Therapies for pulmonary arterial hypertension: where are we today, where do we go tomorrow?

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by remodelling of small pulmonary arteries leading to an increased pulmonary vascular resistance, right ventricular failure and death. Available treatments try to re-establish the equilibrium on three signalling pathways: the prostacyclin, the endothelin (ET)-1 and the nitric oxide. Prostanoids, such as epoprostenol or treprostinil have a vasodilator, antiproliferative and immunomodulatory effect and, despite the administration inconveniences, represent established therapies for severe cases of PAH. Recently oral prostacyclin receptor agonists have shown encouraging results. Many clinical studies targeting the vasoconstrictor ET-1 pathway with receptor antagonists like bosentan and ambrisentan have shown strong results, even more optimism coming from macitentan, the newest drug. Sildenafil and tadalafil, two phosphodiesterase type-5 inhibitors, have shown improved exercise capacity by increasing the nitric oxide level. Riociguat, acting on the same nitric oxide pathway, as a guanylatecyclase activator, has shown promising results in clinical trials and will be available soon. Long-awaited results for tyrosin-kinase inhibitor, imatinib, as an antiproliferative therapy in PAH have been disappointing, due to severe adverse events. In conclusion, although it remains a disease with severe prognosis, the past 20 years have represented a huge progress in terms of treatments for PAH with interesting opportunities for the future.

Figure 1.

Schematic representation of the endothelin system in vascular tissue. ET-1: endothelin type 1; ET_A: endothelin receptor isoform A; ET_B: endothelin receptor isoform B.

Figure 2.

Schematic representation of the guanosine monophosphate (GMP) and nitric oxide pathways. sGC: soluble guanylate cyclase; cGMP: cyclic GMP; PDE-5: phosphodiesterase type 5.