11th May 2025

Pulmonary arterial hypertension pathophysiology

The pathophysiology of PAH remains unclear. Multiple genes have been recognised in the disease pathogenesis. Familial PAH is associated with mutations in BMPR2, and less commonly SMAD9 and ACVRL1; however, penetrance is low and so not all patients with a gene mutation will develop PH across a lifetime. Vascular pathology includes over-proliferation of endothelin-cell and smooth muscle cells within the pulmonary arteries, increased levels of vasoactive mediators and thrombosis. In IPAH levels of endothelin-1 levels are increased and nitric oxide (NO) levels are decreased. Endothelin-1 is a potent vasoconstrictor and pro-proliferative mediator, plasma levels may be used as a marker of severity of IPAH. NO is a potent vasodilator and inhibits smooth muscle proliferation and platelet aggregation. It should also be noted pro-coagulants are elevated within the vasculature of those affected by PAH. Together, these changes contribute to narrowing of the pulmonary vasculature, increasing pulmonary pressures, and ultimately causing right ventricular failure and death.