Pulmonary hypertension begets pulmonary hypertension: mutually reinforcing roles for haemodynamics, inflammation, and cancer-like phenotypes

Abstract

This editorial refers to ‘Haemodynamic unloading reverses occlusive vascular lesions in severe pulmonary hypertension’ by K. Abe et al ., pp. 16–25. Pulmonary arterial hypertension (PAH) is a devastating disease of the pulmonary vasculature in which vasoconstriction, inflammation, and a cancer-like phenotype, defined as excessive cell proliferation, impaired apoptosis, and mitochondrial metabolic abnormalities, contribute to vascular obstruction. The resulting increase in right ventricular (RV) afterload ultimately leads to death from RV failure. The histology of PAH includes a variable mixture of lesions in small pulmonary arteries (PAs), including medial hypertrophy, intimal hyperplasia, adventitial fibrosis, and plexiform lesions, as well as fibrosis and reduced compliance of large PAs. PAH is a heterogeneous syndrome; however, several phenotypes are recognized that offer mechanistic and therapeutic insights. PAH has a haemodynamic phenotype [increased vasoconstriction and mean pulmonary artery pressure (mPAP), due in part to endothelial dysfunction and changes in ion channel function and calcium homeostasis in pulmonary artery smooth muscle cells, PASMC], a cancer-like phenotype (increased PASMC proliferation and apoptosis resistance associated with a glycolytic metabolic shift, epigenetic silencing of key redox regulatory genes such as SOD2,1 and an increased mitochondrial fission/fusion ratio2), and an inflammatory phenotype [increased perivascular accumulation of proinflammatory macrophages and changes in the population of immunoregulatory T-cells (T-Reg)3 and natural killer cells].4 Current PAH therapies (prostanoids, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase activators) are vasodilators and primarily address PAH's haemodynamic phenotype. They improve symptoms and reduce hospitalization but, on average, only decrease mPAP ∼5 mmHg.5 Their limited haemodynamic efficacy and lack of effects on PAH's inflammatory and cancer-like phenotypes suggest that they are unlikely to reverse the histological lesions of …