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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 20, 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. Aistrup, PhD{dagger},*, Roger Villuendas, MD{ddagger},*, Jason Ng, PhD{ddagger}, Annette Gilchrist, PhD§, Thomas W. Lynch, PhD§, David Gordon, MD, PhD{ddagger}, Ivan Cokic, MD{ddagger}, Steven Mottl, MD{ddagger}, Rui Zhou, PhD{ddagger}, David A. Dean, PhD{ddagger}, J. Andrew Wasserstrom, PhD{ddagger}, Jeffrey J. Goldberger, MD{ddagger}, Alan H. Kadish, MD{ddagger} and Rishi Arora, MD{ddagger}

{dagger} Department of Molecular Pharmacology & Biological Chemistry, Northwestern University-Feinberg School of Medicine, Chicago, IL 60611
{ddagger} Department of Medicine, Northwestern University-Feinberg School of Medicine, Chicago, IL 60611
§ Caden Biosciences Madison, WI 53711

Correspondence: Rishi Arora, M.D., Northwestern Memorial Hospital, 251East Huron, Galter 10-240, Chicago, IL 60611, Phone: (312)-695-4954, Fax: (312)-926-0607-6295, E-mail: 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 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.

Conclusions: 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.

Time for primary review: 18 Days

* Both authors contributed equally to this work


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