title: Optogenetics-enabled dynamic modulation of action potential duration in atrial tissue: feasibility of a novel therapeutic approach.
abstract: OBJECTIVE
  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.
  
  
  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 imaging-based model of the human left atrium (LA). Application of an appropriate optical stimulus to a diseased cell dynamically increased APD, producing an excellent match to control AP (<1.5 mV deviation); treatment of a diseased cell with an AP-prolonging 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 non-uniform ChR2-expressing cell distribution and light attenuation were incorporated, optogenetics-based treatment was less effective (APD only increased to 55%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine and Johns Hopkins University, 3400 N. Charles St., Hackerman Hall Room 316, Baltimore, MD 21218, USA.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Karathanos
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine and Johns Hopkins University, 3400 N. Charles St., Hackerman Hall Room 316, Baltimore, MD 21218, USA pmjboyle@jhu.edu.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Boyle
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine and Johns Hopkins University, 3400 N. Charles St., Hackerman Hall Room 316, Baltimore, MD 21218, USA.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Trayanova
mesh_terms: D000200:Action Potentials; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D002738:Chloroquine / Q000627:therapeutic use*; D003198:Computer Simulation; D022062:Electrophysiologic Techniques, Cardiac; D005240:Feasibility Studies; D006325:Heart Atria / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008955:Models, Cardiovascular; D062308:Optogenetics; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D002738:Chloroquine; D012243:Rhodopsin
keywords: Atrial arrhythmia; Cardiac optogenetics; Computational modelling; Short QT syndrome