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: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University.|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 Center, 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.|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.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Piera
authors.affiliation: Duke University Medical Center.|VA Medical Center, Durham, North Carolina.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Duke University Medical Center.|VA Medical Center, Durham, North Carolina.
authors.forename: J Brice
authors.initials: JB
authors.lastname: Weinberg
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University.|Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit.|Lee Kong Chian School of Medicine, Nanyang Technological University.|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.|Department of Infectious Diseases, Royal Darwin Hospital, Darwin, Australia.|Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Anstey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001120:Arginine / Q000097:blood*; D001682:Biological Availability; D042783:Endothelial Cells / Q000502:physiology*; D016021:Epidemiologic Studies; D005260:Female; D006461:Hemolysis; D006801:Humans; D016780:Malaria, Vivax / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D009569:Nitric Oxide; D001120:Arginine
keywords: Plasmodium vivax; arginine; asymmetric dimethylarginine; endothelial function; hemolysis; malaria; nitric oxide