Unlooked-for Significance of Cardiac Versus Vascular Effects of Endothelin-1 in the Pathophysiology of Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and devastating condition that is characterized by pulmonary vascular remodeling resulting in increased pulmonary vascular resistance and raised pulmonary arterial pressure, eventually leading to right ventricular (RV) failure and premature death.1,2 PAH carries a poor prognosis. Even in the current treatment era, the average life expectancy of PAH patients after diagnosis is estimated at 5 to 7 years, with significant morbidity.3–5 Article, see p 347 The pathobiology of PAH remains incompletely understood. The process of pulmonary vascular remodeling involves pathological changes in the intima, media, and adventitial layers of the vessel wall, and each cell type, including endothelial, smooth muscle, and fibroblast, in the pulmonary vascular wall plays a specific role in the pathogenesis.6 Both vascular endothelial and smooth muscle cells exhibit an abnormal growth phenotype, which is characterized by excess cellular proliferation and apoptosis resistance.7 Disorganized endothelial cell proliferation leads to the formation of glomeruloid structure known as the plexiform lesions, which are common pathological features of the pulmonary vessels of PAH patients and are not found in the diseases of the systemic circulation.8,9 In addition, a characteristic feature of severe pulmonary hypertension is the formation of a layer of myofibroblasts and extracellular matrix between the endothelium and the internal elastic lamina, termed neointima.6 These abnormalities in resident vascular cells, in concert with vasoconstriction, thrombosis, and inflammation, …