Novel investigational therapies for treating pulmonary arterial hypertension.

INTRODUCTION: Despite the development of new therapies, pulmonary arterial hypertension (PAH) has a median survival of 6 - 7 years. This is likely because the currently approved therapies affect predominantly pulmonary vasoconstriction. The past two decades have witnessed greater insights into the pathogenesis of PAH, from the role of inflammation to molecular signaling and epigenetics. Multiple pharmacological agents targeting these newly identified pathways are currently being investigated in preclinical and early clinical studies. AREAS COVERED: Herein, the authors review the modalities targeting recently identified molecular targets in PAH. These include: prostaglandin receptor agonists, agents that alter the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways, vasoactive peptides, receptor tyrosine kinase inhibitors, Rho-kinase inhibitors, serotonin pathway inhibitors, anti-inflammatory agents, antioxidants, agents that alter nitric oxide signaling, various cardiac medications, mitochondrial metabolism modifying agents, epigenetic agents and cell-based therapies. The authors also address the gaps in the knowledge and explain why certain agents may or may not be promising PAH pharmacotherapeutics. EXPERT OPINION: Newer agents target multiple pathways including vasoconstriction, cellular proliferation and inflammatory response. And while only a few of the current investigational drugs will likely be further developed, the authors expect that the next two decades will bring some major breakthroughs in PAH management.