What is pulmonary hypertension?

Pulmonary Hypertension

Pulmonary hypertension (PH) is a hemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest as assessed by right heart catheterization. 1

Definition and Classification

Pulmonary hypertension is characterized by elevated pressure in the pulmonary arteries, which can lead to right ventricular failure and death if left untreated. The most recent definition from the 6th World Symposium on Pulmonary Hypertension (2018) has updated the threshold to mPAP >20 mmHg 1, 2.

PH is classified into five major groups based on etiology:

1. Pulmonary Arterial Hypertension (PAH, Group 1)

   • Idiopathic
   • Heritable (BMPR2 mutations and others)
   • Drug/toxin-induced
   • Associated with connective tissue disease, HIV, portal hypertension, congenital heart disease, schistosomiasis

2. PH due to Left Heart Disease (Group 2)

   • Left ventricular systolic/diastolic dysfunction
   • Valvular disease
   • Congenital/acquired left heart inflow/outflow tract obstructions

3. PH due to Lung Diseases and/or Hypoxia (Group 3)

   • Chronic obstructive pulmonary disease
   • Interstitial lung disease
   • Sleep-disordered breathing
   • Alveolar hypoventilation disorders

4. Chronic Thromboembolic PH (CTEPH) and other Pulmonary Artery Obstructions (Group 4)

   • Chronic thromboembolic disease
   • Tumors, arteritis, congenital stenoses

5. PH with Unclear and/or Multifactorial Mechanisms (Group 5)

   • Hematological disorders
   • Systemic disorders (sarcoidosis, etc.)
   • Metabolic disorders
   • Others 1, 3

Hemodynamic Definitions

PH is further categorized based on hemodynamic parameters:

• Pre-capillary PH: mPAP >20 mmHg, PAWP ≤15 mmHg, PVR ≥3 Wood units (Groups 1,3,4,5)
• Isolated post-capillary PH: mPAP >20 mmHg, PAWP >15 mmHg, PVR <3 Wood units (Groups 2,5)
• Combined pre- and post-capillary PH: mPAP >20 mmHg, PAWP >15 mmHg, PVR ≥3 Wood units (Groups 2,5) 3, 2

Pathophysiology

Pulmonary hypertension involves multiple pathogenic mechanisms:

• Vasoconstrictor/vasodilator imbalance
• Imbalance between proliferation and apoptosis favoring proliferation
• Vascular remodeling with medial hypertrophy, intimal proliferation, and adventitial thickening
• Thrombosis in situ
• Inflammation 3

Key molecular pathways involved include:

• Nitric oxide pathway
• Endothelin-1 pathway
• Prostacyclin pathway
• Activin/bone morphogenetic protein pathway 3

Clinical Presentation

The most common symptoms include:

• Exertional dyspnea (most common)
• Fatigue
• Palpitations
• Angina
• Peripheral edema
• Hepatomegaly
• Ascites
• Syncope
• Rarely, unilateral vocal cord paralysis 1, 4

As the disease progresses, signs of right heart failure become more prominent.

Diagnosis

Diagnosis of PH follows a stepwise approach:

1. Clinical suspicion based on symptoms, risk factors, and physical examination
2. Non-invasive screening with echocardiography
3. Confirmation with right heart catheterization (RHC) - the gold standard for diagnosis
4. Classification based on etiology to guide treatment 3, 2

Important diagnostic tests:

• Echocardiography (initial screening)
• Ventilation-perfusion scanning (crucial to exclude CTEPH)
• Pulmonary function tests
• CT scan of the chest
• Right heart catheterization (definitive diagnosis) 3

Treatment

Treatment approaches differ based on PH classification:

1. For PAH (Group 1):

   • PAH-specific therapies targeting three main pathways:
     • Prostacyclin pathway (epoprostenol, treprostinil, iloprost)
     • Endothelin receptor antagonists
     • Phosphodiesterase-5 inhibitors
   • Current guidelines favor upfront or sequential combination therapy 3, 5

2. For PH due to Left Heart Disease (Group 2):

   • Treatment of underlying left heart disease
   • PAH-specific therapies may be harmful 3

3. For PH due to Lung Diseases (Group 3):

   • Optimization of respiratory management
   • Oxygen therapy when indicated 3

4. For CTEPH (Group 4):

   • Pulmonary endarterectomy for eligible patients
   • Riociguat for inoperable cases 3

5. For Group 5 PH:

   • Address underlying condition 3

Prognosis

Prognosis varies by PH group and severity:

• PAH has approximately 15% mortality within 1 year even with modern therapy 3
• Higher mPAP values correlate with increased mortality risk regardless of PH group 3
• The presence of right ventricular dysfunction significantly worsens prognosis 3, 4

Important Considerations and Pitfalls

1. Avoid using PAH-specific therapies in non-PAH forms of PH, especially in PH due to left heart disease, as this can be harmful 3

2. Do not rely solely on echocardiography for diagnosis without confirmatory right heart catheterization, as this can lead to misclassification 3, 2

3. Always perform ventilation-perfusion scanning to avoid missing potentially treatable CTEPH 3

4. Consider the possibility of combined pre- and post-capillary PH in patients with left heart disease 3

5. Recognize that diagnostic delay remains a significant issue in PH, with symptoms often attributed to more common conditions 1

Pulmonary hypertension represents a spectrum of diseases with varying etiologies but similar hemodynamic consequences. Accurate classification is essential for appropriate treatment selection and optimal patient outcomes.