Fibroelastic Remodelling of the Endocardium on the Right Side of the Heart: Endothelial-to-Mesenchymal Transition in Pulmonary Atresia With Intact Ventricular Septum

OBJECTIVES: Patients with pulmonary atresia/critical pulmonary stenosis with intact ventricular septum (PA/cPS-IVS) show fibrous subendocardial tissue of unclear origin accompanied by right ventricular (RV) hypoplasia. While in hypoplastic left heart syndrome, it is known that flow-induced endothelial-to-mesenchymal transition (EndMT) of endocardial endothelial cells (EECs) is the source of this fibrous tissue, it remains unclear whether similar mechanisms exist in PA/cPS-IVS. METHODS: We analysed 13 PA/cPS-IVS patients who underwent staged ventricular rehabilitation surgery aimed at preserving RV function between March 2021 and July 2025 at Boston Children's Hospital. Resected tissue was examined for the degree of fibrosis and elastin and the presence of active EndMT by histology, immunohistochemistry, and flow cytometry. To mimic human disease conditions, isolated EECs were exposed to pathological flow and compared with physiological flow conditions. RESULTS: Flow disturbances across the pulmonary and/or tricuspid valves were present in all patients. Resected RV tissue revealed an active subendocardial fibroelastic remodelling process, infiltrating into the underlying myocardium. Patients showed RV diastolic dysfunction, as evidenced by elevated filling pressures, suggesting a pathophysiological role of fibroelastic remodelling of the endocardium. Mimicking the human disease, exposure of isolated EECs to pathological flow conditions induced loss of endothelial characteristics and transition towards a mesenchymal phenotype through EndMT. CONCLUSIONS: In PA/cPS-IVS patients, restrictive RV physiology and diastolic dysfunction are likely driven by infiltrative fibroelastic remodelling caused by localized fibrogenic activation of EECs through EndMT in response to flow disturbances from valvular defects. Fibrogenic pathway activation may represent a promising therapeutic target in PA/cPS-IVS.