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Claudia R. Morris, MD; Gregory J. Kato, MD; Mirjana Poljakovic, PhD; Xunde Wang, PhD; William C. Blackwelder, PhD; Vandana Sachdev, MD; Stanley L. Hazen, MD, PhD; Elliott P. Vichinsky, MD; Sidney M. Morris, Jr, PhD; Mark T. Gladwin, MD

JAMA. 2005;294:81-90.

Context  Sickle cell disease is characterized by a state of nitric oxide resistance and limited bioavailability of L-arginine, the substrate for nitric oxide synthesis. We hypothesized that increased arginase activity and dysregulated arginine metabolism contribute to endothelial dysfunction, pulmonary hypertension, and patient outcomes.

Objective  To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension, and mortality.

Design  Plasma amino acid levels, plasma and erythrocyte arginase activities, and pulmonary hypertension status as measured by Doppler echocardiogram were prospectively obtained in outpatients with sickle cell disease. Patients were followed up for survival up to 49 months.

Setting  Urban tertiary care center and community clinics in the United States between February 2001 and March 2005.

Participants  Two hundred twenty-eight patients with sickle cell disease, aged 18 to 74 years, and 36 control participants.

Main Outcome Measures  Plasma amino acid levels, plasma and erythrocyte arginase activities, diagnosis of pulmonary hypertension, and mortality.

Results  Plasma arginase activity was significantly elevated in patients with sickle cell disease, with highest activity found in patients with secondary pulmonary hypertension. Arginase activity correlated with the arginine-ornithine ratio, and lower ratios were associated with greater severity of pulmonary hypertension and with mortality in this population (risk ratio, 2.5; 95% confidence interval [CI], 1.2-5.2; P = .006). Global arginine bioavailability, characterized by the ratio of arginine to ornithine plus citrulline, was also strongly associated with mortality (risk ratio, 3.6; 95% CI, 1.5-8.3; P<.001). Increased plasma arginase activity was correlated with increased intravascular hemolytic rate and, to a lesser extent, with markers of inflammation and soluble adhesion molecule levels.

Conclusions  These data support a novel mechanism of disease in which hemolysis contributes to reduced nitric oxide bioavailability and endothelial dysfunction via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges nitric oxide. The ratios of arginine to ornithine and arginine to ornithine plus citrulline are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease.

Author Affiliations: Departments of Emergency Medicine (Dr C. Morris) and Hematology-Oncology (Dr Vichinsky), Children’s Hospital & Research Center at Oakland, Oakland, Calif; Vascular Therapeutics Section, Cardiovascular Branch, National Heart, Lung, and Blood Institute (Drs Kato, Wang, and Gladwin), Critical Care Medicine Department, Clinical Center (Drs Kato, Wang, Blackwelder, and Gladwin), and Echocardiography Laboratory (Dr Sachdev), National Institutes of Health, Bethesda, Md; Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pa (Drs Poljakovic and S. Morris); and Center for Cardiovascular Diagnostics and Prevention, Departments of Cell Biology and Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (Dr Hazen).

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