New Therapeutic Approaches in Pulmonary Arterial Hypertension

Article, see p 2371 Pulmonary arterial hypertension (PAH) is a rare disease that nonetheless casts a large shadow because it most commonly afflicts young women in its idiopathic form and remains a disabling complication of scleroderma and congenital heart disease.1 Treatment advances in the last 20 years have been striking, but high-risk patients still succumb at a rate of 15% annually.2 Moreover, our most effective therapy, the continuous infusion of parenteral prostacyclin, is cumbersome and expensive. Although oral treatments are available, a desperate need remains for convenient therapies that further improve survival and quality of life.3Observations in the last decade have linked the unbridled vascular cell proliferation evident on lung histology with a shift in cell metabolism from mitochondrial oxidative phosphorylation to anaerobic glycolysis reminiscent of cancer (the Warburg effect).4 Moreover, as with cancer, this glycolytic switch accompanies broader changes in cell metabolism that provide the building blocks for rapid cellular proliferation, including glutamine.5 In this issue of Circulation , Dumas et al6 propose that the accumulation of glutamine ultimately stimulates N -methyl-d-aspartate (NMDA) receptors on pulmonary vascular endothelial and smooth muscle cells and so contributes to PAH pathogenesis.NMDA receptor activation is a key mediator of a host of central nervous system processes, from long-term potentiation to traumatic brain injury, and NMDA receptor blockers have been studied as a strategy to limit the magnitude of ischemic stroke. The authors note that NMDA receptor activation has previously been reported to facilitate cancer cell proliferation, but their compelling observations in the diseased pulmonary circulation are highly novel. Using mass spectroscopy, they demonstrate that the vascular PAH lesions identified within end-stage human lung tissue accumulate glutamine and cleave this to the neurotransmitter glutamate. This accumulation of glutamate occurs most clearly in the smaller …