title: Targeted nonviral gene-based inhibition of Gα(i/o)-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation.
abstract: BACKGROUND
  Pharmacologic and ablative therapies for atrial fibrillation (AF) have suboptimal efficacy. Newer gene-based approaches that target specific mechanisms underlying AF are likely to be more efficacious in treating AF. Parasympathetic signaling appears to be an important contributor to AF substrate.
  
  
  OBJECTIVE
  The purpose of this study was to develop a nonviral gene-based strategy to selectively inhibit vagal signaling in the left atrium and thereby suppress vagal-induced AF.
  
  
  METHODS
  In eight dogs, plasmid DNA vectors (minigenes) expressing Gα(i) C-terminal peptide (Gα(i)ctp) was injected in the posterior left atrium either alone or in combination with minigene expressing Gα(o)ctp, followed by electroporation. In five control dogs, minigene expressing scrambled peptide (Gα(R)ctp) was injected. Vagal- and carbachol-induced left atrial effective refractory periods (ERPs), AF inducibility, and Gα(i/o)ctp expression were assessed 3 days following minigene delivery.
  
  
  RESULTS
  Vagal stimulation- and carbachol-induced effective refractory period shortening and AF inducibility were significantly attenuated in atria receiving a Gα(i2)ctp-expressing minigene and were nearly eliminated in atria receiving both Gα(i2)ctp- and Gα(o1)ctp-expressing minigenes.
  
  
  CONCLUSIONS
  Inhibition of both G(i) and G(o) proteins is necessary to abrogate vagal-induced AF in the left atrium and can be achieved via constitutive expression of Gα(i/o)ctps expressed by nonviral plasmid vectors delivered to the posterior left atrium.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University-Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Aistrup
authors.forename: Ivan
authors.initials: I
authors.lastname: Cokic
authors.forename: Jason
authors.initials: J
authors.lastname: Ng
authors.forename: David
authors.initials: D
authors.lastname: Gordon
authors.forename: Hemanth
authors.initials: H
authors.lastname: Koduri
authors.forename: Suzanne
authors.initials: S
authors.lastname: Browne
authors.forename: Dorina
authors.initials: D
authors.lastname: Arapi
authors.forename: Yogita
authors.initials: Y
authors.lastname: Segon
authors.forename: Jacob
authors.initials: J
authors.lastname: Goldstein
authors.forename: Abigail
authors.initials: A
authors.lastname: Angulo
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Wasserstrom
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Goldberger
authors.forename: Alan H
authors.initials: AH
authors.lastname: Kadish
authors.forename: Rishi
authors.initials: R
authors.lastname: Arora
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D002217:Carbachol / Q000494:pharmacology*; D018679:Cholinergic Agonists / Q000494:pharmacology; D004247:DNA / Q000235:genetics*; D004285:Dogs; D044385:GTP-Binding Protein alpha Subunits / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000494:pharmacology; D006325:Heart Atria / Q000294:innervation* / Q000503:physiopathology; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D018679:Cholinergic Agonists; D044385:GTP-Binding Protein alpha Subunits; D002217:Carbachol; D004247:DNA