What are examples of Group 1 Pulmonary Artery Hypertension (PAH)?

Group 1 Pulmonary Arterial Hypertension (PAH): Clinical Subtypes

Group 1 PAH encompasses idiopathic PAH, heritable forms, drug/toxin-induced PAH, and PAH associated with specific conditions including connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and chronic hemolytic anemia. 1

Core Subtypes of Group 1 PAH

Idiopathic and Heritable Forms

• Idiopathic PAH represents cases with no identifiable cause or family history 1
• Heritable PAH includes patients with germline mutations, most commonly:
  • BMPR2 (bone morphogenetic protein receptor type 2) mutations 1
  • EIF2AK4 mutations (associated with pulmonary veno-occlusive disease) 1
  • ALK1 and endoglin mutations, with or without hereditary hemorrhagic telangiectasia 1
  • Other unidentified genetic mutations 1

Drug and Toxin-Induced PAH

• Drug and toxin-induced PAH occurs from exposure to specific medications or substances that trigger pulmonary vascular remodeling 1
• This subtype also includes radiation-induced PAH 1

Associated PAH (APAH) - Specific Conditions

Connective Tissue Disease-Associated PAH:

• Most commonly seen with systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease 1

HIV-Associated PAH:

• Occurs independently of CD4 count or viral load in HIV-infected patients 1

Portal Hypertension-Associated PAH:

• Develops in patients with liver cirrhosis and portal hypertension, regardless of severity 1

Congenital Heart Disease-Associated PAH: This subtype requires specific classification based on defect characteristics 1:

• Eisenmenger syndrome: Large intra- or extra-cardiac defects with severe PVR elevation causing reversed (pulmonary-to-systemic) or bidirectional shunting, with cyanosis and erythrocytosis present 1
• PAH with prevalent systemic-to-pulmonary shunts: Moderate to large defects with mildly to moderately increased PVR, persistent left-to-right shunting, and no resting cyanosis (may be correctable) 1
• PAH with small/coincidental defects: Ventricular septal defects <1 cm or atrial septal defects <2 cm that do not account for the elevated PVR; clinical picture resembles idiopathic PAH, and defect closure is contraindicated 1
• PAH after defect correction: PAH that persists immediately after surgical repair or recurs months to years later without significant residual hemodynamic lesions 1

Schistosomiasis-Associated PAH:

• Added to Group 1 classification in 2008, representing a significant global health burden particularly in endemic regions 1, 2

Chronic Hemolytic Anemia-Associated PAH:

• Includes sickle cell disease and other chronic hemolytic conditions 1, 2

Special Entities Within Group 1

Pulmonary Veno-Occlusive Disease (PVOD) and Pulmonary Capillary Hemangiomatosis:

• Designated as Group 1' due to distinct pathological features affecting pulmonary veins and capillaries 1
• Often associated with EIF2AK4 mutations 1

Persistent Pulmonary Hypertension of the Newborn:

• Neonatal condition included within Group 1 classification 1

Hemodynamic Definition

All Group 1 PAH subtypes share the same hemodynamic criteria 1, 3:

• Mean pulmonary arterial pressure ≥25 mmHg at rest (older definition) or >20 mmHg (newer definition) 3, 4
• Pulmonary arterial wedge pressure ≤15 mmHg (pre-capillary pattern) 1
• Pulmonary vascular resistance >3 Wood units 1, 3

Clinical Significance

These conditions share virtually identical pathological changes affecting the pulmonary microcirculation, including medial hypertrophy, intimal proliferation, and plexiform lesions, despite their different etiologies 1. This common pathobiology justifies their grouping and similar treatment approaches with PAH-specific therapies targeting the nitric oxide, prostacyclin, and endothelin pathways 3.