Modelling the interaction between stem cells derived cardiomyocytes patches and host myocardium to aid non-arrhythmic engineered heart tissue design

Abstract

Application of epicardial patches constructed from human-induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) has been proposed as a long-term therapy to treat scarred hearts post myocardial infarction (MI). Understanding electrical interaction between engineered heart tissue patches (EHT) and host myocardium represents a key step toward a successful patch engraftment. EHT retain different electrical properties with respect to the host heart tissue due to the hiPSC-CMs immature phenotype, which may lead to increased arrhythmia risk. We developed a modelling framework to examine the influence of patch design on electrical activation at the engraftment site. We performed an in-silico investigation of different patch design approaches to restore pre-MI activation properties and evaluated the associated arrhythmic risk. We developed an in silico cardiac electrophysiology model of a transmural cross section of host myocardium. The model featured an infarct region, an epicardial patch spanning the infarct region and a bath region. The patch is modelled as a layer of hiPSC-CM, combined with a layer of conductive polymer (CP). Tissue and patch geometrical dimensions and conductivities were incorporated through 10 modifiable model parameters. We validated our model against 4 independent experimental studies and showed that it can qualitatively reproduce their findings. We performed a global sensitivity analysis (GSA) to isolate the most important parameters, showing that the stimulus propagation is mainly governed by the scar depth, radius and conductivity when the scar is not transmural, and by the EHT patch conductivity when the scar is transmural. We assessed the relevance of small animal studies to humans by comparing simulations of rat, rabbit and human myocardium. We found that stimulus propagation paths and GSA sensitivity indices are consistent across species. We explored which EHT design variables have the potential to restore physiological propagation. Simulations predict that increasing EHT conductivity from 0.28 to 1–1.1 S/m recovered physiological activation in rat, rabbit and human. Finally, we assessed arrhythmia risk related to increasing EHT conductivity and tested increasing the EHT Na+ channel density as an alternative strategy to match healthy activation. Our results revealed a greater arrhythmia risk linked to increased EHT conductivity compared to increased Na+ channel density. We demonstrated that our modeling framework could capture the interaction between host and EHT patches observed in in vitro experiments. We showed that large (patch and tissue dimensions) and small (cardiac myocyte electrophysiology) scale differences between small animals and humans do not alter EHT patch effect on infarcted tissue. Our model revealed that only when the scar is transmural do EHT properties impact activation times and isolated the EHT conductivity as the main parameter influencing propagation. We predicted that restoring physiological activation by tuning EHT conductivity is possible but may promote arrhythmic behavior. Finally, our model suggests that acting on hiPSC-CMs low action potential upstroke velocity and lack of IK1 may restore pre-MI activation while not promoting arrhythmia.

Graft–host coupling changes can lead to engraftment arrhythmia: a computational study

“…Due to this slow graft‐induced focal beating rate, the authors again concluded that a re‐entrant driver mechanism is more likely to contribute to fast EA. Additional studies have tried to look at EA in the context of remuscularization via an hPSC‐CM patch (Yu, Liang, Franceschi et al., 2022; Fassina et al., 2022); however, multiple experimental studies have demonstrated that no electrical coupling occurs in cardiac patches, due to scar‐induced insulation of the graft–host border (Gerbin et al., 2015; Jackman et al., 2018). We believe that this is the key to understanding why prior work undervalued the potential importance of focal EA drivers.…”

“…Scar was modelled either as a non‐conductive insulator (Prakosa et al., 2018) or as slow‐conducting passive tissue (i.e. pure electrical sink) (Connolly & Bishop, 2016; Fassina et al., 2022). To avoid spurious scar‐to‐host excitations from electrotonic current, we set the resting potential of slow‐conducting scar to match that of the human ventricular ionic model (−85.8 mV) (Ten Tusscher & Panfilov, 2006).…”

“…Computational cardiology has emerged as a useful tool to gain mechanistic insights into arrhythmia initiation and perpetuation at various spatial scales (Moreno et al., 2011; Boyle, Franceschi et al., 2019; Fassina et al., 2022). Cell‐, tissue‐ and organ‐scale computational models have helped in understanding arrhythmias in ways difficult to achieve through traditional experimental or clinical techniques (Arevalo et al., 2016; Trayanova et al., 2017; Boyle, Zghaib et al., 2019).…”

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

“…Further simulations are needed to explore more drugs and doses. Recently, in silico simulations in tissue slabs suggested that addressing the slow upstroke velocity and depolarised diastolic potential in hPSC-CMs may increase therapy efficiency increasing the arrhythmic risk [16]. Hence, a sodium current agonist could provide a promising solution to increase conduction velocity and, subsequently, minimise the repolarisation gradient and re-entry susceptibility.…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…The paracrine therapeutic anti-inflammatory and antifibrotic effects of human amniotic MSCs are increased by S100A8/A9 and calcium-binding proteins after MI ( Chen et al, 2021c ). Moreover, subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ cardiac stem cells improves cardiac remodeling and function after MI ( Kompa et al, 2021 ), and stem cells-derived CMs patches restore normal electrical propagation without the risk of arrhythmia ( Fassina et al, 2022 ). Induced cardiosphere (iCS) can be produced by self-replicative RNA approach, differentiating into CMs, while intravenous and intramyocardial injection of C-X-C chemokine receptor four positive subpopulation of iCS-derived cells has similar therapeutic effects in the mice MI model ( Xu et al, 2021a ).…”