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WHAT IS PH?

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WHAT IS PH? : PATHOPHYSIOLOGY

DEFINITION AND CLASSIFICATION / PATHOPHYSIOLOGY / EPIDEMIOLOGY / CLINICAL PRESENTATION / MANAGEMENT / NATURAL HISTORY


Pulmonary Arterial Hypertension (PAH) is characterised by a vasculopathy which primarily affects the distal pulmonary arteries. A combination of vasoconstriction, cellular proliferation in all layers of the vessel wall and perivascular adventitial thickening due to inflammatory infiltrates and increased extracellular matrix deposition all contribute to raised pulmonary vascular resistance. In addition, obstructive remodelling of the vessel due to microthrombosis-in-situ and plexiform lesion formation further elevates the PVR.

 

Multi-hit Hypothesis

 

Although the exact processes behind the initiation of PAH are, as yet, unknown, the aetiology is multifactorial and a multi-hit hypothesis in the formation of the disease exists. These potential hits include genetic predisposition, a co-existing disease (especially those in the APAH category of the Dana Point classification) or environmental exposure, such as appetite suppressants and amphetamines.

 

Genetic Factors

 

  • BMPR2 - The bone morphogenetic protein type 2 receptor (BMPR2) is an important part of the TGF-beta signalling family. Loss-of-function mutations in the gene that codes for BMPR2 are found in at least 70% of heritable PAH and between 11-40% of apparently sporadic idiopathic PAH. Inheritance of this phenotype occurs in an autosomal dominant pattern with a relatively low penetrance of approximately 20%.
  • ALK-1 (ACVRL1) and Endoglin - These receptors are also part of the TGF-beta family. Mutations in the genes for these receptors also predispose to PAH and are most commonly associated with Hereditary Haemorrhagic Telangiectasia (HHT/Osler-Weber-Rendu syndrome).

 

Molecular Mechanisms

 

One of the key contributors towards elevated pulmonary vascular resistance is the vasoconstriction caused by an imbalance in vasoactive mediators. An overexpression of vasoconstrictor/pro-proliferative agents and impaired production of vasodilator/apoptotic substances leads to this imbalance. The major pathways are: 

 

  • Endothelin-1 (ET-1) - a potent vasoconstrictor and pro-proliferative agent produced from endothelial cells and elevated in patients with PAH. It acts via the ETA and ETB receptors, both of which are found in smooth muscle cells where ET-1 mediates vasoconstriction and proliferation. ETB receptors are also found on endothelial cells, where they control release of nitric oxide, prostacyclin and thromboxane.
  • Nitric Oxide (NO) - A potent vasodilator and anti-proliferative agent. NO is produced by the action of NO synthase on arginine in endothelial cells. It stimulates cGMP production, activating K+ channels and inhibiting Ca2+ channels, causing vasodilation. NO levels are decreased in PAH.
  • Prostacyclin (PGI2) - Produced by endothelial cells from arachadonic acid using prostacyclin synthase, it acts as a vasodilator and controls proliferation of vascular smooth muscle cells. It is deficient in PAH.


Other mechanisms which may also play a role include serotonin (5-HT), inflammatory cytokines, deranged coagulation, epigenetic regulation (e.g. by microRNAs) and endothelial cell dysfunction (e.g. shear stress).

 

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