Abstract 4357295: High-Resolution Optical Mapping of hiPSC Cardiac Grafts in Swine Reveals Reentry and Automaticity as Potential Arrhythmia Mechanisms at the Host-Graft Interface

Abstract

Introduction: Recent therapies implanting cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) have shown improved cardiac performance. The implanted tissue must integrate electrically with the host heart for synchronous contractions without causing arrhythmias in the host. Previously, we demonstrated that engineered tissue grafts can electrically couple with the host heart in a swine model. Here, we show the potential for implanted grafts to be a source of arrhythmias in the host heart. Methods: Cardiac spheroids (200-250 µm in diameter) engineered from hiPSC-CMs were implanted into the border zone of an immunosuppressed pig heart immediately after acute myocardial infarction (ischemia-reperfusion) using a 20G hypodermic needle. The spheroids were genetically encoded with a calcium indicator (GCaMP6). One week post implantation, the animal was sacrificed, and 600 µm thick slices of myocardium containing spheroids from the implant zone were obtained. The slices were stained with a voltage-sensitive dye (VSD) for high resolution optical mapping (~50 mm). GCaMP6 and the VSD have different emission spectra allowing electrical activation of the host tissue and grafts to be imaged independently. Results: We observed ~ 4-fold slower propagation in the graft than the host (A, B). Histology showed low connexin-43 expression, scar, and misaligned muscle fibers at the host-graft interface (C). Host-graft electrical bridges were spaced by millimeters. One graft beat spontaneously, but activation did not propagate from graft-to-host in this (D-G) or any other slice. We did not observe reentry, but slow in-graft conduction and sparse electrical bridges provided opportunity for potential reentry induction. Conclusions: Our high-resolution optical mapping demonstrates potential graft-associated arrhythmias arising from both reentry and automaticity 1-week post-transplantation, which may resolve with maturation of the graft and the graft-host interface.