on March 16, 2009
Published online before print March 16, 2009, doi: 10.1161/CIRCULATIONAHA.108.838268
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Submitted on August 30, 2008
From the Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (R.H.B., E.S., R.M., F.S., R.A.B.); Framingham Heart Study, Framingham, Mass (L.M.S., T.J.W., E.J.B., V.X., R.S.V.); Department of Biostatistics (L.M.S., V.X.) and Cardiology Division and Preventive Medicine (E.J.B., R.S.V.), Boston University School of Public Health, Boston, Mass; and Cardiology Division, Massachusetts General Hospital, Boston (T.J.W.). * To whom correspondence should be addressed. E-mail: boeger{at}uke.uni-hamburg.de
or vasan{at}bu.edu.
Background—Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated. Methods and Results—We related plasma ADMA, L-arginine (Arg), and the ratio of Arg to ADMA to the incidence of cardiovascular disease (fatal or nonfatal myocardial infarction, coronary insufficiency, angina pectoris, stroke or transient ischemic attack, intermittent claudication, or heart failure) and death in 3320 Framingham Offspring Study participants (1769 women; mean age, 59 years). Over a follow-up period of 10.9 years, 281 individuals of 2956 free of cardiovascular disease at baseline developed incident cardiovascular disease, and 285 participants died. In multivariable models adjusting for established risk factors and other biomarkers (B-type natriuretic peptide, renin, homocysteine, urine albumin excretion, and C-reactive protein), ADMA and the ratio of Arg to ADMA were significantly associated with all-cause mortality (adjusted-hazard ratio [HR] per 1-SD increment, 1.21; 95% CI, 1.07 to 1.37; and HR per 1-SD increment, 0.80; 95% CI, 0.69 to 0.93, respectively), whereas Arg was not (HR per 1-SD increment, 0.89; 95% CI, 0.77 to 1.02). We noted effect modification by diabetes status; ADMA was associated with death in individuals without diabetes (adjusted HR per 1-SD increment, 1.30; 95% CI, 1.13 to 1.50) but not in individuals with diabetes (adjusted HR per 1-SD increment, 0.85; 95% CI, 0.62 to 1.16). ADMA, Arg, and the ratio of Arg to ADMA were not associated with cardiovascular disease incidence (P>0.10). Conclusions—In our large community-based sample, ADMA was significantly associated with all-cause mortality, particularly in nondiabetic individuals.
Accepted on January 26, 2009
Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community
Rainer H. Böger MD*,
Key words: cardiovascular diseases • epidemiology • nitric oxide • population • risk factors
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Circulation 2009 119: 1553-1555.
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