Progression of vascular remodeling in pulmonary vein obstruction

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 re-suturing the left lower PV followed by weekly hemodynamics 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 (mTOR) in smooth muscle-like cells at the anastomotic neointima. In addition, contractile to synthetic phenotypic transition, i.e., dedifferentiation of smooth muscle cells and mTOR pathway activation in the neointima of upstream PVs were observed. Rapamycin-eluting films externally applied around the anastomotic site inhibited the activation of mTOR in the smooth muscle-like cells of neointima, and delayed PV anastomotic stenosis. Conclusions We demonstrated the evidences on dedifferentiation of smooth muscle-like cells and mTOR 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.