PhysiologyTier 1Medical Sciences concept

Idiopathic pulmonary arterial hypertension - pathophysiology (angioproliferative changes)

Core concept

Three interacting processes in the small pulmonary arteries (<500 micrometres)
- 1. Vasoconstriction - an imbalance of endothelial mediators
  - inc endothelin-1 (vasoconstrictor, mitogenic) and inc thromboxane
  - dec nitric oxide (dec eNOS, inc PDE5 degrading cGMP) and dec prostacyclin (dec prostacyclin synthase)
  - Also dec voltage-gated K+ channels (Kv1.5) -> depolarisation -> inc Ca influx
- 2. Angioproliferative remodelling - the dominant process, and the reason vasodilators alone fail
  - Intimal proliferation, medial hypertrophy, adventitial fibrosis
  - Plexiform lesions - disordered monoclonal-appearing endothelial proliferation; a "quasi-neoplastic" phenotype with apoptosis resistance and a Warburg-like metabolic shift
  - Loss of the small precapillary arterioles ("vascular pruning")
- 3. In situ thrombosis and inflammation (perivascular T cells, macrophages, mast cells; inc IL-6)
-> inc PVR -> RV pressure overload -> RV hypertrophy -> dilatation -> RV failure
- *Death in PAH is right ventricular failure, not hypoxaemia* - RV function determines prognosis, not mPAP

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