Arginine Therapy Shows Promise for Treatment of Sickle Cell Disease Clinical Subphenotypes of Hemolysis and Arginine Deficiency

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I read with interest “Arginase Inhibition Reverses Endothelial Dysfunction, Pulmonary Hypertension, and Vascular Stiffness in Transgenic Sickle Cell Mice.”1 Alterations in the arginine metabolome have been extensively studied in sickle cell disease (SCD) in humans as well as in SCD-transgenic mice.2 Although Steppan et al1 suggest that supplementing L-arginine does not improve nitric oxide (NO) bioavailability, a more comprehensive review of the literature suggests benefits resulting from L-arginine therapy that are likely NO related.2 Pulmonary hypertension (PH), leg ulcers, and vaso-occlusive pain are SCD-clinical subphenotypes of arginine deficiency that are reversed with arginine supplementation.2 Anecdotal cases of immediate improvement in SCD-associated priapism in the emergency department setting have also been reported.2 Low arginine bioavailability is also associated with poor survival.3 In SCD-transgenic mouse models, arginine supplementation inhibits red cell Gardos channels, reduces red cell density, improves perfusion, and reduces inflammation, lung injury, microvascular vaso-occlusion, and mortality. Arginine supplementation also increases erythrocyte glutathione levels in both mouse and human trials.4
When arginine is given to SCD patients at steady state, a paradoxical decrease in NO metabolites (NOx) occurs that is not overcome by higher doses, indicating that arginine is metabolized differently in SCD compared with control subjects. However, when arginine is given during acute pain, a complication associated with an abrupt drop in arginine bioavailability, a robust dose-dependent increase in NOx is observed. This suggests that arginine is also metabolized differently in SCD at steady state compared with times of acute illness.2 Similar observations were made with respect to arginine pharmacokinetics in moderate compared with severe malaria, suggesting that a greater consumption of arginine occurs when the disease state is more severe.
Little et al4 provided arginine supplementation to SCD patients with a mean tricuspid regurgitate jet velocity (TRV) of 2.57 m/s on Doppler echocardiography, which is precariously close to the normal value of TRV < 2.5m/s. Based on studies comparing right heart cardiac catheterization with echocardiography, few, if any, of those patients likely had true PH. However, when arginine therapy is given to patients with clinical symptoms of PH and a mean TRV = 3.47 m/s, a >15% reduction in estimated pulmonary artery pressures occurred after only 5 days of oral therapy (Figure).5 Our previous work has demonstrated that a significant decrease in arginine bioavailability occurs in SCD patients with a TRV ≥ 2.9 m/s, a scenario when PH is more likely and mortality risk is significantly increased.3
For arginine-deficiency syndromes like SCD, improved arginine bioavailability through arginine supplementation may restore important physiologic processes; however, metabolism by excess arginase may limit its potential to maximally impact NO synthesis. Steppan et al1 report promising results because arginase inhibition improved NO bioavailability and attenuated systemic and pulmonary vascular endothelial dysfunction in SCD-transgenic mice. Therefore, arginase represents a potential therapeutic target in the treatment of SCD-related cardiovascular dysfunction in addition to arginine therapy. Future studies evaluating a combination of arginine together with an arginase inhibitor are also worth investigation.
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