Abstract 15649: Open-Chest Intramyocardial Delivery of Exosomes From Cardiosphere-Derived Cells (CDCs) Mimics Cellular Postconditioning: Decreased Infarct Size and Improved Perfusion in a Pig Model of Acute Myocardial Infarction

Abstract

Background: Various lines of evidence indicate that exosomes mediate the therapeutic effects of cardiosphere-derived cells (CDCs). However, retention and efficacy of exosomes may be limited after intracoronary (IC) delivery due to their very small size (30-150 nm diameter). Objectives: We sought to assess the optimal dosing and delivery techniques for exosomes, and their ability to reduce microvascular obstruction (MVO) and infarct size (IS) in a pig model of ischemia/reperfusion. Methods: Acute myocardial infarction (AMI) was induced in 23 mini-pigs by balloon occlusion of the mid-LAD for 1.5h. Thirty minutes after reperfusion, pigs received, by prior random assignment, IC injection of CDC-derived exosomes (1.5mg [n=3] or 15mg [n=5] of exosome protein), vehicle [n=6], or transepicardial intramyocardial injection (IM) of exosomes (15mg [n=4] or 7.5mg [n=5]) via median sternotomy. Pigs were sacrificed 48 hr post-MI to measure area at risk (AAR), IS and MVO utilizing gentian violet, TTC (2,3,5-triphenyl tetrazolium chloride) and thioflavin staining respectively. Left ventricular ejection fraction (LVEF) was measured by contrast ventriculography before injection and at endpoint. Results: AAR was identical in all groups (averaging 22±4% of LV, P=0.65 among groups). Consistently, LVEF was similar in all groups before treatment. IC delivery of high-dose exosomes (15mg) decreased MVO (43±6% vs. 56±7%, P=0.02) whereas IC low-dose (1.5mg) did not (54±6%, P=0.66). However, IC exosomes failed to decrease IS regardless of dose. In contrast, both IM doses decreased MVO (43±6% for 15mg and 25±14% for 7.5mg, P=0.04 and P<0.0001 respectively) and IS (67±6% for 15mg, 57±15% for 7.5mg vs. 80±6 for placebo, P=0.04 and P=0.003 respectively). At both IM doses, LVEF at endpoint was higher in exosome-injected pigs compared to vehicle (P=0.03). Conclusion: Intracoronary injection of CDC-secreted exosomes decreases MVO at high doses, but fails to reduce IS. In contrast, both low- and high-dose exosomes reduce IS and MVO after intramyocardial delivery, mimicking the cardioprotection seen with CDCs themselves (cellular postconditioning). These results indicate that IM delivery may be more suitable for exosome therapy of myocardial disease.