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

Tsin Yeo, D LAMPAH, Retno Gitawati, Emiliana Tijitra, Enny Kenangalem, Yvette McNeil, Christabelle Darcy, D GRANGER, J WEINBERG, B LOPANSRI, Ric Price, S DUFFULL, David S Celermajer, Nicholas Anstey

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    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. JEM � The Rockefeller University Press.
    Original languageEnglish
    Pages (from-to)2693-2704
    Number of pages12
    JournalJournal of Experimental Medicine
    Volume204
    Issue number11
    Publication statusPublished - 2007

    Fingerprint

    Falciparum Malaria
    Biological Availability
    Arginine
    Nitric Oxide
    Confidence Intervals
    Hyperemia
    Manometry
    Hemolysis
    Indonesia
    Malaria
    Endothelium
    Observational Studies
    Lactic Acid
    Cardiovascular Diseases
    Ischemia
    Erythrocytes
    Clinical Trials

    Cite this

    Yeo, Tsin ; LAMPAH, D ; Gitawati, Retno ; Tijitra, Emiliana ; Kenangalem, Enny ; McNeil, Yvette ; Darcy, Christabelle ; GRANGER, D ; WEINBERG, J ; LOPANSRI, B ; Price, Ric ; DUFFULL, S ; Celermajer, David S ; Anstey, Nicholas. / Impaired nitric oxide bioavailability and L-arginine-reversible endothelial dysfunction in adults with falciparum malaria. In: Journal of Experimental Medicine. 2007 ; Vol. 204, No. 11. pp. 2693-2704.
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    title = "Impaired nitric oxide bioavailability and L-arginine-reversible endothelial dysfunction in adults with falciparum malaria",
    abstract = "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. JEM � The Rockefeller University Press.",
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    author = "Tsin Yeo and D LAMPAH and Retno Gitawati and Emiliana Tijitra and Enny Kenangalem and Yvette McNeil and Christabelle Darcy and D GRANGER and J WEINBERG and B LOPANSRI and Ric Price and S DUFFULL and Celermajer, {David S} and Nicholas Anstey",
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    Yeo, T, LAMPAH, D, Gitawati, R, Tijitra, E, Kenangalem, E, McNeil, Y, Darcy, C, GRANGER, D, WEINBERG, J, LOPANSRI, B, Price, R, DUFFULL, S, Celermajer, DS & Anstey, N 2007, 'Impaired nitric oxide bioavailability and L-arginine-reversible endothelial dysfunction in adults with falciparum malaria', Journal of Experimental Medicine, vol. 204, no. 11, pp. 2693-2704.

    Impaired nitric oxide bioavailability and L-arginine-reversible endothelial dysfunction in adults with falciparum malaria. / Yeo, Tsin; LAMPAH, D; Gitawati, Retno; Tijitra, Emiliana; Kenangalem, Enny; McNeil, Yvette; Darcy, Christabelle; GRANGER, D; WEINBERG, J; LOPANSRI, B; Price, Ric; DUFFULL, S; Celermajer, David S; Anstey, Nicholas.

    In: Journal of Experimental Medicine, Vol. 204, No. 11, 2007, p. 2693-2704.

    Research output: Contribution to journalArticleResearchpeer-review

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    T1 - Impaired nitric oxide bioavailability and L-arginine-reversible endothelial dysfunction in adults with falciparum malaria

    AU - Yeo, Tsin

    AU - LAMPAH, D

    AU - Gitawati, Retno

    AU - Tijitra, Emiliana

    AU - Kenangalem, Enny

    AU - McNeil, Yvette

    AU - Darcy, Christabelle

    AU - GRANGER, D

    AU - WEINBERG, J

    AU - LOPANSRI, B

    AU - Price, Ric

    AU - DUFFULL, S

    AU - Celermajer, David S

    AU - Anstey, Nicholas

    PY - 2007

    Y1 - 2007

    N2 - 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. JEM � The Rockefeller University Press.

    AB - 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. JEM � The Rockefeller University Press.

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