Abstract Body (Do not enter title and authors here): Introduction. Advances in material science and cell technology including epicardial cellularized patches using induced pluripotent stem cell (iPSC)-derived cardiomyocyte (CM)s are promising for postinfarction myocardial repair. Feasibility and efficacy studies in a porcine ischemic cardiomyopathy model, representative of human disease, are required for clinical translation.

Methods. We induced posterolateral wall infarction (MI) in pigs (n=12) by 90min balloon inflation in the circumflex artery, started tacrolimus, azathioprine and methylprednisolone immunosuppression 2w later and measured LV function and infarct size (IS) at 4w using MRI. We sutured high-resolution, 3D melt electrowritten multi-layered 4x6cm hexagonal scaffolds containing fibrin hydrogel with (n=5) or without (n=7) 140M human iPSC-derived cells (90% CM/10% fibroblasts) on the infarcted epicardium. We monitored arrhythmias with implantable loop recorders and performed a second MRI at 8w, prior to postmortem histology. We evaluated human cell survival at 1w post-implantation using human-specific DNA stains (Ku80).

Results. Pre-implantation cell-loaded patches spontaneously contracted (84±27 BPM, range 48-108). At 4w, IS averaged 12±3% of LV mass with EF reduced at 49±6%. After 8w, LVEF significantly improved in the cell-loaded group (+5±3% vs -4±4% in CON, P=0.0091), attributable to a greater reduction in end-systolic volume (-8±8 vs 4±7mL/m², P=0.0424) (Fig. 1). Immunosuppression was well tolerated with therapeutic tacrolimus serum levels. One cell-treated animal died at d55 of ventricular fibrillation. Histology confirmed excellent patch biocompatibility at 6w with prominent ingrowth of host vasculature 4w after implantation of cell-loaded patches (Fig.1). No tumour formation was observed and human CM were detected at 1w after implantation but very rare 4w later (Fig.1).
Conclusions. Human iPSC-derived cellular scaffolds of clinically relevant size can be safely implanted on the porcine infarcted myocardium and significantly improve LV functional repair. Transient human cell survival, paracrine mode of action and late, infarct-related arrhythmogenicity require targeted follow up studies prior to clinical translation.