title: Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies.
abstract: BACKGROUND
  Asymmetric dimethylarginine (ADMA) inhibits the production of nitric oxide, a key regulator of the vascular tone, and may be important in the development of cardiovascular disease (CVD). Our aim was to reliably quantify the association of ADMA and its isomer symmetric dimethylarginine (SDMA) with the risk of CVD outcomes in long-term cohort studies.
  
  
  RESULTS
  Data were collated from 22 prospective studies involving a total of 19 842 participants, which have recorded 2339 CVD, 997 coronary heart disease, and 467 stroke outcomes during a mean follow-up of 7.1 years. In a comparison of individuals in the top with those in the bottom third of baseline ADMA values, the combined risk ratios were 1.42 (95% confidence interval: 1.29 to 1.56) for CVD, 1.39 for coronary heart disease (1.19 to 1.62), and 1.60 for stroke (1.33 to 1.91). Broadly similar results were observed according to participants' baseline disease status (risk ratios for CVD: 1.35 [1.18 to 1.54] in general populations; 1.47 [1.16 to 1.87] in individuals with pre-existing CVD; and 1.52 [1.26 to 1.84] in individuals with pre-existing kidney disease) and by different study characteristics, including geographical location, sample type, assay method, number of incident outcomes, and level of statistical adjustment (all P values>0.05). In contrast, in 8 prospective studies involving 9070 participants and 848 outcomes, the corresponding estimate for SDMA concentration was 1.32 (0.92 to 1.90) for CVD.
  
  
  CONCLUSIONS
  Available prospective studies suggest associations between circulating ADMA concentration and CVD outcomes under a broad range of circumstances. Further research is needed to better clarify these associations, particularly in large general population studies.
authors.affiliation: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom (P.W., D.F.F., R.G., E.D.A., R.C.) King's British Heart Foundation Centre, King's College London, United Kingdom (P.W., M.M.) Department of Neurology, Medical University Innsbruck, Austria (P.W.).
authors.forename: Peter
authors.initials: P
authors.lastname: Willeit
authors.affiliation: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom (P.W., D.F.F., R.G., E.D.A., R.C.).
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Freitag
authors.affiliation: Institute of Public Health, School and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland (J.A.L.).
authors.forename: Jari A
authors.initials: JA
authors.lastname: Laukkanen
authors.affiliation: Public Health Genomics Foundation, Cambridge, United Kingdom (S.C.).
authors.forename: Susmita
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom (P.W., D.F.F., R.G., E.D.A., R.C.) School of Medicine, University of Guyana, Guyana (R.G.).
authors.forename: Reeta
authors.initials: R
authors.lastname: Gobin
authors.affiliation: King's British Heart Foundation Centre, King's College London, United Kingdom (P.W., M.M.).
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.affiliation: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom (P.W., D.F.F., R.G., E.D.A., R.C.).
authors.forename: Emanuele
authors.initials: E
authors.lastname: Di Angelantonio
authors.affiliation: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom (P.W., D.F.F., R.G., E.D.A., R.C.).
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chowdhury
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology*; D006801:Humans; D016017:Odds Ratio; D011446:Prospective Studies; D020521:Stroke / Q000097:blood / Q000209:etiology
chemical_list: C018524:N,N-dimethylarginine; D001120:Arginine
keywords: asymmetric dimethylarginine; cardiovascular diseases; meta‐analysis; prospective studies