Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria

Tsin W Yeo, Daniel A Lampah, Retno Gitawati, Emiliana Tjitra, Enny Kenangalem, Yvette R McNeil, Christabelle J Darcy, Donald L Granger, J Brice Weinberg, Bert K Lopansri, Ric N Price, Stephen B Duffull, David S Celermajer, Nicholas M Anstey, Tsin W Yeo, Daniel A Lampah, Retno Gitawati, Emiliana Tjitra, Enny Kenangalem, Yvette R McNeil, Christabelle J Darcy, Donald L Granger, J Brice Weinberg, Bert K Lopansri, Ric N Price, Stephen B Duffull, David S Celermajer, Nicholas M Anstey

Abstract

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia-peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33-1.47) than in MSM (1.82; 95% CI = 1.7-2.02) and controls (1.93; 95% CI = 1.8-2.06; P < 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6-34; P = 0.006) and exhaled NO by 55% (95% CI = 32-73; P < 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.

Figures

Figure 1.
Figure 1.
Study profile of patients recruited in stages 1 and 2 of the study. Stage 1 was an observational study to compare endothelial function among individuals with SM, MSM, and HC. Stage 2 was intervention study to measure the effect of l-arginine or saline infusion on RH-PAT index and exhaled NO in MSM.
Figure 2.
Figure 2.
RH-PAT index, plasma l-arginine concentrations, and exhaled NO in each study group at enrollment. (A) Comparison of RH-PAT index at enrollment among disease categories (P < 0.0001 by ANOVA). Dots and error bars indicate means and 95% CIs. Horizontal line indicates an RH-PAT index of 1.67; values below this represent impaired endothelial function (reference 23). (B) Comparison of plasma l-arginine concentrations among disease categories (P < 0.0001 by ANOVA). Dots and bars indicate means and 95% CIs. (C) Comparison of exhaled NO concentrations at enrollment among disease categories (P = 0.049 by the Kruskal-Wallis test). Central line and box indicate the median and interquartile range. Whiskers indicate range.
Figure 3.
Figure 3.
Change in RH-PAT index and exhaled NO after l-arginine infusion. (A) Change in RH-PAT index in MSM after infusion of 100 ml saline (3%; 95% CI = from −1 to 12) or l-arginine (19%; 95% CI = 8–33). p-values refer to paired comparisons before and after infusion. Dots and bars indicate means and 95% CIs. (B) Dose-related change in RH-PAT index after intravenous l-arginine infusion in the a priori–defined subset of patients with MSM who had baseline endothelial dysfunction (RH-PAT index <1.67; n = 14; P = 0.03). Lines show RH-PAT index before and after intravenous l-arginine at doses of 3, 6, and 12 g. In the 16 patients without baseline impairment of endothelial function (RH-PAT index >1.67), there was no significant change in RH-PAT after l-arginine infusion. (C) Change in exhaled NO concentration in MSM after infusion of 100 ml saline (18%; 95% CI = from −2 to 28) or l-arginine (55%; 95% CI = 39–71). p-values refer to paired comparisons before and after infusion. Dots and bars indicate means and 95% CIs.

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