Targeted nonviral gene-based inhibition of Gαi/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 G alpha(i) C-terminal peptide (G alpha(i)ctp) was injected in the posterior left atrium either alone or in combination with minigene expressing G alpha(o)ctp, followed by electroporation. In five control dogs, minigene expressing scrambled peptide (G alpha(R)ctp) was injected. Vagal- and carbachol-induced left atrial effective refractory periods (ERPs), AF inducibility, and G alpha(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 G alpha(i2)ctp-expressing minigene and were nearly eliminated in atria receiving both G alpha(i2)ctp- and G alpha(o1)ctp-expressing minigenes. CONCLUSION Inhibition of both G(i) and Go proteins is necessary to abrogate vagal-induced AF in the left atrium and can be achieved via constitutive expression of G alpha(i/o)ctps expressed by nonviral plasmid vectors delivered to the posterior left atrium.