What are the etiologies of Pulmonary Artery Hypertension (PAH)?

Etiologies of Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) has multiple distinct etiologies that are classified into five major groups according to the World Health Organization (WHO) classification system, with Group 1 specifically representing PAH with various underlying causes. 1, 2

Group 1: Pulmonary Arterial Hypertension (PAH)

1.1 Idiopathic PAH (IPAH)

• Occurs without any identifiable cause
• Prevalence of approximately 6 per million people 1
• Female/male ratio of 1.7:1 with mean age at diagnosis of 37 years 1
• Cases increasingly reported in patients over 70 years old 1

1.2 Heritable/Familial PAH (FPAH)

• Accounts for 6-10% of PAH cases 1
• Primarily associated with mutations in:
  • BMPR2 gene (50-90% of familial cases) 1
  • BMPR2 mutations also found in 25% of idiopathic PAH cases 1
• Characterized by genetic anticipation and incomplete penetrance 1
• When expressed, occurs at earlier age with more severe disease progression 1

1.3 Drug and Toxin-Induced PAH

• Associated with various substances:
  • Anorexigens (e.g., fenfluramine)
  • BMPR2 mutations found in 15% of fenfluramine-associated PAH 1
  • Other drugs and toxins 1

1.4 Associated PAH (APAH)

• Connective tissue diseases:

  • Most common in limited cutaneous systemic sclerosis (formerly CREST syndrome) 1
  • Also occurs in systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis 1
  • Histopathological changes found in 65-80% of patients at autopsy, though only 10% develop clinically apparent disease 1

• Congenital heart disease:

  • Complication of uncorrected increased pulmonary blood flow with systemic-to-pulmonary shunts 1
  • Higher risk with high-pressure shunts (ventricular septal defect, patent ductus arteriosus, truncus arteriosus) 1
  • Can also occur with low-pressure high-flow defects (atrial septal defects) 1
  • May progress to Eisenmenger syndrome (reversal of shunt flow) 1

• HIV infection:

  • Incidence approximately 0.5% (6-12 times higher than general population) 1
  • Related to duration of HIV infection, independent of CD4 count or previous opportunistic infections 1

• Portal hypertension 1, 2

• Other associated conditions 1, 2:

  • Thyroid disorders
  • Glycogen storage disease
  • Gaucher's disease
  • Hereditary hemorrhagic telangiectasia
  • Hemoglobinopathies
  • Chronic myeloproliferative disorders
  • History of splenectomy
  • Schistosomiasis
  • Chronic hemolytic anemia 3

1.5 PAH with significant venous or capillary involvement

• Pulmonary veno-occlusive disease (PVOD) 1, 2
• Pulmonary capillary hemangiomatosis (PCH) 1, 2

1.6 Persistent pulmonary hypertension of the newborn 1, 2

Other WHO Groups of Pulmonary Hypertension

Group 2: PH due to Left Heart Disease

• Left-sided atrial or ventricular heart disease 1, 2
• Left-sided valvular heart disease 1, 2
• Requires treatment of underlying cardiac condition rather than PAH-specific therapies 2

Group 3: PH due to Lung Diseases and/or Hypoxemia

• Chronic obstructive pulmonary disease 1, 2
• Interstitial lung disease 1, 2
• Sleep-disordered breathing 1, 2
• Alveolar hypoventilation disorders 1, 2
• Chronic exposure to high altitude 1, 2
• Developmental abnormalities 1, 2

Group 4: Chronic Thromboembolic PH (CTEPH)

• Thromboembolic obstruction of proximal pulmonary arteries 1, 2
• Thromboembolic obstruction of distal pulmonary arteries 1, 2
• Non-thrombotic pulmonary embolism (tumor, parasites, foreign material) 1, 2

Group 5: PH with Unclear/Multifactorial Mechanisms

• Sarcoidosis 1, 2
• Histiocytosis X 1, 2
• Lymphangiomatosis 1, 2
• Compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) 1, 2

Pathophysiological Mechanisms

PAH involves multiple pathogenic pathways 1, 4:

• Vasoconstrictor/vasodilator imbalance
• Imbalance between proliferation and apoptosis (favoring proliferation)
• Vascular remodeling with medial hypertrophy, intimal proliferation, and adventitial thickening
• Thrombosis in situ
• Inflammation
• Key molecular pathways involved:
  • Nitric oxide pathway
  • Endothelin-1 pathway
  • Prostacyclin pathway
  • Activin/bone morphogenetic protein pathway

Clinical Implications

• PAH has poor prognosis with approximately 15% mortality within 1 year even with modern therapy 1
• Early diagnosis is challenging due to non-specific symptoms 5
• Definitive diagnosis requires right heart catheterization showing mPAP ≥25 mmHg, PCWP ≤15 mmHg, and PVR >3 Wood units 2, 5
• Treatment options target specific molecular pathways, with FDA-approved medications including prostacyclin analogues (e.g., epoprostenol), endothelin receptor antagonists, and phosphodiesterase-5 inhibitors 6, 5
• Current treatment approaches favor combination therapy targeting multiple pathways 5

Important Considerations

• Ventilation-perfusion scanning is crucial to exclude CTEPH in all patients with suspected PH 2
• PAH-specific therapies should not be used in non-PAH forms of PH, particularly in PH due to left heart disease 2
• Patients with CTD-APAH have higher mortality risk compared to IPAH 7
• Screening is warranted for high-risk populations including those with BMPR2 mutations, scleroderma spectrum diseases, and portal hypertension undergoing liver transplant evaluation 1