Administration of Single or Repeated Doses of CDCs in a Swine Model of Reperfused Myocardial Infarction: Magnetic Resonance and Proteomics Evaluation.

Abstract

Some studies report better outcomes in cell therapy for myocardial infarction (MI) with repeated administrations. We aimed to elucidate the potential differences in terms of cardiac function and protein expression after one or three doses of cardiosphere-derived cells (CDCs) in a porcine MI model. CDCs were isolated from swine cardiac explants, cultured in cardiomyocyte growth medium (CGM), and prepared for administration. Pigs surviving a 90 min balloon occlusion of the mid-left anterior descending coronary artery (LAD) were randomly allocated to receive vehicle (CON), one (D1), or three (D3) doses of 30 × 10 CDCs via the infarct-related coronary artery. Cardiac function was assessed with magnetic resonance at baseline and 10 weeks. Programmed electrical stimulation to study arrhythmogenicity was performed at 10 weeks. High-throughput quantitative proteomic analysis of infarcted tissue was performed to identify biological processes based on protein abundance changes between groups. No significant differences were found between the three groups for any cardiac function parameter at 10 weeks. No increase in ventricular tachycardia inducibility was seen in treated groups. However, gene ontology and topological analyses revealed potentially beneficial molecular adaptations. Upregulation of GYS1, AGL, and GBE1 indicated an increase in glycogen biosynthesis and energy availability, while an increase in ANK2, along with hub proteins ALB and TRAP1, suggested cardioprotective effects. Furthermore, the increase in remodeling-related proteins, including EPHA4, PODN, and ALPK3, pointed to favorable structural adaptation following infarction. In conclusion, the intracoronary administration of single or repeated doses of 30 × 10 CDCs to a porcine reperfused MI model shows only slight differential improvement in both cardiac function and protein profile in this experimental setting, thus presenting limited translational potential.