A comprehensive multiscale framework for simulating optogenetics in the heart

Abstract

Optogenetics has emerged as an alternative method for electrical control of the heart, where illumination is used to elicit a bioelectric response in tissue modified to express photosensitive proteins (opsins). This technology promises to enable evocation of spatiotemporally precise responses in targeted cells or tissues, thus creating new possibilities for safe and effective therapeutic approaches to ameliorate cardiac function. Here, we present a comprehensive framework for multi-scale modelling of cardiac optogenetics, allowing both mechanistic examination of optical control and exploration of potential therapeutic applications. The framework incorporates accurate representations of opsin channel kinetics and delivery modes, spatial distribution of photosensitive cells, and tissue illumination constraints, making possible the prediction of emergent behaviour resulting from interactions at sub-organ scales. We apply this framework to explore how optogenetic delivery characteristics determine energy requirements for optical stimulation and to identify cardiac structures that are potential pacemaking targets with low optical excitation threshold.

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations

“…(13,15,57). At the organ scale, we used a finite element approximation of the steady-state photon diffusion equation to model light attenuation due to scattering and energy absorption in the ventricular myocardium (13,57). The corresponding partial differential equation, which assumes isotropic absorption and homogenous scattering, is given by:…”

“…Data within the first 100 ms (i.e., t = 4-4.1 seconds) were excluded from analysis to ensure that these values were not biased toward either fast upstrokes associated with the initial response to optogenetic stimulation (i.e., directly light-induced action potentials) or low preillumination resting potentials. (13,15,57). At the organ scale, we used a finite element approximation of the steady-state photon diffusion equation to model light attenuation due to scattering and energy absorption in the ventricular myocardium (13,57).…”

“…To simulate optogenetic transduction of the human ventricles via viral gene delivery, we used our previously validated computational modeling framework (13,14,57). Channelrhodopsin expression was modeled by incorporation of a photocycle model (15) in 58.2% of myocardial nodes (normal + PIZ) with a diffuse spatial pattern (Supplemental Figure 4).…”

Toward microendoscopy-inspired cardiac optogeneticsin vivo: technical overview and perspective

“…Larger penetration depths and improved signal qualities have been demonstrated in whole hearts 30,[32][33][34] and heart slices 27,[37][38][39][40] using near-infrared voltage-sensitive dyes; however, imaging depth still remains limited. Thus, optical recordings of important features of the conduction system, such as the PS lying close to the endocardial surface, 41 have remained unexplored in the intact heart due to the inadequacies of current imaging methods.…”

“…85 Experimental data have been used to develop computational models incorporating accurate representations of opsin channel kinetics, 83,86 spatial distribution of photosensitive cells, and tissue illumination constraints to determine the optimal targets for optogenetic stimulation in the whole heart. 41,87 For example, it has been computationally demonstrated that the optogenetic targeting of the PS, found close to the endocardial surface, could be used to optically perform cell-specific sinus-like pacing with lower energies compared with ventricular targets. 41 Although in vivo optical actuation has been demonstrated using openchest procedures in mice, 81 current recording methods are limited to the epicardial surface and subsurface due to photon scattering and absorption, making specific mapping of the internal conduction system infeasible.…”