Asymmetric dimethylarginine, related arginine derivatives, and incident atrial fibrillation.
Oxidative stress plays an important role in the development of atrial fibrillation (AF). Arginine derivatives including asymmetric dimethylarginine (ADMA) are central to nitric oxide metabolism and nitrosative stress. Whether blood concentrations of arginine derivatives are related to incidence of AF is uncertain.



In 3,310 individuals (mean age 58 ± 10 years, 54% women) from the community-based Framingham Study, we prospectively examined the relations of circulating levels of ADMA, l-arginine, symmetric dimethylarginine (SDMA), and the ratio of l-arginine/ADMA to incidence of AF using proportional hazards regression models. Over a median follow-up time of 10 years, 247 AF cases occurred. Using age- and sex-adjusted regression models, ADMA was associated with a hazard ratio of 1.15 per 1-SD increase in loge-biomarker concentration (95% CI 1.02-1.29, P = .02) for AF, which was no longer significant after further risk factor adjustment (hazard ratio 1.09, 95% CI 0.97-1.23, P = .15). Neither l-arginine nor SDMA was related to new-onset AF. A clinical model comprising clinical risk factors for AF (for age, sex, height, weight, systolic blood pressure, diastolic blood pressure, current smoking, diabetes, hypertension treatment, myocardial infarction, and heart failure; c statistic = 0.781; 95% CI 0.753-0.808) was not improved by the addition of ADMA (0.782; 95% CI 0.755-0.809).



Asymmetric dimethylarginine and related arginine derivatives were not associated with incident AF in the community after accounting for other clinical risk factors and confounders. Its role in the pathogenesis of AF needs further refinement.
NHLBI's and Boston University's Framingham Study, Framingham, MA; Department of General and Interventional Cardiology, University Heart Center Hamburg, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany. Electronic address: r.schnabel@uke.de.
Renate B
RB
Schnabel
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Renke
R
Maas
Data Coordinating Center, Boston University School of Public Health, Boston, MA.
Na
N
Wang
NHLBI's and Boston University's Framingham Study, Framingham, MA.
Xiaoyan
X
Yin
NHLBI's and Boston University's Framingham Study, Framingham, MA; Department of Biostatistics, Boston University School of Public Health, Boston, MA.
Martin G
MG
Larson
NHLBI's and Boston University's Framingham Study, Framingham, MA; Evans Memorial Medicine Department, Boston University School of Medicine, Boston, MA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Daniel
D
Levy
Cardiovascular Research Center, University of Massachusetts Medical School, Worcester, MA; Program in Medical Population Genetics, The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Patrick T
PT
Ellinor
Program in Medical Population Genetics, The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Steven A
SA
Lubitz
Cardiology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
David D
DD
McManus
Sections of Cardiology, Boston University School of Medicine, Boston, MA.
Jared W
JW
Magnani
Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
Dorothee
D
Atzler
Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Rainer H
RH
Böger
Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Edzard
E
Schwedhelm
NHLBI's and Boston University's Framingham Study, Framingham, MA; Evans Memorial Medicine Department, Boston University School of Medicine, Boston, MA; Sections of Cardiology, Boston University School of Medicine, Boston, MA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA; Preventive Medicine, Boston University School of Medicine, Boston, MA.
Ramachandran S
RS
Vasan
NHLBI's and Boston University's Framingham Study, Framingham, MA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA; Evans Memorial Medicine Department, Boston University School of Medicine, Boston, MA; Sections of Cardiology, Boston University School of Medicine, Boston, MA; Preventive Medicine, Boston University School of Medicine, Boston, MA; Epidemiology Department, Public Health School, Boston University, Boston, MA.
Emelia J
EJ
Benjamin
D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D001281:Atrial Fibrillation / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D013223:Statistics as Topic
D015415:Biomarkers; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine