What is the classification and treatment of pulmonary hypertension?

Pulmonary Hypertension: Classification and Treatment

Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest as assessed by right heart catheterization, and is classified into five major groups based on etiology, pathophysiology, and treatment approach. 1

Definition and Diagnosis

PH is a hemodynamic disorder characterized by:

• mPAP ≥25 mmHg at rest on right heart catheterization
• Normal mPAP at rest is 14 ± 3 mmHg with upper limit of normal ~20 mmHg
• The clinical significance of mPAP between 21-24 mmHg remains unclear

Right heart catheterization is essential for definitive diagnosis and classification, as it allows measurement of:

• Pulmonary arterial pressure
• Pulmonary vascular resistance (PVR)
• Pulmonary artery wedge pressure (PAWP)

Comprehensive Classification

PH is classified into 5 major groups according to the updated clinical classification 1:

Group 1: Pulmonary Arterial Hypertension (PAH)

• Hemodynamic criteria: Pre-capillary PH with PVR >3 Wood units and PAWP ≤15 mmHg
• Subgroups:
  • Idiopathic PAH
  • Heritable PAH (BMPR2 and other mutations)
  • Drug and toxin-induced PAH
  • Associated PAH (connective tissue disease, HIV, portal hypertension, congenital heart disease, schistosomiasis)
  • Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis
  • Persistent pulmonary hypertension of the newborn

Group 2: PH due to Left Heart Disease

• Most common form of PH
• Subgroups:
  • Left ventricular systolic dysfunction
  • Left ventricular diastolic dysfunction
  • Valvular disease
  • Congenital/acquired left heart inflow/outflow tract obstruction
  • Congenital/acquired pulmonary veins stenosis

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

• Subgroups:
  • Chronic obstructive pulmonary disease
  • Interstitial lung disease
  • Mixed restrictive and obstructive pattern
  • Sleep-disordered breathing
  • Alveolar hypoventilation disorders
  • Chronic high-altitude exposure
  • Developmental lung diseases

Group 4: Chronic Thromboembolic PH (CTEPH)

• Subgroups:
  • Chronic thromboembolic pulmonary hypertension
  • Other pulmonary artery obstructions (tumors, arteritis, congenital stenoses, parasites)

Group 5: PH with Unclear/Multifactorial Mechanisms

• Subgroups:
  • Hematological disorders (chronic hemolytic anemia, myeloproliferative disorders)
  • Systemic disorders (sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis)
  • Metabolic disorders (glycogen storage disease, Gaucher disease, thyroid disorders)
  • Others (tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic renal failure)

Treatment Approach

Treatment strategies vary significantly based on PH classification:

Group 1 (PAH) Treatment

PAH-specific therapies target three main pathways:

1. Nitric oxide pathway:

   • Phosphodiesterase-5 inhibitors: sildenafil, tadalafil
   • Soluble guanylate cyclase stimulator: riociguat

2. Endothelin pathway:

   • Endothelin receptor antagonists: bosentan, ambrisentan, macitentan

3. Prostacyclin pathway:

   • Prostacyclin analogues: epoprostenol, treprostinil, iloprost
   • Prostacyclin receptor agonist: selexipag

Treatment algorithm for PAH:

1. Initial evaluation of risk status (low, intermediate, high)
2. Vasoreactivity testing for idiopathic, heritable, and drug-induced PAH
3. For vasoreactive patients: High-dose calcium channel blockers
4. For non-vasoreactive patients:
   • Low/intermediate risk: Initial combination therapy (e.g., ambrisentan + tadalafil)
   • High risk: Initial combination including IV/SC prostacyclin analogues
5. Treatment goal: Achieve low-risk status (WHO-FC II, 6MWD >440m, good RV function) 1

Group 2-5 Treatment

• Group 2: Optimize treatment of underlying heart disease; PAH-specific therapies not recommended
• Group 3: Treat underlying lung disease and provide oxygen therapy if hypoxemic
• Group 4: Pulmonary endarterectomy for operable cases; balloon pulmonary angioplasty or riociguat for inoperable cases
• Group 5: Treat underlying condition; limited evidence for PAH-specific therapies

Special Considerations

• Sildenafil is FDA-approved for PAH to improve exercise ability and delay clinical worsening 2
• Referral to expert PH centers is crucial for accurate diagnosis and optimal management 1
• Combination therapy targeting multiple pathways has shown improved outcomes compared to monotherapy 3
• Supportive measures include:
  • Supervised exercise training for deconditioned patients
  • Oxygen therapy for hypoxemic patients
  • Diuretics for fluid overload
  • Psychosocial support
  • Avoidance of pregnancy in PAH patients

Common Pitfalls to Avoid

1. Misclassification of PH: Right heart catheterization is essential for definitive diagnosis and classification
2. Delayed diagnosis: Early symptoms are nonspecific (dyspnea, fatigue)
3. Inappropriate use of PAH-specific therapies in Group 2 or 3 PH, which may worsen outcomes
4. Failure to identify potentially treatable causes like CTEPH
5. Inadequate risk assessment in PAH patients, which should guide treatment decisions

The most recent evidence indicates that early combination therapy targeting multiple pathways improves outcomes in PAH patients, and treatment should be guided by comprehensive risk assessment with the goal of achieving low-risk status 1, 3.