Immature human engineered heart tissues engraft in a guinea pig chronic injury model.

Engineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and a first clinical trial has started recently. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage while transplantation in a chronic injury setting was less efficient. When transplanting matured EHTs we noticed that cardiomyocytes (CM) undergo a de-differentiation step before eventually forming structured grafts. Therefore, we wanted to evaluate whether immature EHT patches (EHTIm) can be used for transplantation. Chronic myocardial injury was induced in a guinea pig model. EHTIm (15x106 cells) were transplanted within hours after casting. Cryo-injury lead to large transmural scars amounting to 26% of the left ventricle. Grafts remuscularized 9% of the scar area on average. Echocardiographic analysis showed some evidence for an improvement of left ventricular function after EHTIm transplantation. In a small translational proof-of-concept study human scale EHTIm patches (4.5x108 cells) were epicardially implanted on healthy pig hearts (n=2). In summary, we provide evidence that transplantation of EHTIm patches, i.e. without pre-cultivation, is feasible with similar engraftment results.