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
Stenosis or Obstruction of Pulmonary Veins Following Surgical Repair of Anomalous Pulmonary Venous Connections
Medical Therapy to Prevent Progression of Disease. Efficacy or Lack of Efficacy
Medical Therapy to Prevent Recurrence of Disease after an Intervention. Efficacy or Lack of Efficacy
Catheter-mediated Interventions: Efficacy or Lack of Efficacy
Surgical Interventions for Pulmonary Venous Obstruction After the Onset of Disease
Multidisciplinary, Interdisciplinary and Transdisciplinary Care
Year of Publication: 2026
Age Focus: Pediatric
Article Type: Case Reports or Retrospective Observations in Small Groups of Patients (≤10 patients). Studies of Vascular Biology and Mechanism of Disease.
Article Access: Free PDF File or Full Text Article Available Through PubMed or DOI: Yes