What is the pathophysiology of pulmonary hypertension?

Pathophysiology of Pulmonary Hypertension

Pulmonary hypertension (PH) involves multiple pathogenic pathways including vasoconstrictor/vasodilator imbalance, proliferation/apoptosis imbalance favoring proliferation, vascular remodeling, thrombosis in situ, and inflammation, ultimately leading to right heart failure and death. 1

Definition and Hemodynamic Criteria

• PH is defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest as assessed by right heart catheterization 2
• Normal pulmonary artery pressure is 14 ± 3 mmHg with an upper limit of normal of approximately 20 mmHg 1
• Pulmonary arterial hypertension (PAH, Group 1) is characterized by:
  • Pre-capillary PH
  • Pulmonary vascular resistance >3 Wood units
  • Absence of other causes of pre-capillary PH 2

Pathophysiological Mechanisms

Vascular Remodeling

• Medial hypertrophy of pulmonary arteries
• Intimal proliferation and fibrosis
• Adventitial thickening
• Progressive narrowing of pulmonary vessel lumen 1, 3

Cellular and Molecular Pathways

• Vasoconstrictor/vasodilator imbalance:

  • Reduced production of vasodilators (nitric oxide, prostacyclin)
  • Increased production of vasoconstrictors (endothelin-1) 1, 3

• Proliferation/apoptosis imbalance:

  • Excessive proliferation of pulmonary vascular cells
  • Resistance to apoptosis
  • Results in obstructive lesions in pulmonary vasculature 1

• Inflammatory processes:

  • Recruitment of inflammatory cells (macrophages, monocytes, T and B-lymphocytes, dendritic cells, mast cells)
  • Perivascular inflammation contributing to vascular remodeling 4

• Thrombosis in situ:

  • Endothelial dysfunction
  • Platelet activation
  • Abnormal coagulation pathways 1

Consequences on Right Ventricle

• Increased afterload on right ventricle
• Right ventricular hypertrophy (adaptive response)
• Eventually right ventricular dilation and failure (maladaptive response)
• Right ventricular failure is the main cause of death in PH 5, 6

Classification of Pulmonary Hypertension

PH is classified into five groups based on etiology, each with distinct pathophysiological mechanisms:

Group 1: Pulmonary Arterial Hypertension (PAH)

• Idiopathic PAH
• Heritable PAH (BMPR2 mutations and others)
• Drug and toxin-induced PAH
• Associated PAH (connective tissue disease, HIV, portal hypertension, congenital heart disease, schistosomiasis) 2, 1

Group 2: PH due to Left Heart Disease

• Left ventricular systolic dysfunction
• Left ventricular diastolic dysfunction
• Valvular disease
• Congenital/acquired left heart inflow/outflow tract obstruction
• Pathophysiology: Passive backward transmission of elevated left atrial pressure leading to pulmonary venous congestion 2, 7

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

• Chronic obstructive pulmonary disease
• Interstitial lung disease
• Sleep-disordered breathing
• Pathophysiology: Hypoxic pulmonary vasoconstriction, destruction of pulmonary vasculature, and mechanical factors 2

Group 4: Chronic Thromboembolic PH (CTEPH)

• Pathophysiology: Mechanical obstruction of pulmonary arteries by organized thrombi, coupled with vascular remodeling 2

Group 5: PH with Unclear and/or Multifactorial Mechanisms

• Hematological disorders
• Systemic disorders
• Metabolic disorders
• Others 2

Special Pathophysiological Considerations

Congenital Heart Disease-Associated PAH

• Systemic-to-pulmonary shunts lead to increased pulmonary blood flow
• Progressive vascular remodeling due to chronic volume and pressure overload
• May progress to Eisenmenger's syndrome with reversed shunt direction 2

Combined Pre- and Post-capillary PH

• Initially passive elevation of pulmonary pressures due to left heart disease
• Chronic elevation leads to secondary pulmonary vascular remodeling
• Results in "reactive" component with increased pulmonary vascular resistance 7

Clinical Implications of Pathophysiology

• The pathophysiological mechanisms determine treatment approaches:

  • PAH-specific therapies target the nitric oxide, endothelin, and prostacyclin pathways
  • These therapies should not be used in non-PAH forms of PH, particularly in PH due to left heart disease 1

• Right ventricular function is a critical determinant of prognosis:

  • Higher mPAP values correlate with increased mortality risk regardless of PH group
  • The presence of right ventricular dysfunction significantly worsens prognosis 1

• Understanding the specific pathophysiological mechanisms is essential for:

  • Accurate classification of PH
  • Selection of appropriate therapy
  • Prediction of prognosis 1, 5