What causes pulmonary artery hypertension (PAH)?

Causes of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is caused by a complex interplay of genetic factors, molecular abnormalities, and environmental exposures that lead to vascular remodeling, vasoconstriction, thrombosis, and inflammation of the pulmonary arteries, resulting in increased pulmonary vascular resistance and ultimately right heart failure. 1

Pathophysiological Mechanisms

PAH is characterized by a "multi-hit model" where multiple factors contribute to disease development:

• Endothelial dysfunction: Characterized by increased production of vasoconstrictors (endothelin, thromboxane A2) and decreased production of vasodilators (prostacyclin, nitric oxide), creating an imbalance that promotes vasoconstriction and cell proliferation 1

• Vascular remodeling: Involves intimal hyperplasia, medial hypertrophy, adventitial proliferation, and plexiform arteriopathy that progressively narrows pulmonary vessel lumens 1

• Thrombosis in situ: Elevated levels of fibrinopeptide A and plasminogen activator inhibitor-1 with reduced tissue plasminogen activator contribute to a procoagulant state 1

• Inflammation: Excessive activation of adventitial metalloproteases and perivascular inflammatory cell accumulation (macrophages, lymphocytes, dendritic cells) 2

• Altered cellular phenotype: Decreased ratio of apoptosis/proliferation in pulmonary artery smooth muscle cells (PASMCs) leading to excessive proliferation 1

Specific Causes by Category

1. Genetic Factors

• BMPR2 mutations: Present in 75% of familial PAH cases and up to 25% of idiopathic PAH cases, causing loss of function in the SMAD signaling pathway that normally regulates vascular cell growth 1

• Activin-like kinase 1 (ALK1) mutations: Found in patients with hereditary hemorrhagic telangiectasia and PAH, affecting SMAD-dependent signaling 1

• Other genetic polymorphisms: Serotonin transporter gene, nitric oxide synthase, and carbamyl-phosphate synthase gene may act as additional triggers 1

2. Associated Medical Conditions

• Connective tissue diseases: Particularly the limited cutaneous form of systemic sclerosis (CREST syndrome), systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis 1

• Congenital heart disease: Left-to-right shunts (ventricular septal defects, atrial septal defects, patent ductus arteriosus) causing increased pulmonary blood flow and pressure, potentially leading to Eisenmenger syndrome 1

• HIV infection: Occurs in approximately 0.5% of HIV-infected individuals, independent of CD4 count but related to duration of infection 1

• Portal hypertension: Associated with portopulmonary hypertension 1

• Hematological disorders: Chronic hemolytic anemias, myeloproliferative disorders, and post-splenectomy states 1

3. Drug and Toxin Exposure

• Anorexigens: Aminorex, fenfluramine, dexfenfluramine have been linked to PAH development 1

• Other substances: Toxic rapeseed oil, amphetamines, L-tryptophan, and certain chemotherapeutic agents 1

4. Molecular Abnormalities

• Serotonin abnormalities: Elevated plasma serotonin levels and platelets depleted of serotonin 1

• Potassium channel dysfunction: Downregulation of voltage-gated potassium channels (Kv1.5) leading to membrane depolarization and increased intracellular calcium 1

• Prostacyclin and thromboxane A2 imbalance: Reduced prostacyclin (vasodilator) and increased thromboxane A2 (vasoconstrictor) 1

Clinical Implications

• PAH can develop years to decades after closure of congenital heart defects, suggesting ongoing pathological processes 1

• Severity ranges from mild pressure elevation to profound systemic or suprasystemic levels of pulmonary artery pressure 1

• When an anatomic defect allowing shunting is present, shunt reversal and cyanosis may develop as pulmonary resistance rises above systemic resistance (Eisenmenger syndrome) 1

Diagnostic Considerations

• Patients with septal or great artery shunts should undergo periodic screening for pulmonary hypertension with echocardiography 1

• Cardiac catheterization is recommended for definitive diagnosis and hemodynamic assessment in patients with clinical symptoms, signs, or echocardiographic findings suggestive of pulmonary hypertension 1

• BNP, chest x-ray, 6-minute walk test, and cardiac catheterization are useful for initial and follow-up evaluation 1

Important Distinctions

• PAH (WHO Group 1) must be distinguished from other forms of pulmonary hypertension:
  • PH due to left heart disease (Group 2)
  • PH due to lung diseases and/or hypoxemia (Group 3)
  • Chronic thromboembolic PH (Group 4)
  • PH with unclear or multifactorial mechanisms (Group 5) 1

Understanding these diverse causes is essential for appropriate management strategies, as treatments may target specific pathways involved in PAH pathogenesis, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors 3, 4.