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

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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.",
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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.

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AU - Anstey, Nicholas M.

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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

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KW - Nitric oxide

KW - Plasmodium falciparum

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