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Cardiovascular Research Advance Access first published online on May 20, 2009
This version [Corrected Proof] published online on June 8, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp148
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Targeted G-protein inhibition as a novel approach to decrease vagal atrial fibrillation by selective parasympathetic attenuation

Gary L. Aistrup1,{dagger}, Roger Villuendas2,{dagger}, Jason Ng2, Annette Gilchrist3, Thomas W. Lynch3, David Gordon2, Ivan Cokic2, Steven Mottl2, Rui Zhou2, David A. Dean2, J. Andrew Wasserstrom2, Jeffrey J. Goldberger2, Alan H. Kadish2 and Rishi Arora2,*

1 Department of Molecular Pharmacology and Biological Chemistry, Northwestern University-Feinberg School of Medicine, Northwestern Memorial Hospital, 251 East Huron, Galter 10-240, Chicago, IL 60611, USA
2 Department of Medicine, Northwestern University-Feinberg School of Medicine, Chicago, IL 60611, USA
3 Caden Biosciences Madison, Madison, WI 53711, USA

* Corresponding author. Tel: +1 312 695 4954; fax: +1 312 695 6295. E-mail address: r-arora{at}northwestern.edu

Aims: The parasympathetic nervous system is thought to play a key role in atrial fibrillation (AF). Since parasympathetic signalling is primarily mediated by the heterotrimeric G-protein, G{alpha}iβ{gamma}, we hypothesized that targeted inhibition of G{alpha}i interactions in the posterior left atrium (PLA) would modify the substrate for vagal AF.

Methods and results: Cell-penetrating(cp)-G{alpha}i1/2 and cp-G{alpha}i3 C-terminal peptides were assessed for their ability to attenuate cholinergic-parasympathetic signalling in isolated feline atrial myocytes and in canine left atrium (LA). Confocal fluorescence microscopy indicated that cp-G{alpha}i1/2 and/or cp-G{alpha}i3 peptides moderated carbachol attenuation of cellular Ca2+ transients in isolated atrial myocytes. High-density epicardial mapping of dog PLA, left atrial pulmonary veins (PVs), and left atrial appendage (LAA) indicated that the delivery of cp-G{alpha}i1/2 peptide or cp-G{alpha}i3 peptide into the PLA prolonged effective refractory periods at baseline and during vagal stimulation in the PLA and to varying extents also in the LAA and PV regions. After delivery of cp-G{alpha}i peptides into the PLA, AF inducibility during vagal stimulation was significantly diminished.

Conclusion: These results demonstrate the feasibility of using specific Gi-protein inhibition to achieve selective parasympathetic denervation in the PLA, with a resulting change in vagal responsiveness across the entire LA.

KEYWORDS Atrial fibrillation; G-proteins; Muscarinic; Parasympathetic; Signal transduction; Atrial refractoriness; E-C coupling; Calcium transient

Time for primary review: 18 days

{dagger} Both the authors contributed equally to this work.


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