title: Optogenetic manipulation of anatomical re-entry by light-guided generation of a reversible local conduction block.
abstract: Anatomical re-entry is an important mechanism of ventricular tachycardia, characterized by circular electrical propagation in a fixed pathway. It's current investigative and therapeutic approaches are non-biological, rather unspecific (drugs), traumatizing (electrical shocks), or irreversible (ablation). Optogenetics is a new biological technique that allows reversible modulation of electrical function with unmatched spatiotemporal precision using light-gated ion channels. We therefore investigated optogenetic manipulation of anatomical re-entry in ventricular cardiac tissue.
  
  
  
  Transverse, 150-μm-thick ventricular slices, obtained from neonatal rat hearts, were genetically modified with lentiviral vectors encoding Ca2+-translocating channelrhodopsin (CatCh), a light-gated depolarizing ion channel, or enhanced yellow fluorescent protein (eYFP) as control. Stable anatomical re-entry was induced in both experimental groups. Activation of CatCh was precisely controlled by 470-nm patterned illumination, while the effects on anatomical re-entry were studied by optical voltage mapping. Regional illumination in the pathway of anatomical re-entry resulted in termination of arrhythmic activity only in CatCh-expressing slices by establishing a local and reversible, depolarization-induced conduction block in the illuminated area. Systematic adjustment of the size of the light-exposed area in the re-entrant pathway revealed that re-entry could be terminated by either wave collision or extinction, depending on the depth (transmurality) of illumination. In silico studies implicated source-sink mismatches at the site of subtransmural conduction block as an important factor in re-entry termination.
  
  
  
  Anatomical re-entry in ventricular tissue can be manipulated by optogenetic induction of a local and reversible conduction block in the re-entrant pathway, allowing effective re-entry termination. These results provide distinctively new mechanistic insight into re-entry termination and a novel perspective for cardiac arrhythmia management.
authors.forename: Masaya
authors.initials: M
authors.lastname: Watanabe
authors.forename: Iolanda
authors.initials: I
authors.lastname: Feola
authors.forename: Rupamanjari
authors.initials: R
authors.lastname: Majumder
authors.forename: Wanchana
authors.initials: W
authors.lastname: Jangsangthong
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Teplenin
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Ypey
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Schalij
authors.forename: Katja
authors.initials: K
authors.lastname: Zeppenfeld
authors.forename: Antoine A F
authors.initials: AA
authors.lastname: de Vries
authors.forename: Daniël A
authors.initials: DA
authors.lastname: Pijnappels
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D015220:Calcium Channels / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects*; D003198:Computer Simulation; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics; D008027:Light; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000528:radiation effects*; D062308:Optogenetics; D017208:Rats, Wistar; D012243:Rhodopsin / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects*; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D001426:Bacterial Proteins; D015220:Calcium Channels; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D012243:Rhodopsin
keywords: Anatomical re-entry; Computer-based model; Optical mapping; Optogenetics; Tissue culture