Targeted nonviral gene-based inhibition of Gα(i/o)-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation

Heart Rhythm. 2011 Nov;8(11):1722-9. doi: 10.1016/j.hrthm.2011.06.018. Epub 2011 Aug 25.

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.

Conclusion: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Fibrillation / genetics
  • Atrial Fibrillation / physiopathology
  • Atrial Fibrillation / therapy*
  • Carbachol / pharmacology*
  • Cholinergic Agonists / pharmacology
  • DNA / genetics*
  • Dogs
  • GTP-Binding Protein alpha Subunits / biosynthesis
  • GTP-Binding Protein alpha Subunits / drug effects
  • GTP-Binding Protein alpha Subunits / genetics*
  • Gene Expression
  • Genetic Therapy / methods*
  • Genetic Vectors / pharmacology
  • Heart Atria / innervation*
  • Heart Atria / physiopathology
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiopathology*

Substances

  • Cholinergic Agonists
  • GTP-Binding Protein alpha Subunits
  • Carbachol
  • DNA