11th May 2025

Aetiology

The exact cause of pulmonary hypertension (PH) is unknown, although most cases are associated with an underlying condition and so are secondary in aetiology. The World Health Organization (WHO) has classified PH into five categories, with group one being further subclassified as described below. 

• Group 1: Pulmonary arterial hypertension (PAH) 
  • Idiopathic (IPAH) – commonly presents in females ages 20-50 years 
  • Heritable 
  • Related to an underlying condition:
    • Connective tissues disease – structural lung damage and chronic hypoxaemia: systemic sclerosis (most commonly anti-centromere autoantibodies), rheumatoid arthritis 
    • Congenital heart disease – left-to-right shunt causing Eisenmenger’s syndrome 
    • Portal hypertension
    • HIV infection
    • Drug or toxin induced (cocaine/amphetamines, appetite suppressants such as aminorex)
  • PH of the new-born
• Group 2: PH related to left heart disease – resulting from raised left atrial pressures
  • Left heart systolic/diastolic dysfunction 
  • Valvular disease 
• Group 3: PH related to lung disease or chronic hypoxia – resulting from damage lung structure and hypoxic vasoconstriction 
  • Interstitial pulmonary fibrosis (IPF)
  • Chronic Obstructive Pulmonary Disease (COPD)
  • Obstructive Sleep Apnoea 
  • Chronic high-altitude exposure
• Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH) – resulting from chronic arterial obstruction
  • Unresolved thrombus from pulmonary embolism 
• Group 5: Unclear or multifactorial 
  • Sickle cell disease
  • Chronic haemolytic anaemia
  • Sarcoidosis 
  • Vasculitis

Pulmonary arterial hypertension pathophysiology

The pathophysiology of PAH remains unclear. Multiple genes have been recognised in the disease pathogenesis. Familial PAH is associated with mutations in BMPR2, and less commonly SMAD9 and ACVRL1; however, penetrance is low and so not all patients with a gene mutation will develop PH across a lifetime. Vascular pathology includes over-proliferation of endothelin-cell and smooth muscle cells within the pulmonary arteries, increased levels of vasoactive mediators and thrombosis. In IPAH levels of endothelin-1 levels are increased and nitric oxide (NO) levels are decreased. Endothelin-1 is a potent vasoconstrictor and pro-proliferative mediator, plasma levels may be used as a marker of severity of IPAH. NO is a potent vasodilator and inhibits smooth muscle proliferation and platelet aggregation. It should also be noted pro-coagulants are elevated within the vasculature of those affected by PAH. Together, these changes contribute to narrowing of the pulmonary vasculature, increasing pulmonary pressures, and ultimately causing right ventricular failure and death.