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

Abstract

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.

Figure 1

Spline graphs displaying the relationship between mortality and ADMA (panel A), L-arginine (panel B) and the Arg/ADMA ratio (panel C) at baseline. Mean (SD) were: ADMA, 0.55 (0.13) μmol/l; L-arginine, 78.9 (20.7) μmol/l; L-arginine/ADMA, 149.4 (44.4). Data are expressed as SD difference from the mean for each biomarker. The bold line shows the association of each biomarker with mortality risk, 95% CI are plotted as fine grey lines. The horizontal, grey line is the line of no association between the biomarker and risk.

Figure 1

Spline graphs displaying the relationship between mortality and ADMA (panel A), L-arginine (panel B) and the Arg/ADMA ratio (panel C) at baseline. Mean (SD) were: ADMA, 0.55 (0.13) μmol/l; L-arginine, 78.9 (20.7) μmol/l; L-arginine/ADMA, 149.4 (44.4). Data are expressed as SD difference from the mean for each biomarker. The bold line shows the association of each biomarker with mortality risk, 95% CI are plotted as fine grey lines. The horizontal, grey line is the line of no association between the biomarker and risk.

Figure 1

Spline graphs displaying the relationship between mortality and ADMA (panel A), L-arginine (panel B) and the Arg/ADMA ratio (panel C) at baseline. Mean (SD) were: ADMA, 0.55 (0.13) μmol/l; L-arginine, 78.9 (20.7) μmol/l; L-arginine/ADMA, 149.4 (44.4). Data are expressed as SD difference from the mean for each biomarker. The bold line shows the association of each biomarker with mortality risk, 95% CI are plotted as fine grey lines. The horizontal, grey line is the line of no association between the biomarker and risk.

Figure 2

Hazards ratio for death according to cross-classification of quartiles of plasma ADMA and L-arginine at baseline. The first quartile of ADMA and fourth quartile of L-arginine were defined as referent.