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.

Keywords: Atrial fibrillation, Atrial fibrillation inducibility, Autonomic nervous system, Effective refractory period, Muscarinic cholinergic receptor, Pertussis toxin-sensitive G proteins, Vagal signaling

Abbreviations: ACh, acetylcholine, AF, atrial fibrillation, CCh, carbachol, DF, dominant frequency, ERP, effective refractory period, Gα_i/octp, Gα_i/o C-terminal peptide(s), Gα_Rp, Gα random-sequence peptide, I_K-ACh, acetylcholine-activated inward rectifying potassium channel, LAA, left atrial appendage, M₂R, type 2 muscarinic cholinergic receptor, PLA, posterior left atrium, PV, pulmonary vein, VS, vagal stimulation