Abstract 9422: Assessment of Cardiotoxicity Following Thoracic Radiotherapy and Systemic Stem-Cell Derived Extracellular Vesicle Treatments

Abstract

Introduction: Radiotherapeutic management of certain cancers provides distinct benefits, but also results in variable degrees of cardiac exposure. Resultant radiation-induced heart disease (RIHD) typically manifests at protracted post-irradiation times and can involve a wide range of underlying pathologies including heart failure. Past work from our lab has identified an intervention involving systemic administration of human embryonic stem cell (hESC) derived extracellular vesicles (EV) shown to resolve radiation-induced lung disease (RILD). However, potential treatment-associated complications to the heart were not investigated. Hypothesis: In this study, we hypothesized that 1) radiation would cause a certain level of heart dysfunction, and 2) that stem cell-derived EV would not further confound RIHD. Methods: Separate cohorts of control (no radiation +/- EV) and treated (radiation +/- EV) mice were implemented in this study. For the treatment groups, mice were subjected to a single dose of image guided thoracic irradiation (14 Gy) and then systemically injected with hESC-derived EV at different time points. Echocardiography was performed in 4 cohorts (n=46); control arm (n=9), radiation alone arm (n=24), EV alone arm (no radiation) (n=5) and toxicity control arm involving 4 EV doses at weeks 0, 1, 2, 3) (n=8). The following parameters were compared between the 4 cohorts: E/A ratio, ejection fraction (EF), shortening fraction (SF), left ventricular mass (LV mass), end diastolic volume (EDV). Results: Radiation caused statistically significant lower E/A ratios compared with mice that did not receive radiation, with non-significant changes in other key indicators of cardiac function. Importantly, EV treatments had no effect on E/A ratio or any other indices of cardiac function among the different cohorts. Conclusions: Irradiated mice had lower E/A ratios but EF was unchanged, suggesting that thoracic exposures compromised diastolic function without impacting EF. Diastolic dysfunction was most likely linked to increased radiation-induced fibrosis and myocardium stiffness. Importantly, EV treatments were not observed to adversely impact cardiac function, pointing to the safety of this potential intervention for RILD.