Pulmonary Arterial Hypertension: Pathophysiology and Treatment

Abstract

Pulmonary arterial hypertension (PAH), the first category of pulmonary hypertension, is a chronic and progressive disorder characterised by angioproliferative vasculopathy in the pulmonary arterioles, leading to endothelial and smooth muscle proliferation and dysfunction, inflammation and thrombosis. These changes increase pulmonary vascular resistance and subsequent pulmonary arterial pressure, causing right ventricular failure which leads to eventual death if untreated. The management of PAH has advanced rapidly in recent years due to improved understanding of the condition's pathophysiology, specifically the nitric oxide, prostacyclin-thromboxane and endothelin-1 pathways. Five classes of drugs targeting these pathways are now available: phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogues, prostacyclin receptor agonists and endothelin receptor antagonists. These developments have led to substantial improvements in mortality rate in recent decades. Recently, long-term studies have demonstrated sustained progression-free survival and have created a new paradigm of initial combination therapy. Despite these targeted therapies, PAH is still associated with significant morbidity and mortality. As such, further research into broadening our understanding of PAH pathophysiology is underway with potential of increasing the repertoire of drugs available.

Keywords: endothelin receptor antagonists; endothelin-1; mortality; nitric oxide; phosphodiesterase-5 inhibitor; prostacyclin analogues; prostacyclin receptor agonists; prostacyclin-thromboxane; pulmonary arterial hypertension; soluble guanylate cyclase stimulators.

Figure 1

The key abnormal pathways targeted in the pharmacological treatment of pulmonary arterial hypertension and the mechanism of action for contemporary drugs. The dashed line from ET_B denotes action of endothelial ET_B activation via NO and PGI₂ production. Adapted from Prior et al. MJA 2016 [28].

Figure 2

The European Society of Cardiology and the European Respiratory Society (ESC/ERS) evidence-based treatment algorithm for pulmonary arterial hypertension patients. Adapted from ECS/ERS guidelines for the diagnosis and treatment of pulmonary hypertension [13].