Optogenetic manipulation of anatomical re-entry by light-guided generation of a reversible local conduction block

Watanabe, Masaya; Feola, Iolanda; Majumder, Rupamanjari; Jangsangthong, Wanchana; Teplenin, Alexander; Ypey, Dirk L.; Schalij, Martin J.; Zeppenfeld, Katja; Vries, Antoine A.F. de; Pijnappels, Daniël A.

doi:10.1093/cvr/cvx003

Cited by 30 publications

(25 citation statements)

References 40 publications

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“…One possible explanation could be the change in penetration depth when using higher light intensities for photostimulation, hence depolarizing a greater number of cells and creating a thicker reversible conduction pattern. This was also described by Watanabe et al in experiments with ventricular slices, where they showed a temporal decrease on the effective size available for the arrhythmia to wander (Watanabe et al, 2017 ). In their work, Watanabe et al proved that by increasing the transmurality of illumination, the chances of terminating an anatomical re-entry on the slices increased.…”

Section: Discussionsupporting

confidence: 68%

Energy-Reduced Arrhythmia Termination Using Global Photostimulation in Optogenetic Murine Hearts

2018

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Complex spatiotemporal non-linearity as observed during cardiac arrhythmia strongly correlates with vortex-like excitation wavelengths and tissue characteristics. Therefore, the control of arrhythmic patterns requires fundamental understanding of dependencies between onset and perpetuation of arrhythmia and substrate instabilities. Available treatments, such as drug application or high-energy electrical shocks, are discussed for potential side effects resulting in prognosis worsening due to the lack of specificity and spatiotemporal precision. In contrast, cardiac optogenetics relies on light sensitive ion channels stimulated to trigger excitation of cardiomyocytes solely making use of the inner cell mechanisms. This enables low-energy, non-damaging optical control of cardiac excitation with high resolution. Recently, the capability of optogenetic cardioversion was shown in Channelrhodopsin-2 (ChR2) transgenic mice. But these studies used mainly structured and local illumination for cardiac stimulation. In addition, since optogenetic and electrical stimulus work on different principles to control the electrical activity of cardiac tissue, a better understanding of the phenomena behind optogenetic cardioversion is still needed. The present study aims to investigate global illumination with regard to parameter characterization and its potential for cardioversion. Our results show that by tuning the light intensity without exceeding 1.10 mW mm-2, a single pulse in the range of 10–1,000 ms is sufficient to reliably reset the heart into sinus rhythm. The combination of our panoramic low-intensity photostimulation with optical mapping techniques visualized wave collision resulting in annihilation as well as propagation perturbations as mechanisms leading to optogenetic cardioversion, which seem to base on other processes than electrical defibrillation. This study contributes to the understanding of the roles played by epicardial illumination, pulse duration and light intensity in optogenetic cardioversion, which are the main variables influencing cardiac optogenetic control, highlighting the advantages and insights of global stimulation. Therefore, the presented results can be modules in the design of novel illumination technologies with specific energy requirements on the way toward tissue-protective defibrillation techniques.

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Section: Discussionsupporting

confidence: 68%

Energy-Reduced Arrhythmia Termination Using Global Photostimulation in Optogenetic Murine Hearts

2018

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“…On the contrary, at r C >1.10 mm, detachment and relocation was possible only when there was physical overlap between the inhomogeneities, or the two inhomogeneities were so close that the cells occupying the domain space between them constituted part of the composite inhomogeneity (conduction+light-induced), due to the inexcitability zone created by depolarization gradients of the light-induced inhomogeneity [38]. At r C >1.10 mm and > + d r r C L ( ), relocation occurred very rarely (e.g.…”

Section: Resultsmentioning

confidence: 99%

In silico optical control of pinned electrical vortices in an excitable biological medium

2020

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Vortices of excitation are generic to any complex excitable system. In the heart, they occur as rotors, spirals (2D) and scroll waves (3D) of electrical activity that are associated with rhythm disorders, known as arrhythmias. Lethal cardiac arrhythmias often result in sudden death, which is one of the leading causes of mortality in the industrialized world. Irrespective of the nature of the excitable medium, the rotation of a rotor is driven by its dynamics at the (vortex) core. In a recent study, Majumder et al (2018 eLife 7 e41076) demonstrated, using in silico and in vitro cardiac optogenetics, that light-guided manipulation of the core of free rotors can be used to establish real-time spatiotemporal control over the position, number and rotation of these rotors in cardiac tissue. Strategic application of this method, called 'Attract-Anchor-Drag' (AAD) can also be used to eliminate free rotors from the heart and stop cardiac arrhythmias. However, rotors in excitable systems, can pin (anchor) around local heterogeneities as well, thereby limiting their dynamics and possibility for spatial control. Here, we expand our results and numerically demonstrate, that AAD method can also detach anchored vortices from inhomogeneities and subsequently control their dynamics in excitable systems. Thus, overall we demonstrate that AAD control is one of the first universal methods that can be applied to both free and pinned vortices, to ensure their spatial control and removal from the heart and, possibly, other excitable systems.

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“…Since successful application of optogenetics depends on production of a photocurrent large enough to trigger depolarization, expression levels can be critical determinants of experimental outcome. A number of viral [18,25,29,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] and non-viral methods [9,10,25,29,31,32,48,[54][55][56][57][58][59][60][61][62][63] have been successfully applied to the cardiomyocyte. For in vivo cardiac application tissue tropism with adeno-associated virus (AAV) types 1 or 6 might be preferable to type 9 used in vitro [64].…”

Section: Optogenetic Tools and Their Deliverymentioning

confidence: 99%

“…1 ) are possible, and can be combined with surface electrodes [ 10 , 50 , 60 , 61 ] pacing electrodes ( e.g . to trigger ventricular tachycardia [ 31 ]) or imaging based mapping of tissue level activation [ 32 , 51 , 53 , 60 , 61 ]. Applications have tended to focus on dissecting out the role of the autonomic nervous system, as expression of the optical control tool can be restricted to certain cell types, or investigation the potential for optical pacing or defibrillation as an alternative to the current electrode based methods.…”

Section: Expanded Examplesmentioning

confidence: 99%

Feasibility of Using Adjunctive Optogenetic Technologies in Cardiomyocyte Phenotyping – from the Single Cell to the Whole Heart

Bub

Daniels

2020

CPB

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In 1791, Galvani established that electricity activated excitable cells. In the two centuries that followed, electrode stimulation of neuronal, skeletal and cardiac muscle became the adjunctive method of choice in experimental, electrophysiological, and clinical arenas. This approach underpins breakthrough technologies like implantable cardiac pacemakers that we currently take for granted. However, the contact dependence, and field stimulation that electrical depolarization delivers brings inherent limitations to the scope and experimental scale that can be achieved. Many of these were not exposed until reliable in vitro stem-cell derived experimental materials, with genotypes of interest, were produced in the numbers needed for multi-well screening platforms (for toxicity or efficacy studies) or the 2D or 3D tissue surrogates required to study propagation of depolarization within multicellular constructs that mimic clinically relevant arrhythmia in the heart or brain. Here the limitations of classical electrode stimulation are discussed. We describe how these are overcome by optogenetic tools which put electrically excitable cells under the control of light. We discuss how this enables studies in cardiac material from the single cell to the whole heart scale. We review the current commercial platforms that incorporate optogenetic stimulation strategies, and summarize the global literature to date on cardiac applications of optogenetics. We show that the advantages of optogenetic stimulation relevant to iPS-CM based screening include independence from contact, elimination of electrical stimulation artefacts in field potential measuring approaches such as the multi-electrode array, and the ability to print re-entrant patterns of depolarization at will on 2D cardiomyocyte monolayers.

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Optogenetic manipulation of anatomical re-entry by light-guided generation of a reversible local conduction block

Cited by 30 publications

References 40 publications

Energy-Reduced Arrhythmia Termination Using Global Photostimulation in Optogenetic Murine Hearts

Energy-Reduced Arrhythmia Termination Using Global Photostimulation in Optogenetic Murine Hearts

In silico optical control of pinned electrical vortices in an excitable biological medium

Feasibility of Using Adjunctive Optogenetic Technologies in Cardiomyocyte Phenotyping – from the Single Cell to the Whole Heart

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