Optogenetics-enabled dynamicmodulation of action potential duration in atrial tissue: Feasibility of a novel therapeutic approach

Abstract

Aims: Diseases that abbreviate the cardiac action potential (AP) by increasing the strength of repolarizing transmembrane currents are highly arrhythmogenic. It has been proposed that optogenetic tools could be used to restore normal AP duration (APD)in the heart under such disease conditions. This study aims to evaluate the efficacy of an optogenetic treatment modality for prolonging pathologically shortened APs in a detailed computational model of short QT syndrome (SQTS) in the human atria, and compare it to drug treatment. Methods and results: We used a human atrial myocyte model with faster repolarization caused by SQTS; light sensitivity was inscribed via the presence of channelrhodopsin-2 (ChR2).We conducted simulations in single cells and in a magnetic resonance imagingbased model of the human left atrium (LA). Application of an appropriate optical stimulus to a diseased cell dynamically increasedAPD, producing an excellentmatch to controlAP(<1.5 mVdeviation); treatment of a diseased cell with an APprolonging drug (chloroquine) also increased APD, but the match to control AP was worse (<5 mV deviation). Under idealized conditions in the LA (uniform ChR2-expressing cell distribution, no light attenuation), optogenetics-based therapy outperformed chloroquine treatment (APD increased to 87% and 81% of control). However, when nonuniform ChR2-expressing cell distribution and light attenuation were incorporated, optogenetics-based treatment was less effective (APD only increased to 55%). Conclusion: This study demonstrates proof of concept for optogenetics-based treatment of diseases that alter atrial AP shape.We identified key practical obstacles intrinsic to the optogenetic approach that must be overcome before such treatments can be realized. Published on behalf of the European Society of Cardiology. All rights reserved.