A comprehensive, multiscale framework for evaluation of arrhythmias arising from cell therapy in the whole post-myocardial infarcted heart

Abstract

Direct remuscularization approaches to cell-based heart repair seek to restore ventricular contractility following myocardial infarction (MI) by introducing new cardiomyocytes (CMs) to replace lost or injured ones. However, despite promising improvements in cardiac function, high incidences of ventricular arrhythmias have been observed in animal models of MI injected with pluripotent stem cell-derived cardiomyocytes (PSC-CMs). The mechanisms of arrhythmogenesis remain unclear. Here, we present a comprehensive framework for computational modeling of direct remuscularization approaches to cell therapy. Our multiscale 3D whole-heart modeling framework integrates realistic representations of cell delivery and transdifferentiation therapy modalities as well as representation of spatial distributions of engrafted cells, enabling simulation of clinical therapy and the prediction of emergent electrophysiological behavior and arrhythmogenensis. We employ this framework to explore how varying parameters of cell delivery and transdifferentiation could result in three mechanisms of arrhythmogenesis: focal ectopy, heart block, and reentry.

Figure 1

Hierarchy of the multi-scale whole-heart framework for simulating the electrophysiological effects of cell-based heart repair with de novo cardiomyocytes. (a) At the cell scale, two therapy modalities are represented: cell delivery (top) or transdifferentiation (bottom). (b) At the tissue scale, heterogeneous spatial distributions of remuscularized tissue (blue) among the native myocardium (red) is modeled. (c) At the organ scale, localized delivery is simulated into individualized 3D heart models of post-MI patients and the emergence of arrhythmia can be observed. Models are reconstructed from contrast-enhanced clinical MRIs and represent the distributions of grey zone (i.e., peri-infarct) and scar tissue.

Figure 2

Cell scale therapy modalities and resulting action potentials. (a) In cell delivery, remuscularized regions are represented as comprised of PSC-CMs only; shown are ionic currents of the PSC-CM membrane model. (b) Simulated PSC-CMs action potentials illustrate intrinsic automaticity arising from immaturity; a beat is generated every 1.6 s. (c) Induced cardiomyocytes (iCMs) arising from the transdifferentiation of fibroblasts electrically couple and exert an electrotonic effect on an adjacent, host ventricular CM; remuscularized regions are represented as comprised of a ventricular CM resistively coupled to multiple iCMs. The electrotonic effect of iCMs on a ventricular CM action potential is modulated by (d) the number of iCMs and (e) the junctional conductance. (d) Increasing the number of coupled iCMs from 0 to 8 results in prolongation of the ventricular CM action potential duration and increase in the phase I repolarization notch (inset); junctional conductance is 0.75 nS. (e) Spontaneous action potentials are observed in a ventricular CM coupled to 4 iCMs with junctional conductance of 1.25 nS. Transient subthreshold depolarizations occur at lower values of junctional conductance.

Figure 3

Tissue scale spatial distribution of cell engraftment following cell delivery or transdifferentiation. Stochastic spatial distributions of remuscularized tissue grafts (blue) arising from cell delivery or transdifferentiation are generated within a prescribed delivery zone (dark red) around the site of injection. (a–c) Generated clusters of engrafted cells for three different combinations of d (density) and p (clustering).

Figure 4

Organ scale transplantation of PSC-CMs into a personalized 3D heart model of ischemic cardiomyopathy. (a) Any combination of delivery locations and cell dosages can be simulated in an individualized, 3D whole heart model; PSC-CMs can be distributed across multiple sites around the scar, grey zone, and non-infarcted tissue. (b) In the context of PSC-CM cell sheets, cell dosage can be adjusted by altering sheet size or thickness. (c) Myofibril discontinuity arising from the misorientation of cell sheets with aligned PSC-CMs can also be simulated.

Figure 5

Ectopic propagation arising from PSC-CM automaticity following intramyocardial injection cell delivery is sensitive to spatial clustering (tissue scale) of engrafted PSC-CMs and delivery site location (organ scale). Cell delivery via intramyocardial injection into (a) the LV apex and (b) and the LV posterior wall was simulated. Representative spatial distributions of simulated PSC-CM engraftment ((a) d = 0.40, p = 0.95, (b) d = 0.60, p = 0.65) are shown for a delivery zone with radius = 1.6 cm. (c,d) The probability of ectopic propagation is plotted as a function of d and p for delivery into (c) the LV apex and (d) LV posterior wall.

Figure 6

Arrhythmogenic consequences of iCM engraftment onto the Purkinje system following transdifferentiation in a rabbit ventricular model. (a) Purkinje system with iCM engraftment onto a contiguous segment of the right bundle branch (RBB, white); 20 iCMs were coupled to a single Purkinje cell along the affected segment. Illustration of how collateral iCM engraftment onto the Purkinje could arise from transdifferentiation (inset). (b) RBB block occurred superior to the site of iCM engraftment when iCM-Purkinje junctional conductance was greater than 0.100 nS. Colors indicate time sequence of activation (ms) relative to simulated sinus beat. (c) Action potential traces obtained from RBB sites indicated in (a,b) for different values of iCM-Purkinje junctional conductance. All paced beats propagated through the RBB at 0.100 nS (left); 3:1 block and 2:1 block in the RBB was observed at junctional conductances of 1.000 (middle) and 8.000 nS (right), respectively.

Figure 7

Transplantation of PSC-CM cell sheets results in reentrant VT in a 3D personalized heart model of ischemic cardiomyopathy. (a) Cell sheet transplantation (radius, r = 3.2 cm) was simulated at two sites: the lateral LV (middle) and posterior, superior LV (right). Five different cell sheet conditions (anisotropic [0°, ±45°, 90°] isotropic) were simulated (left). (b,c) Induced reentrant arrhythmias in the treated post-MI heart obtained following pacing from the site indicated by the star. Geometric models are presented together with electrical activation isochronal maps. Colors indicate time sequence of activation (ms). White arrows represent the direction of propagation of reentrant arrhythmias. (b) Reentrant VT morphology following cell sheet transplantation onto the lateral LV epicardium. (c) Reentrant VT morphologies following cell sheet transplantation onto the posterior, superior LV epicardium.