Optogenetic Stimulation Using Anion Channelrhodopsin (GtACR1) Facilitates Termination of Reentrant Arrhythmias With Low Light Energy Requirements: A Computational Study.
Optogenetic Stimulation Using Anion Channelrhodopsin (GtACR1) Facilitates Termination of Reentrant Arrhythmias With Low Light Energy Requirements: A Computational Study.
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使用阴离子通道Ropopsin（GTACR1）的光遗传学刺激有助于终止具有低光能需求的重新进入心律不齐：一项计算研究。
DOI：
10.3389/fphys.2021.718622
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发表时间：
2021
影响因子：
4
通讯作者：
Boyle PM
中科院分区：
文献类型：
--
作者：
Ochs AR;Karathanos TV;Trayanova NA;Boyle PM
表达光敏阳离子通道（如ChR2）的心脏的光基因除颤已被提出作为传统电疗的替代方案。过去的建模工作表明，ChR2刺激可以使足够的心肌去极化以中断心律失常，但其效果受到光衰减和高能量需求的限制。这些缺点可以通过使用新的光遗传蛋白来缓解，比如吉迪亚阴离子通道视紫红质（GtACR1），它在照明时产生向外再极化电流。因此，我们设计了一项研究来评估基于gtacr1的光遗传终止人类心脏心律失常的可行性。我们在基于mri的心房或心室模型（各n = 3）中进行了电生理模拟，分别有房颤或缺血性心肌病的病理重构。我们通过三种不同视蛋白（ChR2，红移ChR2， GtACR1）的病毒基因传递和适当波长（分别为蓝光，红光或绿光）的均匀心内膜照明来模拟光致敏。为了分析心律失常终止的一致性，我们改变了脉冲时间（三个均匀间隔跨越重入周期）和强度（心房：0.001-1 mW/mm2；心室：0.001-10 mW/mm2）。在心房模型中，0.005 mW/mm2绿光刺激GtACR1持续终止再入；这比chr2介导的除颤阈值水平弱10 - 100倍。在心室模型中，0.005 mW/mm2的GtACR1刺激（比ChR2病例弱100 - 200倍）在2/3的模型中观察到除颤。在第三心室模型中，除颤几乎在所有病例中都失败，这表明衰减问题和患者特定的器官/疤痕几何形状可能会阻碍某些病例的终止。在所有模型中，gtacr1介导的除颤机制是被照射组织的电压强迫达到- 40 mV的通道逆转电位，这使得传播无法通过受影响的区域。因此，我们的研究结果表明，基于gtacr1的人类心脏光基因除颤可能是可行的，其能量比ChR2低约2-3个数量级。
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.
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影响因子：
3.8
作者：
Bayer, J. D.;Blake, R. C.;Plank, G.;Trayanova, N. A.
通讯作者：
Trayanova, N. A.
DOI：
10.1016/j.pbiomolbio.2014.07.001
发表时间：
2014-08
影响因子：
3.8
作者：
Ambrosi CM;Klimas A;Yu J;Entcheva E
通讯作者：
Entcheva E
影响因子：
10.8
作者：
Bingen, Brian O.;Engels, Marc C.;de Vries, Antoine A. F.
通讯作者：
de Vries, Antoine A. F.
影响因子：
3.4
作者：
Bishop, MJ;Rodriguez, B;Gavaghan, DJ
通讯作者：
Gavaghan, DJ
影响因子：
16.6
作者：
Boyle, Patrick M.;Williams, John C.;Trayanova, Natalia A.
通讯作者：
Trayanova, Natalia A.