(G-271) Propensity of Microreentry within hPSC-CM Grafts is Modulated by Levels of Ionic Currents

Introduction:: Complications following myocardial infarction significantly contribute to cardiovascular mortality worldwide [1]. Preclinical studies in large animal models have shown that engraftment of human stem cell-derived cardiomyocytes (hPSC-CMs) can remuscularize infarcted myocardium but can also lead to engraftment arrhythmia (EA) [2]. Current evidence implicates focal sources originating within the graft as the underlying mechanism of EA [2] [3]. However, the possibility remains that apparent focal sources might actually be manifestations of rapid, self-sustaining closed loop intra-graft electrical activity (i.e., microreentry). The aim of this study was to test the hypothesis that the theoretical propensity for sustained intra-graft microreentry is modulated by the levels of five major ionic currents.

Materials and Methods:: We tested our hypothesis in a circular two-dimensional model composed entirely of hPSC-CMs with a diameter of 5 mm. To investigate how changes at the sub-cellular scale could lead to sustained microreentry in a tissue scale graft we perturbed five major ionic currents by ±50%. These five currents were the inward rectifier potassium (I_K1), delayed rectifier potassium (I_Kr), fast sodium (I_Na), L-type calcium (I_CaL), and hyperpolarization-activated (i.e., “funny”; I_f) currents (Fig 1A). We modeled membrane kinetics of graft tissue using the Kernik et al. model [4]. Simulations of bioelectrical activity were performed with openCARP [5]. To simulate the initiation of microreentrant rotors, we used the method described by Hussaini et al. [6]; briefly, the model graft was split into four quadrants, each of which was initialized at a different action potential phase (depolarization, 30% repolarization, 90% repolarization, full repolarization) (Fig 1B). Microreentry was considered sustained if the rotor was present for at least three full cycles. Microreentrant rotor frequency was calculated as the number of complete revolutions over a period of four seconds.

Results, Conclusions, and Discussions:: Sustained microreentry was observed in the baseline simulation (i.e., unmodified ionic currents) and five of the ten (50%) test conditions with perturbed cell-scale electrophysiology. At baseline, the microreentrant rotor completed each full revolution in approximately 400 ms (Fig 1C). Microreentrant rotor propensity was affected by changes to the five major ionic currents (Fig 1D). Decreases to I_K1, I_Na, and I_CaL resulted in sustained microreentry. Increases to I_K1, I_Na, and I_CaL resulted in collapse of microreentry. Increases to I_Na and I_K1 result in faster conduction of electrical activity through the graft due to increased depolarization and a more negative mean diastolic potential, respectively. Increased I_CaL lengthens the plateau phase of the action potential. These results indicate microreentry vulnerability is reduced when conduction velocity is increased or action potential duration is prolonged. Microreentry persisted when I_Kr was changed in either direction; in contrast, for both configurations involving modified I_f, microreentry collapsed. In simulations with sustained microreentry, rotor frequency was most affected by changes to I_Kr. Decreased I_Kr resulted in a 19% decrease relative to baseline. Reduction of I_Kr prolongs action potential duration, thus slowing microreentrant rotors. Increased I_Kr resulted in disproportionate increase in rotor frequency, with only a 9% increase relative to baseline. Rotor frequency was comparable to baseline in other simulations. Future work will involve a full factorial analysis of the five major ionic currents to analyze interdependencies in their effects on microreentry vulnerability. Additional cell scale properties such as action potential duration and spontaneous beating rate will be included in order to comprehensively investigate the mechanism of intra-graft microreentry.

Acknowledgements (Optional): : This work was facilitated through the use of advanced computational, storage and networking infrastructure provided by the Hyak supercomputer system at the University of Washington. Funding support for this project was provided by NIH grant R01HL158667 and by an NSF Graduate Research Fellowship under Grant No. DGE-2140004.

References (Optional): : [1] G. W. Reed, J. E. Rossi, and C. P. Cannon, “Acute myocardial infarction,” The Lancet, vol. 389, no. 10065, pp. 197–210, Jan. 2017, doi: 10.1016/S0140-6736(16)30677-8.
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