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


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.
Böger
Rainer H
RH
Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Sullivan
Lisa M
LM
Schwedhelm
Edzard
E
Wang
Thomas J
TJ
Maas
Renke
R
Benjamin
Emelia J
EJ
Schulze
Friedrich
F
Xanthakis
Vanessa
V
Benndorf
Ralf A
RA
Vasan
Ramachandran S
RS
D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000401:mortality; D002423:Cause of Death; D003920:Diabetes Mellitus; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009026:Mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models
C018524:N,N-dimethylarginine; D001120:Arginine