % in hyperhomocysteinaemic subjects (P = 0.02 compared with placebo), but had no effect on FMD ( + 0.5 + − 0.6 % compared with − 0.7 + − 0.5 %; P = 0.17 compared with placebo). In healthy subjects with hyperhomocysteinaemia, but without additional cardiovascular risk, endothelial function is unimpaired and folic acid supplementation has no additional effect. INTRODUCTION Hyperhomocysteinaemia is now considered an inde- pendent and graded risk factor for atherosclerotic vascular disease [1] and for mortality in patients with coronary artery disease (CAD) [2]. Mildly elevated levels of homocysteine occur commonly in the general population as a result of either genetic influences or suboptimal nutrition [3,4]. Since supplementation with folic acid lowers total plasma homocysteine (tHcy) in both healthy individuals and those with existing CAD [5], Key words: atherosclerosis, endothelial function, folic acid supplementation, homocysteine, ultrasound. Abbreviations: CAD, coronary artery disease; CV, coefficient of variation; FMD, flow-mediated dilatation; GTNMD, glyceryl trinitrate-mediated dilatation; %FMD, percentage increase in FMD response from baseline diameter; %GTN, percentage increase in GTNMD response from baseline diameter; LDL, low-density lipoprotein; NO, nitric oxide; RCF, red cell folic acid; tHcy, total plasma homocysteine. Correspondence: Dr Richard Woodman (e-mail rwoodman@cyllene.uwa.edu.au). folic acid supplementation may be a simple and effective method for both primary and secondary prevention of CAD. Experimental evidence suggests that hyperhomo- cysteinaemia may cause vascular damage and dysfunction [4,6] and, indeed, hyperhomocysteinaemia has been associated with impaired endothelial function in healthy volunteers [7,8]. Supplementation with folic acid lowers homocysteine and also improves endothelial function in subjects with CAD [9–11] or those with other risk factors for CAD [12]. However, the effects of homocysteine on C  2004 The Biochemical Society