17th January 2024

Background

Epidemiology

Pulmonary hypertension is defined as an increase in pulmonary artery pressure (PAP) to more than 25mmHg at rest when measured on right heart catheterisation studies. Comparatively, the average PAP in a healthy individual is around 14mmHg (1). Due to formal diagnosis relying on this invasive testing, we can assume that case numbers are largely underreported on a global scale. In the U.K., incidence is reported as 97 cases per million, with a slightly increased prevalence in females.

Pathophysiology

Pulmonary hypertension is a broad term which encompasses five distinct aetiological categories. The pathophysiology of all subcategories is defined by an increased pulmonary vascular resistance, resulting in progressively increased pulmonary artery pressures and eventually right ventricular failure and death. The disease course generally follows a progressive deterioration interspersed with acute episodes of decompensation.

The World Health Organisation (WHO) has classified pulmonary hypertension into five groups (2):

• Group 1 – Pulmonary Arterial Hypertension (PAH) – defined by sustained vascular remodelling of the pulmonary arteries. There are a range of causes, including:
  • Idiopathic
  • Inherited – account for approximately 10% of cases, most commonly associated with a mutation in the BMPR2 gene
  • Drugs and toxins, such as fenfluramine
  • Congenital heart disease associated with left-right shunting, e.g., ASD, VSD
  • Connective tissue diseases
  • Vasculitis
  • Human Immunodeficiency Virus (HIV)
  • Schistosomiasis
  • Pulmonary veno-occlusive disease
• Group 2 – Pulmonary hypertension secondary to left heart disease is thought to be the most common subgroup due to the frequency of left heart disease. Pathophysiology involves the passive backflow of blood from a poorly functioning left-sided system (due to either systolic, diastolic or valvular dysfunction), causing increased right-sided pressures. Causes include:
  • Left ventricular systolic dysfunction
  • Left ventricular diastolic dysfunction
  • Valvular disease
  • Congenital or acquired left ventricular inflow or outflow tract obstruction, such as hypertrophic obstructive cardiomyopathy (HOCM)
  • Congenital or acquired pulmonary venous stenosis
• Group 3 – Pulmonary hypertension due to lung diseases and/or hypoxaemia. Hypoxia induces vasoconstriction and endothelial cell damage and remodelling via neo-muscularisation and collagen deposition. Causes include:
  • Interstitial lung disease – often associated with severe PH
  • Chronic Obstructive Pulmonary Disease (COPD) – commonly associated with mild PH
  • Obstructive sleep apnoea
  • Alveolar hypoventilation disorders
  • Chronic exposure to high-altitude
  • Neuromuscular causes such as myasthenia gravis and motor neurone disease
• Group 4 – Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with prolonged occlusion of the pulmonary vasculature, most typically by a thrombus. Sometimes occurs when a pulmonary embolism has not been diagnosed and treated in the acute setting, but can also be due to poor resolution of thrombi despite anticoagulant treatment. Rarely, can also occur with other pulmonary artery obstructions such as angiosarcoma or hydatid cyst disease.
• Group 5 – Pulmonary hypertension with unclear and/or multifactorial mechanism, including:
  • Haematological, e.g., sickle cell disease, myeloproliferative diseases, chronic haemolytic anaemia
  • Systemic, e.g., sarcoidosis, neurofibromatosis, pulmonary histiocytosis
  • Metabolic disorders, e.g., Gaucher’s disease, thyroid disease, disorders of glycogen storage
  • Others, e.g., pulmonary capillary haemangiomatosis, fibrosing mediastinitis, chronic renal failure