What is Pulmonary Arterial Hypertension (PAH)?

Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a hemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, with a pulmonary arterial wedge pressure ≤15 mmHg and pulmonary vascular resistance >3 Wood units, as assessed by right heart catheterization. 1

Definition and Pathophysiology

PAH is characterized by progressive remodeling of the distal pulmonary arteries, resulting in:

• Increased pulmonary vascular resistance
• Elevated pulmonary arterial pressure
• Right ventricular failure if untreated
• Ultimately death without appropriate intervention

The pathophysiology involves multiple mechanisms:

• Vasoconstriction
• Vascular proliferation
• In situ thrombosis
• Remodeling of all three levels of the vascular walls
• Imbalance in vasoconstrictor/vasodilator milieu
• Imbalance of proliferation and apoptosis (favoring proliferation) 2

Classification

PAH is part of a broader classification system for pulmonary hypertension, which includes five main groups:

1. Group 1: Pulmonary Arterial Hypertension (PAH)

   • Idiopathic PAH
   • Heritable PAH (BMPR2, ALK1, endoglin mutations)
   • Drug and toxin-induced
   • Associated with (APAH):
     • Connective tissue diseases
     • HIV infection
     • Portal hypertension
     • Congenital heart disease
     • Schistosomiasis
     • Chronic hemolytic anemia
   • Persistent pulmonary hypertension of the newborn
   • Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis

2. Group 2: PH due to left heart disease

   • Systolic dysfunction
   • Diastolic dysfunction
   • Valvular disease

3. Group 3: PH due to lung diseases and/or hypoxemia

   • COPD
   • Interstitial lung disease
   • Sleep-disordered breathing
   • Alveolar hypoventilation disorders
   • Chronic exposure to high altitude
   • Developmental abnormalities

4. Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Group 5: PH with unclear/multifactorial mechanisms

   • Hematological disorders
   • Systemic disorders
   • Metabolic disorders
   • Others (tumor obstruction, fibrosing mediastinitis, chronic renal failure) 2

Diagnosis

The diagnosis of PAH requires a systematic approach:

1. Clinical Presentation:

   • Nonspecific symptoms: breathlessness, fatigue, weakness
   • More advanced symptoms: angina, syncope, abdominal distension
   • 90% of patients with idiopathic PAH have abnormal chest radiographs at diagnosis 2

2. Diagnostic Testing:

   • Echocardiography: Initial screening tool that estimates pulmonary pressures
   • Right Heart Catheterization: Gold standard for diagnosis, confirming:
     • Mean PAP ≥25 mmHg at rest
     • Pulmonary wedge pressure ≤15 mmHg
     • Pulmonary vascular resistance >3 Wood units 1
   • Additional Tests:
     • Pulmonary function tests
     • Ventilation/perfusion scanning (to rule out CTEPH)
     • CT scans
     • Blood tests for associated conditions

Prognosis and Mortality

Without treatment, PAH has a poor prognosis:

• Approximately 15% mortality within 1 year even on modern therapy 2
• 5-year mortality of ~40% for mPAP ≥25 mmHg 1
• Even mildly elevated pulmonary pressures are associated with increased mortality

Poor prognostic indicators include:

• Advanced functional class
• Poor exercise capacity
• Right ventricular dysfunction 1

Management Approach

Treatment of PAH has evolved significantly and now includes:

1. General Measures:

   • Oral anticoagulation (target INR 1.5-2.5)
   • Diuretics for fluid retention
   • Oxygen therapy when indicated
   • Avoidance of excessive physical activity
   • Effective contraception for women of childbearing age 2, 3

2. PAH-Specific Therapies targeting three main pathways:

   • Nitric oxide pathway: Sildenafil, tadalafil, riociguat
   • Prostacyclin pathway: Epoprostenol, treprostinil
   • Endothelin pathway: Bosentan, ambrisentan 4

3. Combination Therapy:

   • Current guidelines favor upfront or sequential combination therapy targeting multiple pathways
   • This approach has shown improved morbidity and mortality compared to monotherapy 4

Clinical Considerations and Pitfalls

• Delayed Diagnosis: Due to nonspecific early symptoms, diagnosis is often delayed until advanced stages
• Misclassification: Essential to distinguish between different types of PH as treatments vary
• Inadequate Assessment: Right heart catheterization is mandatory for definitive diagnosis and should not be replaced by echocardiography alone
• Specialized Care: Patients with suspected PAH should be referred to specialized PH centers for optimal management 1

With advances in understanding and treatment options, the prognosis of PAH has improved significantly, with 5-year survival increasing from 34% in 1991 to more than 60% in 2015 4.