Opsin spectral sensitivity determines the effectiveness of optogenetic termination of ventricular fibrillation in the human heart: a simulation study

Abstract

Optogenetics-based defibrillation has been proposed as a novel and potentially pain-free approach to enable cardiomyocyte-selective defibrillation in humans, but the feasibility of such a therapy remains unknown. This study aimed to (1) assess the feasibility of terminating sustained ventricular fibrillation (VF) via light-induced excitation of opsins expressed throughout the myocardium and (2) identify the ideal (theoretically possible) opsin properties and light source configurations that would maximise therapeutic efficacy. We conducted electrophysiological simulations in an MRI-based human ventricular model with VF induced by rapid pacing; light sensitisation via systemic, cardiac-specific gene transfer of channelrhodopsin-2 (ChR2) was simulated. In addition to the widely used blue light-sensitive ChR2-H134R, we also modelled theoretical ChR2 variants with augmented light sensitivity (ChR2+), red-shifted spectral sensitivity (ChR2-RED) or both (ChR2-RED+). Light sources were modelled as synchronously activating LED arrays (LED radius: 1 mm; optical power: 10 mW mm ; array density: 1.15-4.61 cm ). For each unique optogenetic configuration, defibrillation was attempted with two different optical pulse durations (25 and 500 ms). VF termination was only successful for configurations involving ChR2-RED and ChR2-RED+ (for LED arrays with density ≥ 2.30 cm ), suggesting that opsin spectral sensitivity was the most important determinant of optogenetic defibrillation efficacy. This was due to the deeper penetration of red light in cardiac tissue compared with blue light, which resulted in more widespread light-induced propagating wavefronts. Longer pulse duration and higher LED array density were associated with increased optogenetic defibrillation efficacy. In all cases observed, the defibrillation mechanism was light-induced depolarisation of the excitable gap, which led to block of reentrant wavefronts.

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations

“…We have recently shown in computer stimulations that for optogenetic defibrillation of a structurally normal heart by simultaneous epicardial and endocardial illumination, red light and increased opsin light sensitivity (increased 2.2-fold vs. normal ChR2) are needed (16). These changes are consistent with the biophysical properties of red-shifted ChR2 variants (17,18) and the CatCh variant of ChR2 (19), respectively.…”

Real‐time optical manipulation of cardiac conduction in intact hearts

“…, ; Karathanos et al . ). The first therapeutic approach based on optogenetics was demonstrated in 2015 (Nussinovitch & Gepstein, ), where optogenetic resynchronization was performed employing a fibre‐optics‐based multi‐site illumination of a rat heart in which viral vectors were used for infection to express Channelrhodopsin‐2 (ChR2).…”

Termination of re‐entrant atrial tachycardia via optogenetic stimulation with optimized spatial targeting: insights from computational models

“…; Karathanos et al . ). In terms of atrial applications, optogenetic modulation of action potential duration (APD) has been explored via computational modelling (Karathanos et al .…”

“…) or punctate (Karathanos et al . ) spatial patterns. In contrast, experiments in cardiac cell monolayers have highlighted the intricate spatiotemporal control of electrophysiology enabled by optogenetics (e.g.…”