Pulmonary hypertension associated with advanced systolic heart failure: dysregulated arginine metabolism and importance of compensatory dimethylarginine dimethylaminohydrolase-1 - PubMed (original) (raw)

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

Zhili Shao et al. J Am Coll Cardiol. 2012.

Abstract

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.

Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Schematic illustration of arginine metabolic pathways and nitric oxide production

Abbreviations: NOS = nitric oxide synthase; PRMT = protein arginine methyltransferases; ADMA = asymmetric dimethylaminohydrolase; MMA = N-monomethylarginine; SDMA = symmetric dimethylarginine; DDAH = dimethylarginine dimethylaminohydrolase; CAT = cationic amino acid transport.

Figure 2

Figure 2. Comparison of plasma ADMA and GABR levels between advanced decompensated and chronic heart failure patients

Abbreviations: ADMA = asymmetric dimethylarginine; GABR = global arginine bioavailability ratio; ADHF = advanced decompensated heart failure; CHF = chronic systolic heart failure.

Figure 3

Figure 3. Increased Myocardial DDAH-1 Protein Levels in Human Failing Myocardium Caption: Upper Panel

Upper Panel. Immunohistochemistry staining of DDAH-1 in donor hearts (A) and failing human hearts (B), as well as IgG control staining of failing human hearts (C). Arrows showing increased staining in the interstitial and perivascular areas. Lower Panel. Myocardial levels of DDAH-1/2 and PRMT-1 proteins among “Controls” (n=10), “HF-L” (“low” sPAP <50 mmHg, n=10) and “HF-H” groups (“high” sPAP ≥50 mmHg, n=10). Band densities were normalized to those of GAPDH.

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