Emerging therapies and future directions in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a complex obliterative vascular disease. It remains deadly despite an explosion of basic research over the past 20 years that identified myriads of potential therapeutic targets, few of which have been translated into early phase trials. Despite the agreement over the past decade that its pathogenesis is based on an antiapoptotic and proproliferative environment within the pulmonary arterial wall, and not vasoconstriction, all the currently approved therapies were developed and tested in PAH because of their vasodilatory properties. Numerous potential therapies identified in preclinical research fail to be translated in clinical research. Here we discuss 7 concepts that might help address the "translational gap" in PAH. These include: a need to approach the "pulmonary arteries-right ventricle unit" comprehensively and develop right ventricle-specific therapies for heart failure; the metabolic and inflammatory theories of PAH that put many "diverse" abnormalities under 1 mechanistic roof, allowing the identification of more effective targets and biomarkers; the realization that PAH might be a systemic disease with primary abnormalities in extrapulmonary tissues including the right ventricle, skeletal muscle, immune system, and perhaps bone marrow, shifting our focus toward more systemic targets; the realization that many heritable components of PAH have an epigenetic basis that can be therapeutically targeted; and novel approaches like cell therapy or devices that can potentially improve access to transplanted organs. This progress marks the entrance into a new and exciting stage in our understanding and ability to fight this mysterious deadly disease.