Atherosclerosis 193 (2007) 168–176 Effects of combined supplementation with B vitamins and antioxidants on plasma levels of asymmetric dimethylarginine (ADMA) in subjects with elevated risk for cardiovascular disease B. Schmitt a,∗ , M. Wolters a , G. Kressel a , O. H ¨ ulsmann a , A. Str ¨ ohle a , W.N. K¨ uhn-Velten b , R. Lichtinghagen c , A. Bub d , S.W. Barth d , D.O. Stichtenoth e , A. Hahn a a Nutrition Physiology and Human Nutrition Unit, Institute of Food Science, University of Hannover, Wunstorfer Str. 14, D-30453 Hannover, Germany b MLHB Medical Laboratory Bremen, Bremen, Germany c Department of Clinical Chemistry, Hannover Medical School, Hannover, Germany d Institute of Nutritional Physiology, Federal Research Centre for Nutrition and Food, Karlsruhe, Germany e Department of Clinical Pharmacology, Hannover Medical School, Hannover, Germany Received 21 February 2006; received in revised form 22 May 2006; accepted 2 June 2006 Available online 28 July 2006 Abstract Elevated plasma asymmetric dimethylarginine (ADMA) concentrations have been suggested as a potential risk factor for cardiovascular disease (CVD). Studies indicate a linkage between hyperhomocysteinemia, oxidative stress and ADMA metabolism. We tested the hypothesis that combined supplementation of B vitamins and antioxidants reduces ADMA concentrations in subjects with at least two CVD risk factors. A total of 123 men and women (58 ± 8.1 years) were randomly assigned to take either a preparation including B vitamins and antioxidants (verum) or placebo for 6 months in a double-blind design. Blood concentrations of ADMA, symmetric dimethylarginine (SDMA), l-arginine, B vitamins, total homocysteine (tHcy), -tocopherol, antioxidant capacity (TEAC), and oxLDL were measured pre- and post-intervention. Treatment with verum significantly decreased tHcy (-2.14 mol/L; P < 0.001) and significantly increased TEAC values (+39.3 M; P < 0.022), but no effect on ADMA was observed. OxLDL was significantly reduced in verum (-7.3 U/L; P = 0.001) and placebo (-9.2 U/L; P < 0.001). At baseline, significant correlations were found only between ADMA and SDMA (r = 0.281; P = 0.002), l-arginine/ADMA and SDMA (r = -0.294; P < 0.001), l-arginine/ADMA and oxLDL (r = -0.281; P = 0.016), and l-arginine/ADMA and age (r = -0.231; P = 0.010). Our results indicate that combined supplementation of B vitamins and antioxidants is not an adequate strategy to reduce ADMA plasma levels in subjects with elevated CVD risk. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Asymmetric dimethylarginine; Homocysteine; Oxidized LDL; Folic acid; Antioxidants 1. Introduction In the last few years, several studies have suggested ADMA, an endogenous competitive inhibitor of all three isoforms of nitric oxide synthase (NOS) [1,2], as a poten- tial risk factor for endothelial dysfunction and cardiovas- cular disease [3–6]. Increased plasma ADMA levels have ∗ Corresponding author. Tel.: +49 511 762 2987; fax: +49 511 762 5729. E-mail address: birgit.schmitt@lw.uni-hannover.de (B. Schmitt). been observed in patients with coronary artery disease [6,5], ischemic stroke [7], peripheral arterial occlusive dis- ease [8], and congestive heart failure [9] and were associ- ated with established cardiovascular risk factors, including hypercholesterolemia [3,10,11], hypertriglyceridemia [12], hypertension [13,14], type 2 diabetes [15], and hyperho- mocysteinemia [16]. Recently, experimental and clinical data suggested that even small modifications of plasma ADMA significantly change the vascular l-arginine–NO- system and thus may contribute to endothelial dysfunc- 0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2006.06.007