Nitric oxide-dependent endothelial dysfunction and reduced arginine bioavailability in plasmodium vivax malaria but no greater increase in intravascular hemolysis in severe disease

Bridget E. Barber, Timothy William, Matthew J. Grigg, Kim A. Piera, Youwei Chen, Hao Wang, J. Brice Weinberg, Tsin W. Yeo, Nicholas M. Anstey

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Pathogenesis of severe Plasmodium vivax malaria is poorly understood. Endothelial dysfunction and reduced nitric oxide (NO) bioavailability characterize severe falciparum malaria, but have not been assessed in severe vivax malaria.

    Methods: In patients with severe vivax malaria (n = 9), patients with nonsevere vivax malaria (n = 58), and healthy controls (n = 79), we measured NO-dependent endothelial function by using reactive hyperemia-peripheral arterial tonometry (RH-PAT) and assessed associations with arginine, asymmetric dimethylarginine (ADMA), and hemolysis.

    Results: The L-arginine level and the L-arginine to ADMA ratio (a measure of L-arginine bioavailability) were reduced in patients with severe vivax malaria and those with nonsevere vivax malaria, compared with healthy controls (median L-arginine level, 65, 66, and 98 μmol/mL, respectively [P =. 0001]; median L-arginine to ADMA ratio, 115, 125, and 187, respectively [P =. 0001]). Endothelial function was impaired in proportion to disease severity (median RH-PAT index, 1.49, 1.73, and 1.97 in patients with severe vivax malaria, those with nonsevere vivax malaria, and healthy controls, respectively; P =. 018) and was associated with the L-arginine to ADMA ratio. While the posttreatment fall in hemoglobin level was greater in severe vivax malaria as compared to nonsevere vivax malaria (2.5 vs 1 g/dL; P =. 0001), markers of intravascular hemolysis were not higher in severe disease.

    Conclusions: Endothelial function is impaired in nonsevere and severe vivax malaria, is associated with reduced L-arginine bioavailability, and may contribute to microvascular pathogenesis. Severe disease appears to be more associated with extravascular hemolysis than with intravascular hemolysis.

    Original languageEnglish
    Pages (from-to)1557-1564
    Number of pages8
    JournalJournal of Infectious Diseases
    Volume214
    Issue number10
    DOIs
    Publication statusPublished - 15 Nov 2016

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    Vivax Malaria
    Hemolysis
    Biological Availability
    Arginine
    Nitric Oxide
    Hyperemia
    Manometry
    Falciparum Malaria
    Hemoglobins

    Cite this

    @article{2b26364281e442dbbe284c4fdb84a621,
    title = "Nitric oxide-dependent endothelial dysfunction and reduced arginine bioavailability in plasmodium vivax malaria but no greater increase in intravascular hemolysis in severe disease",
    abstract = "Background: Pathogenesis of severe Plasmodium vivax malaria is poorly understood. Endothelial dysfunction and reduced nitric oxide (NO) bioavailability characterize severe falciparum malaria, but have not been assessed in severe vivax malaria. Methods: In patients with severe vivax malaria (n = 9), patients with nonsevere vivax malaria (n = 58), and healthy controls (n = 79), we measured NO-dependent endothelial function by using reactive hyperemia-peripheral arterial tonometry (RH-PAT) and assessed associations with arginine, asymmetric dimethylarginine (ADMA), and hemolysis. Results: The L-arginine level and the L-arginine to ADMA ratio (a measure of L-arginine bioavailability) were reduced in patients with severe vivax malaria and those with nonsevere vivax malaria, compared with healthy controls (median L-arginine level, 65, 66, and 98 μmol/mL, respectively [P =. 0001]; median L-arginine to ADMA ratio, 115, 125, and 187, respectively [P =. 0001]). Endothelial function was impaired in proportion to disease severity (median RH-PAT index, 1.49, 1.73, and 1.97 in patients with severe vivax malaria, those with nonsevere vivax malaria, and healthy controls, respectively; P =. 018) and was associated with the L-arginine to ADMA ratio. While the posttreatment fall in hemoglobin level was greater in severe vivax malaria as compared to nonsevere vivax malaria (2.5 vs 1 g/dL; P =. 0001), markers of intravascular hemolysis were not higher in severe disease. Conclusions: Endothelial function is impaired in nonsevere and severe vivax malaria, is associated with reduced L-arginine bioavailability, and may contribute to microvascular pathogenesis. Severe disease appears to be more associated with extravascular hemolysis than with intravascular hemolysis.",
    keywords = "arginine, asymmetric dimethylarginine, endothelial function, hemolysis, malaria, nitric oxide, Plasmodium vivax",
    author = "Barber, {Bridget E.} and Timothy William and Grigg, {Matthew J.} and Piera, {Kim A.} and Youwei Chen and Hao Wang and Weinberg, {J. Brice} and Yeo, {Tsin W.} and Anstey, {Nicholas M.}",
    year = "2016",
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    doi = "10.1093/infdis/jiw427",
    language = "English",
    volume = "214",
    pages = "1557--1564",
    journal = "Journal of Infectious Diseases",
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    }

    Nitric oxide-dependent endothelial dysfunction and reduced arginine bioavailability in plasmodium vivax malaria but no greater increase in intravascular hemolysis in severe disease. / Barber, Bridget E.; William, Timothy; Grigg, Matthew J.; Piera, Kim A.; Chen, Youwei; Wang, Hao; Weinberg, J. Brice; Yeo, Tsin W.; Anstey, Nicholas M.

    In: Journal of Infectious Diseases, Vol. 214, No. 10, 15.11.2016, p. 1557-1564.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Nitric oxide-dependent endothelial dysfunction and reduced arginine bioavailability in plasmodium vivax malaria but no greater increase in intravascular hemolysis in severe disease

    AU - Barber, Bridget E.

    AU - William, Timothy

    AU - Grigg, Matthew J.

    AU - Piera, Kim A.

    AU - Chen, Youwei

    AU - Wang, Hao

    AU - Weinberg, J. Brice

    AU - Yeo, Tsin W.

    AU - Anstey, Nicholas M.

    PY - 2016/11/15

    Y1 - 2016/11/15

    N2 - Background: Pathogenesis of severe Plasmodium vivax malaria is poorly understood. Endothelial dysfunction and reduced nitric oxide (NO) bioavailability characterize severe falciparum malaria, but have not been assessed in severe vivax malaria. Methods: In patients with severe vivax malaria (n = 9), patients with nonsevere vivax malaria (n = 58), and healthy controls (n = 79), we measured NO-dependent endothelial function by using reactive hyperemia-peripheral arterial tonometry (RH-PAT) and assessed associations with arginine, asymmetric dimethylarginine (ADMA), and hemolysis. Results: The L-arginine level and the L-arginine to ADMA ratio (a measure of L-arginine bioavailability) were reduced in patients with severe vivax malaria and those with nonsevere vivax malaria, compared with healthy controls (median L-arginine level, 65, 66, and 98 μmol/mL, respectively [P =. 0001]; median L-arginine to ADMA ratio, 115, 125, and 187, respectively [P =. 0001]). Endothelial function was impaired in proportion to disease severity (median RH-PAT index, 1.49, 1.73, and 1.97 in patients with severe vivax malaria, those with nonsevere vivax malaria, and healthy controls, respectively; P =. 018) and was associated with the L-arginine to ADMA ratio. While the posttreatment fall in hemoglobin level was greater in severe vivax malaria as compared to nonsevere vivax malaria (2.5 vs 1 g/dL; P =. 0001), markers of intravascular hemolysis were not higher in severe disease. Conclusions: Endothelial function is impaired in nonsevere and severe vivax malaria, is associated with reduced L-arginine bioavailability, and may contribute to microvascular pathogenesis. Severe disease appears to be more associated with extravascular hemolysis than with intravascular hemolysis.

    AB - Background: Pathogenesis of severe Plasmodium vivax malaria is poorly understood. Endothelial dysfunction and reduced nitric oxide (NO) bioavailability characterize severe falciparum malaria, but have not been assessed in severe vivax malaria. Methods: In patients with severe vivax malaria (n = 9), patients with nonsevere vivax malaria (n = 58), and healthy controls (n = 79), we measured NO-dependent endothelial function by using reactive hyperemia-peripheral arterial tonometry (RH-PAT) and assessed associations with arginine, asymmetric dimethylarginine (ADMA), and hemolysis. Results: The L-arginine level and the L-arginine to ADMA ratio (a measure of L-arginine bioavailability) were reduced in patients with severe vivax malaria and those with nonsevere vivax malaria, compared with healthy controls (median L-arginine level, 65, 66, and 98 μmol/mL, respectively [P =. 0001]; median L-arginine to ADMA ratio, 115, 125, and 187, respectively [P =. 0001]). Endothelial function was impaired in proportion to disease severity (median RH-PAT index, 1.49, 1.73, and 1.97 in patients with severe vivax malaria, those with nonsevere vivax malaria, and healthy controls, respectively; P =. 018) and was associated with the L-arginine to ADMA ratio. While the posttreatment fall in hemoglobin level was greater in severe vivax malaria as compared to nonsevere vivax malaria (2.5 vs 1 g/dL; P =. 0001), markers of intravascular hemolysis were not higher in severe disease. Conclusions: Endothelial function is impaired in nonsevere and severe vivax malaria, is associated with reduced L-arginine bioavailability, and may contribute to microvascular pathogenesis. Severe disease appears to be more associated with extravascular hemolysis than with intravascular hemolysis.

    KW - arginine

    KW - asymmetric dimethylarginine

    KW - endothelial function

    KW - hemolysis

    KW - malaria

    KW - nitric oxide

    KW - Plasmodium vivax

    UR - http://www.scopus.com/inward/record.url?scp=85006511787&partnerID=8YFLogxK

    U2 - 10.1093/infdis/jiw427

    DO - 10.1093/infdis/jiw427

    M3 - Article

    VL - 214

    SP - 1557

    EP - 1564

    JO - Journal of Infectious Diseases

    JF - Journal of Infectious Diseases

    SN - 0022-1899

    IS - 10

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