(G-243) Bioelectric Cooperativity Between Transplanted Cell Clusters as a Mechanism for Engraftment Arrhythmia: Proof of Concept from Computational Simulations

Introduction:: Ischemic heart disease is the leading cause of death worldwide.¹ Cardiac regeneration using human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) transplantation following myocardial infarction (MI) is a promising therapy but can lead to engraftment arrhythmia (EA).² EA is a transient phenomenon, arising shortly after transplantation then spontaneously resolving after a few weeks. hPSC-CM are characterized by their automaticity and function as focal trigger for EA. Previous work has found that focal EA phenomena may be partially explained by spatially heterogeneous graft-host electrical coupling², however, the roles of specific graft features remain poorly characterized. We hypothesize that interaction between multiple grafts gives rise to high EA propensity.


Materials and Methods:: We tested our hypothesis using a computational slice model derived from a post-MI macaque ventricle, as described in our previous study.³ Human ventricular,⁴ and hPSC-CM³ cellular models were used in the corresponding myocardial regions. Infarcted tissue (scar) was modeled as non-conductive. We divided the fifteen grafts into three clusters (Fig 1A); to account for potential overlapping effects, one graft was assigned to clusters 2 and 3. To probe for cooperativity in each cluster, we systematically added or removed (i.e., treated as host myocardium instead of hPSC-CM) individual grafts to test each possible permutation (Fig 1B). In all cases, 10% electrical connectedness was modeled by disconnecting elements along the graft-host boundary with 40 stochastically generated spatial configurations. Simulations of bioelectrical activity were conducted using openCARP.5 Graft-host excitation, was used as a surrogate measurement of EA. To assess overall bioelectric cooperativity effects, we aggregated results for models across all simulations with the same number of grafts present.


Results, Conclusions, and Discussions:: When all grafts were included, we observed EA in all 40 spatial electric coupling configurations. In contrast, across all fifteen sets of single-graft simulations (40 configurations per graft), we did not see a single case of EA (Fig 1C, “One”). EA incidence increased as a function of the number of grafts present; for each cluster, peak EA rate was when all member grafts were included (Fig 1C – cluster 1, “Four”: 27.5%; cluster 2, “Six”: 35%; cluster 3, “Six”: 80%). The overall EA rate was highest for cluster 3, which had the largest aggregate graft size and the most proximity to scar.



Graft-host excitation only occurred in the presence of multiple grafts. Each cluster had the capacity to drive EA as long as two or more grafts were present, but the highest EA propensity was seen when all grafts in a particular cluster were included. Cluster 3 consistently had the highest EA propensity, indicating that total graft burden and proximity to scar may be important driving factors in minimizing the risk of transplanted hPSC-CM arrhythmogenicity. More work is needed to identify exactly how EA propensity is modulated by spatial factors including graft size, graft location, and graft-host boundary tortuosity.


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References (Optional): : [1] Vos T et al. Lancet 396, 1204–16222 (2020). [2] Liu, YW, et al. Nat Biotechnol 36, 597–605 (2018). [3] Gibbs, CE, et al. J Physiol doi.org/10.1113/JP284244 (2023). [4] Ten Tusscher, KHWJ et al. Am J Physiol - Heart Circ Physiol 291, 1088–1100 (2006). [5] Plank, G, et al. Comput Methods Programs Biomed 208, 106223 (2021).