What are the causes of Group 1 Pulmonary Arterial Hypertension (PAH)?

Comprehensive List of Causes of Group 1 Pulmonary Arterial Hypertension (PAH)

Group 1 Pulmonary Arterial Hypertension (PAH) includes several distinct etiologies, with idiopathic PAH being the most common form according to registry data. 1

Classification of Group 1 PAH

1. Idiopathic PAH (IPAH)

• Sporadic disease with no identifiable family history or risk factors
• More prevalent in women with a female/male ratio of 1.7:1 1
• Mean age at diagnosis of 37 years, though recent data suggests increasing diagnosis in patients over 70 years 1

2. Heritable/Familial PAH (HPAH/FPAH)

• Genetic mutations identified in:
  • BMPR2 (bone morphogenetic protein receptor type 2) - found in 50-90% of familial cases 1
  • ALK-1 (activin receptor-like kinase 1) 1
  • ENG (endoglin) 2
  • SMAD4 and SMAD8 3
  • EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4) 1
  • KCNK3 (potassium channel subfamily K member 3) 3
  • CAV1 (caveolin 1) 3
• Characterized by genetic anticipation and incomplete penetrance 1

3. Drug and Toxin-Induced PAH

• Associated with:
  • Anorexigens (aminorex, fenfluramine, dexfenfluramine)
  • Toxic rapeseed oil
  • Amphetamines
  • Methamphetamines
  • Dasatinib
  • Interferon 1

4. Associated PAH (APAH)

• Connective tissue disorders:

  • Systemic sclerosis (most common in Western countries) 4
  • Systemic lupus erythematosus (more common in Asia) 4
  • Mixed connective tissue disease 4
  • Rheumatoid arthritis 1

• Congenital heart disease:

  • Eisenmenger's syndrome (systemic-to-pulmonary shunts leading to reversed or bidirectional flow) 1
  • PAH with prevalent systemic-to-pulmonary shunts (correctable or non-correctable) 1
  • PAH with small/coincidental defects 1
  • PAH after defect correction 1

• Portal hypertension 1

• HIV infection (incidence approximately 0.5%, 6-12 times that of general population) 1

• Schistosomiasis 1

• Other conditions:

  • Thyroid disorders
  • Glycogen storage disease
  • Gaucher's disease
  • Hereditary hemorrhagic telangiectasia
  • Hemoglobinopathies
  • Chronic myeloproliferative disorders
  • Post-splenectomy 1

5. PAH with Significant Venous or Capillary Involvement

• Pulmonary veno-occlusive disease (PVOD):

  • Idiopathic
  • Heritable (EIF2AK4 mutations)
  • Drug/toxin/radiation-induced
  • Associated with connective tissue disease and HIV 1

• Pulmonary capillary hemangiomatosis (PCH) 1

6. Persistent Pulmonary Hypertension of the Newborn 1

Pathophysiological Mechanisms

PAH results from restricted flow through the pulmonary arterial circulation causing increased pulmonary vascular resistance and ultimately right heart failure. Key mechanisms include:

• Imbalance in vasoconstrictor/vasodilator pathways
• Imbalance between proliferation and apoptosis (favoring proliferation)
• Endothelial dysfunction
• Smooth muscle cell dysfunction
• Adventitial remodeling
• Inflammation
• In situ thrombosis 1

Clinical Considerations

• PAH is defined hemodynamically as mean pulmonary arterial pressure ≥25 mmHg at rest with pulmonary capillary wedge pressure ≤15 mmHg and pulmonary vascular resistance >3 Wood units 1, 5
• Prognosis is poor with approximately 15% mortality within 1 year even with modern therapy 1
• Early diagnosis is critical as advanced disease at presentation correlates with worse outcomes
• Right heart catheterization remains mandatory for definitive diagnosis 5

Common Pitfalls in Diagnosis

• Misclassifying Group 2-5 PH as Group 1 PAH
• Failing to perform comprehensive testing to identify underlying causes
• Not recognizing rare associated conditions that may require specific management
• Overlooking genetic testing in familial cases and young patients with idiopathic PAH
• Confusing pulmonary veno-occlusive disease with other forms of PAH, which can lead to inappropriate treatment decisions

Understanding the specific etiology of Group 1 PAH is crucial for appropriate management, as treatment approaches may differ based on the underlying cause, and some associated conditions may require specific additional interventions.