Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community

Rainer H. Böger, Lisa M. Sullivan, Edzard Schwedhelm, Thomas J. Wang, Renke Maas, Emelia J. Benjamin, Friedrich Schulze, Vanessa Xanthakis, Ralf A. Benndorf, Ramachandran S. Vasan

Research output: Contribution to journalArticlepeer-review

326 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1592-1600
Number of pages9
Issue number12
StatePublished - Mar 31 2009
Externally publishedYes


  • Cardiovascular diseases
  • Epidemiology
  • Nitric oxide
  • Population
  • Risk factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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