Renate B Schnabel1, Renke Maas2, Na Wang3, Xiaoyan Yin4, Martin G Larson5, Daniel Levy6, Patrick T Ellinor7, Steven A Lubitz8, David D McManus9, Jared W Magnani10, Dorothee Atzler11, Rainer H Böger12, Edzard Schwedhelm12, Ramachandran S Vasan13, Emelia J Benjamin14. 1. 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. 2. Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 3. Data Coordinating Center, Boston University School of Public Health, Boston, MA. 4. NHLBI's and Boston University's Framingham Study, Framingham, MA. 5. NHLBI's and Boston University's Framingham Study, Framingham, MA; Department of Biostatistics, Boston University School of Public Health, Boston, MA. 6. 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. 7. 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. 8. 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. 9. Cardiology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA. 10. Sections of Cardiology, Boston University School of Medicine, Boston, MA. 11. Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom. 12. Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 13. 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. 14. 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.
Abstract
BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.
BACKGROUND: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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.
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