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 above-baseline 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.
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia; Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit.
authors.forename: Bridget E
authors.initials: BE
authors.lastname: Barber
authors.affiliation: Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit; Jesselton Medical Centre, Kota Kinabalu, Malaysia.
authors.forename: Timothy
authors.initials: T
authors.lastname: William
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia; Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Grigg
authors.affiliation: Global and Tropical Health Division , Menzies School of Health Research and Charles Darwin University , Darwin , Australia.
authors.forename: Uma
authors.initials: U
authors.lastname: Parameswaran
authors.affiliation: Global and Tropical Health Division , Menzies School of Health Research and Charles Darwin University , Darwin , Australia.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Piera
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia; Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Infectious Disease and Epidemiology, Tan Tock Seng Hospital, Singapore.
authors.forename: Tsin W
authors.initials: TW
authors.lastname: Yeo
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia; Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit; Department of Infectious Diseases, Royal Darwin Hospital, Australia.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Anstey
keywords: ADMA; Plasmodium falciparum; arginine; malaria; nitric oxide