Causes of Pulmonary Hypertension
Pulmonary hypertension is classified into five distinct groups based on underlying etiology, with left heart disease (Group 2) and chronic lung disease (Group 3) being the most common causes, while pulmonary arterial hypertension (Group 1) represents a rarer subset requiring disease-specific therapy. 1
Hemodynamic Definition
Pulmonary hypertension is defined as a mean pulmonary artery pressure ≥25 mmHg at rest measured by right heart catheterization. 1 The classification into five groups is determined by specific hemodynamic patterns, underlying pathophysiology, and therapeutic approach. 2
Group 1: Pulmonary Arterial Hypertension (PAH)
Hemodynamic criteria: Mean PAP ≥25 mmHg, pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular resistance >3 Wood units. 1, 2
Idiopathic and Heritable Forms
- Idiopathic PAH occurs without identifiable triggers, with a prevalence of approximately 6 per million and a female-to-male ratio of 1.7:1. 3
- Heritable PAH accounts for 6-10% of PAH cases, with BMPR2 mutations present in 75% of familial cases and up to 25% of idiopathic cases. 3
- Other genetic mutations include ALK1 and endoglin genes (associated with hereditary hemorrhagic telangiectasia). 1
Drug and Toxin-Induced PAH
- Definite causative agents include appetite suppressants (aminorex, fenfluramine, dexfenfluramine) and the tyrosine kinase inhibitor dasatinib. 1, 3
- Other implicated substances include toxic rapeseed oil, amphetamines, L-tryptophan, and certain chemotherapeutic agents. 3
Associated Conditions (Associated PAH)
- Connective tissue diseases, particularly systemic sclerosis (CREST syndrome), systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis. 3
- Congenital heart disease with systemic-to-pulmonary shunts (atrial septal defects, ventricular septal defects, patent ductus arteriosus) can progress to Eisenmenger syndrome when pulmonary resistance exceeds systemic resistance. 1, 3
- Portal hypertension secondary to chronic liver disease, with risk increasing with severity of hepatic dysfunction. 1, 3
- HIV infection occurs in approximately 0.5% of HIV-infected individuals, independent of CD4 count but related to duration of infection. 1, 3
- Schistosomiasis is an important cause in endemic regions. 1, 3
- Chronic hemolytic anemias including sickle cell disease, thalassemia, and hereditary spherocytosis. 1, 3
- Myeloproliferative disorders and post-splenectomy states. 1
Pulmonary Veno-Occlusive Disease (PVOD) and Pulmonary Capillary Hemangiomatosis (PCH)
- These are distinct entities with prominent venous or capillary involvement, which may be idiopathic, heritable (EIF2AK4 mutations), or secondary to drugs, radiation, connective tissue disease, or HIV infection. 1, 2
Group 2: Pulmonary Hypertension Due to Left Heart Disease
This is the most prevalent form of pulmonary hypertension, 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 criteria: Mean PAP ≥25 mmHg with pulmonary artery wedge pressure >15 mmHg, distinguishing it from pre-capillary PH. 1, 2
Principal Etiologies
- Left ventricular systolic dysfunction of any origin. 1
- Left ventricular diastolic dysfunction, commonly secondary to chronic systemic hypertension leading to LV hypertrophy and impaired relaxation. 1, 2
- Valvular heart disease: virtually all patients with severe symptomatic mitral valve disease and up to 65% with symptomatic aortic stenosis develop PH. 1
- Congenital or acquired obstruction of left heart inflow/outflow tracts and pulmonary vein stenosis. 1
Hemodynamic Subtypes
- Isolated post-capillary PH (transpulmonary gradient ≤12 mmHg). 2
- Combined pre- and post-capillary PH (transpulmonary gradient >12 mmHg), indicating a "reactive" or "out-of-proportion" component due to superimposed pulmonary vascular remodeling. 2
Group 3: Pulmonary Hypertension Due to Lung Diseases and/or Hypoxia
PH secondary to chronic lung disease is common, though severe elevation (mean PAP ≥35 mmHg) is relatively rare. 2
Key Pulmonary Causes
- Chronic obstructive pulmonary disease (COPD) is the most frequently encountered lung disease linked to PH. 1, 2
- Interstitial lung disease, including idiopathic pulmonary fibrosis. 1, 2
- Sleep-disordered breathing (obstructive sleep apnea, obesity-hypoventilation syndrome). 1, 2
- Alveolar hypoventilation disorders. 1
- Chronic exposure to high altitude. 1
- Developmental lung abnormalities. 1
Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
CTEPH results from organized thrombotic material obstructing pulmonary arteries, producing a pre-capillary hemodynamic pattern. 1, 2
Specific Etiologies
- Organized thrombi obstructing proximal or distal pulmonary arteries. 1, 2
- Non-thrombotic obstructions including:
Group 5: Pulmonary Hypertension with Unclear or Multifactorial Mechanisms
Hematologic Disorders
Systemic Disorders
- Sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, and neurofibromatosis. 1, 2
Metabolic Disorders
Miscellaneous Causes
- Pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis causing vascular compression, and chronic renal failure (with or without dialysis). 1, 2
Critical Clinical Pitfalls
Right heart catheterization is mandatory to confirm the diagnosis and classify the hemodynamic type before initiating any PAH-specific therapy. 2 Echocardiography alone is insufficient because Doppler-derived pressure estimates may be inaccurate in individual patients. 2
PAH-specific drugs (endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostacyclins) are contraindicated in Group 2 PH because they may exacerbate pulmonary edema by increasing pulmonary blood flow without lowering left-sided pressures. 2 Empiric use without hemodynamic confirmation can precipitate life-threatening pulmonary edema. 2
Calcium channel blockers must not be used empirically without documented vasoreactivity testing, as they can be harmful in non-responders. 2 Only approximately 10% of idiopathic PAH patients exhibit a positive vasoreactivity response and are candidates for high-dose calcium channel blocker therapy. 2