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

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 _ictp) was injected in the posterior left atrium either alone or in combination with minigene expressing Gα _octp, followed by electroporation. In five control dogs, minigene expressing scrambled peptide (Gα _Rctp) was injected. Vagal- and carbachol-induced left atrial effective refractory periods (ERPs), AF inducibility, and Gα _i/octp 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 _i2ctp-expressing minigene and were nearly eliminated in atria receiving both Gα _i2ctp- and Gα _o1ctp- 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/octps expressed by nonviral plasmid vectors delivered to the posterior left atrium.