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Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome

Yeo, Tsin W., Lampah, Daniel A., Tjitra, Emiliana, Gitawati, Retno, Darcy, Christabelle J., Jones, Catherine E., Kenangalem, Enny, McNeil, Yvette R., Granger, Donald L., Lopansri, Bert K., Weinberg, J. Brice, Price, Ric N., Duffull, Stephen B., Celermajer, David S. and Anstey, Nicholas M. (2010). Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome. PLoS Pathogens,6(4):e1000868.

Document type: Journal Article
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IRMA ID 81704288xPUB214
NHMRC Grant No. 605807
Title Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome
Author Yeo, Tsin W.
Lampah, Daniel A.
Tjitra, Emiliana
Gitawati, Retno
Darcy, Christabelle J.
Jones, Catherine E.
Kenangalem, Enny
McNeil, Yvette R.
Granger, Donald L.
Lopansri, Bert K.
Weinberg, J. Brice
Price, Ric N.
Duffull, Stephen B.
Celermajer, David S.
Anstey, Nicholas M.
Journal Name PLoS Pathogens
Publication Date 2010
Volume Number 6
Issue Number 4
ISSN 1553-7366   (check CDU catalogue  open catalogue search in new window)
Start Page e1000868
Total Pages 8
Editor Kazura, James W.
Place of Publication United States
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DEST)
Abstract 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.
Keywords Asymmetrical dimethylarginine (ADMA)
nitric oxide synthase (NOS)
Severe Falciparum Malaria
DOI http://dx.doi.org/10.1371/journal.ppat.1000868   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)


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