Pulmonary vein stenosis and the pathophysiology of "upstream" pulmonary veins

J Thorac Cardiovasc Surg. 2014 Jul;148(1):245-53. doi: 10.1016/j.jtcvs.2013.08.046. Epub 2013 Sep 29.

Abstract

Background: Surgical and catheter-based interventions on pulmonary veins are associated with pulmonary vein stenosis (PVS), which can progress diffusely through the "upstream" pulmonary veins. The mechanism has been rarely studied. We used a porcine model of PVS to assess disease progression with emphasis on the potential role of endothelial-mesenchymal transition (EndMT).

Methods: Neonatal piglets underwent bilateral pulmonary vein banding (banded, n = 6) or sham operations (sham, n = 6). Additional piglets underwent identical banding and stent implantation in a single-banded pulmonary vein 3 weeks postbanding (stented, n = 6). At 7 weeks postbanding, hemodynamics and upstream PV pathology were assessed.

Results: Banded piglets developed pulmonary hypertension. The upstream pulmonary veins exhibited intimal thickening associated with features of EndMT, including increased transforming growth factor (TGF)-β1 and Smad expression, loss of endothelial and gain of mesenchymal marker expression, and coexpression of endothelial and mesenchymal markers in banded pulmonary vein intimal cells. These immunopathologic changes and a prominent myofibroblast phenotype in the remodeled pulmonary veins were consistently identified in specimens from patients with PVS, in vitro TGF-β1-stimulated cells isolated from piglet and human pulmonary veins, and human umbilical vein endothelial cells. After stent implantation, decompression of a pulmonary vein was associated with reappearance of endothelial marker expression, suggesting the potential for plasticity in the observed pathologic changes, followed by rapid in-stent restenosis.

Conclusions: Neonatal pulmonary vein banding in piglets recapitulates critical aspects of clinical PVS and highlights a pathologic profile consistent with EndMT, supporting the rationale for evaluating therapeutic strategies designed to exploit reversibility of upstream pulmonary vein pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biomarkers / metabolism
  • Cells, Cultured
  • Constriction, Pathologic
  • Disease Models, Animal
  • Disease Progression
  • Epithelial-Mesenchymal Transition
  • Hemodynamics
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / pathology
  • Hyperplasia
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / physiopathology
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Neointima
  • Phenotype
  • Pulmonary Veins / metabolism
  • Pulmonary Veins / pathology
  • Pulmonary Veins / physiopathology*
  • Pulmonary Veno-Occlusive Disease / complications
  • Pulmonary Veno-Occlusive Disease / metabolism
  • Pulmonary Veno-Occlusive Disease / pathology
  • Pulmonary Veno-Occlusive Disease / physiopathology*
  • Recurrence
  • Smad Proteins / metabolism
  • Swine
  • Time Factors
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Biomarkers
  • Smad Proteins
  • Transforming Growth Factor beta1