Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cardiology Stem cells

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

  • Text
  • PDF
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

×

Figure 2

Optogenetic APD modulation in ChR2-expressing hiPSC-CMs.

Options: View larger image (or click on image) Download as PowerPoint
Optogenetic APD modulation in ChR2-expressing hiPSC-CMs.
(A) Optogenetic...
(A) Optogenetic protocols included 7 electrically stimulated APs at 1 Hz with delivery of optogenetic stimuli at a specific timing following the last electrical pacing stimulation (onset). (B–D) Light-induced ChR2 activation during phase 3 prolongs APD in whole-cell current clamp recordings. (B) Representative AP traces acquired during darkness (black) and following different optogenetic stimuli (blue) of various durations (dashed lines). Note the tight correlation between optical stimulus duration and the resulting APD prolongation. (C) A plot depicting the correlation between the timings of the end of the optical stimuli and the resulting APD80 values. Both continuous (black circles) and pulsed (gray squares) illumination protocols resulted in high correlations (r = 0.99 and 0.99, n = 12; regression models are presented). (D) Comparison of continuous and pulsed (20 ms on/30 ms off) illumination effects showing similar APD prolongations. (E–G) Early light-induced ChR2 activation shortens APD. (E) Representative AP traces from 9 experiments acquired during darkness (black) and with early optical stimuli of various durations (onset, 20 ms). (F) Comparing the effects achieved by varying optical stimulus durations (50 ms, 100 ms, and 150 ms, n = 9) on the relative APD80 shortening using both continuous (black) and pulsed (gray) stimulation protocols. Note that, due to the limited time window for APD shortening, the longest continuous illumination tested (150 ms) is significantly less. *P < 0.05 and **P < 0.01 using 2-way ANOVA test for repeated measurements, followed by post-hoc Tukey test. (G) Shortening of the measured APD80 values following early optogenetic stimulation (onset, 20 ms; duration, 100 ms) (*P < 0.05 using paired Student’s t test, n = 9). (H) Summary of the bidirectional APD modulating effects of ChR2 light activation as function of the timing and duration of the optical stimulus. Scale bars: 20 mV and 200 ms for the y and x axes, respectively (B, D, E, and H).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts