Modelling and Simulation Reveals Density-Dependent Re-Entry Risk in the Infarcted Ventricles after Stem Cell-Derived Cardiomyocyte Delivery

Leto Riebel1, Zhinuo Wang1, Hector Martinez-Navarro1, Cristian Trovato1, Jacopo Biasetti2, Rafael Sachetto Oliveira3, Rodrigo Weber dos Santos4, Blanca Rodriguez1
1University of Oxford, 2AstraZeneca AB R&D, 3Universidade Federal de São João del-Rei, 4Universidade Federal de Juiz de Fora


Abstract

Recent research has explored delivery of human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) to repair and prolong cardiac function after cardiac injury. However, hPSC-CMs express immature electrophysiological and structural properties presenting a potentially pro-arrhythmic substrate when introduced into the adult human heart. Here we simulate the delivery of hPSC-CMs into a human-based multiscale electrophysiological model of infarction. Membrane kinetics are based on the state-of-the-art ToR-ORd and Paci2020 models. A transmural infarct zone with a surrounding border zone is introduced, exhibiting conduction slowing and ionic remodelling based on experimental data characterising relevant ionic current conductances and time constants. We introduce hPSC-CMs by sampling from a normal distribution taking the middle of the infarct as delivery centre and considering experimentally reported hPSC-CM patch sizes. Three densities are modelled by varying the sampling size and cover 4%, 22%, and 39% of the infarct and border zone. Re-entry is induced by applying an ectopic stimulus in the remote zone proximal to the border zone by varying coupling intervals from 360 to 480 ms after the last sinus beat. The vulnerable window increases once hPSC-CMs are introduced and are longest in the medium and high-density scenarios. Increased refractory period of the hPSC-CMs compared to the infarcted adult tissue enables these re-entries. Repolarisation times in the hPSC-CM region are increased from 355 ms in the low to 475 ms in the high-density scenario, which causes an increase in local repolarisation dispersion around the delivery site, thus facilitating re-entry. We furthermore model the effect of different therapeutic agents on re-entry susceptibility and show the sensitivity of the vulnerable window to IKr and ICaL block.
Our results highlight the density-dependent effect of hPSC-CMs delivery on arrhythmic risk in the infarcted ventricles and show the effect of drugs on the increased re-entry susceptibility.