What are the causes of pulmonary hypertension?

Causes of Pulmonary Hypertension

Pulmonary hypertension is classified into seven distinct groups based on underlying etiology, with left heart disease being the most common cause globally, followed by lung diseases and hypoxia, while pulmonary arterial hypertension represents a rarer but important category. 1

Classification Framework

The 2015 ESC/ERS guidelines provide the definitive clinical classification system that organizes PH causes into seven major groups 1:

Group 1: Pulmonary Arterial Hypertension (PAH)

This group encompasses conditions affecting the pulmonary arterial microcirculation:

• Idiopathic PAH: No identifiable cause; more prevalent in women 2
• Heritable PAH: BMPR2 mutations (autosomal dominant with incomplete penetrance) and other genetic mutations 1, 2
• Drug and toxin-induced: Appetite suppressants, dasatinib, and other medications with definite, likely, or possible associations 1
• Associated PAH includes:
  • Connective tissue diseases (particularly scleroderma spectrum)
  • HIV infection
  • Portal hypertension
  • Congenital heart disease (including Eisenmenger's syndrome)
  • Schistosomiasis 1, 2

Group 2: Pulmonary Hypertension Due to Left Heart Disease

This is the most common cause of PH worldwide 3, 4:

• Left ventricular systolic dysfunction: Up to 60% of patients with severe LV dysfunction develop PH 1
• Left ventricular diastolic dysfunction (HFpEF): Up to 70% of these patients present with PH 1
• Valvular disease:
  • Virtually all patients with severe symptomatic mitral valve disease develop PH
  • Up to 65% of patients with symptomatic aortic stenosis have PH 1
• Congenital/acquired left heart inflow/outflow obstruction
• Pulmonary vein stenosis 1

Group 3: Pulmonary Hypertension Due to Lung Diseases and/or Hypoxia

This represents the second most common cause globally 4:

• Chronic obstructive pulmonary disease (COPD)
• Interstitial lung disease
• Mixed restrictive and obstructive pulmonary diseases
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic high-altitude exposure
• Developmental lung diseases 1, 2

Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

• Chronic thromboembolic obstruction of pulmonary arteries
• Other pulmonary artery obstructions:
  • Angiosarcoma and intravascular tumors
  • Arteritis
  • Congenital pulmonary artery stenoses
  • Parasitic infections (hydatidosis) 1

Group 5: Pulmonary Veno-Occlusive Disease and Pulmonary Capillary Hemangiomatosis

• Idiopathic forms
• Heritable (EIF2AK4 mutations)
• Drug, toxin, and radiation-induced
• Associated with connective tissue disease and HIV
• Persistent pulmonary hypertension of the newborn 1

Group 6 & 7: PH with Unclear and/or Multifactorial Mechanisms

• Hematological disorders: Chronic hemolytic anemia, myeloproliferative disorders, post-splenectomy 1, 2
• Systemic disorders: Sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis 1
• Metabolic disorders: Glycogen storage disease, Gaucher disease, thyroid disorders 1, 2
• Other causes: Pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic renal failure 1

Epidemiological Context

Approximately 1% of the global population is affected by PH, increasing to 10% in individuals over 65 years 4. About 80% of affected patients live in developing countries, where infectious causes (schistosomiasis, HIV, rheumatic heart disease) and congenital heart disease predominate in younger populations 4.

Critical Clinical Pitfall

The most important distinction is between pre-capillary PH (Groups 1,3,4,5) and post-capillary PH (Group 2). This differentiation requires right heart catheterization showing pulmonary capillary wedge pressure >15 mmHg for post-capillary PH versus ≤15 mmHg with pulmonary vascular resistance >3 Wood units for pre-capillary PH 1, 5. Misclassification leads to inappropriate treatment, as PAH-specific therapies are contraindicated in Group 2 PH and may cause harm 5.