WHAT IS PH? : PATHOPHYSIOLOGY

PAH arises because of a predisposing state and one or more inciting stimuli ? ?multiple hit hypothesis?. The hits may consist of a genetic substrate, a coexisting disease or an environmental exposure. The increased vascular resistance arises due to a combination of vasoconstriction, proliferation of cells in all layers of the vessel wall and thrombosis-in-situ.

Genetic Substrate

Genotypes associated with the occurrence of PAH have been identified.

• BMPR2 gene. This gene product is a member of the TGF? family. A defect in one allele of the gene is seen in 75% of familial cases of PAH and 25% of sporadic cases. Inheritance of the phenotype occurs in an autosomal dominant pattern with penetrance of 15-20%. The inherited condition shows anticipation, presenting earlier in successive generations.
• ALK1 gene. This is also a member of the TGF? family. Some patients with PAH and hereditary haemorrhagic telangiectasia have a mutation in this gene.

Molecular Mechanisms

The molecular mechanisms responsible for pulmonary arterial hypertension result in vasoconstriction and cellular proliferation (or reduced apoptosis). The major pathways are thought to be as follows:

• Prostacyclin (PGI2) is a vasodilator and antiproliferative molecule which is produced by the action of prostacyclin synthase on arachidonic acid in endothelial cells. It has its effect by acting on the cAMP pathway in vascular smooth muscle cells. It is deficient in PAH and levels of thromboxane (a vasoconstrictor) are increased.
• Endothelin (ET-1) is a vasoconstrictor and promoter of cell proliferation and is produced from big endothelin in endothelial cells. It is elevated in patients with PAH. It acts via two receptors:
  • ETA: present on vascular smooth muscle cells mediating proliferation and vasoconstriction
  • ETB: present on vascular smooth muscle cells and pulmonary artery endothelial cells. The muscle receptors mediate vasoconstriction whilst the endothelial receptors cause release of both vasodilators (PGI2, NO) and vasoconstrictors (thromboxane) and clear ET-1.
• Nitric oxide (NO) is a vasodilator and antiproliferative molecule produced in endothelial cells from arginine by NO synthase. It acts by stimulating the production of cGMP in vascular smooth muscle cells and thereby cGMP kinase activation, opening of K+ channels, K+ ion efflux, membrane depolarisation, Ca2+ channel inhibition, decreased Ca2+ entry and hence vasodilation. Patients with PAH have decreased NO synthase expression.

Other mechanisms which may also play a role include serotonin (5-HT), voltage dependent K+ channels (Kv), inflammation, deranged coagulation and endothelial cell dysfunction (e.g. shear stress).