Abstract 15886: Induced Pluripotent Stem Cell Derived Cardiomyocyte Exosomes Preserve Myocardial Viability and Reduce Negative Remodeling in a Porcine Model of Ischemia Reperfusion

Introduction:Coronary artery disease is a leading cause of death worldwide. Ischemic injury leads to myocardial dysfunction, resulting in heart failure (HF) and ventricular arrhythmias. Exosomes have emerged as promising a biologic target for restoring the failing heart. Fundamental questions such as the cell of origin and molecular cargo for optimal therapeutic effects are areas of intense research. Our lab has shown that the exosomes from bone marrow derived mesenchymal stem cells (bmMSC-Ex) and induced pluripotent stem cell derived cardiomyocytes (iCM-Ex) both augment the injured myocardium in a murine injury model. Based on our small animal experience, we evaluated the therapeutic effects of bmMSC-Ex and iCM-Ex in a porcine myocardial ischemia reperfusion (IR) injury model.Hypothesis:bmMSC-Ex and iCM-Ex restore the injured myocardium.Methods and Results:Transient immunosuppression was administered for 1 week to 40 ? 50kg Yorkshire pigs with a daily course of cyclosporine (100mg/kg) and methylprednisolone (2mg/kg) from 3 days prior to 4 days after exosome injection. Pigs underwent ischemia reperfusion (IR) injury, which consisted of 1 hour of percutaneous balloon occlusion at the proximal LAD immediately distal to the first septal artery. Immediately following IR injury, 5 x 1011exosomes were delivered in ten, 500?L intramyocardial injections using a BioCardio Helix? catheter. Biplane ventriculography was used to help target the peri-infarct region. At 2- and 4-weeks post-infarct, pigs underwent cardiac MRI (cMRI) with cin?, delayed-enhanced (DEMRI) and manganese-enhanced (MEMRI) MRI. Pigs treated with iCM-Ex (n = 5) demonstrated significantly improved LVEF compared to the control (34?5.3% vs. 23?3.6, p 0.02) with preserved indexed left ventricular end diastolic volume (LVEDVi, 94?11mL vs. 108?1.65mL, p 0.02) while bmMSC-Ex (N = 3) did not demonstrate significant improvement. DEMRI and MEMRI demonstrated significantly decreased scar % (19?3.3% vs. 29?4.6%, p 0.05) in iCM-Ex group when compared to control while bmMSC-Ex group showed no difference.Conclusion:iCM-Ex preserved LVEF, myocardial viability, and LV volume following porcine IR injury model. Further investigation is underway to delineate the mechanism of action.