Sacubitril/valsartan for radiation-induced heart disease in children: preclinical and clinical findings

BACKGROUND AND AIMS: Radiation-induced heart disease (RIHD) is a life-threatening sequela for cancer survivors. A proactive preventive strategy is urgently needed but remains elusive, particularly for the vulnerable paediatric population where prospective data are scarce. To address this gap, this study aimed to evaluate the prophylactic efficacy of sacubitril/valsartan against RIHD in children through a comprehensive translational research pipeline. METHODS: A prospective observational study was first conducted in 40 paediatric solid tumour patients, comparing cardiac function before and 1 week after radiotherapy, with 80 healthy controls. A juvenile rat RIHD model was then established, in which the efficacy of sacubitril/valsartan was assessed and validated through longitudinal echocardiography, cardiac magnetic resonance imaging, histopathology, bulk RNA-seq, and single-nucleus RNA-seq. Finally, a prospective clinical cohort (n = 15 sacubitril/valsartan, n = 15 control) was conducted in paediatric patients post-radiotherapy, with a 12-month follow-up for efficacy and safety. RESULTS: In paediatric patients, radiotherapy significantly impaired biventricular function, notably reducing left ventricular global longitudinal strain, and mean heart radiation dose was significantly correlated with cardiac function impairment. In juvenile rats, sacubitril/valsartan attenuated pathological ventricular wall thickening, myocardial fibrosis, diastolic dysfunction, and perfusion deficits. Mechanistically, it mitigated endothelial cell damage and immune cell activation, promoted a macrophage phenotypic shift from M1 to M2, suppressed fibroblast-to-myofibroblast transition, and broadly attenuated pro-fibrotic and inflammatory cell-cell communication. In the clinical cohort, sacubitril/valsartan significantly improved left ventricular global longitudinal strain and aortic compliance vs controls, with a favourable safety profile. CONCLUSIONS: This first-in-kind translational study demonstrates that early prophylaxis with sacubitril/valsartan is a feasible and effective strategy to mitigate radiation-induced cardiotoxicity in children. These findings, underpinned by multi-modal validation from bench to bedside, challenge the reactive management paradigm in paediatric cardio-oncology and establish a foundational evidence base for a new standard of proactive heart care in childhood cancer survivors.