Optogenetic manipulation of cardiac repolarization gradients using sub-threshold illumination

Year: 2023

Authors: Marchal GA., Biasci V., Loew LM., Biggeri A., Campione M., Sacconi L.

Autors Affiliation: European Lab Nonlinear Spect LENS, Florence, Italy; Natl Inst Opt INO CNR, Florence, Italy; Inst Clin Physiol IFC CNR, Pisa, Italy; Univ Florence, Dept Expt & Clin Med, Florence, Italy; Univ Connecticut, Ctr Cell Anal & Modeling, Farmington, CT USA; Univ Padua, Dept Cardiac Thorac Vasc Sci & Publ Hlth, Padua, Italy; Univ Padua, Dept Biomed Sci, Padua, Italy; Univ Padua, Inst Neurosci IN CNR, Padua, Italy; Univ Freiburg, Med Fac, Freiburg, Germany; Univ Freiburg, Univ Heart Ctr, Inst Expt Cardiovasc Med, Freiburg, Germany.

Abstract: Introduction: Mechanisms underlying cardiac arrhythmias are typically driven by abnormalities in cardiac conduction and/or heterogeneities in repolarization time (RT) across the heart. While conduction slowing can be caused by either electrophysiological defects or physical blockade in cardiac tissue, RT heterogeneities are mainly related to action potential (AP) prolongation or abbreviation in specific areas of the heart. Importantly, the size of the area with altered RT and the difference between the short RT and long RT (RT gradient) have been identified as critical determinators of arrhythmogenicity. However, current experimental methods for manipulating RT gradient rely on the use of ion channel inhibitors, which lack spatial and temporal specificity and are commonly only partially reversible. Therefore, the conditions facilitating sustained arrhythmia upon the presence of RT heterogeneities and/or defects in cardiac conduction remain to be elucidated.Methods: We here employ an approach based on optogenetic stimulation in a low-intensity fashion (sub-threshold illumination), to selectively manipulate cardiac electrical activity in defined areas of the heart.Results: As previously described, subthreshold illumination is a robust tool able to prolong action potentials (AP), decrease upstroke velocity as well as slow cardiac conduction, in a fully reversible manner. By applying a patterned sub-threshold illumination in intact mouse hearts constitutively expressing the light-gated ion channel channelrhodopsin-2 (ChR2), we optically manipulate RT gradients and cardiac conduction across the heart in a spatially selective manner. Moreover, in a proof-of-concept assessment we found that in the presence of patterned sub-threshold illumination, mouse hearts were more susceptible to arrhythmias. Hence, this optogenetic-based approach may be able to mimic conduction slowing and RT heterogeneities present in pathophysiological conditions.

Journal/Review: FRONTIERS IN PHYSIOLOGY

Volume: 14      Pages from: 1167524-1  to: 1167524-13

More Information: This study was funded by Fondazione CR Firenze, SALUS project. Additional funding was provided by the European Union’s HORIZON programme through a MSCA postdoctoral fellowship awarded to GM (No. 101110977, OPTOCARD). LS is member of the German Research Foundation Collaborative Research Centre SFB1425 (DFG #422681845). We acknowledge support by the Open Access Publication Fund of the University of Freiburg.
KeyWords: optogenetics; sub-threshold illumination; optical mapping; electrophysiological modulation; repolarization gradients
DOI: 10.3389/fphys.2023.1167524

Citations: 5
data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2024-11-17
References taken from IsiWeb of Knowledge: (subscribers only)
Connecting to view paper tab on IsiWeb: Click here
Connecting to view citations from IsiWeb: Click here