Pathophysiology of PAH

PAH is a complex, multifactorial condition involving numerous biochemical pathways and different cell types.1,2
Pathological changes in pulmonary arterioles
Endothelial dysfunction, an abnormality of the inner lining of blood vessels, is believed to occur early in disease pathogenesis.2 This leads to endothelial and smooth muscle cell proliferation followed by structural changes, or remodelling, of the pulmonary vascular bed.2 Vascular remodelling results in an increase in pulmonary vascular resistance (PVR), which is related to several progressive changes in the pulmonary arterioles, including:3
  • Vasoconstriction
  • Obstructive remodelling of the pulmonary blood vessel walls
  • Inflammation
  • In situ thrombosis

Increased pulmonary artery pressure puts strain on the heart

The increase in pulmonary arterial pressure (afterload) makes the right heart work harder, resulting in right ventricular hypertrophy, and leading to the typical symptoms of PAH.3 Initially, the heart is able to compensate for the increased pressure;2 however, as the disease progresses, the right ventricle (RV) becomes dilated, eventually resulting in a number of potential consequences:

  • Right ventricular hypertrophy, which can, on occasion, reduce blood flow and lead to ischaemia of the right ventricle1,2
  • Right heart failure, including all typical signs of systemic venous hypertension, whilst also occurring during a low cardiac output state. Syncope is a severe manifestation of right heart failure3
  • Dyspnoea at progressively lower levels of exercise, eventually presenting at rest and often with frank syncope2,3
  • Disability and death, occurring sooner if effective treatment plans are not initiated3
References
  1. Galiè N, et al. Eur Heart J 2016; 37:67–119.
  2. McLaughlin VV, et al. Circulation 2009; 119:2250–94.
  3. Montani D, et al. Orphanet Rare J Dis 2013; 8:97.
Footnotes
PAH=pulmonary arterial hypertension; PVR=pulmonary vascular resistance; RV=right ventricle.

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World Health Organization functional class (WHO-FC) for patients with PH3,5

This system grades PH severity according to the patient’s functional status, by linking symptoms with activity limitations. WHO-FC remains a powerful predictor of outcomes in patients with PAH.

WHO - FC Description
I
Patients with PH in whom there is no limitation of usual physical activity; ordinary physical activity does not cause increased dyspnoea, fatigue, chest pain, or presyncope.
II
Patients with PH who have mild limitation of physical activity. There is no discomfort at rest, but normal physical activity causes increased dyspnoea, fatigue, chest pain, or presyncope.
III
Patients with PH who have a marked limitation of physical activity. There is no discomfort at rest, but less than ordinary activity causes increased dyspnoea, fatigue, chest pain, or presyncope.
IV
Patients with PH who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Dyspnoea and/or fatigue may be present at rest, and symptoms are increased by almost any physical activity.
Adapted from McGoon M, et al. 2004.5
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