What are the causes of pulmonary hypertension?

Causes of Pulmonary Hypertension

Pulmonary hypertension is classified into 7 major groups based on underlying etiology, with left heart disease and lung diseases being the most common causes globally, while pulmonary arterial hypertension represents a distinct group requiring specific diagnostic criteria. 1

Classification Framework

The 2015 ESC/ERS guidelines provide the definitive clinical classification system that organizes PH causes into distinct groups based on pathophysiology, hemodynamics, and treatment approaches 1:

Group 1: Pulmonary Arterial Hypertension (PAH)

This group requires specific hemodynamic criteria: mean pulmonary arterial pressure ≥25 mmHg, pulmonary vascular resistance >3 Wood units, and absence of other causes of pre-capillary PH 1.

Causes within Group 1:

• Idiopathic PAH - no identifiable cause
• Heritable PAH - BMPR2 mutations and other genetic mutations
• Drug and toxin-induced - appetite suppressants (definite association), dasatinib (likely association), attention deficit disorder medications (possible association) 1
• Associated PAH:
  • Connective tissue disease
  • HIV infection
  • Portal hypertension
  • Congenital heart disease (including Eisenmenger's syndrome)
  • Schistosomiasis 1

Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis are included as a distinct subgroup with similar triggers (idiopathic, heritable with EIF2AK4 mutations, drug/toxin/radiation-induced, or associated with connective tissue disease and HIV) 1.

Group 2: PH Due to Left Heart Disease

This is one of the most prevalent causes globally 2. The prevalence increases dramatically with disease severity:

• Up to 60% of patients with severe LV systolic dysfunction develop PH
• Up to 70% of patients with heart failure with preserved ejection fraction present with PH
• Virtually all patients with severe symptomatic mitral valve disease have PH
• Up to 65% of patients with symptomatic aortic stenosis develop PH 1

Specific causes:

• Left ventricular systolic dysfunction
• Left ventricular diastolic dysfunction
• Valvular disease (mitral and aortic predominate)
• Congenital/acquired left heart inflow/outflow tract obstruction
• Congenital cardiomyopathies
• Congenital/acquired pulmonary vein stenosis 1

Group 3: PH Due to Lung Diseases and/or Hypoxia

Causes include:

• Chronic obstructive pulmonary disease (COPD) - most common cause in this group 3
• Interstitial lung disease
• Mixed restrictive and obstructive pulmonary diseases
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental lung diseases 1

Critical clinical point: PH associated with underlying lung disease carries worse survival than lung disease alone 4. This group shows male predominance (74.5% male) unlike Groups 1 and 2 which are female-predominant 3.

Group 4: Chronic Thromboembolic PH (CTEPH) and Other Pulmonary Artery Obstructions

Causes:

• Chronic thromboembolic pulmonary hypertension
• Angiosarcoma
• Other intravascular tumors
• Arteritis
• Congenital pulmonary artery stenoses
• Parasites (hydatidosis) 1

Group 5: PH with Unclear and/or Multifactorial Mechanisms

Hematological disorders:

• Chronic hemolytic anemia
• Myeloproliferative disorders
• Splenectomy

Systemic disorders:

• Sarcoidosis
• Pulmonary histiocytosis
• Lymphangioleiomyomatosis
• Neurofibromatosis

Metabolic disorders:

• Glycogen storage disease
• Gaucher disease
• Thyroid disorders

Other causes:

• Pulmonary tumoral thrombotic microangiopathy
• Fibrosing mediastinitis
• Chronic renal failure (with/without dialysis)
• Segmental pulmonary hypertension 1

Global Epidemiological Patterns

The distribution of PH causes varies significantly by geography and development status:

• In developed countries: Left heart disease and lung diseases predominate 2
• In developing countries (where ~80% of PH patients live): Congenital heart disease, schistosomiasis, HIV, and rheumatic heart disease are more common 2
• In China specifically: Rheumatic heart disease (43.48%) and congenital heart disease (27.60%) are the leading causes, followed by COPD (14.28%) 3

Age and gender patterns:

• Overall PH prevalence: ~1% of global population, increasing to 10% in those >65 years 2
• Peak incidence: 41-50 years old 3
• Female predominance overall (ratio 1:1.69), particularly in Groups 1 and 2 (>70% female) 3
• Male predominance in Group 3 (74.5% male) 3

Critical Clinical Pitfalls

Do not miss these diagnostic considerations:

• Always exclude Group 2 (left heart disease) and Group 3 (lung disease) causes first, as these are the most common and require different management than PAH 1
• Drug-induced PAH can resolve with cessation of exposure (e.g., dasatinib), making medication history essential 1
• Congenital heart disease with small defects (<1 cm VSD, <2 cm ASD) can still cause severe PAH that is out of proportion to the defect size 1
• The presence of PH in any underlying condition substantially increases mortality risk, regardless of the primary disease 2