Naoki Masaki, Osamu Adachi, Shintaro Katahira, Yuriko Saiki, Akira Horii, Shunsuke Kawamoto, Yoshikatsu Saiki
Tohoku University Graduate School of Medicine.
Japan
Journal of Thoracic and Cardiovascular Surgery
J Thorac Cardiovasc Surg 2020; 160: 777-790.e5
DOI: 10.1016/j.jtcvs.2020.01.098
Abstract
Objectives: Pulmonary vein obstruction (PVO) frequently occurs after repair of total anomalous pulmonary vein connection with progression of intimal hyperplasia from the anastomotic site toward upstream pulmonary veins (PVs). However, the understanding of mechanism in PVO progression is constrained by lack of data derived from a physiological model of the disease, and no prophylaxis has been established. We developed a new PVO animal model, investigated the mechanisms of PVO progression, and examined a new prophylactic strategy.
Methods: We developed a chronic PVO model using infant domestic pigs by cutting and resuturing the left lower PV followed by weekly hemodynamic parameter measurement and angiographic assessment of the anastomosed PV. Subsequently, we tested a novel therapeutic strategy with external application of rapamycin-eluting film to the anastomotic site.
Results: We found the pig PVO model mimicked human PVO hemodynamically and histopathologically. This model exhibited increased expression levels of Ki-67 and phospho-mammalian target of rapamycin in smooth muscle-like cells at the anastomotic neointima. In addition, contractile to synthetic phenotypic transition; that is, dedifferentiation of smooth muscle cells and mammalian target of rapamycin pathway activation in the neointima of upstream PVs were observed. Rapamycin-eluting films externally applied around the anastomotic site inhibited the activation of mammalian target of rapamycin in the smooth muscle-like cells of neointima, and delayed PV anastomotic stenosis.
Conclusions: We demonstrate the evidence on dedifferentiation of smooth muscle-like cells and mammalian target of rapamycin pathway activation in the pathogenesis of PVO progression. Delivery of rapamycin to the anastomotic site from the external side delayed PV anastomotic stenosis, implicating a new therapeutic strategy to prevent PVO progression.
Category
Stenosis or Obstruction of Normal Pulmonary Venous Connections
Stenosis or Obstruction of Pulmonary Veins Following Surgical Repair of Anomalous Pulmonary Venous Connections
Medical Therapy to Prevent or Reverse the Onset of Disease. Efficacy or Lack of Efficacy
Medical Therapy to Prevent Progression of Disease. Efficacy or Lack of Efficacy
Year of Publication: 2020
Age Focus: Pediatric
Article Type: Animal Models of Disease and Therapy. Studies of Vascular Biology and Mechanism of Disease.
Article Access: Free PDF File or Full Text Article Available Through PubMed or DOI: Yes