ORIGINAL CONTRIBUTION Effect of supplementation with B vitamins and antioxidants on levels of asymmetric dimethylarginine (ADMA) and C-reactive protein (CRP): a double-blind, randomised, factorial design, placebo-controlled trial Mark G. O’Doherty • Sarah E. C. M. Gilchrist • Ian S. Young • Michelle C. McKinley • John W. G. Yarnell • K. Fred Gey • Alun Evans • Paula M. L. Skidmore • Jayne V. Woodside Received: 1 December 2009 / Accepted: 1 April 2010 / Published online: 18 April 2010 Ó Springer-Verlag 2010 Abstract Purpose Cardiovascular risk factors such as elevated levels of asymmetric dimethylarginine (ADMA)/C-reactive protein (CRP) and homocysteine are potentially related to essential micronutrients such as certain B vitamins and antioxidant vitamins. The aim of the present study was to investigate whether supplementation with moderate doses of B vitamins and/or antioxidants could alter either ADMA and/or CRP concentrations in middle-aged, apparently healthy men with mildly elevated homocysteine levels. Methods A randomised, double-blind, factorial design, intervention study was carried out on 132 men with mildly elevated homocysteine levels, allocated to four groups (a) B vitamins alone—1 mg folic acid, 7.2 mg pyridoxine, 0.02 mg cyanocobalamin daily, (b) antioxidants alone— 150 mg ascorbic acid, 67 mg vitamin E, 9 mg b-carotene daily, (c) B vitamins with antioxidant vitamins, or (d) pla- cebo. A total of 101 men completed the study to 8 weeks. Results When the percentage of baseline ADMA and CRP was examined at 8 weeks, no statistically significant differences were observed between the four groups (p = 0.21 and p = 0.90, respectively). Similar non-sig- nificant results were observed when analysis was stratified based on baseline CRP levels ( \ 1.0 mg/L, p = 0.10; C1.0 mg/L, p = 0.64) and smoking status (all p C 0.05). Conclusions Supplementation with moderate doses of B vitamins and/or antioxidants did not alter either ADMA or CRP concentrations in these middle-aged, apparently healthy men with mildly elevated homocysteine levels. Keywords Asymmetric dimethylarginine Á C-reactive protein Á Cardiovascular disease Á Homocysteine Á B vitamins Á Antioxidant vitamins Introduction Evidence indicates a central role for the endothelium and inflammation in all phases of atherosclerosis. Therefore, a reduction in inflammatory levels and improvement in endothelial function by traditional and novel treatment strategies, such as micronutrients, may lead to a reduction in cardiovascular events. Increased ADMA, an endogenous inhibitor of nitric oxide synthase, has been observed in subjects with car- diovascular disease (CVD) [1–3], where it results in reduced nitric oxide bioavailability, leading to endothelial dysfunction and CVD [4, 5]. Therapies that lower ADMA and reduce endothelial dysfunction may therefore reduce CVD risk. Knowledge of ADMA synthesis and metabolism reveals a potential for antioxidants to lower ADMA. ADMA is synthesised when arginine residues in proteins are M. G. O’Doherty Á S. E. C. M. Gilchrist Á I. S. Young Á M. C. McKinley Á J. W. G. Yarnell Á A. Evans Á J. V. Woodside School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, UK K. F. Gey Vitamin Research Unit, University of Berne, Berne, Switzerland P. M. L. Skidmore University of Otago, Dunedin, New Zealand M. G. O’Doherty (&) Cancer Epidemiology Health Services Research Group, Centre for Public Health, Queens University Belfast, Mulhouse Building, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BJ, UK e-mail: m.odoherty@qub.ac.uk 123 Eur J Nutr (2010) 49:483–492 DOI 10.1007/s00394-010-0107-x