title: Symmetric dimethylarginine predicts all-cause mortality following ischemic stroke.
abstract: OBJECTIVE
  Methylarginines have been shown to interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA, and monomethylarginine, NMMA) and the cellular l-arginine uptake system (ADMA, NMMA and symmetric dimethylarginine, SDMA), thereby causing endothelial dysfunction. ADMA is a predictor of cardiovascular events and mortality in diverse populations.
  
  
  METHODS
  We investigated whether methylarginines are predictors of mortality in 394 patients after acute ischemic stroke during 7.4 years of follow-up.
  
  
  RESULTS
  Patients who died (N=231) were older and more frequently had one of the traditional risk factors for stroke (previous stroke/TIA, atrial fibrillation, prevalent ischemic heart disease, peripheral vascular disease, each p<0.05). ADMA (0.52 micromol/l vs. 0.50 micromol/l, p=0.015) and SDMA (0.56 micromol/l vs. 0.43 micromol/l, p<0.001) were higher in patients who died. In multivariable-adjusted hazard models, SDMA but not ADMA or NMMA was an independent predictor of all-cause mortality after stroke (SDMA, hazard ratio 2.41 (1.55-3.72), p<0.001; ADMA, hazard ratio 1.43 (0.99-2.07), p=0.06). SDMA was significantly associated with atrial fibrillation (0.55 micromol/l vs. 0.50 micromol/l, p=0.03) but there was no significant interaction between SDMA and AF in relation to mortality (p=0.81). SDMA remained significantly associated with mortality after adjusting for eGFR and also additionally adjusting for C-reactive protein, albumin, beta-thromboglobulin, and von Willebrand factor.
  
  
  CONCLUSIONS
  Our study demonstrates that SDMA is an independent predictor of total mortality after acute stroke irrespective of renal function. SDMA is associated with atrial fibrillation, endothelial and platelet activation, and may therefore play a previously unknown role in the pathophysiology of stroke.
authors.affiliation: Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Schulze
authors.forename: Angela M
authors.initials: AM
authors.lastname: Carter
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Ramzi
authors.initials: R
authors.lastname: Ajjan
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
authors.forename: Rouven-Alexander
authors.initials: RA
authors.lastname: von Holten
authors.forename: Dorothee
authors.initials: D
authors.lastname: Atzler
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007511:Ischemia / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012307:Risk Factors; D020521:Stroke / Q000401:mortality / Q000473:pathology*; D001620:beta-Thromboglobulin / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D000418:Albumins; D004791:Enzyme Inhibitors; D001620:beta-Thromboglobulin; D014841:von Willebrand Factor; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; D002097:C-Reactive Protein; D001120:Arginine; D019001:Nitric Oxide Synthase