Abstract 12755: Effects of Intravenously Delivered Extracellular Vesicles on Cardiac Function in Chemotherapy-Induced Cardiomyopathy

Abstract

Introduction: Extracellular Vesicles (EV) are increasingly recognized as key mediators of the effects of cellular therapy but repeated dosing is likely required for optimizing their therapeutic benefits. This, in turn, requires a noninvasive delivery route. Hypothesis: Repeated intravenous (IV) EV infusions might improve cardiac function in chemotherapy-induced cardiomyopathy. Methods: All EV were collected from human iPSC-derived cardiovascular progenitor cells. In vitro experiments : iPSC-derived cardiomyocytes were stressed 3 times by doxorubicin (Dox, 0.2 μM), once every 48 hours (D0, D2, D4), and then exposed to EV once (D6) or twice (D6 and D8). Outcomes were assessed on D8 and D10 on mitochondrial function and intracellular ATP levels assessed by the Seahorse XF Cell Mito Stress Test and ATPlite Luminescence Assay System, respectively. In vivo experiments : Male BALB/c mice were subjected to 3 weekly injections of Dox (total cumulated dose: 12 mg/kg) followed by 3 IV infusions of EV (10 9 per dose, n=11) or an equivalent volume of saline (n=14) over 1-2 weeks. The main outcome measure was Global Longitudinal Strain (GLS), a robust and early marker of LV dysfunction, blindly assessed by MRI at baseline and 8-11 weeks following the onset of Dox treatment. Explanted hearts were then processed for histology and transcriptomics. Results: Compared with Dox-stressed controls, EV increased ATP levels by 30%±8% (n=7, each in triplicate, p=0.047; m±SEM) and enhanced both mitochondrial respiration and anaerobic glycolysis. In vivo , GLS at baseline averaged -14.98±0.24. It was well preserved after EV treatment with a decrease at end-study of only 2.96%±7.18% from baseline while it fell by 11.90%±3.51% in PBS-injected controls. Similar patterns of changes were seen for longitudinal endocardial strain which declined by 0.22%±7.29% and 8.39%±3.42% from baseline in EV- and PBS-injected hearts, respectively, while the corresponding declines for epicardial strains were 3.92%±7.20% and 13.44%±3.28%. Basal global circumferential strain was also better preserved in EV-treated hearts. Conclusions: Repeated IV infusions of EV decrease chemo-triggered cardiomyocyte toxicities and help preserving cardiac function in chemotherapy-induced cardiomyopathy.