What is the pathophysiology of pulmonary hypertension?

Pathophysiology of Pulmonary Hypertension

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

Definition and Classification

• PH is defined as mPAP ≥25 mmHg at rest measured via right heart catheterization, with more recent guidelines suggesting a redefinition threshold of >20 mmHg 1, 2
• PH is classified into five major groups based on etiology, pathophysiology, and therapeutic approaches 3:
  • Group 1: Pulmonary Arterial Hypertension (PAH)
  • Group 2: PH Due to Left Heart Disease
  • Group 3: PH Due to Lung Diseases and/or Hypoxia
  • Group 4: Chronic Thromboembolic PH (CTEPH)
  • Group 5: PH with Unclear and/or Multifactorial Mechanisms

Hemodynamic Classifications

• Pre-capillary PH: mPAP ≥25 mmHg with pulmonary wedge pressure (PWP) ≤15 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood units 1
• Post-capillary PH: mPAP ≥25 mmHg with PWP >15 mmHg 1
• Combined pre- and post-capillary PH: mPAP >20 mmHg, PAWP >15 mmHg, and PVR ≥3 Wood units 1

Core Pathophysiological Mechanisms

• PH is characterized by progressive loss and remodeling of pulmonary arteries, resulting in increased pulmonary vascular resistance and right heart failure 4
• The fundamental pathophysiological changes include:
  • Vascular obstruction
  • Arterial stiffening
  • Vasoconstriction
  • Adverse vascular remodeling 2
• Without proactive management, these changes lead to right ventricular hypertrophy and ultimately failure, which is the main cause of death 2

Molecular Pathways in PAH

• Imbalanced TGF-β superfamily signaling plays a critical role in the pathogenesis of PAH 5:
  • Overactive pro-proliferative SMAD2/3 signaling
  • Deficient anti-proliferative SMAD1/5/8 signaling
• This imbalance contributes to dysregulated vascular cell proliferation, a hallmark of PAH 5
• Rho-kinase activation has been directly observed in the pulmonary arteries of PAH patients, contributing to vasoconstriction and remodeling 6

Systemic Manifestations

• Although traditionally viewed as limited to the pulmonary circulation, PH also exhibits systemic vascular dysfunction 4:
  • Impaired brachial artery flow-mediated dilation
  • Abnormal cerebral blood flow
  • Skeletal myopathy
  • Intrinsic kidney disease
• These systemic manifestations may share common pathophysiological mechanisms with pulmonary vascular changes 4

Pathophysiological Progression

• The pathophysiological sequence in PH typically involves:
  1. Initial vascular injury (genetic, inflammatory, toxic, or hemodynamic)
  2. Endothelial dysfunction and smooth muscle cell proliferation
  3. Progressive vascular remodeling and obstruction
  4. Increased pulmonary vascular resistance
  5. Right ventricular adaptation (hypertrophy)
  6. Right ventricular failure 7, 2

Group-Specific Pathophysiology

• Group 1 (PAH): Characterized by pre-capillary PH with PVR >3 Wood units due to pulmonary arterial remodeling 3
• Group 2 (Left Heart Disease): Post-capillary PH with PCWP >15 mmHg due to backward transmission of elevated left atrial pressure 3
• Group 3 (Lung Diseases/Hypoxia): PH due to alveolar hypoxia causing pulmonary vasoconstriction and vascular remodeling 3
• Group 4 (CTEPH): Persistent obstruction of pulmonary arteries following pulmonary embolism 3
• Group 5 (Unclear/Multifactorial): Includes hematological disorders and systemic conditions with complex mechanisms 3

Clinical Implications of Pathophysiology

• The median life expectancy from diagnosis in patients with idiopathic PAH, before disease-specific therapy, was only 2.8 years 1
• Understanding the pathophysiology has led to targeted therapies addressing specific pathways:
  • Vasodilators (conventional therapy)
  • Rho-kinase inhibitors (e.g., fasudil)
  • Soluble guanylate cyclase activators (e.g., riociguat)
  • Tyrosine kinase inhibitors (e.g., imatinib) 6

Pathophysiological Considerations in Special Populations

• In pregnancy, the normal cardiovascular adaptations (increased cardiac output, blood volume) can severely exacerbate PH pathophysiology, leading to high maternal and fetal mortality 8
• The pathophysiological changes in PH are influenced by metabolic abnormalities, genetic factors, and systemic vascular dysfunction 4