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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 3

Optogenetic APD modulation in ChR2-expressing LQTS– and SQTS–hiPSC-CMs.

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Optogenetic APD modulation in ChR2-expressing LQTS– and SQTS–hiPSC-CMs.
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(A and B) Light-induced ChR2 activation during the repolarization phase prolonged APD of SQTS–hiPSC-CMs with the degree of APD prolongation correlating with illumination duration (A). Application of a 250 ms–long optical stimulus (onset = 80 ms) was able to significantly prolong APD80 (n = 6, P < 0.05 using paired t test) in the SQTS–hiPSC-CMs (B). (C and D) Light-induced ChR2 activation, early during the AP, could shorten the abnormally long APD of the LQTS–hiPSC-CMs (C). Scale bars: (A and C) 20 mV and 200 ms for the y and x axes, respectively. The degree of APD80 shortening achieved by the optimal stimulation protocol (onset, 40 ms; duration, 100 ms) was statistically significant (*P < 0.05, n = 5) using paired t test (D). (E) Light-induced ChR2 activation during early phase 2 of the AP phase suppresses EAD formation in LQTS–hiPSC-CMs. Shown are AP recordings from the LQTS–hiPSC-CMs at baseline (1 Hz electrical pacing), during the application of the illumination protocol (onset, 40 ms; duration, 100 ms) for each individual AP and following termination of illumination. The lower 3 panels present higher time resolution of the upper panel, showing the development of EADs at baseline in some paced beats; the suppression of EADs in all APs following illumination (blue lines); and resumption of arrhythmogenic activity following illumination termination. EADs are highlighted with green circles. Scale bars: 20 mV for the y axis, 2 seconds for the x axis of the upper panel, and 1 second for the 3 lower panels.

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