Asymmetric dimethylarginine in adult falciparum malaria

Relationships with disease severity, antimalarial treatment, hemolysis, and inflammation

Bridget E. Barber, Timothy WILLIAM, Matthew J. Grigg, Uma Parameswaran, Kim A. Piera, Tsin W. Yeo, Nicholas M. Anstey

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Endothelial nitric oxide (NO) bioavailability is impaired in severe falciparum malaria (SM). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (NOS), contributes to endothelial dysfunction and is associated with mortality in adults with falciparum malaria. However, factors associated with ADMA in malaria, including the NOS-substrate L-arginine, hemolysis, and antimalarial treatment, are not well understood.

    Methods: In a prospective observational study of Malaysian adults with SM (N = 22) and non-SM (NSM; N = 124) and healthy controls (HCs), we investigated factors associated with plasma ADMA including the effects of antimalarial treatment.

    Results: Compared with HCs, ADMA levels were lower in NSM (0.488 μM vs 0.540 μM, P = .001) and in the subset of SM patients enrolled before commencing treatment (0.453 μM [N = 5], P = .068), but levels were higher in SM patients enrolled after commencing antimalarial treatment (0.610 μM [N = 17], P = .026). In SM and NSM, ADMA levels increased significantly to abovebaseline levels by day 3. Baseline ADMA was correlated with arginine and cell-free hemoglobin in SM and NSM and inversely correlated with interleukin-10 in NSM. Arginine and the arginine/ADMA ratio (reflective of arginine bioavailability) were lower in SM and NSM compared with HCs, and the arginine/ADMA ratio was lower in SM compared with NSM.

    Conclusions: Pretreatment ADMA concentrations and L-arginine bioavailability are reduced in SM and NSM. Asymmetric dimethylarginine increases to above-baseline levels after commencement of antimalarial treatment. Arginine, hemolysis, and posttreatment inflammation all likely contribute to ADMA regulation, with ADMA likely contributing to the reduced NO bioavailability in SM.

    Original languageEnglish
    Article numberofw027
    Pages (from-to)1-9
    Number of pages9
    JournalOpen Forum Infectious Diseases
    Volume3
    Issue number1
    DOIs
    Publication statusPublished - 1 Jan 2016

    Fingerprint

    Falciparum Malaria
    Antimalarials
    Hemolysis
    Inflammation
    Arginine
    Biological Availability
    Therapeutics
    Nitric Oxide Synthase
    N,N-dimethylarginine
    Nitric Oxide
    Interleukin-10
    Malaria
    Observational Studies
    Hemoglobins
    Prospective Studies

    Cite this

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    title = "Asymmetric dimethylarginine in adult falciparum malaria: Relationships with disease severity, antimalarial treatment, hemolysis, and inflammation",
    abstract = "Background: Endothelial nitric oxide (NO) bioavailability is impaired in severe falciparum malaria (SM). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (NOS), contributes to endothelial dysfunction and is associated with mortality in adults with falciparum malaria. However, factors associated with ADMA in malaria, including the NOS-substrate L-arginine, hemolysis, and antimalarial treatment, are not well understood. Methods: In a prospective observational study of Malaysian adults with SM (N = 22) and non-SM (NSM; N = 124) and healthy controls (HCs), we investigated factors associated with plasma ADMA including the effects of antimalarial treatment. Results: Compared with HCs, ADMA levels were lower in NSM (0.488 μM vs 0.540 μM, P = .001) and in the subset of SM patients enrolled before commencing treatment (0.453 μM [N = 5], P = .068), but levels were higher in SM patients enrolled after commencing antimalarial treatment (0.610 μM [N = 17], P = .026). In SM and NSM, ADMA levels increased significantly to abovebaseline levels by day 3. Baseline ADMA was correlated with arginine and cell-free hemoglobin in SM and NSM and inversely correlated with interleukin-10 in NSM. Arginine and the arginine/ADMA ratio (reflective of arginine bioavailability) were lower in SM and NSM compared with HCs, and the arginine/ADMA ratio was lower in SM compared with NSM. Conclusions: Pretreatment ADMA concentrations and L-arginine bioavailability are reduced in SM and NSM. Asymmetric dimethylarginine increases to above-baseline levels after commencement of antimalarial treatment. Arginine, hemolysis, and posttreatment inflammation all likely contribute to ADMA regulation, with ADMA likely contributing to the reduced NO bioavailability in SM.",
    keywords = "ADMA, Arginine, Malaria, Nitric oxide, Plasmodium falciparum",
    author = "Barber, {Bridget E.} and Timothy WILLIAM and Grigg, {Matthew J.} and Uma Parameswaran and Piera, {Kim A.} and Yeo, {Tsin W.} and Anstey, {Nicholas M.}",
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    Asymmetric dimethylarginine in adult falciparum malaria : Relationships with disease severity, antimalarial treatment, hemolysis, and inflammation. / Barber, Bridget E.; WILLIAM, Timothy; Grigg, Matthew J.; Parameswaran, Uma; Piera, Kim A.; Yeo, Tsin W.; Anstey, Nicholas M.

    In: Open Forum Infectious Diseases, Vol. 3, No. 1, ofw027, 01.01.2016, p. 1-9.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Asymmetric dimethylarginine in adult falciparum malaria

    T2 - Relationships with disease severity, antimalarial treatment, hemolysis, and inflammation

    AU - Barber, Bridget E.

    AU - WILLIAM, Timothy

    AU - Grigg, Matthew J.

    AU - Parameswaran, Uma

    AU - Piera, Kim A.

    AU - Yeo, Tsin W.

    AU - Anstey, Nicholas M.

    PY - 2016/1/1

    Y1 - 2016/1/1

    N2 - Background: Endothelial nitric oxide (NO) bioavailability is impaired in severe falciparum malaria (SM). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (NOS), contributes to endothelial dysfunction and is associated with mortality in adults with falciparum malaria. However, factors associated with ADMA in malaria, including the NOS-substrate L-arginine, hemolysis, and antimalarial treatment, are not well understood. Methods: In a prospective observational study of Malaysian adults with SM (N = 22) and non-SM (NSM; N = 124) and healthy controls (HCs), we investigated factors associated with plasma ADMA including the effects of antimalarial treatment. Results: Compared with HCs, ADMA levels were lower in NSM (0.488 μM vs 0.540 μM, P = .001) and in the subset of SM patients enrolled before commencing treatment (0.453 μM [N = 5], P = .068), but levels were higher in SM patients enrolled after commencing antimalarial treatment (0.610 μM [N = 17], P = .026). In SM and NSM, ADMA levels increased significantly to abovebaseline levels by day 3. Baseline ADMA was correlated with arginine and cell-free hemoglobin in SM and NSM and inversely correlated with interleukin-10 in NSM. Arginine and the arginine/ADMA ratio (reflective of arginine bioavailability) were lower in SM and NSM compared with HCs, and the arginine/ADMA ratio was lower in SM compared with NSM. Conclusions: Pretreatment ADMA concentrations and L-arginine bioavailability are reduced in SM and NSM. Asymmetric dimethylarginine increases to above-baseline levels after commencement of antimalarial treatment. Arginine, hemolysis, and posttreatment inflammation all likely contribute to ADMA regulation, with ADMA likely contributing to the reduced NO bioavailability in SM.

    AB - Background: Endothelial nitric oxide (NO) bioavailability is impaired in severe falciparum malaria (SM). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (NOS), contributes to endothelial dysfunction and is associated with mortality in adults with falciparum malaria. However, factors associated with ADMA in malaria, including the NOS-substrate L-arginine, hemolysis, and antimalarial treatment, are not well understood. Methods: In a prospective observational study of Malaysian adults with SM (N = 22) and non-SM (NSM; N = 124) and healthy controls (HCs), we investigated factors associated with plasma ADMA including the effects of antimalarial treatment. Results: Compared with HCs, ADMA levels were lower in NSM (0.488 μM vs 0.540 μM, P = .001) and in the subset of SM patients enrolled before commencing treatment (0.453 μM [N = 5], P = .068), but levels were higher in SM patients enrolled after commencing antimalarial treatment (0.610 μM [N = 17], P = .026). In SM and NSM, ADMA levels increased significantly to abovebaseline levels by day 3. Baseline ADMA was correlated with arginine and cell-free hemoglobin in SM and NSM and inversely correlated with interleukin-10 in NSM. Arginine and the arginine/ADMA ratio (reflective of arginine bioavailability) were lower in SM and NSM compared with HCs, and the arginine/ADMA ratio was lower in SM compared with NSM. Conclusions: Pretreatment ADMA concentrations and L-arginine bioavailability are reduced in SM and NSM. Asymmetric dimethylarginine increases to above-baseline levels after commencement of antimalarial treatment. Arginine, hemolysis, and posttreatment inflammation all likely contribute to ADMA regulation, with ADMA likely contributing to the reduced NO bioavailability in SM.

    KW - ADMA

    KW - Arginine

    KW - Malaria

    KW - Nitric oxide

    KW - Plasmodium falciparum

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    U2 - 10.1093/ofid/ofw027

    DO - 10.1093/ofid/ofw027

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    JO - Open Forum Infectious Diseases

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    SN - 2328-8957

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