The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20070819
The Journal of Experimental Medicine, Vol. 204, No. 11, 2693-2704
The Rockefeller University Press, 0022-1007 $30.00
© Yeo et al.
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ARTICLE

 Impaired nitric oxide bioavailability and L-arginine–reversible endothelial dysfunction in adults with falciparum malaria

Tsin W. Yeo1, Daniel A. Lampah2, Retno Gitawati3, Emiliana Tjitra3, Enny Kenangalem2, Yvette R. McNeil1, Christabelle J. Darcy1, Donald L. Granger4, J. Brice Weinberg5, Bert K. Lopansri4, Ric N. Price1,6, Stephen B. Duffull7, David S. Celermajer8,9, and Nicholas M. Anstey1

1 International Health Division, Menzies School of Health Research and Charles Darwin University, Darwin NT 0810, Australia
2 Menzies School of Health Research-National Institute of Health Research and Development Research Program and District Health Authority, Timika, Papua, Indonesia
3 National Institute of Health Research and Development, Jakarta 10560, Indonesia
4 Division of Infectious Diseases, University of Utah and Veterans' Affairs Medical Center, Salt Lake City, UT 84132
5 Division of Hematology-Oncology, Duke University and Veterans' Affairs Medical Centers, Durham, NC 27710
6 Centre for Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford OX37LJ, England, UK
7 School of Pharmacy, University of Otago, Dunedin 9054, New Zealand
8 Department of Medicine, University of Sydney, Sydney NSW 2006, Australia
9 Department of Cardiology, Royal Prince Alfred Hospital, Sydney NSW 2050, Australia

CORRESPONDENCE Nicholas M. Anstey: anstey{at}menzies.edu.au

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, L-arginine. Endothelial function has not been characterized in SM but can be improved by L-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia–peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33–1.47) than in MSM (1.82; 95% CI = 1.7–2.02) and controls (1.93; 95% CI = 1.8–2.06; P < 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous L-arginine in 30 more patients with MSM, L-arginine increased the RH-PAT index by 19% (95% CI = 6–34; P = 0.006) and exhaled NO by 55% (95% CI = 32–73; P < 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with L-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including L-arginine, are warranted.

Abbreviations used: ANOVA, analysis of variance; ARDS, acute respiratory distress syndrome; CI, confidence interval; HC, healthy controls; HRP2, histidine-rich protein 2; ICAM-1, intercellular adhesion molecule 1; LDH, lactate dehydrogenase; MSM, moderately severe falciparum malaria; NOS, NO synthase; ppb, parts per billion; RH-PAT, reactive hyperemia–peripheral arterial tonometry; SCD, sickle cell disease; SM, severe falciparum malaria.


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