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

Abstract

After myocardial infarction (MI), a significant portion of heart muscle is replaced with scar tissue, progressively leading to heart failure. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CM) offer a promising option for improving cardiac function after MI. However, hPSC‐CM transplantation can lead to engraftment arrhythmia (EA). EA is a transient phenomenon arising shortly after transplantation then spontaneously resolving after a few weeks. The underlying mechanism of EA is unknown. We hypothesize that EA may be explained partially by time‐varying, spatially heterogeneous, graft–host electrical coupling. Here, we created computational slice models derived from histological images that reflect different configuration of grafts in the infarcted ventricle. We ran simulations with varying degrees of connection imposed upon the graft–host perimeter to assess how heterogeneous electrical coupling affected EA with non‐conductive scar, slow‐conducting scar and scar replaced by host myocardium. We also quantified the effect of variation in intrinsic graft conductivity. Susceptibility to EA initially increased and subsequently decreased with increasing graft–host coupling, suggesting the waxing and waning of EA is regulated by progressive increases in graft–host coupling. Different spatial distributions of graft, host and scar yielded markedly different susceptibility curves. Computationally replacing non‐conductive scar with host myocardium or slow‐conducting scar, and increasing intrinsic graft conductivity both demonstrated potential means to blunt EA vulnerability. These data show how graft location, especially relative to scar, along with its dynamic electrical coupling to host, can influence EA burden; moreover, they offer a rational base for further studies aimed to define the optimal delivery of hPSC‐CM injection. Key points Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CM) hold great cardiac regenerative potential but can also cause engraftment arrhythmias (EA). Spatiotemporal evolution in the pattern of electrical coupling between injected hPSC‐CMs and surrounding host myocardium may explain the dynamics of EA observed in large animal models. We conducted simulations in histology‐derived 2D slice computational models to assess the effects of heterogeneous graft–host electrical coupling on EA propensity, with or without scar tissue. Our findings suggest spatiotemporally heterogeneous graft–host coupling can create an electrophysiological milieu that favours graft‐initiated host excitation, a surrogate metric of EA susceptibility. Removing scar from our models reduced but did not abolish the propensity for this phenomenon. Conversely, reduced intra‐graft electrical connectedness increased the incidence of graft‐initiated host excitation. The computational framework created for this study can be used to generate new hypotheses, targeted delivery of hPSC‐CMs.

Casein Kinase 1 Phosphomimetic Mutations Negatively Impact Connexin-43 Gap Junctions in Human Pluripotent Stem Cell-Derived Cardiomyocytes

“…This same mutation had been previously reported to improve Cx43 GJ stability in cardiomyocytes and reduce arrhythmia vulnerability in germline knock-in mice [41]. While our focus here was on comparing in vitro outcomes between Cx43-S3E versus WT hPSC-CMs, we had hoped that the successful demonstration of enhanced Cx43 GJ stability in vitro would provide a strong rationale for an in vivo study to investigate whether Cx43-S3E hPSC-CMs would also exhibit better electromechanical integration and reduced pro-arrhythmic behavior following transplantation in injured hearts [56,57]. Contrary to our hypothesis, Cx43-S3E hPSC-CMs actually had reduced total and membranous Cx43 expression, higher spon-taneous beating rates, and a predilection for irregular [Ca 2+ ] i cycling.…”

In SilicoEvaluation of Cell Therapy in Acute versus Chronic Infarction: Role of Automaticity, Heterogeneity and Purkinje in Human

“…In our study, chronic infarction, modelled as conductive but non-excitable, promoted spontaneous beating but large scars slowed its upstroke and propagation. According to Gibbs et al slow-conducting passive scars may reduce the occurrence of spontaneous beats compared to non-conducting scars (Gibbs et al, 2023). Results by Fassina et al, suggest that cells with a CV 20 % or less that of healthy myocardium, like chosen here, may promote arrhythmic events (Fassina et al, 2022, 2023).…”

“…In our study, chronic infarction, modelled as conductive but non-excitable, promoted spontaneous beating but large scars slowed its upstroke and propagation. According to Gibbs et al slow-conducting passive scars may reduce the occurrence of spontaneous beats compared to non-conducting scars (Gibbs et al, 2023).…”

“…Human modelling and simulation of cardiac electrophysiology is a mature and well-established technology enabling multiscale investigations into disease mechanisms (Arevalo et al, 2013;Martinez-Navarro et al, 2019;Wang et al, 2021), therapeutic interventions such as ablation (Roney et al, 2020), diagnostics (O'Hara et al, 2022) and pharmacological treatment (Dasí et al, 2022). While several studies have provided insights into specific pro-arrhythmic mechanisms following cell delivery (Fassina et al, 2022(Fassina et al, , 2023Gibbs et al, 2023;Yu et al, 2019Yu et al, , 2021, they so far did not include thorough multi-scale validation from ionic to ECG level, nor did they address crucial factors such as disease progression, scar size and cell heterogeneity caused by differences in differentiation and purification protocols (Ban et al, 2017;Jiang et al, 2020).…”

Cell diversity and signalling in the cardiovascular system

“…As suggested in the accompanying translational perspective, arrhythmia is likely to J Physiol 601.13 reflect the balance between macro-structure and functional control, whereby neural remodelling might play a key regulatory role of arrhythmogenesis in the setting of scars (Shivkumar et al, 2023). In a computational study included in this special issue, Gibbs et al (2023) explore the impact of graft-host connectivity and conductivity on graft-initiated arrhythmias in human pluripotent stem cell-derived cardiomyocyte grafts within the infarcted ventricle. The results suggest spatiotemporally heterogeneous graft-host coupling can create an electrophysiological milieu that favours graft-initiated host excitation.…”