Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations
Tobias Bruegmann, … , Natalia A. Trayanova, Philipp Sasse
Tobias Bruegmann, … , Natalia A. Trayanova, Philipp Sasse
Published September 12, 2016
Citation Information: J Clin Invest. 2016;126(10):3894-3904. https://doi.org/10.1172/JCI88950.
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Research Article Cardiology

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations

Abstract

Ventricular arrhythmias are among the most severe complications of heart disease and can result in sudden cardiac death. Patients at risk currently receive implantable defibrillators that deliver electrical shocks to terminate arrhythmias on demand. However, strong electrical shocks can damage the heart and cause severe pain. Therefore, we have tested optogenetic defibrillation using expression of the light-sensitive channel channelrhodopsin-2 (ChR2) in cardiac tissue. Epicardial illumination effectively terminated ventricular arrhythmias in hearts from transgenic mice and from WT mice after adeno-associated virus–based gene transfer of ChR2. We also explored optogenetic defibrillation for human hearts, taking advantage of a recently developed, clinically validated in silico approach for simulating infarct-related ventricular tachycardia (VT). Our analysis revealed that illumination with red light effectively terminates VT in diseased, ChR2-expressing human hearts. Mechanistically, we determined that the observed VT termination is due to ChR2-mediated transmural depolarization of the myocardium, which causes a block of voltage-dependent Na+ channels throughout the myocardial wall and interrupts wavefront propagation into illuminated tissue. Thus, our results demonstrate that optogenetic defibrillation is highly effective in the mouse heart and could potentially be translated into humans to achieve nondamaging and pain-free termination of ventricular arrhythmia.

Authors

Tobias Bruegmann, Patrick M. Boyle, Christoph C. Vogt, Thomas V. Karathanos, Hermenegild J. Arevalo, Bernd K. Fleischmann, Natalia A. Trayanova, Philipp Sasse

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Figure 1

Optogenetic defibrillation in transgenic hearts.

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Optogenetic defibrillation in transgenic hearts. (A) Representative ECG ...
(A) Representative ECG (black) from an explanted heart expressing ChR2. Sustained VT was induced by electrical burst stimulation (50 Hz, red bar) and terminated by epicardial illumination with blue light (blue bar, 470 nm, 1 second, 0.4 mW/mm2, 143 mm2, n = 36). (B) Arrhythmia termination rate in ChR2 hearts after one 1-second-long light pulse (0.4 mW/mm2, 143 mm2, blue) applied 3, 5, and 10 seconds after induction of arrhythmia compared with control conditions (i.e., no illumination, black) in the same time window (see Supplemental Figure 1B for experimental protocol; Wilcoxon matched pairs test, P < 0.04, n = 6). (C) Arrhythmia termination rate in response to a 4-light-pulse protocol (Supplemental Figure 1C) in ChR2 mouse hearts with illumination (1 second, 0.4 mW/mm2, 143 mm2, blue) and without illumination (black), as well as in hearts expressing only EGFP (green) and in CD1 WT hearts (red) with illumination (Kruskal-Wallis test, P < 0.0001, with Dunn’s multiple-comparison post-test; ChR2 light: n = 29; ChR2 no light: n = 6; EGFP: n = 4; CD1 WT: n = 6). (D–F) Influence of illumination duration (D, 0.4 mW/mm2, 29 mm2, n = 7, P = 0.0007), area (E, 1 second, 0.4 mW/mm2, n = 9, P = 0.031), and light intensity (F, 1 second, 15 mm2, n = 5, P = 0.013) on arrhythmia termination rate (Friedman test). Each point shows the percentage of successful optogenetic defibrillation attempts in 1 heart. Data are shown as the mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001.