Causes of Pulmonary Hypertension
Pulmonary hypertension is classified into five distinct clinical groups based on underlying etiology, with the most common causes being left heart disease (Group 2) and chronic lung disease (Group 3), while pulmonary arterial hypertension (Group 1) represents a rare but important subset requiring specialized therapy. 1
Classification Framework
The World Health Organization classification divides pulmonary hypertension into five groups based on shared pathophysiology, hemodynamics, and treatment approaches 1:
Group 1: Pulmonary Arterial Hypertension (PAH)
This group is characterized by pre-capillary pulmonary hypertension with mean pulmonary artery pressure ≥25 mmHg, pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular resistance >3 Wood units 1, 2.
Idiopathic and Heritable Forms
- Idiopathic PAH (IPAH) occurs without identifiable cause and is more prevalent in women 1
- Familial/Heritable PAH results from mutations in bone morphogenetic protein receptor-2 (BMPR2) and is inherited as an autosomal dominant disease with incomplete penetrance 1
Drug and Toxin-Induced PAH
- Definite associations include anorexigens (appetite suppressants) and dasatinib 1
- Clinical and hemodynamic recovery may occur after stopping exposure 1
Associated PAH (APAH)
- Connective tissue diseases, particularly systemic sclerosis (scleroderma spectrum), which carries the highest risk and worst prognosis 1
- Congenital heart disease with systemic-to-pulmonary shunts, including atrial septal defects and ventricular septal defects 1, 3
- Portal hypertension in patients with liver disease 1
- HIV infection 1
- Schistosomiasis 1
- Hemoglobinopathies including sickle cell disease and chronic hemolytic anemia 1, 2
- Chronic myeloproliferative disorders and post-splenectomy states 1, 2
Pulmonary Veno-Occlusive Disease and Pulmonary Capillary Hemangiomatosis
- These represent distinct entities with significant venous or capillary involvement 1
- May be idiopathic, heritable (EIF2AK4 mutation), or associated with drugs, toxins, radiation, connective tissue disease, or HIV 1
Group 2: Pulmonary Hypertension Due to Left Heart Disease
This is the most common form of pulmonary hypertension overall, affecting up to 60% of patients with severe left ventricular systolic dysfunction and up to 70% of those with heart failure with preserved ejection fraction. 1, 2
Hemodynamic Definition
- Mean pulmonary artery pressure ≥25 mmHg with pulmonary artery wedge pressure >15 mmHg 1, 2
- This distinguishes post-capillary from pre-capillary pulmonary hypertension 2
Specific Causes
- Left ventricular systolic dysfunction from any cause 1, 2
- Left ventricular diastolic dysfunction, commonly from chronic hypertension leading to left ventricular hypertrophy 1, 2
- Valvular heart disease: virtually all patients with severe symptomatic mitral valve disease and up to 65% with symptomatic aortic stenosis develop pulmonary hypertension 1
- Congenital or acquired left heart inflow/outflow tract obstruction 1
- Congenital or acquired pulmonary vein stenosis 1
Pathophysiologic Subtypes
- Isolated post-capillary PH: transpulmonary gradient ≤12 mmHg 2
- Combined pre- and post-capillary PH: transpulmonary gradient >12 mmHg, indicating "reactive" or "out-of-proportion" pulmonary hypertension from superimposed pulmonary vascular remodeling 1, 2
Group 3: Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxemia
This is a common form of pulmonary hypertension, though severe elevation (mean PAP ≥35 mmHg) is uncommon 4.
Specific Causes
- Chronic obstructive pulmonary disease (COPD), the most frequently encountered cause in this group 1, 4
- Interstitial lung disease including idiopathic pulmonary fibrosis 1, 4
- Combined pulmonary fibrosis and emphysema syndrome, which demonstrates particularly high prevalence of pulmonary hypertension 4
- Sleep-disordered breathing including obstructive sleep apnea and obesity hypoventilation syndrome 1, 4
- Alveolar hypoventilation disorders 1, 4
- Chronic exposure to high altitude 1, 4
- Developmental lung abnormalities 1, 4
Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
This group is characterized by organized thrombi obstructing pulmonary arteries, resulting in pre-capillary pulmonary hypertension 1, 2.
Specific Causes
- Thromboembolic obstruction of proximal pulmonary arteries 1
- Thromboembolic obstruction of distal pulmonary arteries 1
- Non-thrombotic pulmonary embolism from tumor, parasites (hydatidosis), or foreign material 1
- Angiosarcoma and other intravascular tumors 1
- Arteritis 1
- Congenital pulmonary artery stenoses 1
Group 5: Pulmonary Hypertension with Unclear and/or Multifactorial Mechanisms
Hematological Disorders
Systemic Disorders
- Sarcoidosis 1, 2
- Pulmonary histiocytosis X (Langerhans cell histiocytosis) 1, 2
- Lymphangioleiomyomatosis 1, 2
- Neurofibromatosis 1
Metabolic Disorders
Miscellaneous
- Pulmonary tumoral thrombotic microangiopathy 1, 2
- Fibrosing mediastinitis with compression of pulmonary vessels 1, 2
- Chronic renal failure with or without dialysis 1, 2
- Segmental pulmonary hypertension 1
Critical Diagnostic Considerations
Right heart catheterization is mandatory to confirm the diagnosis, classify the hemodynamic type, and guide all treatment decisions; echocardiography alone is insufficient and may be inaccurate. 2
Key Hemodynamic Parameters
- Mean pulmonary artery pressure ≥25 mmHg defines pulmonary hypertension 1, 2
- Pulmonary artery wedge pressure distinguishes pre-capillary (≤15 mmHg) from post-capillary (>15 mmHg) pulmonary hypertension 1, 2
- Pulmonary vascular resistance >3 Wood units confirms pre-capillary pulmonary arterial hypertension 1, 2
Common Pitfall
The most challenging diagnosis occurs when a patient does not fit cleanly into one group but meets criteria overlapping several groups; this makes treatment particularly difficult because each group is managed differently. 5 In such cases, right heart catheterization with meticulous attention to pulmonary artery wedge pressure measurement is essential to avoid misclassifying patients, particularly those with occult left heart disease 2.