title: Increased levels of symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease.
abstract: OBJECTIVE
  Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD).
  
  
  METHODS
  In 238 patients with symptomatic PAD and an ABI of <0.8, l-arginine, asymmetric dimethyl-arginine (ADMA) and SDMA levels were measured by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry.
  
  
  RESULTS
  The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality (P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI (r = -0.236, N = 216, P < .001; r = -0.209, N = 208, P = .002, respectively).
  
  
  CONCLUSIONS
  The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Staniszewska
authors.affiliation: Vascular Surgery Department, Aberdeen Royal Infirmary, Aberdeen, United Kingdom.
authors.forename: Sriram
authors.initials: S
authors.lastname: Rajagopalan
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Al-Shaheen
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Thies
authors.affiliation: Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom. Electronic address: j.brittenden@abdn.ac.uk.
authors.forename: Julie
authors.initials: J
authors.lastname: Brittenden
mesh_terms: D000368:Aged; D055109:Ankle Brachial Index; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001157:Arterial Occlusive Diseases / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D015415:Biomarkers / Q000097:blood*; D002423:Cause of Death; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007383:Intermittent Claudication / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D007511:Ischemia / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests
chemical_list: D015415:Biomarkers; C487735:dimethylarginine; C024917:symmetric dimethylarginine; D001120:Arginine