Targeted nonviral gene-based inhibition of Gαi/o-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation
GL Aistrup, I Cokic, J Ng, D Gordon, H Koduri… - Heart Rhythm, 2011 - Elsevier
GL Aistrup, I Cokic, J Ng, D Gordon, H Koduri, S Browne, D Arapi, Y Segon, J Goldstein…
Heart Rhythm, 2011•ElsevierBACKGROUND: 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 …
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 …
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 Gαi C-terminal peptide (Gαictp) was injected in the posterior left atrium either alone or in combination with minigene expressing Gαoctp, followed by electroporation. In five control dogs, minigene expressing scrambled peptide (GαRctp) was injected. Vagal- and carbachol-induced left atrial effective refractory periods (ERPs), AF inducibility, and Gαi/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 Gαi2ctp-expressing minigene and were nearly eliminated in atria receiving both Gαi2ctp- and Gαo1ctp-expressing minigenes.
CONCLUSION
Inhibition of both Gi and Go proteins is necessary to abrogate vagal-induced AF in the left atrium and can be achieved via constitutive expression of Gαi/octps expressed by nonviral plasmid vectors delivered to the posterior left atrium.
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