What is the classification system for pulmonary hypertension?

Classification of Pulmonary Hypertension

Pulmonary hypertension is classified into 5 distinct clinical groups based on shared pathophysiology, hemodynamic characteristics, and treatment strategies, as established by the European Society of Cardiology (ESC) and European Respiratory Society (ERS). 1

Hemodynamic Definition

• Pulmonary hypertension is defined as mean pulmonary arterial pressure (PAPm) ≥25 mmHg at rest measured by right heart catheterization 1
• Pre-capillary PH is characterized by PAPm ≥25 mmHg with pulmonary artery wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) >3 Wood Units 1
• Post-capillary PH is defined by PAPm ≥25 mmHg with PAWP >15 mmHg 1
• Post-capillary PH is further subdivided into isolated post-capillary PH (diastolic pressure gradient <7 mmHg and/or PVR ≤3 WU) versus combined post-capillary and pre-capillary PH (diastolic pressure gradient ≥7 mmHg and/or PVR >3 WU) 1

The 5 Clinical Groups

Group 1: Pulmonary Arterial Hypertension (PAH)

This group encompasses conditions with similar clinical presentation and nearly identical pathological changes in the pulmonary microcirculation 1:

• 1.1 Idiopathic PAH (formerly primary pulmonary hypertension) 1
• 1.2 Heritable PAH, including:
  • BMPR2 mutations (most common) 1
  • ALK1, endoglin mutations (with or without hereditary hemorrhagic telangiectasia) 1
  • EIF2AK4 mutations 1
  • Other rare mutations 1
• 1.3 Drug and toxin-induced PAH 1
• 1.4 Associated PAH (APAH), including:
  • Connective tissue diseases 1
  • HIV infection 1
  • Portal hypertension 1
  • Congenital heart disease 1
  • Schistosomiasis 1
• 1' Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) - expanded in 2015 guidelines to include idiopathic, heritable, drug-, toxin-, and radiation-induced forms 1
• 1'' Persistent pulmonary hypertension of the newborn - subcategorized separately as it differs from classical PAH 1

Group 2: PH Due to Left Heart Disease

This represents post-capillary PH secondary to left-sided cardiac dysfunction 1:

• Left ventricular systolic dysfunction 1
• Left ventricular diastolic dysfunction 1
• Valvular disease 1
• Congenital/acquired obstruction and cardiomyopathies 1
• Congenital/acquired pulmonary vein stenosis 1

Clinical note: Group 2 is the most common form of PH in adults (34.2% alone, 29.3% combined with Group 3), yet PH occurs in only 3.6% of people with left heart disease 2

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

This group includes PH associated with primary respiratory pathology 1:

• 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 abnormalities 1

Clinical note: Groups 2 and 3 combined represent the most common and lethal forms of PH, with PH occurring in only 0.7% of patients with lung disease 2

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

This group is distinguished by mechanical obstruction of pulmonary arteries 1:

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

Critical distinction: All patients with suspected PH without confirmed left heart or lung disease must have ventilation-perfusion scanning to exclude CTEPH 3

Group 5: PH with Unclear and/or Multifactorial Mechanisms

This heterogeneous group includes conditions where PH pathophysiology is incompletely defined 1:

• Hematological disorders: chronic hemolytic anemia (moved from Group 1 in 2015 guidelines due to different pathology and hemodynamics), 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 (with/without dialysis), segmental PH 1

Key Updates from 2015/2016 Guidelines

The most recent ESC/ERS guidelines introduced several important modifications 1:

• Chronic hemolytic anemia was moved from Group 1 to Group 5 due to distinct pathological findings (absence of plexiform lesions), different hemodynamics (low PVR, high cardiac output), and lack of response to PAH-specific therapies 1
• PVOD/PCH (Group 1') was expanded to include multiple etiologies beyond idiopathic forms 1
• Persistent PH of the newborn was subcategorized as Group 1'' to reflect its heterogeneous nature 1
• New genetic mutations beyond BMPR2 were incorporated into heritable PAH classification 1
• Pediatric conditions were integrated throughout the classification to make it comprehensive for both adult and pediatric populations 1

Clinical Implications

The classification system is essential for: standardizing diagnosis and treatment, conducting clinical trials with homogeneous patient populations, communicating about individual patients, and analyzing pathobiological mechanisms 1. Right heart catheterization remains mandatory for accurate diagnosis and proper classification 1, 3.