Imatinib Mesylate and Sirolimus Inhibit Vascular Fibroproliferative Remodeling in Pulmonary Vein Stenosis

Abstract

Highlights What are the main findings? In three patients with pulmonary vein stenosis (PVS), fibroproliferative remodeling was observed in pulmonary veins resected during surgical anatomical repair, which exhibited increased wall shear stress (WSS). The cellular substrate underlying this process appeared to be driven by endothelial-to-mesenchymal transition (EndMT) of endothelial cells (ECs). In vitro studies demonstrated that clinically relevant concentrations of imatinib mesylate and sirolimus significantly inhibited EndMT in ECs derived from sites of PVS. What is the implication of the main finding? Fibroproliferative ECs undergoing EndMT are likely the cellular drivers of PVS and may be amenable to targeted therapy with imatinib mesylate and sirolimus. Abstract Background: Pulmonary vein stenosis (PVS) is a progressive disease characterized by neointimal hyperplasia with poor outcomes. Clinical observations show that adjunctive therapy with imatinib mesylate and sirolimus is associated with improved survival and reduced rates of reintervention. In this study, we aimed to investigate the cellular mechanisms underlying PVS development and progression and to elucidate how these targeted therapies modulate these processes. Methods: We retrospectively analyzed cardiac catheterization and computed tomography, and lung scan data from three patients with PVS to estimate wall shear stress (WSS) at multiple time points. Tissue specimens resected during anatomical repair surgery were analyzed for tissue composition and fibrosis using hematoxylin and eosin staining, Masson’s trichrome staining, and flow cytometric analysis of endothelial cell (ECs) and fibroblast markers to determine endothelial-to-mesenchymal transition (EndMT). The safety and efficacy of imatinib mesylate and sirolimus were evaluated in healthy and PVS-derived ECs using cellular viability and proliferation assays, and by assessing fibrotic marker expression indicative of EndMT. Results: Patients exhibited severely elevated WSS estimates at multiple time points throughout disease progression. Disproportionate fibrotic remodeling driven by ECs transitioning into mesenchymal cells through EndMT was the cellular substrate of resected tissue in PVS. Targeted therapy with clinically relevant concentrations of imatinib mesylate and sirolimus was safe and significantly inhibited fibroproliferation and EndMT. At follow-up, all patients were alive and free of surgical and stent-based reintervention after anatomic repair surgery and adjunctive imatinib mesylate and sirolimus therapy. Conclusions: Fibroproliferative ECs undergoing EndMT are likely the cellular substrate underlying PVS development and progression. A multimodal approach consisting of anatomically focused surgical repair with adjunctive imatinib mesylate and sirolimus therapy may attenuate fibroproliferative remodeling.