Pathways in pulmonary arterial hypertension: the future is here

Abstract

It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways.However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options.This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.

Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension

“…Three major mechanistic pathways, the endothelin, prostacyclin and nitric oxide pathways, are known to be involved in the pathogenesis of PAH and therapies that target these pathways are available [1][2][3]. Combining agents that target more than one pathway is an attractive option for the treatment of PAH and may offer additional long-term benefits compared with monotherapy [4,5].…”

Functional Prostacyclin Synthase Promoter Polymorphisms. Impact in Pulmonary Arterial Hypertension

“…Presentation occurs most commonly in the third and fourth decades in women and men, respectively, although with treatment the 1-, 3-, and 5-year survival rates are 92, 75, and 66% (4). Currently, there is no cure for this disease, but targeted therapies that focus on altering vascular tone using prostacyclin analogs, dual endothelin antagonists, or phosphodiesterase-5 inhibitors have improved patient survival (1,2,4).…”

“…Pulmonary arterial hypertension (PAH) is a rare disease, with annual incidence of 2-15 per million, with a female preponderance (>2:1), characterized by elevations in mean pulmonary artery pressure (mPAP) of more than 25 mm Hg at rest, a pulmonary capillary wedge pressure of less than 15 mm Hg, vascular remodeling, and hyperproliferation of pulmonary artery endothelial and smooth muscle cells (1,2). The incidence of new PAH cases is estimated to be approximately 1,000 per year in the United States (3).…”

Selexipag for the treatment of pulmonary arterial hypertension

“…Activation of the IP receptor leads to vasodilation in the pulmonary circulation and inhibition of the proliferation of vascular smooth muscle cells. [8] Selexipag is structurally distinct from the other drugs targeting the PGI 2 pathway as it is a non-prostanoid IP receptor agonist rather than PGI 2 or a PGI 2 analogue. [9] Selexipag: clinical efficacy Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where participants were randomized in a 3:1 ratio to selexipag or placebo.…”