Abstract

Introduction: Myocardial injury leads to an irreversible loss of cardiomyocytes (CM). The implantation of human engineered heart tissue (EHT) has become a promising therapeutic approach to regenerate the heart after myocardial injury. Previous studies exhibited beneficial, dose-dependent effects of human induced pluripotent stem cell (hiPSC)–derived EHT patch transplantation in a guinea pig model in the subacute phase of myocardial infarction (one week after injury). As advanced failure often results from a chronic remodeling process it is worthwhile from a clinical standpoint to explore the ability to repair myocardial function in the chronic phase of myocardial injury.

Methods: Human EHT patches were generated from hiPSC–derived CMs (15x10⁶ cells). Myocardial cryoinjury was induced in guinea pigs. EHT patches were implanted epicardially four weeks after injury. Control animals received cell-free patches. Cardiac function was evaluated by serial echocardiography after a follow-up period of four weeks. Animals were sacrificed and hearts were harvested for histological analysis.

Results: Hearts revealed large transmural myocardial injuries amounting to 27% of the left ventricle. EHT recipient hearts demonstrated compact muscle islands of human origin in the scar region, as indicated by a positive staining for human Ku80 and dystrophin, remuscularizing 5% of the scar area. Grafts were vascularized by host derived vessels. Grafts consisted of human cardiomyocytes that mainly expressed the ventricular myosin light chain isoform and demonstrated readily identifiable sarcomeres. Echocardiographic analysis demonstrated no significant difference between animals that received EHT patches and animals in the control group (fractional area change 36% vs. 34%).

Discussion: EHT patches engrafted in the chronically injured heart model, but the grafts were approximately 50% smaller than after transplantation of similar EHT patches in the subacute model, indicating that the chronically scarred heart represents a less receptive environment for cell engraftment. In contrast to the subacute model, EHT patch transplantation did not improve left ventricular function, highlighting the difficulties for a regenerative approach.