Dose-dependent improvement of cardiac function in a swine model of acute myocardial infarction after intracoronary administration of allogeneic heart-derived cells

BackgroundAllogeneic cardiac-derived progenitor cells (CPC) without immunosuppression could provide an effective ancillary therapy to improve cardiac function in reperfused myocardial infarction. We set out to perform a comprehensive preclinical feasibility and safety evaluation of porcine CPC (pCPC) in the infarcted porcine model, analyzing biodistribution and mid-term efficacy, as well as safety in healthy non-infarcted swine.MethodsThe expression profile of several pCPC isolates was compared with humans using both FACS and RT-qPCR. ELISA was used to compare the functional secretome. One week after infarction, female swine received an intracoronary (IC) infusion of vehicle (CON), 25x10(6) pCPC (25M), or 50x10(6) pCPC (50M). Animals were followed up for 10weeks using serial cardiac magnetic resonance imaging to assess functional and structural remodeling (left ventricular ejection fraction (LVEF), systolic and diastolic volumes, and myocardial salvage index). Statistical comparisons were performed using Kruskal-Wallis and Mann-Whitney U tests. Biodistribution analysis of F-18-FDG-labeled pCPC was also performed 4h after infarction in a different subset of animals.ResultsPhenotypic and functional characterization of pCPC revealed a gene expression profile comparable to their human counterparts as well as preliminary functional equivalence. Left ventricular functional and structural remodeling showed significantly increased LVEF 10weeks after IC administration of 50M pCPC, associated to the recovery of left ventricular volumes that returned to pre-infarction values (LVEF at 10weeks was 42.110.0% in CON, 46.5 +/- 7.4% in 25M, and 50.2 +/- 4.9% in 50M, p<0.05). Infarct remodeling was also improved following pCPC infusion with a significantly higher myocardial salvage index in both treated groups (0.35 +/- 0.20 in CON; 0.61 +/- 0.20, p=0.04, in 25M; and 0.63 +/- 0.17, p=0.01, in 50M). Biodistribution studies demonstrated cardiac tropism 4h after IC administration, with substantial myocardial retention of pCPC-associated tracer activity (18% of labeled cells in the heart), and no obstruction of coronary flow, indicating their suitability as a cell therapy product.Conclusions IC administration of allogeneic pCPC at 1week after acute myocardial infarction is feasible, safe, and associated with marked structural and functional benefit. The robust cardiac tropism of pCPC and the paracrine effects on left ventricle post-infarction remodeling established the preclinical bases for the CAREMI clinical trial (NCT02439398).