Pulmonary Hypertension Classification
Pulmonary hypertension is classified into five distinct clinical groups based on shared pathophysiology, hemodynamics, and treatment approaches, with the fundamental definition being a mean pulmonary arterial pressure ≥25 mmHg at rest measured by right heart catheterization. 1, 2
Hemodynamic Definition
- PH is defined as mean PAP ≥25 mmHg at rest on right heart catheterization, which remains the gold standard for diagnosis 1, 2, 3
- Pre-capillary PH is characterized by pulmonary artery wedge pressure (PAWP) ≤15 mmHg 1, 2
- Post-capillary PH shows PAWP >15 mmHg 2
- Pulmonary arterial hypertension specifically requires pulmonary vascular resistance >3 Wood units in addition to pre-capillary hemodynamics 1, 2
Group 1: Pulmonary Arterial Hypertension (PAH)
This group represents pre-capillary PH with elevated pulmonary vascular resistance in the absence of other causes such as lung disease or chronic thromboembolism. 1, 2
Subtypes of PAH:
- Idiopathic PAH - no identifiable cause 1, 2
- Heritable PAH - BMPR2 mutations are most common, though other genetic mutations exist 1, 2
- Drug and toxin-induced PAH - certain appetite suppressants, methamphetamines, and other agents carry definite or likely risk 1, 2
- Associated PAH includes:
- Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis - distinct entities with idiopathic, heritable (EIF2AK4 mutation), drug/toxin/radiation-induced, or associated forms 1, 2
Group 2: PH Due to Left Heart Disease
This is the most prevalent form of PH, occurring in up to 60% of patients with severe LV systolic dysfunction and up to 70% with heart failure with preserved ejection fraction. 1
Causes include:
- Left ventricular systolic dysfunction 1, 2
- Left ventricular diastolic dysfunction 1, 2
- Valvular disease - virtually all patients with severe symptomatic mitral valve disease and up to 65% with symptomatic aortic stenosis develop PH 1, 2
- Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 1, 2
- Congenital/acquired pulmonary vein stenosis 1, 2
Group 3: PH Due to Lung Diseases and/or Hypoxia
This group encompasses PH secondary to chronic respiratory conditions and chronic hypoxemia. 2
Specific causes:
- Chronic obstructive pulmonary disease (COPD) 1, 2
- Interstitial lung disease 1, 2
- Other pulmonary diseases with mixed restrictive and obstructive patterns 1, 2
- Sleep-disordered breathing 1, 2
- Alveolar hypoventilation disorders 1, 2
- Chronic exposure to high altitude 1, 2
- Developmental lung diseases 1, 2
Group 4: Chronic Thromboembolic PH (CTEPH) and Other Pulmonary Artery Obstructions
CTEPH results from organized thrombi causing persistent pulmonary artery obstruction and is the only potentially curable form of PH through surgical pulmonary endarterectomy. 2, 4
Subtypes:
Group 5: PH with Unclear and/or Multifactorial Mechanisms
This heterogeneous group includes conditions where PH pathophysiology involves multiple or poorly understood mechanisms. 2, 5
Hematological disorders:
- Chronic hemolytic anemia (affects approximately 10% of adults with sickle cell disease) 5
- Myeloproliferative disorders 1, 5
- Post-splenectomy state 1, 5
Systemic disorders:
- Sarcoidosis - causes PH through granulomatous infiltration of pulmonary vasculature 1, 5
- Pulmonary histiocytosis 1, 5
- Lymphangioleiomyomatosis 1, 5
- Neurofibromatosis 1, 5
Metabolic disorders:
Other causes:
- Pulmonary tumoral thrombotic microangiopathy 1, 5
- Fibrosing mediastinitis 1, 5
- Chronic renal failure (with or without dialysis) 1, 5
- Segmental pulmonary hypertension 1
Treatment Approach by Group
Group 1 (PAH) Treatment:
Combination therapy targeting multiple biological pathways is now first-line for most PAH patients, with initial monotherapy reserved only for low-risk patients. 3
FDA-approved therapies target three dysfunctional endothelial pathways:
Low or intermediate-risk patients: initial monotherapy or initial oral combination therapy 8
High-risk patients: initial combination therapy including intravenous prostacyclin analogues 8
Inadequate response to triple therapy: assess for lung transplantation 8
5-year survival has improved from 34% in 1991 to over 60% in 2015 with modern combination therapy 3
Group 2,3, and 5 Treatment:
PAH-specific therapeutics are NOT recommended for these groups; treatment focuses on the underlying causal disease. 8, 4
- Group 2: Optimize management of left heart disease (heart failure therapy, valve repair/replacement) 4
- Group 3: Treat underlying lung disease, optimize oxygenation 4
- Group 5: Disease-specific therapy (enzyme replacement for Gaucher disease, thyroid optimization, immunosuppression for sarcoidosis when indicated, volume management for renal failure) 5
Group 4 (CTEPH) Treatment:
Surgical pulmonary endarterectomy is the treatment of choice for eligible patients with CTEPH. 4
- For inoperable or persistent/recurrent CTEPH: riociguat is the only licensed targeted therapy 4
- Balloon pulmonary angioplasty may be considered for inoperable cases 8
Critical Diagnostic Pitfall
Right heart catheterization is mandatory to confirm PH diagnosis and accurately classify the hemodynamic subtype before initiating any PAH-specific therapy. 5, 4 Echocardiography alone provides only probability estimates and cannot definitively diagnose or classify PH 4. All patients with suspected PAH or CTEPH must be referred to a specialist center 4.