Pulmonary hypertension associated with advanced systolic heart failure: Dysregulated arginine metabolism and importance of compensatory dimethylarginine dimethylaminohydrolase-1

Zhili Shao, Zeneng Wang, Kevin Shrestha, Akanksha Thakur, Allen G. Borowski, Wendy Sweet, James D. Thomas, Christine S. Moravec, Stanley L. Hazen, W. H Wilson Tang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Objectives: 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.

Original languageEnglish (US)
Pages (from-to)1150-1158
Number of pages9
JournalJournal of the American College of Cardiology
Issue number13
StatePublished - Mar 27 2012


  • asymmetric dimethylarginine
  • heart failure
  • nitric oxide synthase
  • pulmonary hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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