Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate the Infarcted Pig Heart but Induce Ventricular Tachyarrhythmias

TLDR

Human embryonic stem cell‑derived cardiomyocytes hold promise for regenerating injured hearts, prompting investigation of their engraftment in a translational pig infarct model. The study aimed to assess whether hESC‑CMs can stably engraft in the infarcted pig heart. Immature hESC‑CMs were transplanted into the infarct scar, where they formed mature myocardial implants with vascular integration and minimal rejection, and electroanatomical mapping revealed that graft‑related tachyarrhythmias arose from focal activation patterns rather than macro‑reentry. hESC‑CM recipients experienced frequent monomorphic ventricular tachycardia that resolved by four weeks, demonstrating the pig model’s suitability for preclinical hESC‑based cardiac therapy and revealing focal mechanisms underlying graft‑related arrhythmias.

Abstract

Highlights•hESC-CM transplantation partially remuscularizes the infarcted pig heart•hESC-CM recipients show frequent tachyarrhythmias at early time points•Graft-related arrhythmias arise from focal mechanisms rather than macro-reentrySummaryHuman embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation.