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.}",
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language = "English",
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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

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DO - 10.1093/infdis/jiw427

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