Increased Asymmetric Dimethylarginine in Severe Falciparum Malaria: Association with Impaired Nitric Oxide Bioavailability and Fatal Outcome

PLoS Pathogens

David S. Celermajer¹  Ric N. Price²  J. Brice Weinberg³  Bert K. Lopansri⁴  Donald L. Granger⁴  Nicholas M. Anstey⁵  Christabelle J. Darcy⁶  Catherine Jones⁶  Tsin W. Yeo⁶  Stephen B. Duffull⁶  Yvette R. McNeil⁶  Daniel A. Lampah⁷  Enny Kenangalem⁷  Retno Gitawati⁸  Emiliana Tjitra⁸ 

[1] Centre for Vaccinology & Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, United Kingdom;Division of Hematology-Oncology, Duke and VA Medical Centers, Durham, North Carolina, United States of America;Division of Infectious Disease, Loyola University Medical Center, Maywood, Illinois, United States of America;Division of Infectious Diseases, University of Utah and VA Medical Centers,Salt Lake City, Utah, United States of America;Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia;International Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia;Menzies School of Health Research-National Institute of Health Research and Development Research Program, and District Ministry of Health, Timika, Papua, Indonesia;National Institute of Health Research and Development, Jakarta, Indonesia

关键词: Malaria;    Nitric oxide;    Malarial parasites;    Blood plasma;    Death rates;    Hemoglobin;    Creatinine;    Bilirubin;   

DOI  :  10.1371/journal.ppat.1000868

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 µM; 95% CI 0.74–0.96) compared to those with MSM (0.54 µM; 95%CI 0.5–0.56) and HCs (0.64 µM; 95%CI 0.58–0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0–181; p = 0.01). ADMA was independently associated with decreased exhaled NO (rs = −0.31) and endothelial function (rs = −0.32) in all malaria patients, and with reduced exhaled NO (rs = −0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria.

【 授权许可】

CC BY