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

Gary L. Aistrup, Ivan Cokic, Jason Ng, David Gordon, Hemanth Koduri, Suzanne Browne, Dorina Arapi, Yogita Segon, Jacob Goldstein, Abigail Angulo, J. Andrew Wasserstrom, Jeffrey Goldberger, Alan H. Kadish, Rishi Arora

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1722-1729
Number of pages8
JournalHeart Rhythm
Volume8
Issue number11
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Fingerprint

Heart Atria
Atrial Fibrillation
Genes
Carbachol
Plasmids
Gi-Go GTP-Binding Protein alpha Subunits
Dogs
Peptides
Electroporation
DNA

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Targeted nonviral gene-based inhibition of Gα i/o-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation. / Aistrup, Gary L.; Cokic, Ivan; Ng, Jason; Gordon, David; Koduri, Hemanth; Browne, Suzanne; Arapi, Dorina; Segon, Yogita; Goldstein, Jacob; Angulo, Abigail; Wasserstrom, J. Andrew; Goldberger, Jeffrey; Kadish, Alan H.; Arora, Rishi.

In: Heart Rhythm, Vol. 8, No. 11, 01.11.2011, p. 1722-1729.

Research output: Contribution to journalArticle

Aistrup, GL, Cokic, I, Ng, J, Gordon, D, Koduri, H, Browne, S, Arapi, D, Segon, Y, Goldstein, J, Angulo, A, Wasserstrom, JA, Goldberger, J, Kadish, AH & Arora, R 2011, 'Targeted nonviral gene-based inhibition of Gα i/o-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation', Heart Rhythm, vol. 8, no. 11, pp. 1722-1729. https://doi.org/10.1016/j.hrthm.2011.06.018
Aistrup, Gary L. ; Cokic, Ivan ; Ng, Jason ; Gordon, David ; Koduri, Hemanth ; Browne, Suzanne ; Arapi, Dorina ; Segon, Yogita ; Goldstein, Jacob ; Angulo, Abigail ; Wasserstrom, J. Andrew ; Goldberger, Jeffrey ; Kadish, Alan H. ; Arora, Rishi. / Targeted nonviral gene-based inhibition of Gα i/o-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation. In: Heart Rhythm. 2011 ; Vol. 8, No. 11. pp. 1722-1729.
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abstract = "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.",
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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

AU - Kadish, Alan H.

AU - Arora, Rishi

PY - 2011/11/1

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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.

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KW - Atrial fibrillation inducibility

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KW - Effective refractory period

KW - Muscarinic cholinergic receptor

KW - Pertussis toxin-sensitive G proteins

KW - Vagal signaling

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