title: Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease.
abstract: BACKGROUND
  Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis causing endothelial dysfunction, an early sign of atherogenesis. Symmetric dimethylarginine (SDMA) does not inhibit NO synthases. Peripheral arterial disease (PAD) is a systemic indication of atherosclerosis.
  
  
  METHODS
  We assessed the associations between both ADMA and SDMA blood levels and major cardiovascular and cerebrovascular events or death from any cause within a 5-year follow-up in the multicentre getABI trial. From a cohort of 6821 primary care patients, aged ≥65 years, all 1260 patients with prevalent PAD were compared with a random sample of 1187 non-PAD controls. A total of 11,544 patient-years were documented. Multivariate risks were calculated by Cox proportional hazard models, adjusting for PAD, renal dysfunction and other important cardiovascular risk factors.
  
  
  RESULTS
  We documented 390 deaths, 296 cardiovascular events and 98 cerebrovascular events. Increased ADMA levels in the 4th quartile were significantly associated with total mortality [hazard ratio (HR) 1.41; 95% CI 1.14-1.74] and with cardiovascular events (HR 1.32; 95% CI 1.03-1.69), but there was a nonsignificant association with cerebrovascular events (HR 1.50; 95% CI 0.98-2.29). Increased SDMA was only just significantly associated with mortality (HR 1.27; 95% CI 1.01-1.59). In PAD patients compared with non-PAD controls, only mean SDMA concentration was considerably increased (0.52 μmol L(-1) vs. 0.48 μmol L(-1); P < 0.001) mainly because of a highly significant association with impaired renal function.
  
  
  CONCLUSIONS
  These data suggest that ADMA but not SDMA is an independent risk marker for death from any cause or from cardiovascular events. The association between SDMA and mortality is in part explained by a close link between SDMA and renal function.
authors.affiliation: Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. boeger@uke.uni-hamburg.de
authors.forename: R H
authors.initials: RH
authors.lastname: Böger
authors.forename: H G
authors.initials: HG
authors.lastname: Endres
authors.forename: E
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: H
authors.initials: H
authors.lastname: Darius
authors.forename: D
authors.initials: D
authors.lastname: Atzler
authors.forename: N
authors.initials: N
authors.lastname: Lüneburg
authors.forename: B
authors.initials: B
authors.lastname: von Stritzky
authors.forename: R
authors.initials: R
authors.lastname: Maas
authors.forename: U
authors.initials: U
authors.lastname: Thiem
authors.forename: R A
authors.initials: RA
authors.lastname: Benndorf
authors.forename: C
authors.initials: C
authors.lastname: Diehm
mesh_terms: D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000401:mortality; D002561:Cerebrovascular Disorders / Q000097:blood / Q000401:mortality; D004791:Enzyme Inhibitors / Q000097:blood; D004812:Epidemiologic Methods; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000401:mortality; D011379:Prognosis
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase