Julia Gaal, Sophie C. Doettl, Kerstin Saraci, Cindy Zajac, Alexa von Mueffling, Peter E. Hammer, Magnus von Piechowski, Verena Gebert, Andrei-Antonio M. Caracioni, Daniel Diaz-Gil, Viktoria Weixler, Pedro J. Del Nido, Kathy Jenkins, Ingeborg Friehs
Boston Children’s Hospital and Harvard Medical School. German Heart Center of Charité-Universitätsmedizin Berlin.
United States and Germany
Children
Children 2026; 13:
DOI: 10.3390/children13091280
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.
Category
Segmental Pulmonary Venous Disease. Without a Focus on Pulmonary Hypertension
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Surgical and Catheter-mediated Interventions for Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes