Why are the arteries in the outer two-thirds of each lung disproportionately smaller in diameter than those at the hila in pulmonary arterial hypertension (PAH)?

Pathophysiology of Arterial Size Disparity in Pulmonary Arterial Hypertension

In pulmonary arterial hypertension (PAH), the arteries in the outer two-thirds of each lung are disproportionately smaller in diameter than those at the hila due to preferential pathological remodeling of distal pulmonary arteries (<500 μm in diameter) with relative sparing of proximal vessels. 1

Pathological Mechanisms Explaining This Disparity

Preferential Distal Arterial Involvement

• PAH pathological lesions specifically target the distal pulmonary arteries (<500 μm diameter) while largely sparing proximal vessels 1
• These distal vessels undergo several pathological changes:
  • Medial hypertrophy (smooth muscle thickening)
  • Intimal proliferative and fibrotic changes (both concentric and eccentric)
  • Adventitial thickening with moderate perivascular inflammatory infiltrates
  • Complex lesions (plexiform and dilated lesions)
  • Thrombotic lesions

Cellular and Molecular Mechanisms

The disparity in vessel size occurs due to:

1. Endothelial Dysfunction in Small Vessels

   • Impaired production of vasodilators (nitric oxide, prostacyclin)
   • Overexpression of vasoconstrictors (thromboxane A2, endothelin-1)
   • Reduced levels of other vasodilators like vasoactive intestinal peptide 1

2. Abnormal Cellular Proliferation

   • Proliferative changes affect multiple cell types in distal vessels:
     • Endothelial cells
     • Smooth muscle cells
     • Fibroblasts
   • Increased extracellular matrix production in the adventitia 1

3. Multifactorial Pathobiology

   • PAH has a complex pathobiology involving various biochemical pathways
   • Increased pulmonary vascular resistance (PVR) results from:
     • Vasoconstriction
     • Proliferative and obstructive remodeling
     • Inflammation
     • Thrombosis 1

Anatomical Distribution of Pathology

The European Society of Cardiology (ESC) guidelines clearly state that in PAH, pathological lesions specifically affect the distal pulmonary arteries while pulmonary veins remain classically unaffected 1. This selective involvement explains why:

• Proximal pulmonary arteries (at the hila) maintain relatively normal diameter
• Distal pulmonary arteries (in the outer two-thirds of lungs) become narrowed
• The disparity becomes more pronounced as the disease progresses

Clinical Implications

This anatomical disparity has important clinical and diagnostic implications:

• On imaging studies, enlargement of central pulmonary arteries with pruning of peripheral vessels is a characteristic finding 1
• CT findings in PAH include a main pulmonary artery diameter >29 mm (87% sensitive, 89% specific) 1
• The ratio of segmental pulmonary artery to accompanying bronchus >1:1 in central vessels with narrowing of peripheral vessels 1

Pathophysiological Progression

The disease progression follows this pattern:

1. Initial pathological changes begin in small distal pulmonary arteries
2. Progressive narrowing of these vessels increases pulmonary vascular resistance
3. Increased resistance leads to pulmonary arterial pressure elevation
4. Right ventricular afterload increases, leading to right heart failure
5. Central pulmonary arteries dilate in response to increased pressure while peripheral vessels continue to narrow

Common Pitfalls in Understanding PAH Pathology

• Pitfall #1: Confusing PAH with other forms of pulmonary hypertension. Each group has distinct pathological features - PAH specifically targets distal arteries while other forms may affect different vascular segments 1

• Pitfall #2: Assuming uniform vascular involvement. The disparity in vessel size is a characteristic feature of PAH and helps distinguish it from other vascular pathologies 1

• Pitfall #3: Overlooking the progressive nature of the disease. The disparity becomes more pronounced as the disease advances, with ongoing remodeling of distal vessels while proximal vessels dilate in response to increased pressure 1

This pattern of disproportionate narrowing of peripheral pulmonary arteries with relative preservation or dilation of central vessels is a hallmark radiographic and pathological finding in PAH that directly results from the disease's predilection for affecting small pulmonary arteries while sparing larger proximal vessels.