Abstract Body (Do not enter title and authors here): 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/m², 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.