Abstract 9563: Intravenously Infused Extracellular Vesicles Preserve Function of Anthracycline-Treated Hearts

Abstract

Introduction: Current treatments of chemotherapy-induced cardiomyopathy (CCM) are of limited efficacy. Hypothesis: Extracellular vesicles (EV) might represent a new therapeutic option. Methods: Male immunocompetent mice were subjected to 3 intraperitoneal (IP) injections of doxorubicin (DOX, 4mg/kg) followed by 3 sequential intravenous injections of EV (10x10 9 /injection) collected from human induced pluripotent stem cell (hiPSC)-differentiated cardiovascular progenitor cells. Outcomes were assessed 8-11 weeks after the onset of DOX treatment on MRI and compared with those of mice injected with saline (controls) or DOX-untreated (sham). Explanted hearts were subjected to transcriptomics. Next, female rats received 5 IP injections of DOX (3mg/kg) followed by 3 IV injections of EV (33x10 9 /injection) similar to those of the mouse study except that they had been GMP-manufactured to be of clinical grade. Control rats were saline-injected or DOX-untreated (sham). Outcomes were assessed 1 month after the onset of DOX treatment on echocardiography. In additional in vitro experiments, hiPSC-derived cardiomyocytes were stressed by DOX w/wo EV and assessed for ATP content. Results: In mice, DOX+saline-injected hearts (n=14) incurred a significant decline in basal (global, epi- and endocardial) circumferential strain compared with the 14 sham mice (p=0.04 for each) while EV (n=11) preserved these indices which did not significantly differ from those of sham mice. Global longitudinal strain followed a similar pattern. EV also upregulated genes involved in the limitation of cardiac remodeling and preservation of contractile function. In rats, LV endsystolic volumes were significantly increased in saline-injected hearts (n=11) compared with the 6 sham (p=0.03) but were preserved after EV injections (n=12). Likewise, the percentages of "responder" rats which did not increase their enddiastolic LV volumes by more than 5% from their post-DOX pre-treatment values were 58% vs . 28% in EV- and saline-injected hearts, respectively. In vitro , EV increased ATP levels of DOX-stressed cardiomyocytes by 30% compared to placebo. Conclusions: The cardioprotective effects of IV-injected EV make them an attractive user-friendly option for the treatment of CCM.