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Received on October 18, 2006
Accepted on January 19, 2007
Lipids, Lipoproteins, and Cardiovascular Risk Factors |
1 Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
2 GSF, Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany
3 Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
* To whom correspondence should be addressed. E-mail: wolfgang.koenig{at}uniklinik-ulm.de.
Background: An increased plasma concentration of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predicts adverse clinical outcome in patients with coronary heart disease. We investigated the association between plasma concentrations of ADMA and risk in initially healthy smoking and nonsmoking men.
Methods: Participants for this nested case-control study came from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study. ADMA was measured by liquid chromatography-tandem mass spectrometry in 88 men with incident coronary events (fatal and nonfatal myocardial infarction and sudden cardiac death) and 254 age-matched controls, with a median (interquartile range) follow-up of 6.2 (3.3-7.9) years.
Results: After adjustment for potential confounders, the relative risk for a future coronary event was 2.00 [95% confidence interval (CI) 1.27-3.16; P = 0.003] for smokers compared with nonsmokers and 1.35 (95% CI 0.78-2.33; P = 0.282) for the top vs the bottom tertile of the ADMA distribution. In cases and controls, lower ADMA plasma concentrations were observed in smokers. Analysis of ADMA-associated risk in smokers and nonsmokers separately revealed substantial differences: the adjusted relative risk for future coronary events (top vs bottom tertile of the ADMA distribution) was 0.48 (95% CI 0.16-1.46; P = 0.198) in smokers and 2.40 (95% CI 1.14-5.08; P = 0.021) in nonsmokers. Exposure of human endothelium-derived EAhy 926 cells to tobacco smoke enhanced expression of the ADMA metabolizing enzyme dimethylarginine dimethylaminohydrolase 2 and reduced ADMA concentration.
Conclusions: In apparently healthy men, increased ADMA predicts the risk for coronary events in nonsmokers, but not in smokers. This may be explained in part by an alteration of ADMA metabolism by tobacco smoke.
The following articles in journals at HighWire Press have cited this article:
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  E. Schwedhelm, V. Xanthakis, R. Maas, L. M. Sullivan, F. Schulze, U. Riederer, R. A. Benndorf, R. H. Boger, and R. S. Vasan Asymmetric Dimethylarginine Reference Intervals Determined with Liquid Chromatography-Tandem Mass Spectrometry: Results from the Framingham Offspring Cohort Clin. Chem., August 1, 2009; 55(8): 1539 - 1545. [Abstract] [Full Text] [PDF]
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 R. Maas, V. Xanthakis, J. F. Polak, E. Schwedhelm, L. M. Sullivan, R. Benndorf, F. Schulze, R. S. Vasan, P. A. Wolf, R. H. Boger, et al. Association of the Endogenous Nitric Oxide Synthase Inhibitor ADMA With Carotid Artery Intimal Media Thickness in the Framingham Heart Study Offspring Cohort Stroke, August 1, 2009; 40(8): 2715 - 2719. [Abstract] [Full Text] [PDF]
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 C. Antoniades, C. Shirodaria, P. Leeson, A. Antonopoulos, N. Warrick, T. Van-Assche, C. Cunnington, D. Tousoulis, R. Pillai, C. Ratnatunga, et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis Eur. Heart J., May 1, 2009; 30(9): 1142 - 1150. [Abstract] [Full Text] [PDF]
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 R. H. Boger, L. M. Sullivan, E. Schwedhelm, T. J. Wang, R. Maas, E. J. Benjamin, F. Schulze, V. Xanthakis, R. A. Benndorf, and R. S. Vasan Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community Circulation, March 31, 2009; 119(12): 1592 - 1600. [Abstract] [Full Text] [PDF]
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M. R. Andersen, U. Simonsen, N. Uldbjerg, C. Aalkjaer, and S. Stender Smoking Cessation Early in Pregnancy and Birth Weight, Length, Head Circumference, and Endothelial Nitric Oxide Synthase Activity in Umbilical and Chorionic Vessels: An Observational Study of Healthy Singleton Pregnancies Circulation, February 17, 2009; 119(6): 857 - 864. [Abstract] [Full Text] [PDF]
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 M. Zeller, C. Korandji, J.-C. Guilland, P. Sicard, C. Vergely, L. Lorgis, J.-C. Beer, L. Duvillard, A.-C. Lagrost, D. Moreau, et al. Impact of Asymmetric Dimethylarginine on Mortality After Acute Myocardial Infarction Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 954 - 960. [Abstract] [Full Text] [PDF]
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T. Leong, D. Zylberstein, I. Graham, L. Lissner, D. Ward, J. Fogarty, C. Bengtsson, C. Bjorkelund, D. Thelle, and for The Swedish-Irish-Norwegian (SIN) Collaboratio Asymmetric Dimethylarginine Independently Predicts Fatal and Nonfatal Myocardial Infarction and Stroke in Women: 24-Year Follow-Up of the Population Study of Women in Gothenburg Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 961 - 967. [Abstract] [Full Text] [PDF]
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