Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses

Pulmonary arterial hypertension (PAH) is a rare and severe clinical condition characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and premature death ( Figure 1 ).1 Its prevalence ranges from 15 to 50 patients per million population2,3 and it affects a relatively young patient population (average age of 50 years) when compared with the more common thoracic organ diseases such as coronary artery disease and chronic obstructive lung disease. PAH in adults includes at least nine clinical subgroups with virtually identical obstructive pathologic changes ( Figures 1 and 2 ) in the distal pulmonary arteries: idiopathic, heritable, drug- and toxin-induced, associated with, connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and chronic haemolytic anaemia.1 The exact processes that initiate the pathological changes seen in PAH are largely unknown. It is hypothesized that the interaction between genetic predisposition and environmental risk factors ( Figure 1 ) may be involved in the initial stages of the disease. However, even the exact role of the auto-antibodies in connective tissue diseases or the viral involvement in HIV infection is unclear. It appears that a specific injury on the vessel wall of distal pulmonary arteries may initiate, in predisposed individuals, a pathobiological cascade of events which leads to a common final pathological obstructive condition ( Figures 1B and C and 2 ). In the initial phases of these processes, the disease is asymptomatic, and detectable pathophysiological changes and symptoms limiting exercise capacity appear usually when the pathological lesions are fully developed ( Figure 1 ). Pathological lesions in PAH patients affect the distal pulmonary arteries (<500 µm), in particular. The lesions are characterized by medial hypertrophy, intimal proliferative and fibrotic changes (concentric and/or eccentric), adventitial thickening with moderate peri-vascular inflammatory infiltrates ( Figures 1 B and C and 2 ), complex …