Optogenetic Modulation of Arrhythmia Triggers: Proof-of-Concept from Computational Modeling.

IF 2.3 4区医学 Q3 BIOPHYSICS Cellular and molecular bioengineering Pub Date : 2023-08-24 eCollection Date: 2023-08-01 DOI:10.1007/s12195-023-00781-z

Alexander R Ochs, Patrick M Boyle

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Abstract

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.

Supplementary information: The online version contains supplementary material available at 10.1007/s12195-023-00781-z.

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心律失常触发因素的光遗传学调节：来自计算建模的概念证明。

引言：早期后去极化（EADs）是与复极储备（RRR）降低相关的二次电压去极化，可引发致命性心律失常。将EAD与触发的活动联系起来很难研究，因此抑制或激发EAD的能力在实验上是有用的。在这里，我们使用计算模拟来评估阈下光遗传学刺激调节EADs（细胞尺度）和EAD相关异位搏动（器官尺度）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，以产生具有变化严重性的RRR条件。我们在心肌梗死后患者MRI扫描的单个心肌细胞和左心室模型中进行了模拟。使用ChR2（去极化）或GtACR1（复极）视蛋白模拟光遗传学刺激。结果：在没有照明的细胞规模模拟中，416种RRR条件中有164种出现EAD。GtACR1的阈下刺激可将EAD发生率降低84.8%（25/416 RRR条件；0.1μW/mm2）；相反，亚阈值ChR2激发使EAD发生率增加了136.6%（388/416 RRR条件；50μW/mm2）。在器官尺度上，我们假设心外膜和心内膜表面同时均匀照明。GtACR1介导的对EAD相关异位搏动的抑制（10-50μW/mm2）和ChR2介导的揭露（50-100μW/m2）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，光遗传学可以用来抑制或激发EAD和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。补充信息：在线版本包含补充材料，可访问10.1007/s12195-023-00781-z。

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来源期刊

Cellular and molecular bioengineering 生物-生物物理

CiteScore

5.60

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.