Charles Darwin University Increased Asymmetric Dimethylarginine in Severe Falciparum Malaria Association with Impaired Nitric Oxide Bioavailability and Fatal Outcome Yeo,

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 mM; 95% CI 0.74–0.96) compared to those with MSM (0.54 mM; 95%CI 0.5–0.56) and HCs (0.64 mM; 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 = 20.31) and endothelial function (rs = 20.32) in all malaria patients, and with reduced exhaled NO (rs = 20.72) 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. Citation: Yeo TW, Lampah DA, Tjitra E, Gitawati R, Darcy CJ, et al. (2010) Increased Asymmetric Dimethylarginine in Severe Falciparum Malaria: Association with Impaired Nitric Oxide Bioavailability and Fatal Outcome. PLoS Pathog 6(4): e1000868. doi:10.1371/journal.ppat. 1000868 Editor: James W. Kazura, Case Western Reserve University, United States of America Received November 30, 2009; Accepted March 22, 2010; Published April 22, 2010 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: The study was funded National Health and Medical Research Council of Australia (NHMRC ICRG ID 283321, Program Grants 290208 and 496600, and Practitioner Fellowship to Nicholas M. Anstey), the Wellcome Trust (ICRG GR071614MA and Career Development Award to Ric Price [074637]), VA Research Service, the National Institutes of Health (AI55982 and AI041764) and the Tudor Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: tsin.yeo@menzies.edu. au