The etiology and pathogenesis of pulmonary arterial hypertension

Abstract

The term pulmonary arterial hypertension (PAH) refers to idiopathic and familiar pulmonary hypertension, furthermore to PAH in collagen vascular disease, PAH in congenital left-to-right shunt defects, PAH in portal hypertension, PAH in HIV infection and after anorectic drugs or toxic agent abuse. The body of our knowledge regarding the pathogenesis of PAH has expanded dramatically, as reflected in novel therapeutic modalities. PAH is a condition associated with proliferation (of smooth muscle and endothelial cells) and vascular occlusion due both to thrombosis and proliferative changes. Remodeling may be triggered by mechanical (vascular wall stress) or humoral (inflammation mediators) stimuli. The pulmonary arterial endothelium responds to these stimuli, resulting in endothelial dysfunction followed by excess production of vasoconstrictors and growth factors. e. g., endothelin-1, thromboxane, also contributing to thrombosis formation in tiny pulmonary arterioles, and platelet growth factor. The above agents result not only in vasoconstriction, they presumably stimulate vascular remodeling. PAH is associated with an imbalance between prostacyclin and thromboxane in favor of thromboxane. As regards vasoconstrictors, mention should be of endothelin-1, a potent vasoconstrictor also stimulating pulmonary arterial smooth muscle proliferation. The plasma levels of endothelin-1 are increased in PAH. Endothelin levels correlate with PAH severity and even with PAH prognosis. A reduction in prostacyclin levels and excess endothelin production in PAH are actually the reasons why prostanoids and endothelin receptor inhibitors have become the mainstay of PAH therapy.