Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms

Year: 2022

Authors: Biasci V.; Santini L.; Marchal G.A.; Hussaini S.; Ferrantini C.; Coppini R.; Loew L.M.; Luther S.; Campione M.; Poggesi C.; Pavone F.S.; Cerbai E.; Bub G.; Sacconi L.

Autors Affiliation: European Laboratory for Non-Linear Spectroscopy – LENS, Sesto Fiorentino, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Department of Neurology, Psychology, Drug Sciences and Child Health, University of Florence, Florence, Italy; National Institute of Optics (INO-CNR), Sesto Fiorentino, Italy; Max Planck Institute for Dynamics and Self-Organization, Gottingen, Germany; Center for Cell Analysis and Modeling, University of Connecticut, Farmington, CT, USA, United States; Institute of Neuroscience (IN-CNR) and Department of Biomedical Science, University of Padua, Padua, Italy; Department of Physics and Astronomy, University of Florence, Sesto Fiorentino, Italy; Department of Physiology, McGill University, Montreal, Canada; Department of Physiology, McGill University, Montreal, Canada; Institute for Experimental Cardiovascular Medicine, University Heart Center and Medical Faculty, University of Freiburg, Freiburg, Germany

Abstract: Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channel recovery and intracellular Ca2+ cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion channel inhibitors that lack spatial and temporal specificity. In this work, we propose an approach based on optogenetics to manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to elicit APs (sub-threshold illumination), but are sufficient to fine-tune AP electrical dynamics. We investigated the effects of sub-threshold illumination in isolated cardiomyocytes and whole hearts by using transgenic mice constitutively expressing a light-gated ion channel (channelrhodopsin-2, ChR2). We find that ChR2-mediated depolarizing current prolongs APs and reduces conduction velocity (CV) in a space-selective and reversible manner. Sub-threshold manipulation also affects the dynamics of cardiac electrical activity, increasing the magnitude of cardiac alternans. We used an optical system that uses real-time feedback control to generate re-entrant circuits with user-defined cycle lengths to explore the role of cardiac alternans in spontaneous termination of ventricular tachycardias (VTs). We demonstrate that VT stability significantly decreases during sub-threshold illumination primarily due to an increase in the amplitude of electrical oscillations, which implies that cardiac alternans may be beneficial in the context of self-termination of VT.


Volume: 117 (1)      Pages from: 25-1  to: 25-15

KeyWords: Cardiac alternans; Ventricular tachycardias; Voltage imaging; Optogenetics
DOI: 10.1007/s00395-022-00933-8