Abstract 13899: Engineered Tissue Graft Electrically Couples With Swine Host Heart

Abstract

Introduction: Adult mammalian hearts are unable to replenish myocytes lost in myocardial infarction (MI). Recent therapies that implant myocytes derived from human induced pluripotent stem cells (hiPSC-CMs) have shown structural integration of the graft, improved cardiac function, and reduced scar size. However, to successfully remuscularize the heart, implanted tissue must integrate electrically. Here, we directly image electrical coupling between engineered grafts and the host. Methods: We created anterior LV MI in 3 immunosuppressed pigs using ischemia-reperfusion. Cardiac spheroids engineered from hiPSC-CMs were implanted into the border zone right after the procedure. Spheroids were transfected with a calcium indicator (GCaMP6). One week post implantation, the animal was sacrificed, and 0.6 mm thick slices of myocardium containing spheroids were obtained (Fig. A). The slices were stained with a voltage-sensitive dye (VSD) for optical mapping. GCaMP6 and the VSD have different emission spectra allowing electrical activation of the host tissue and spheroids to be imaged independently. The slices were activated with both global field stimuli and focal stimuli applied distant from the spheroids. Results: During field stimulation, action potentials in the slice and calcium transients (CaT) in the spheroids were simultaneous. However, during focal pacing, there was propagation across the slices and latency between the pacing pulses and spheroid CaTs (Fig. B, C). This indicates spheroid activation arose from electrical coupling with the host myocardium and not from direct stimulation by the pacing pulse. We observed coupling at 12 spheroid sites in 10 slices. At 6 sites, 1:1 coupling could be maintained at pacing rates up to 4 Hz (Fig. D). Conclusions: To our knowledge, this is the first demonstration of swine host myocardium coupling electrically with a human engineered tissue graft. Coupling occurred within 1 week and enabled the host to drive the graft.