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 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.
Highlights
Plasmodium falciparum causes,1 million deaths annually [1,2]
Severe falciparum malaria is associated with impaired microvascular perfusion, lung injury and decreased bioavailability of nitric oxide (NO), but the causes of these processes are not fully understood
The major novel findings of this study in malaria are that Asymmetrical dimethylarginine (ADMA) is an independent predictor of death in falciparum malaria, and is associated with decreased availability of nitric oxide in at least two organ systems affected by malaria parasites, the lining of blood vessels and the lungs
Summary
Plasmodium falciparum causes ,1 million deaths annually [1,2]. Despite rapid parasite clearance with the anti-parasitic drug artesunate, the mortality rate in severe malaria remains high [3,4]. Endothelial activation, parasite sequestration, impaired microvascular perfusion and dysregulated inflammatory responses are all thought to contribute to severe and fatal malaria [5,6,7,8,9]. Increased understanding of these pathogenic mechanisms may identify targets for adjunctive therapies to further improve outcomes. In adults with moderately severe malaria, L-arginine concentrations are at least as low as those seen with severe malaria, yet there is no impairment of vascular and pulmonary NO bioavailability as found in severe disease [6]. This suggests that factors other than substrate limitation contribute to impaired NO bioavailability in severe malaria
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