Abstract 15989: Intracoronary Infusion of Multicellular Cardiospheres Can Be Safely Used to Prevent Adverse Remodeling in a Pig Model of Myocardial Infarction

Abstract

Background: Pre-clinical studies in rodents and pigs indicate that the self-assembling microtissues known as cardiospheres (CSp), when administered intramyocardially, may be more effective than dispersed CSp-derived cells (CDCs). However, the more desirable intracoronary (IC) route has been assumed to be unsafe for CSp delivery: CSp are large (>35 μm), raising concerns about likely microembolization. Objective: We sought to evaluate the safety and efficacy of IC delivery of allogeneic CSp in a porcine model of convalescent MI. Methods: Dosage was optimized by infusing CSp (3.25x10 5 particles [n=2], 6.5 x10 5 [n=3] and 1.3x10 6 [n=2], size=44±23, 29%>50μm) in the LAD of naïve pigs, looking for acute adverse effects (troponin I [TnI] leak, low TIMI flow, stunning). We next tested the efficacy of IC allogeneic Csp (1.3x10 6 ; n=7) or vehicle (n=8) in a minipig model of chronic MI. Animals underwent MRI before infusion and 1 month later. Left ventricular (LV) ejection fraction (EF), scar mass and viable mass were evaluated at both time points. Results: In the dosing study, we observed no impairment of TIMI flow or LVEF after CSp infusion. TnI at 24 hours was 0.7±0.5ng/mL and did not differ among groups (P=0.11). In the post-MI study, EF was identical in the two groups at baseline. One month post-infusion, LV function was preserved in the CSp group but not in controls (ΔEF=+0.5±1.6% vs. -4.5±1.8%, p<0.001). CSp reduced scar mass (P<0.001) and increased viable mass (+17±8% vs. +6±6% from baseline, P=0.04) compared to controls. IC CSp also decreased LV end diastolic pressure (-7±4mmHg vs. -1±4 mmHg in control, P<0.01)) and increased cardiac output (+0.5±0.4 mL/min vs. -0.1±0.3mL/min, P<0.01. Conclusions: IC delivery of allogeneic CSp is safe and preserves LV function after MI. In addition, global hemodynamic improvement is observed, which may have significant clinical implications. The decision to use CDCs or CSp is not forced, therefore, by an inability to infuse CSp safely via the IC route.