What are the causes and classification of Pulmonary Arterial Hypertension (PAH)?

Causes and Classification of Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is defined as a hemodynamic condition characterized by a mean pulmonary arterial pressure >20 mmHg at rest, pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular resistance ≥3 Wood units, in the absence of other causes of precapillary pulmonary hypertension. 1

Current Classification of Pulmonary Hypertension

The most recent clinical classification of pulmonary hypertension was updated at the Sixth World Symposium on Pulmonary Hypertension in 2018, which simplified the previous classifications into 5 main groups: 1

Group 1: Pulmonary Arterial Hypertension (PAH)

• Idiopathic PAH (IPAH) 1
• Heritable PAH (HPAH) - associated with genetic mutations, particularly in BMPR2 gene 1
• Drug and toxin-induced PAH 1
• PAH associated with other conditions:
  • Connective tissue diseases (e.g., systemic sclerosis, lupus) 1
  • HIV infection 1
  • Portal hypertension 1
  • Congenital heart disease 1
  • Schistosomiasis 1
• PAH long-term responders to calcium channel blockers 2
• PAH with features of venous/capillary involvement:
  • Pulmonary veno-occlusive disease (PVOD) 1
  • Pulmonary capillary hemangiomatosis (PCH) 1
• Persistent pulmonary hypertension of the newborn 1

Group 2: PH Due to Left Heart Disease

• Left ventricular systolic dysfunction 1
• Left ventricular diastolic dysfunction 1
• Valvular heart disease 1
• Congenital/acquired left heart inflow/outflow tract obstruction 1
• Congenital/acquired pulmonary veins stenosis 1

Group 3: PH Due to Lung Diseases and/or Hypoxia

• Chronic obstructive pulmonary disease (COPD) 1
• Interstitial lung disease 1
• Other pulmonary diseases with mixed restrictive and obstructive patterns 1
• Sleep-disordered breathing 1
• Alveolar hypoventilation disorders 1
• Chronic exposure to high altitude 1
• Developmental lung diseases 1

Group 4: PH Due to Pulmonary Artery Obstructions

• Chronic thromboembolic pulmonary hypertension (CTEPH) 1
• Other pulmonary artery obstructions:
  • Angiosarcoma 1
  • Other intravascular tumors 1
  • Arteritis 1
  • Congenital pulmonary artery stenoses 1
  • Parasites (hydatidosis) 1

Group 5: PH with Unclear and/or Multifactorial Mechanisms

• Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 1
• Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis 1
• Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 1
• Others: pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension 1

Specific Classification of PAH Associated with Congenital Heart Disease

PAH associated with congenital heart disease is further classified into four categories: 1

1. Eisenmenger's syndrome: Large intra- and extra-cardiac defects with severe PAH and reversed (pulmonary-to-systemic) or bidirectional shunting 1
2. PAH with prevalent systemic-to-pulmonary shunts: Moderate to large defects with mild to moderate increase in PVR 1
3. PAH with small/coincidental defects: Small defects (VSD <1 cm, ASD <2 cm) with marked elevation in PVR similar to idiopathic PAH 1
4. PAH after defect correction: Persistent or recurrent PAH after repair of congenital heart defects 1

Hemodynamic Definitions

Pulmonary hypertension is now defined as: 1

• Mean pulmonary arterial pressure (mPAP) >20 mmHg at rest 1

Further hemodynamic classifications include: 1

• Precapillary PH: mPAP >20 mmHg, PAWP ≤15 mmHg, PVR ≥3 Wood units (groups 1,3,4, and some group 5) 1
• Isolated postcapillary PH: mPAP >20 mmHg, PAWP >15 mmHg, PVR <3 Wood units (group 2 and some group 5) 1
• Combined pre- and postcapillary PH: mPAP >20 mmHg, PAWP >15 mmHg, PVR ≥3 Wood units (some group 2 and 5) 1

Clinical Implications

• If left untreated, PAH leads to right ventricular failure and premature death 1, 2
• The prevalence of PAH is approximately 10.6 cases per million adults in the US 2
• Early symptoms are nonspecific and typically include dyspnea on exertion and fatigue 2
• With current PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015 2

Diagnostic Approach

• Definitive diagnosis requires right heart catheterization to confirm hemodynamic parameters 1
• Screening tests include echocardiography, which can estimate pulmonary artery pressure based on tricuspid regurgitation velocity 3
• Additional testing should include evaluation for underlying causes, including connective tissue diseases, HIV, liver disease, and congenital heart disease 1