What are the five groups of pulmonary hypertension and the recommended therapeutic approaches for each group?

Classification of Pulmonary Hypertension

Pulmonary hypertension is classified into five distinct clinical groups based on shared pathophysiology, hemodynamic characteristics, and treatment approaches, as defined by the 2015 ESC/ERS guidelines. 1

Hemodynamic Definition

Pulmonary hypertension is defined as a mean pulmonary arterial pressure ≥25 mmHg at rest measured by right heart catheterization. 1 This hemodynamic threshold applies across all five groups, though the specific patterns differ between pre-capillary and post-capillary forms.

The Five Groups

Group 1: Pulmonary Arterial Hypertension (PAH)

This is pre-capillary PH characterized by pulmonary artery wedge pressure ≤15 mmHg and pulmonary vascular resistance >3 Wood units. 1

Subcategories include: 1

• Idiopathic PAH (sporadic disease without familial history or known triggers)
• Heritable PAH (BMPR2 mutations and other genetic mutations)
• Drug and toxin-induced PAH (including appetite suppressants, dasatinib)
• Associated PAH:
  • Connective tissue disease
  • HIV infection
  • Portal hypertension
  • Congenital heart disease
  • Schistosomiasis
• Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (includes idiopathic, heritable with EIF2AK4 mutations, drug/toxin/radiation-induced)

Therapeutic approach: PAH-specific medications targeting three dysfunctional endothelial pathways are indicated: 2, 3

• Nitric oxide pathway (phosphodiesterase-5 inhibitors: sildenafil, tadalafil; soluble guanylate cyclase stimulators: riociguat)
• Endothelin pathway (endothelin receptor antagonists: bosentan, ambrisentan)
• Prostacyclin pathway (prostacyclin analogues: epoprostenol, treprostinil)

Critical caveat: These PAH-specific drugs are approved ONLY for Group 1 and should NOT be used in Groups 2 or 3, where they have shown potential for significant harm. 2

Group 2: PH Due to Left Heart Disease

This is post-capillary PH defined by pulmonary artery wedge pressure >15 mmHg. 1

Prevalence patterns: 1

• Up to 60% of patients with severe LV systolic dysfunction
• Up to 70% of patients with heart failure with preserved ejection fraction
• Virtually all patients with severe symptomatic mitral valve disease
• Up to 65% of patients with symptomatic aortic stenosis

Subcategories include: 1

• LV systolic dysfunction
• LV diastolic dysfunction
• Valvular disease
• Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
• Congenital/acquired pulmonary vein stenosis

Therapeutic approach: Treatment focuses on optimizing management of the underlying left heart disease. 2, 4 PAH-specific therapies are NOT approved and may cause harm in this group.

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

This is pre-capillary PH resulting from chronic lung disease or chronic hypoxemia. 1

Subcategories include: 1

• Chronic obstructive pulmonary disease
• Interstitial lung disease
• Other pulmonary diseases with mixed restrictive/obstructive pattern
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental lung diseases

Therapeutic approach: Treatment targets the underlying lung disease and correction of hypoxemia. 2, 4 PAH-specific medications are NOT recommended and have not demonstrated benefit in this group.

Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Other Pulmonary Artery Obstructions

This is pre-capillary PH caused by organized thrombi in pulmonary arteries. 1

Subcategories include: 1

• Chronic thromboembolic pulmonary hypertension
• Other pulmonary artery obstructions (angiosarcoma, other intravascular tumors, arteritis, congenital pulmonary artery stenoses, parasites)

Therapeutic approach: 2, 4, 3

• Surgical pulmonary thromboendarterectomy is the treatment of choice for eligible patients and should be evaluated at experienced centers
• Riociguat (soluble guanylate cyclase stimulator) is approved for inoperable or persistent/recurrent CTEPH
• Balloon pulmonary angioplasty may be considered for inoperable cases

Critical point: Failure to identify CTEPH denies patients potentially curative surgical treatment. 2 All patients with suspected pre-capillary PH without confirmed left heart or lung disease should undergo ventilation-perfusion scanning to exclude CTEPH. 4

Group 5: PH with Unclear and/or Multifactorial Mechanisms

This heterogeneous group includes conditions where PH mechanisms are unclear or involve multiple factors. 1

Subcategories include: 1

• Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
• Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis
• Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
• Others: pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic renal failure (with/without dialysis), segmental pulmonary hypertension

Therapeutic approach: Treatment focuses on the underlying causal disease. 4 PAH-specific therapeutics are not routinely recommended for this group.

Critical Clinical Pitfalls

Accurate diagnosis MUST precede therapy. 2 The most challenging scenarios involve patients who don't fit cleanly into one group but have overlapping features. 5 Right heart catheterization is essential for accurate diagnosis and classification, as echocardiographic estimates often differ from invasive measurements. 5

The distinction between groups has life-or-death implications: using PAH-specific drugs in Groups 2 or 3 can cause significant harm rather than benefit. 2 Conversely, failing to identify Group 1 PAH or Group 4 CTEPH denies patients access to potentially life-saving therapies.