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Figure 1: Targets for current or emerging therapies in PAH. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cardiology (O’Callaghan et al. 2011;8:526–38), copyright (2011). O’Callaghan et al. Nat Rev Cardiol 2011;8:526–38.

clue to the diagnosis of the type of PAH. Physical signs of PH include a parasternal heave, an accentuated second heart sound and a palpable pulsation of the pulmonary artery in the second left intercostal space. A pulmonic flow murmur may be heard. If present, these relatively specific signs help to point the diagnostic evaluation in the right direction, but the signs are subtle and are easy to miss unless one is minded to finding them. Signs of right heart failure such as pedal oedema, jugular venous distension and tender hepatomegaly may be present in more advanced disease. Exercise desaturation in a patient without significant lung disease is highly suggestive of pulmonary vascular disease. Decreased breath sounds, wheezes or crackles suggest lung disease that may be the cause of PH; crackles may also be heard in left heart failure (pulmonary congestion). Murmurs suggestive of significant valvular disease also suggest a left-heart aetiology.


It is beyond the scope of this chapter to mention all causes of associated PAH and their suggestive signs, therefore only a few illustrative examples are mentioned. Sclerodactyly and telangiectasiae suggest scleroderma, a relatively common cause of associated PAH. Signs of cirrhosis may suggest porto-PH.

Pathogenesis Early initiatives to treat PAH drew an analogy between systemic hypertension and PAH and many attempts were made to treat PAH with vasodilators. These treatments failed until it was realised that while vasoconstriction is a feature of PAH, its contribution to the pathogenesis is relatively minor. PAH is the result of a pulmonary arteriopathy, which probably starts with pulmonary endothelial dysfunction. Remodelling of the pulmonary arteries occurs, involving medial hypertrophy, intimal proliferation (leading to formation of plexiform lesions, one of the pathological hallmarks of PAH) and in situ thrombosis. This remodelling leads to narrowing and even complete obstruction of the pulmonary arterioles, increasing the pulmonary vascular resistance. The cardiac right ventricle strains to overcome this increased resistance, becomes hypertrophic and/or dilated and eventually fails.

Signalling pathways

Three signalling pathways implicated in the pathogenesis of PAH have been successfully targeted by drug therapy (see Figure 1) – the soluble mediators involved are nitric oxide (NO), prostacyclin and endothelin. Intriguingly, mediators long known to be

pulmonary vasodilators, such as prostacyclin and NO, were also found to be inhibitors of pulmonary artery endothelial and medial smooth muscle cell proliferation and of thrombosis. Conversely pulmonary vasoconstrictors, such as endothelin and serotonin, are also mitogens of vascular smooth muscle and endothelial cells, and enhance thrombosis. Thus in the pulmonary vascular world, mediators are generally ‘all good’ or ‘all bad’.

PAH may be familial, typically with dominant heritance and partial penetrance. In 2000–2001 it was found that 75% of familial cases of PAH, and up to 25% of sporadic cases, harbour a mutation of the gene encoding BMP-R-2. BMP is a cytokine of the transforming growth factor (TGF) superfamily. Another form of familial PAH is associated with hereditary haemorrhagic telangiectasia, a disease caused by mutations of endoglin or Alk-1, also proteins of the TGF superfamily, strongly implicating this family of cytokines in the pathogenesis of PAH. Despite these insights, the BMP pathway has not been successfully targeted with drugs so far.

The following articles will discuss in greater detail the diagnostic evaluation of PH, available therapies and future directions in treatment. ●

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