Abstract 4362807: Tissue-engineered Patches loaded with Human Induced Pluripotent Stem Cell-derived Cardiac Cells Improve Cardiac Repair in Porcine Ischemic Cardiomyopathy

Abstract

Introduction: Advances in material science and cell technology offer new possibilities in myocardial repair. Epicardial biocompatible scaffolds loaded with human (h)iPSC-derived cardiac cells may be promising but require safety, feasibility and efficacy studies in a porcine ischemic cardiomyopathy model, representative of human disease. Methods: We induced myocardial infarction (MI) in domestic pigs by 90min LCx occlusion and evaluated functional and structural LV remodelling using MRI 4w later. We printed multi-layered, 4x6cm scaffolds with a hexagonal regenerative zone using 3D printing technology, and populated them with 140 million hiPSC-derived cells (90% cardiomyocytes/10% cardiac fibroblasts) loaded in fibrin hydrogel. We confirmed stable beating rates in vitro and sutured the patches at 4w on the epicardial surface of the infarct area. Cell-free patches served as control. All pigs received immunosuppression with tacrolimus, azathioprine, and methylprednisolone, started 2w before patch implantation and continued 4w thereafter, when a 2nd MRI was performed. We continuously monitored arrhythmias using implantable loop recorders (ILR) and performed histological analysis. Results: At 4w after MI, infarct size was 12±3% of LV mass, and was associated with reduced global systolic function (LVEF 51±2%, n=12). We implanted spontaneously contracting scaffolds (beating rates of 84±27/min, range 48-108) on the infarcted heart, and measured significantly improved LVEF 4w later in the cell-loaded group (56±1% vs 46±6% in CON, P=0.003, n=6 for both), which was attributable to a smaller indexed end-systolic volume (50±6 vs 71±14 mL/m 2 , P=0.01). Immunosuppression was well tolerated (normal LFTs and eGFR) and no major arrhythmias were recorded on ILR. Human Ku80-positive cardiac cells were readily detectable in the patch 1w after implantation, but human cell survival 4w later was limited. Cell-loaded patches significantly promoted neovascularisation in the infarct (P=0.011) and border zone (P=0.015) and reduced myocardial fibrosis (P=0.020) without a prohibitive inflammatory response (Fig 1). Conclusions: Implantation of hiPSC-derived cellular scaffolds of clinically relevant size in the infarcted porcine heart is safe and significantly improves LV functional repair. The contractile benefit is predominantly attributable to paracrine pro-angiogenic and anti-fibrotic mechanisms and supports further development of this innovative treatment for ischemic cardiomyopathy.