title: Pulmonary hypertension associated with advanced systolic heart failure: dysregulated arginine metabolism and importance of compensatory dimethylarginine dimethylaminohydrolase-1.
abstract: OBJECTIVE
  This study sought to examine the hemodynamic determinants of dysregulated arginine metabolism in patients with acute decompensated heart failure and to explore possible mechanisms of arginine dysregulation in human heart failure.
  
  
  BACKGROUND
  Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear.
  
  
  METHODS
  This study prospectively determined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and global arginine bioavailability ratio [GABR = arginine/(ornithine + citrulline)] by tandem mass spectrometry in subjects with advanced decompensated heart failure in the intensive care unit (n = 68) and with stable chronic heart failure (n = 57).
  
  
  RESULTS
  Compared with chronic heart failure subjects, plasma ADMA was significantly higher (median [interquartile range]: 1.29 [1.04 to 1.77] μmol/l vs. 0.87 [0.72 to 1.05] μmol/l, p < 0.0001), and global arginine bioavailability ratio significantly lower (median [interquartile range]: 0.90 [0.69 to 1.22] vs. 1.13 [0.92 to 1.37], p = 0.002) in advanced decompensated heart failure subjects. Elevated ADMA and diminished global arginine bioavailability ratio were associated with higher systolic pulmonary artery pressure (sPAP) and higher central venous pressure, but not with other clinical or hemodynamic indices. We further observed myocardial levels of dimethylarginine dimethylaminohydrolase-1 were increased in chronic heart failure without elevated sPAP (<50 mm Hg), but diminished with elevated sPAP (≥50 mm Hg, difference with sPAP <50 mm Hg, p = 0.02).
  
  
  CONCLUSIONS
  Dysregulated arginine metabolism was observed in advanced decompensated heart failure, particularly with pulmonary hypertension and elevated intracardiac filling pressures. Compared with hearts of control subjects, we observed higher amounts of ADMA-degradation enzyme dimethylarginine dimethylaminohydrolase-1 (but similar amounts of ADMA-producing enzyme, protein methyltransferase-1) in the human failing myocardium.
authors.affiliation: Center for Cardiovascular Diagnostics and Prevention, Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Shao
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.forename: Kevin
authors.initials: K
authors.lastname: Shrestha
authors.forename: Akanksha
authors.initials: A
authors.lastname: Thakur
authors.forename: Allen G
authors.initials: AG
authors.lastname: Borowski
authors.forename: Wendy
authors.initials: W
authors.lastname: Sweet
authors.forename: James D
authors.initials: JD
authors.lastname: Thomas
authors.forename: Christine S
authors.initials: CS
authors.lastname: Moravec
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
mesh_terms: D000368:Aged; D000581:Amidohydrolases / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D054143:Heart Failure, Systolic / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged
chemical_list: C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase