Abstract 14151: G-alphai/o Protein C-Terminal Peptides Constitutively Expressed in the Posterior Left Atrium by Non-Viral Plasmid Vectors Significantly Attenuate Vagal-Induced Atrial Fibrillation
Present drug and ablative therapies for atrial fibrillation (AF) have suboptimal efficacy largely due to insufficient targeting and the accompanying systemic side-effects. Constitutive expression of an antiarrhythmic agent–necessarily a peptide/protein–specifically in the atria could circumvent present AF therapy shortcomings. Short peptides identical to the C-terminus of Galpha subunints of heterotrimeric G-proteins can disrupt the latter's coupling to their respective receptors and the corresponding signaling. Atrial vagal signaling, an important contributor to AF substrate, is mediated via muscarinic type-2 receptor(M2R)|Gi/o-protein signaling, which if attenuated upon the constitutive atrial expression of Galphai/o C-terminal peptides should suppress vagal-induced AF. To test this hypothesis, plasmid DNA vectors expressing Galphai C-terminal peptide (Gictp minigene), either alone or in combination with Goctp minigene, were delivered (direct myocardia injection + electroporation) into the posterior left atrium (PLA) of 8 dogs. In 5 dogs, scrambled peptide (GRp) minigene was delivered. Left atrial effective refractory periods (ERPs) and AF inducibility ±vagal-stimulation(VS) or ±carbachol(CCh)-administration were assessed 3 days post minigene delivery. VS- and CCh-induced ERP shortening and AF inducibility (Figure shows VS-induced results) were significantly attenuated in atria receiving a Gictp minigene, and were nearly eliminated in atria receiving both Gictp and Goctp minigenes vs. that in atria receiving GRp minigene (peptide expression was confirmed in these PLAs). These results demonstrate that disruption of M2R coupling to both Gi- and Go-proteins is necessary to abrogate vagal-induced AF in the left atrium, and can be achieved via constitutive expression of Gi/octps expressed by non-viral plasmid vectors delivered to the PLA.
- © 2011 by American Heart Association, Inc.