Optogenetic Stimulation Using Anion Channelrhodopsin (GtACR1) Facilitates Termination of Reentrant Arrhythmias With Low Light Energy Requirements: A Computational Study

Abstract

Optogenetic defibrillation of hearts expressing light-sensitive cation channels (e.g., ChR2) has been proposed as an alternative to conventional electrotherapy. Past modeling work has shown that ChR2 stimulation can depolarize enough myocardium to interrupt arrhythmia, but its efficacy is limited by light attenuation and high energy needs. These shortcomings may be mitigated by using new optogenetic proteins like Guillardia theta Anion Channelrhodopsin (GtACR1), which produces a repolarizing outward current upon illumination. Accordingly, we designed a study to assess the feasibility of GtACR1-based optogenetic arrhythmia termination in human hearts. We conducted electrophysiological simulations in MRI-based atrial or ventricular models (n = 3 each), with pathological remodeling from atrial fibrillation or ischemic cardiomyopathy, respectively. We simulated light sensitization via viral gene delivery of three different opsins (ChR2, red-shifted ChR2, GtACR1) and uniform endocardial illumination at the appropriate wavelengths (blue, red, or green light, respectively). To analyze consistency of arrhythmia termination, we varied pulse timing (three evenly spaced intervals spanning the reentrant cycle) and intensity (atrial: 0.001–1 mW/mm2; ventricular: 0.001–10 mW/mm2). In atrial models, GtACR1 stimulation with 0.005 mW/mm2 green light consistently terminated reentry; this was 10–100x weaker than the threshold levels for ChR2-mediated defibrillation. In ventricular models, defibrillation was observed in 2/3 models for GtACR1 stimulation at 0.005 mW/mm2 (100–200x weaker than ChR2 cases). In the third ventricular model, defibrillation failed in nearly all cases, suggesting that attenuation issues and patient-specific organ/scar geometry may thwart termination in some cases. Across all models, the mechanism of GtACR1-mediated defibrillation was voltage forcing of illuminated tissue toward the modeled channel reversal potential of −40 mV, which made propagation through affected regions impossible. Thus, our findings suggest GtACR1-based optogenetic defibrillation of the human heart may be feasible with ≈2–3 orders of magnitude less energy than ChR2.

Synaptic Connectivity of Sensorimotor Circuits for Vocal Imitation in the Songbird

“…First, the amplitude and likelihood of recording oPSCs directly depends on the expression rate and tropism of our viruses and this may differ in subtle ways across the 4 pathways we report on here. Second, measurement of optically evoked PPR at 50ms should be interpreted cautiously because of the off kinetics of eGtACR1 32,33 . Lastly, there are intrinsic limitations to mapping synaptic connectivity in brain slices due to the potential of severing dendrites and other neuronal processes.…”

“…The use of eGtACR1, while granting high amplitude photocurrents, limits our ability to precisely study synaptic properties due to its slow off kinetics (≈ 100ms) 32,33,52 . This directly affects the steady state of the presynaptic terminals, especially upon multiple stimulations in a short timeframe (such as our protocol for PPR calculation).…”

“…Future studies will need to employ conditions of minimal stimulation that may further characterize the specific properties of monosynaptic and polysynaptic neurotransmission in the examined inputs. • The use of eGtACR1, while granting high amplitude photocurrents, limits our ability to precisely study synaptic properties due to its slow off kinetics (≈ 100ms) 32,33,52 . This directly affects the steady state of the presynaptic terminals, especially upon multiple stimulations in a short timeframe (such as our protocol for PPR calculation).…”

Applications and challenges of rhodopsin-based optogenetics in biomedicine

“…Such an approach would address some of the limitations of electric defibrillators, such as reducing the risk of myocardial tissue damage and pain. A recent paper utilizing computational simulation pointed out that GtACR1 may be used to defibrillate human hearts (Ochs et al, 2021). Majumder et al (2020) developed a theoretical ion channel called the Biologically Integrated Cardiac Defibrillator (BioICD), whose activation can lead to a rapid and repeated restoration of normal rhythm for arrhythmia in the human atrium and ventricle (Majumder et al, 2020).…”

Ultra‐low power deep sustained optogenetic excitation of human ventricular cardiomyocytes with red‐shifted opsins: a computational study

“…Co‐expression of ChR2 and NpHR allows blocking of intrinsic activation or pacing of the zebrafish heart at specific rates using light pulses at different wavelengths (Arrenberg et al., 2010). Recently, activation of anion channelrhodopsin during the repolarization phase of the action potential (AP) enabled precisely controlled shortening of AP duration (Ochs et al., 2021; Ordog et al., 2021).…”