TY - JOUR
T1 - Targeted nonviral gene-based inhibition of Gα i/o-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation
AU - Aistrup, Gary L.
AU - Cokic, Ivan
AU - Ng, Jason
AU - Gordon, David
AU - Koduri, Hemanth
AU - Browne, Suzanne
AU - Arapi, Dorina
AU - Segon, Yogita
AU - Goldstein, Jacob
AU - Angulo, Abigail
AU - Wasserstrom, J. Andrew
AU - Goldberger, Jeffrey J.
AU - Kadish, Alan H.
AU - Arora, Rishi
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
KW - Atrial fibrillation
KW - Atrial fibrillation inducibility
KW - Autonomic nervous system
KW - Effective refractory period
KW - Muscarinic cholinergic receptor
KW - Pertussis toxin-sensitive G proteins
KW - Vagal signaling
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U2 - 10.1016/j.hrthm.2011.06.018
DO - 10.1016/j.hrthm.2011.06.018
M3 - Article
C2 - 21689540
AN - SCOPUS:80055024244
VL - 8
SP - 1722
EP - 1729
JO - Heart Rhythm
JF - Heart Rhythm
SN - 1547-5271
IS - 11
ER -