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Optogenetic modulation of cardiac action potential properties may prevent arrhythmogenesis in short and long QT syndromes
Amit Gruber, … , Michal Landesberg, Lior Gepstein
Amit Gruber, … , Michal Landesberg, Lior Gepstein
Published June 8, 2021
Citation Information: JCI Insight. 2021;6(11):e147470. https://doi.org/10.1172/jci.insight.147470.
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Research Article Cardiology Stem cells

Optogenetic modulation of cardiac action potential properties may prevent arrhythmogenesis in short and long QT syndromes

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Abstract

Abnormal action potential (AP) properties, as occurs in long or short QT syndromes (LQTS and SQTS, respectively), can cause life-threatening arrhythmias. Optogenetics strategies, utilizing light-sensitive proteins, have emerged as experimental platforms for cardiac pacing, resynchronization, and defibrillation. We tested the hypothesis that similar optogenetic tools can modulate the cardiomyocyte’s AP properties, as a potentially novel antiarrhythmic strategy. Healthy control and LQTS/SQTS patient–specific human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) were transduced to express the light-sensitive cationic channel channelrhodopsin-2 (ChR2) or the anionic-selective opsin, ACR2. Detailed patch-clamp, confocal-microscopy, and optical mapping studies evaluated the ability of spatiotemporally defined optogenetic protocols to modulate AP properties and prevent arrhythmogenesis in the hiPSC-CMs cell/tissue models. Depending on illumination timing, light-induced ChR2 activation induced robust prolongation or mild shortening of AP duration (APD), while ACR2 activation allowed effective APD shortening. Fine-tuning these approaches allowed for the normalization of pathological AP properties and suppression of arrhythmogenicity in the LQTS/SQTS hiPSC-CM cellular models. We next established a SQTS–hiPSC-CMs–based tissue model of reentrant-arrhythmias using optogenetic cross-field stimulation. An APD-modulating optogenetic protocol was then designed to dynamically prolong APD of the propagating wavefront, completely preventing arrhythmogenesis in this model. This work highlights the potential of optogenetics in studying repolarization abnormalities and in developing novel antiarrhythmic therapies.

Authors

Amit Gruber, Oded Edri, Irit Huber, Gil Arbel, Amira Gepstein, Assad Shiti, Naim Shaheen, Snizhana Chorna, Michal Landesberg, Lior Gepstein

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Figure 5

Optogenetic protocols to suppress cardiomyocyte excitability.

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Optogenetic protocols to suppress cardiomyocyte excitability.
(A and B) ...
(A and B) Whole-cell patch-clamp recordings from ChR2-expressing (A) or ACR2-expressing (B) hiPSC-CMs. Notice how continuous prolonged 1.3 mW/mm2 blue light illumination clamps membrane potential to either a depolarized (in the case of ChR2; A) or hyperpolarized (ACR2; B) potential and suppresses spontaneous AP generation. Scale bar: 40 mV. (C) Representative optical AP recording (using voltage-dye imaging), acquired during continuous electrical field stimulation (1 Hz) of hiPSC-CMs expressing either ChR2 (representing 7 experiments, top panel), ACR2 (representing 19 experiments, middle panel), or eGFP (representing 17 experiments, bottom panel). Note that prolonged illumination with 1.3 mW/mm2 blue light completely suppressed AP development in ChR2-expressing (top panel) and ACR2-expressing (middle panel) hiPSC-CMs. The same illumination protocol, however, did not affect control eGFP-expressing hiPSC-CMs (bottom panel). Illumination timing is represented in all tracings by the blue background.

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ISSN 2379-3708

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