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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1150-1158 |
| Number of pages | 9 |
| Journal | Journal of the American College of Cardiology |
| Volume | 59 |
| Issue number | 13 |
| DOIs | |
| State | Published - Mar 27 2012 |
Funding
This research was supported by National Institutes of Health grant nos. 1RO1 HL103931-02 (to Dr. Tang), P01 HL076491-055328 (to Dr. Hazen), P01 HL087018-020001 (to Dr. Hazen), 1P01 HL098055-01 (to Dr. Hazen), P50 HL077107-050004 (to Dr. Hazen), the Cleveland Clinic Clinical Research Unit of the Cleveland Clinic/Case Western Reserve University CTSA 1UL1RR024989 (to Drs. Borowski, Hazen, and Tang), American College of Cardiology Foundation (to Dr. Tang), and the American Society of Echocardiography (to Dr. Borowski). Dr. Hazen is named as coinventor on issued and pending patents filed by the Cleveland Clinic that relate to the use of biomarkers in inflammatory and cardiovascular disease. Dr. Hazen is the scientific founder of Cleveland Heart Lab; he has received speaking honoraria or consulting fees from Pfizer, AstraZeneca, Merck, Merck Schering Plough, Lilly, Esperion, Liposciences, Prognosti X Inc., Wyeth, BioPhysical, and Abbott Laboratories; and has received research grant support from Abbott Laboratories , Liposciences , and Cleveland Heart Lab . Dr. Tang has previously received research grant support from Abbott Laboratories . All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Wilson Colucci, MD, has served as Guest Editor for this paper.
Keywords
- asymmetric dimethylarginine
- heart failure
- nitric oxide synthase
- pulmonary hypertension
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
