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.
Highlights
Cardiac optogenetics is an emerging field that stems from work involving genetic transduction of light-sensitive ion channels into mammalian neurons (Boyden et al, 2005; Arrenberg et al, 2010)
Attempted optogenetic defibrillation in the ChR2-expressing model did not disrupt reentrant activity transmurally (Figure 5B); endocardial action potentials were blunted, but remained temporally synchronized with epicardial excitations, which were largely unaffected by optogenetic stimulation
We showed that Guillardia theta anion channelrhodopsin-1 (GtACR1)-mediated optogenetic defibrillation of the atria or ventricles is feasible and more efficacious than a ChR2-based approach, the limitations of which are well known from prior work
Summary
Cardiac optogenetics is an emerging field that stems from work involving genetic transduction of light-sensitive ion channels into mammalian neurons (Boyden et al, 2005; Arrenberg et al, 2010). The use of light for current induction in cardiac tissue with precise spatial and temporal precision has led to in vivo studies describing selective excitation of specific cell populations (Jia et al, 2011; Addis et al, 2013), control of spiral waves (Burton et al, 2015; Hussaini et al, 2021), and cardiac pace-making (Bruegmann et al, 2010; Ambrosi and Entcheva, 2014; Nussinovitch and Gepstein, 2015a; Vogt et al, 2015) or arrhythmia termination in animal models (Bruegmann et al, 2016; Nyns et al, 2017, 2019; Cheng et al, 2020). Optogenetic defibrillation has the potential to circumvent these drawbacks, but prior modeling studies (Bruegmann et al, 2016, 2018; Karathanos et al, 2016; Boyle et al, 2018b) suggest that it would be very difficult to accomplish with current tools, like the channelrhodopsin-2 (ChR2) H134R variant, due to light-attenuating properties of myocardium and high energy requirements
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
