Computational Simulations Show Proof-of-Concept for Optogenetic Suppression of Ectopic Activity in Cardiac Stem Cell Therapy.

Abstract

Purpose: Myocardial infarction results in extensive cardiac remodeling that can lead to heart failure. Human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) injection can improve heart function but may lead to engraftment-associated ventricular tachycardia (VT). Optogenetics uses light stimulation to control electrical activity of cells genetically modified to express light-sensitive proteins (opsins). This study aims to use computational simulations to test the feasibility of optogenetically suppressing hPSC-CM ectopic activity without inhibiting the ability to undergo excitation by upstream wavefronts (i.e., engrafted cells could activate harmoniously with surrounding host myocardium during propagation of a normal sinus beat).

Methods: We simulated electrophysiology in single-cell hPSC-CM and tissue-scale ventricular models derived from histology images. The latter comprised host myocardium, hPSC-CM graft, and non-conductive scar. Ventricular and hPSC-CM cellular models were used in the host myocardium and hPSC-CM graft regions, respectively. Optogenetic modification of hPSC-CMs was simulated via incorporation of a photocycle model with the approximate properties of WiChR, a light-sensitive potassium channel. To test the efficacy of the proposed approach for silencing graft activity, we simulated sustained blue light illumination at 488 nm.

Results: Sustained optogenetic stimulation suppressed spontaneous excitation altogether in opsin-expressing hPSC-CM models while maintaining cellular excitability. At the tissue scale, optogenetic suppression of VT-associated ectopic excitations was feasible with epicardial illumination. Opsin-expressing grafts in optogenetically silenced histology models remained excitable under simulated sinus rhythm-like excitation from the endocardium; however, potentially arrhythmogenic spatial heterogeneity of action potential duration was seen in model geometries with greater wall thickness.

Conclusions: Our simulations suggest WiChR-based optogenetic suppression of hPSC-CM graft-associated arrhythmia is likely feasible but must be carefully calibrated to avoid inadvertently pro-arrhythmic side effects.