Computational modeling of cardiac optogenetics: Methodology overview & review of findings from simulations

Abstract

Cardiac optogenetics is emerging as an exciting new potential avenue to enable spatiotemporally precise control of excitable cells and tissue in the heart with low-energy optical stimuli. This approach involves the expression of exogenous light-sensitive proteins (opsins) in target heart tissue via viral gene or cell delivery. Preliminary experiments in optogenetically-modified cells, tissue, and organisms have made great strides towards demonstrating the feasibility of basic applications, including the use of light stimuli to pace or disrupt reentrant activity. However, it remains unknown whether techniques based on this intriguing technology could be scaled up and used in humans for novel clinical applications, such as pain-free optical defibrillation or dynamic modulation of action potential shape. A key step towards answering such questions is to explore potential optogenetics-based therapies using sophisticated computer simulation tools capable of realistically representing opsin delivery and light stimulation in biophysically detailed, patient-specific models of the human heart. This review provides (1) a detailed overview of the methodological developments necessary to represent optogenetics-based solutions in existing virtual heart platforms and (2) a survey of findings that have been derived from such simulations and a critical assessment of their significance with respect to the progress of the field.

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).…”

“…As described previously (57), w is set to zero and the equation is solved with Dirichlet boundary conditions derived from the placement of simulated light sources. We validated this approach in earlier work concerned with simulation of optical mapping experiments (20).…”

“…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).…”

In silico optical control of pinned electrical vortices in an excitable biological medium

“…In the simplest case, we assume homogeneous absorption and isotropic scattering of light photons. Thus the irradiance can be approximated by an exponential function, as explained in detail in [59]. For our 3D studies, irradiance E e (r) inside the tissue was modeled using the simple distribution function [59] [8], and δ=0.588 mm, the penetration deption for blue light in cardiac tissue [60].…”