Circulation Research. 2005;97:e53-e59
Published online before print August 11, 2005, doi: 10.1161/01.RES.0000181286.44222.61
Published online before print August 11, 2005, doi: 10.1161/01.RES.0000181286.44222.61
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© 2005 American Heart Association, Inc.
UltraRapid Communication |
Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease
Results from the AtheroGene Study
From the Departments of Medicine II (R.S., S.B., E.L., H.J.R., C.E.-K., F.P., T.M.) and Clinical Chemistry and Laboratory Medicine (K.J.L., N.J., D.P.), Johannes Gutenberg-University Mainz, Germany; INSERM U525 (F.C., L.T.), Faculté de Médecine Pitié-Salpétrière, Paris, France; Innere Abteilung (C.B.), Bundeswehrzentralkrankenhaus Koblenz, Germany.
Correspondence to Stefan Blankenberg, MD, Department of Medicine II, Johannes Gutenberg-University Mainz, Langenbeckstr 1, 55131 Mainz, Germany. E-mail stefan.blankenberg{at}uni-mainz.de
As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6±1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than among those who did not (0.70 versus 0.63 µmol/L; P<0.001). The risk of future cardiovascular event was associated with increasing thirds of baseline ADMA (P for trend, <0.001) such that individuals in the highest third at entry had a hazard ratio 2.48 times higher than those in the lowest third (95% confidence interval, 1.52 to 4.06; P<0.001). This relationship remained nearly unchanged after adjustment for most potential confounders. Prediction models that simultaneously incorporated ADMA, B-type natriuretic peptide, C-reactive protein, and creatinine in addition to traditional risk factors revealed B-type natriuretic peptide (hazard ratio, 1.96; 95% confidence interval, 1.3 to 3.0; P=0.002) and ADMA (hazard ratio, 1.90; 95% confidence interval, 1.3 to 2.8; P=0.001) as the strongest risk predictors. High levels of baseline ADMA independently predict future cardiovascular risk. ADMA has prognostic value beyond traditional risk factors and novel biomarkers and might guide therapeutic strategies.
Key Words: asymmetric dimethylarginine • cardiovascular risk • coronary artery disease
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|
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