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Heart, Lung and Circulation

Cellular Heterogeneity of Pluripotent Stem Cell Derived Cardiomyocyte Grafts is Mechanistically Linked to Treatable Arrhythmias

      Background and Objective

      Exciting pre-clinical data have confirmed human cardiomyocytes derived from pluripotent stem cells (PSC-CMs) can remuscularise and improve cardiac function in the injured or diseased heart. Several clinical trials are now in planning or recruitment stages worldwide. However, the development of ventricular arrhythmias has emerged as a predictable complication following the engraftment of intramyocardially injected PSC-CMs. There is an urgent need to gain mechanistic insights and treatment strategies to control or prevent these engraftment arrhythmias (EAs).

      Methods and Results

      Here we show, in a porcine model of myocardial infarction and PSC-CM transplantation, that EAs are focal and automatic in nature, and are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Through single cell ribonucleic acid sequencing and high-parameter flow cytometry analysis, we further describe two unique surface marker signatures which isolate arrhythmogenic and non-arrhythmogenic cardiomyocytes respectively. In addition, we show that anti-arrhythmic drugs and catheter ablation are feasible therapeutic strategies which can control and potentially abolish these arrhythmias.

      Conclusions

      Our data deepens mechanistic understanding of EAs and suggests that modifications to current PSC-CM production protocols and treatment with clinically available anti-arrhythmic strategies could eliminate this dangerous complication, an important safety consideration given several impending clinical trials.