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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 3-4, (2003)
© 2003 American Thoracic Society

Editorial

Hemolytic Anemia–associated Pulmonary Hypertension of Sickle Cell Disease and the Nitric Oxide/Arginine Pathway

Maria L. Jison, M.D. and Mark T. Gladwin, M.D.

Critical Care Medicine Department National Institutes of Health Bethesda, Maryland

Twenty years before leading the Human Genome Project and with substantially less fanfare, Collins and colleagues reported the clinical history, cardiac catheterization results, and autopsy findings in three patients with sickle cell disease who had developed pulmonary hypertension (1). They concluded "Although specific therapy has yet to be defined, the ominous prognosis of this complication of sickle hemoglobinopathy supports the application of experimental modalities such as continuous oxygen therapy, partial exchange transfusion, or even limited phlebotomy." Although there has been recent progress in the understanding of the prevalence of pulmonary hypertension in patients with sickle cell disease and an appreciation of its attributable mortality, little progress has been made in understanding the mechanism responsible for its development or the effects of therapeutic interventions.

It has become increasingly clear that there is a syndrome of hemolytic anemia–associated pulmonary hypertension, which is common not only to sickle cell disease but also to thalassemia (2), hereditary spherocytosis (3, 4), and paroxysmal nocturnal hemoglobinuria (5, 6). In patients with sickle cell disease, the prevalence ranges from 20 to 40% (7–9), with 2-year mortality rates approaching 50% (10). This poor prognosis occurs despite lower pulmonary pressures and higher s than was observed in patients with primary pulmonary hypertension (11). Increasing reports of sudden death in patients with sickle cell disease, in the absence of significant coronary artery disease, suggest an emerging role for pulmonary hypertension in the pathogenesis of sickle cell disease.

In the current issue of AJRCCM (pp. 63–69), Morris and colleagues (12) investigate the potential role of reduced arginine bioavailability in patients with pulmonary hypertension secondary to sickle cell disease and evaluate the effects of oral arginine therapy on pulmonary artery pressures. Ten patients with sickle cell disease complicated by secondary pulmonary hypertension were treated for 5 days with oral L-arginine (0.1 g/kg divided thrice daily). Pulmonary artery systolic pressures were estimated by echocardiographic measurement of the tricuspid regurgitant jet velocity before and after the 5 days of treatment; the pressures decreased by 15.2% (64–54 mm Hg; p = 0.002). Pulmonary pressures decreased in 9 of 10 patients, suggesting greater vascular responsiveness and less end-stage vasculopathy than was commonly observed in patients with primary pulmonary hypertension. Furthermore, the study showed a trend toward a 20% improvement in v oxygen saturation after L-arginine supplementation, consistent with an increased . The therapy was well tolerated with no reported adverse events. Plasma L-arginine levels rose significantly after therapy and methemoglobin levels increased from 0.55 to 1.10%, suggesting an increase in nitric oxide production.

Nitric oxide is a critical endogenous vasodilator that is synthesized in endothelial cells from the amino acid L-arginine by the constitutive calcium- and calmodulin-dependent enzyme, nitric oxide synthase. Morris and colleagues have provided evidence that L-arginine levels are depressed in patients with sickle cell disease, particularly during vaso-occlusive pain crisis and during the acute chest syndrome. They now confirm these observations: their patients had lower plasma arginine levels than control subjects, although the levels were not lower than in sickle cell patients without pulmonary hypertension. Interestingly, the patients with pulmonary hypertension did have a lower arginine/ornithine ratio. This ratio reflects in vivo arginase activity because arginine is metabolized by this enzyme to ornithine and urea. Also consistent with this idea, the plasma arginase activity tended to be higher in the patients with pulmonary hypertension.

These observations add to a growing body of data supporting the notion that bioavailability of nitric oxide is altered in patients with sickle cell disease. It is increasingly apparent that sickle cell disease is characterized by a homeostatic increase in the production of nitric oxide by nitric oxide synthase but countered by a severe systemic scavenging of nitric oxide by both superoxide and plasma hemoglobin released during hemolysis (13–16). Superoxide production by xanthine oxidase and plasma hemoglobin released during hemolysis likely intensify during vaso-occlusive crisis and the acute chest syndrome. Active production of nitric oxide necessary to maintain blood flow coupled with augmented destruction of nitric oxide rapidly deplete blood levels of L-arginine. Additional effects of arginase, potentially released from the red blood cell during hemolysis, further deplete the system and contribute to vascular instability. Reduced bioavailability of nitric oxide will further amplify signaling pathways contributing to lung injury and pulmonary hypertension, such as vascular cell adhesion molecule, e-selectin, and endothelin-1 (15, 16).

The present work advances our knowledge of the mechanisms involved in the pathogenesis of hemolytic anemia–associated pulmonary hypertension and reveals a significant vasodilatory effect of L-arginine, an inexpensive, safe, and clinically available oral neutrapharmaceutical. Further study is needed to evaluate the efficacy over longer periods of administration and to measure the potential effects on important clinical endpoints such as sickle cell–related complications, exercise performance, and mortality.

REFERENCES

  1. Collins FS, Orringer EP. Pulmonary hypertension and cor pulmonale in the sickle hemoglobinopathies. Am J Med 1982;73:814–821.[CrossRef][Medline]
  2. Aessopos A, Farmakis D, Karagiorga M, Voskaridou E, Loutradi A, Hatziliami A, Joussef J, Rombos J, Loukopoulos D. Cardiac involvement in thalassemia intermedia: a multicenter study. Blood 2001;97:3411–3416.[Abstract/Free Full Text]
  3. Hayag-Barin JE, Smith RE, Tucker FC Jr. Hereditary spherocytosis, thrombocytosis, and chronic pulmonary emboli: a case report and review of the literature. Am J Hematol 1998;57:82–84.[CrossRef][Medline]
  4. Verresen D, De Backer W, Van Meerbeeck J, Neetens I, Van Marck E, Vermeire P. Spherocytosis and pulmonary hypertension coincidental occurrence or causal relationship? Eur Respir J 1991;4:629–631.[Abstract]
  5. Uchida T, Miyake T, Matsuno M, Nishihara T, Ide M, Kawachi Y, Shichishima T. Fatal pulmonary thromboembolism in a patient with paroxysmal nocturnal hemoglobinuria. Rinsho Ketsueki 1998;39:150–152.[Medline]
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  7. Castro O. Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am 1996;10:1289–1303.[CrossRef][Medline]
  8. Sutton LL, Castro O, Cross DJ, Spencer JE, Lewis JF. Pulmonary hypertension in sickle cell disease. Am J Cardiol 1994;74:626–628.[CrossRef][Medline]
  9. Simmons BE, Santhanam V, Castaner A, Rao KR, Sachdev N, Cooper R. Sickle cell heart disease: two-dimensional echo and Doppler ultrasonographic findings in the hearts of adult patients with sickle cell anemia. Arch Intern Med 1988;148:1526–1528.[Abstract/Free Full Text]
  10. Castro OL, Hoque M, Brown BD. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 2003;101:1257–1261.[Abstract/Free Full Text]
  11. Minter KR, Gladwin MT. Pulmonary complications of sickle cell anemia: a need for increased recognition, treatment, and research. Am J Respir Crit Care Med 2001;164:2016–2019.[Free Full Text]
  12. Morris CR, Morris SM Jr, Hagar W, van Warmerdam J, Claster S, Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003;168:63–69.[Abstract/Free Full Text]
  13. Nath KA, Shah V, Haggard JJ, Croatt AJ, Smith LA, Hebbel RP, Katusic ZS. Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease. Am J Physiol Regul Integr Comp Physiol 2000;279:R1949–R1955.[Abstract/Free Full Text]
  14. Aslan M, Ryan TM, Adler B, Townes TM, Parks DA, Thompson JA, Tousson A, Gladwin MT, Patel RP, Tarpey MM, et al. Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci USA 2001;98:15215–15220.[Abstract/Free Full Text]
  15. Gladwin MT, Schechter AN, Ognibene FP, Coles WA, Reiter CD, Schenke WH, Csako G, Waclawiw MA, Panza JA, Cannon RO III. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation 2003;107:271–278.[Abstract/Free Full Text]
  16. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002;8:1383–1389.[CrossRef][Medline]



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