Introduction

Early afterdepolarizations (EADs) are secondary voltage depolarizations associated with reduced repolarization reserve (RRR) that can trigger lethal arrhythmias. Relating EADs to triggered activity is difficult to study, so the ability to suppress or provoke EADs would be experimentally useful. Here, we use computational simulations to assess the feasibility of subthreshold optogenetic stimulation modulating the propensity for EADs (cell-scale) and EAD-associated ectopic beats (organ-scale).

Methods

We modified a ventricular ionic model by reducing rapid delayed rectifier potassium (0.25–0.1 × baseline) and increasing L-type calcium (1.0–3.5 × baseline) currents to create RRR conditions with varying severity. We ran simulations in models of single cardiomyocytes and left ventricles from post-myocardial infarction patient MRI scans. Optogenetic stimulation was simulated using either ChR2 (depolarizing) or GtACR1 (repolarizing) opsins.

Results

In cell-scale simulations without illumination, EADs were seen for 164 of 416 RRR conditions. Subthreshold stimulation of GtACR1 reduced EAD incidence by up to 84.8% (25/416 RRR conditions; 0.1 μW/mm²); in contrast, subthreshold ChR2 excitation increased EAD incidence by up to 136.6% (388/416 RRR conditions; 50 μW/mm²). At the organ scale, we assumed simultaneous, uniform illumination of the epicardial and endocardial surfaces. GtACR1-mediated suppression (10–50 μW/mm²) and ChR2-mediated unmasking (50–100 μW/mm²) of EAD-associated ectopic beats were feasible in three distinct ventricular models.

Conclusions

Our findings suggest that optogenetics could be used to silence or provoke both EADs and EAD-associated ectopic beats. Validation in animal models could lead to exciting new experimental regimes and potentially to novel anti-arrhythmia treatments.

中文翻译：

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心律失常触发的光遗传学调节：计算模型的概念验证

介绍

早期后除极 (EAD) 是与复极储备 (RRR) 减少相关的二次电压除极，可引发致命性心律失常。将 EAD 与触发活动联系起来很难研究，因此抑制或激发 EAD 的能力在实验上很有用。在这里，我们使用计算模拟来评估阈下光遗传学刺激调节 EAD（细胞规模）和 EAD 相关异位搏动（器官规模）倾向的可行性。

方法

我们通过减少快速延迟整流钾（0.25–0.1 × 基线）和增加 L 型钙（1.0–3.5 × 基线）电流来修改心室离子模型，以创建不同严重程度的 RRR 条件。我们对心肌梗塞后患者 MRI 扫描的单个心肌细胞和左心室模型进行了模拟。使用 ChR2（去极化）或 GtACR1（复极化）视蛋白模拟光遗传学刺激。

结果

在无照明的细胞规模模拟中，416 个 RRR 条件中的 164 个条件下出现了 EAD。GtACR1 的阈下刺激可将 EAD 发生率降低高达 84.8%（25/416 RRR 条件；0.1 μW/mm ²）；相反，阈下 ChR2 激发使 EAD 发生率增加高达 136.6%（388/416 RRR 条件；50 μW/mm ²）。在器官尺度上，我们假设心外膜和心内膜表面同时、均匀地照明。GtACR1介导的EAD相关异位搏动抑制（10-50 μW/mm ²）和ChR2介导的暴露（50-100 μW/mm ^{2 ）在三种不同的心室模型中是可行的。}

结论

我们的研究结果表明，光遗传学可用于抑制或激发 EAD 和与 EAD 相关的异位搏动。动物模型的验证可能会带来令人兴奋的新实验方案，并有可能带来新的抗心律失常治疗方法。