title: Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure.
abstract: OBJECTIVE
  To investigate the association of arginine methylation with myocardial function and prognosis in chronic systolic heart failure patients.
  
  
  RESULTS
  Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), as well as N-mono-methylarginine (MMA) and methyl-lysine, were simultaneously measured by tandem mass spectrometry in 132 patients with chronic systolic heart failure with echocardiographic evaluation and follow-up. Increasing ADMA and SDMA levels were associated with elevated natriuretic peptide levels (both P < 0.001), and increasing SDMA levels were associated with worsening renal function (P < 0.001). Higher plasma levels of methylated arginine metabolites (but not methyl-lysine) were associated with the presence of left ventricular (LV) diastolic dysfunction (E/septal E', Spearman's r = 0.31-0.36, P < 0.001). Patients taking beta-blockers had lower ADMA levels than those not taking beta-blockers [0.42 (0.33, 0.50) vs. 0.51 (0.40, 0.58), P < 0.001]. Only increasing ADMA levels were associated with advanced right ventricular (RV) systolic dysfunction. Elevated ADMA levels remained a consistent independent predictor of adverse clinical events (hazard ratio = 1.64, 95% CI: 1.20-2.22, P = 0.002).
  
  
  CONCLUSIONS
  In chronic systolic heart failure, accumulation of methylated arginine metabolites is associated with the presence of LV diastolic dysfunction. Among the methylated derivatives of arginine, ADMA provides the strongest independent prediction of disease progression and adverse long-term outcomes.
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. tangw@ccf.org
authors.forename: Wai Hong Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Wilson
authors.initials: W
authors.lastname: Tong
authors.forename: Kevin
authors.initials: K
authors.lastname: Shrestha
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.forename: Brian
authors.initials: B
authors.lastname: Delfraino
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Richard W
authors.initials: RW
authors.lastname: Troughton
authors.forename: Allan L
authors.initials: AL
authors.lastname: Klein
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D001120:Arginine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D003971:Diastole / Q000187:drug effects; D018450:Disease Progression; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D005260:Female; D054143:Heart Failure, Systolic / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D045265:Natriuretic Peptides / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D011237:Predictive Value of Tests; D011446:Prospective Studies; D051437:Renal Insufficiency / Q000139:chemically induced; D053719:Tandem Mass Spectrometry / Q000379:methods; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D015415:Biomarkers; D045265:Natriuretic Peptides; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; D001120:Arginine