Present and Future Treatment Strategies for Pulmonary Arterial Hypertension

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a rare progressive disorder historically associated with mortality in <3 years post-diagnosis. The etiology of PAH is complex, multifactorial, and likely involves the interplay between genetic and environmental factors. These are reviewed with emphasis on the nitric oxide pathway. Use of treatment modalities including vasodilator therapy have resulted in improved symptoms, hemodynamics, and survival in these patients. Vasodilators, including the calcium channel antagonists, prostanoids, and endothelin receptor antagonists, have been used to counteract potential imbalances in vasoactive mediators in PAH patients; all have produced improved long-term symptomatology and hemodynamics. Only the prostanoid epoprostenol has improved survival in IPAH patients. Although these medications have worked well in many patients with PAH, each of them has limitations. The phosphodiesterase-5 (PDE-5) inhibitors are a relatively new form of treatment for PAH. They are designed to potentiate the effects of cyclic guanosine monophosphate, thereby mimicking endogenous nitric oxide within the vasculature. PDE-5 inhibitors are selective pulmonary vasodilators effective in animal models of pulmonary hypertension. The published clinical studies evaluating their use have been small in size to date but appear to demonstrate benefit. The recently completed 12-week randomized placebo-controlled Sildenafil Use in Pulmonary Hypertension (SUPER-1) trial demonstrated improvement in 6-minute walk distance and hemodynamics in patients receiving sildenafil. These data suggest that the PDE-5 inhibitors are effective in treating PAH and that it is likely that their usage will increase over time. The purpose of this review is to present a current view of the pathogenesis and treatment of PAH, with an emphasis on the use of PDE-5 inhibitors in these patients.