Pulmonary Hypertension

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1. Definition

Pulmonary hypertension (PH) is a hemodynamic and pathophysiological condition defined by an increase in mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg at rest, as assessed by right heart catheterization (RHC). This updated threshold is based on the 2022 ESC/ERS Guidelines. It is distinct from systemic hypertension and represents an elevated afterload specific to the right ventricle.

2. General Information & Classification (World Health Organization Groups)

PH is not a single disease but a complication of multiple disorders. The WHO classifies PH into five groups based on etiology and pathological mechanism. Understanding this classification is critical for appropriate management.

Most Common Causes & Approximate Prevalence:

• Group 2: PH due to left heart disease (~65-80% of all PH cases). Most common etiology overall.
• Group 3: PH due to lung diseases and/or hypoxia (~10-20% of cases). Includes COPD and ILD.
• Group 1: Pulmonary arterial hypertension (PAH) (~1-5% of cases). A rare but distinct vasculopathy.
• Group 4: PH due to pulmonary artery obstructions (CTEPH) (~2-5%). [Chronická tromboembolická plicní hypertenze / Chronic Thrombo-Embolic Pulmonary Hypertension]
• Group 5: PH with unclear/multifactorial mechanisms.

3. Etiologies & Pathophysiological Mechanisms of the Three Most Common Groups

A. Group 1: Pulmonary Arterial Hypertension (PAH)

• Etiologies: Idiopathic (IPAH), heritable (e.g., BMPR2 mutations), drug/toxin-induced, and associated conditions (connective tissue disease, HIV, portal hypertension).
• Core Mechanisms: A pre-capillary vasculopathy characterized by:
  1. Vasoconstriction: Imbalance favoring endothelin-1 over nitric oxide and prostacyclin.
  2. Vascular Remodeling: Hyperplasia/hypertrophy of pulmonary artery smooth muscle cells, leading to medial thickening.
  3. Plexiform Lesions: Focal proliferation of endothelial cells forming glomerular-like structures that obliterate the arterial lumen. This is driven by endothelial dysfunction, apoptosis resistance, and a cancer-like proliferative phenotype.
  4. In-situ Thrombosis: A pro-thrombotic state within small arteries.

B. Group 2: PH due to Left Heart Disease (Post-capillary PH)

• Etiologies: Left ventricular systolic/diastolic dysfunction, valvular heart disease (e.g., mitral stenosis/regurgitation).
• Core Mechanisms: Passive backward transmission of elevated left atrial pressure.
  1. Increased Pulmonary Venous Pressure: Elevated left ventricular filling pressure (e.g., LVEDP) is transmitted retrograde to the pulmonary veins, capillaries, and ultimately the arterial circuit.
  2. Pulmonary Venous Remodeling: Chronic venous congestion leads to structural changes in pulmonary veins (arterialization, intimal fibrosis).
  3. Reactive Arterial Vasoconstriction & Remodeling: Chronic elevation in venous pressure can trigger a "reactive" component of pre-capillary PH (combined pre- and post-capillary PH) via mechanisms similar to Group 1, worsening prognosis.

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

Etiologies: Chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, alveolar hypoventilation disorders.

• Core Mechanisms: Hypoxic pulmonary vasoconstriction and vascular destruction.
  1. Hypoxic Pulmonary Vasoconstriction (HPV): Alveolar hypoxia triggers constriction of small pulmonary arteries, a physiologic reflex to shunt blood away from poorly ventilated areas. In chronic lung disease, this becomes diffuse and sustained.
  2. Vascular Remodeling: Chronic hypoxia induces smooth muscle hyperplasia and extension of muscle into normally non-muscular arterioles.
  3. Vascular Loss & Parenchymal Destruction: In emphysema (COPD) and fibrotic lung disease (ILD), the capillary bed is physically destroyed, increasing vascular resistance.

4. Diagnostic Approach

Diagnosis requires a systematic sequence to confirm PH, determine severity, and correctly assign the WHO group.

1. Clinical Suspicion: Symptoms (dyspnea, fatigue, chest pain, syncope), signs (loud P2, TR murmur, RV heave, peripheral edema).
2. Non-Invasive Screening: Transthoracic echocardiogram estimates pulmonary artery systolic pressure (PASP) and assesses right ventricular size/function, and left heart/valvular pathology.
3. Confirmatory Testing & Phenotyping:
   • Right Heart Catheterization (RHC): Gold standard. Confirms mPAP ≥20 mmHg and determines hemodynamic profile:
     • Pre-capillary PH (PAWP ≤15 mmHg, PVR >2 WU) [Wood Units (WU) are a simplified unit of measurement for vascular resistance, most commonly used in cardiology to quantify Pulmonary Vascular Resistance (PVR)]
     • Post-capillary PH (PAWP >15 mmHg).
   • Etiologic Work-up: CT chest (lung parenchyma, thromboembolic disease), pulmonary function tests + DLCO, ventilation/perfusion scan (for CTEPH), serology (connective tissue disease, HIV, liver disease), sleep study.
4. Assessment of Severity: Functional class (WHO-FC), 6-minute walk distance, BNP/NT-proBNP, cardiac imaging (RV function).

5. Therapeutic Strategies and Mechanisms of Action

Therapy is entirely group-specific. Misapplication (e.g., PAH therapy in Group 2) can cause harm.

• Group 2 (Left Heart Disease): Treat the underlying left heart condition. Diuretics (reduce volume overload), guideline-directed medical therapy for heart failure (Beta-blockers, ACEi/ARB/ARNI, MRAs), valvular intervention. PAH-specific therapies are contraindicated.
• Group 3 (Lung Disease): Maximize treatment of the underlying lung disease and correct hypoxia. Long-term oxygen therapy (LTOT) to attenuate hypoxic vasoconstriction, pulmonary rehabilitation, CPAP for sleep apnea. Role of PAH-specific therapy is limited and under investigation; may be considered in severe, disproportionate PH in select ILD patients.
  
• Group 1 (PAH): Target the pathogenic pathways of the pulmonary vasculopathy.
  1. Calcium Channel Blockers: For the small subset of acute vasoresponders. MOA: Direct pulmonary arterial vasodilation.
  2. Disease-Targeting Therapies (Used in combination):
     • Endothelin Receptor Antagonists (ERA: bosentan, ambrisentan, macitentan): MOA: Block endothelin-1 binding to ETA/ETB receptors, inhibiting vasoconstriction and smooth muscle proliferation.
     • Phosphodiesterase-5 Inhibitors (PDE5i: sildenafil, tadalafil) & Guanylate Cyclase Stimulators (riociguat): MOA: Enhance NO signaling. PDE5i prevents breakdown of cGMP; riociguat directly stimulates soluble guanylate cyclase, increasing cGMP. This promotes vasodilation and has anti-proliferative effects.
     • Prostacyclin Pathway Agonists (epoprostenol, treprostinil, iloprost, selexipag): MOA: Mimic prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet aggregation and smooth muscle proliferation. Epoprostenol is continuous IV; others are subcutaneous, inhaled, or oral.
  3. Initial Combination Therapy: Early, aggressive dual or triple oral combination therapy is standard for most patients to improve long-term outcomes.
  4. Advanced Therapies: Balloon pulmonary angioplasty (for CTEPH/Group 4), atrial septostomy, lung transplantation.

6. Recommended Course of Action

1. Confirm & Classify: Use RHC to confirm PH and definitively determine pre- vs. post-capillary physiology. Perform exhaustive etiologic work-up to assign the correct WHO Group.
2. Treat the Cause: Direct all initial efforts toward the underlying disease in Groups 2, 3, 4, and 5.
3. PAH-Specific Management: For confirmed Group 1 PAH, refer to a specialized center. Initiate combination therapy based on risk stratification (low, intermediate, high). Monitor response closely with clinical, biochemical, and hemodynamic parameters.
4. Supportive Care: Diuretics for volume overload, oxygen for hypoxemia, anticoagulation (consider in IPAH).