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

Aistrup, Gary L.; Villuendas, Roger; Ng, Jason; Gilchrist, Annette; Lynch, Thomas W.; Gordon, David; Cokic, Ivan; Mottl, Steven; Zhou, Rui; Dean, David A.; Wasserstrom, J. Andrew; Goldberger, Jeffrey J.; Kadish, Alan H.; Arora, Rishi

doi:10.1093/cvr/cvp148

Cited by 32 publications

(33 citation statements)

References 45 publications

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“…After the completion of the terminal electrophysiological study, the heart was removed and the atria snap frozen as previously described by us 15,23 . The explanted left atrium (PLA/PVs and LAA) were subjected to the following analysis: Real-time PCR, Western Blot, Immunofluroscnece, Masson-Trichrome staining, Immunohistochemical analysis for macrophages and Protein oxidation (Carbonylation).…”

Section: Methodsmentioning

confidence: 99%

Constitutive Expression of a Dominant-Negative TGF-β Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate

Kunamalla

Parini

et al. 2016

Circulation Research

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Rationale Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure (HF). TGF-β signaling is thought to be intricately involved in creation of atrial fibrosis. Objective We hypothesized that gene-based expression of dominant-negative type II TGF-β receptor (TGF-β-RII-DN) in the posterior left atrium (PLA) in a canine HF model will sufficiently attenuate fibrosis induced changes in atrial conduction and/or restitution to decrease AF. Since AF electrograms (EGMs) are thought to reflect AF substrate, we further hypothesized that TGF-β-RII-DN would lead to increased fractionation and decreased organization of AF EGMs. Methods and Results 21 dogs underwent injection + electroporation in the PLA of plasmid expressing a dominant negative TGF-β type II receptor (pUBc-TGFβ-DN-RII) (N=9) or control vector (pUBc-LacZ) (N=12), followed by 3–4 weeks of right ventricular tachypacing (VTP) (240 bpm). Compared to controls, dogs treated with pUBC-TGFβ-DN-RII demonstrated an attenuated increase in conduction inhomogeneity (CI), flattening of restitution slope and decreased duration of induced AF, with AF EGMs being more fractionated and less organized in pUBc-TGFβ-DN-RII versus pUBc-LacZ dogs. Tissue analysis revealed a significant decrease in replacement/interstitial fibrosis, pSMAD2/3 and pERK1/2. Conclusions Targeted, gene-based reduction of TGF-β signaling in the PLA – with resulting decrease in replacement fibrosis – led to beneficial remodeling of both conduction and restitution characteristics of the PLA, translating into a decrease in AF and increased complexity of AF EGMs. In addition to providing mechanistic insights, this data may have important diagnostic and therapeutic implications for AF.

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Section: Methodsmentioning

confidence: 99%

Constitutive Expression of a Dominant-Negative TGF-β Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate

Kunamalla

Parini

et al. 2016

Circulation Research

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“…As mentioned previously, M2-receptor stimulation by the parasympathetic nervous system leads to activation of the I K-ACh through a G-protein coupled mechanism, leading to increased potassium current and atrial effective refractory period shortening that promotes initiation and maintenance of AF. Aistrup et al have shown in two studies that inhibition of G-protein signaling in the atrium can lead to attenuated parasympathetic effects in the atrium [45, 46]. In a proof of concept animal study, G-protein inhibitory peptides targeting the C-terminus of the Gα i/o subunit, the subunit associated with parasympathetic M2-receoptors, were used to inhibit parasympathetic signaling in the atrium [46].…”

Section: Modulation Of Autonomic Effects On Atrial Potassium Current mentioning

confidence: 99%

“…Aistrup et al have shown in two studies that inhibition of G-protein signaling in the atrium can lead to attenuated parasympathetic effects in the atrium [45, 46]. In a proof of concept animal study, G-protein inhibitory peptides targeting the C-terminus of the Gα i/o subunit, the subunit associated with parasympathetic M2-receoptors, were used to inhibit parasympathetic signaling in the atrium [46]. Peptides targeting the C-terminal portion of Gα i were selectively delivered to the PLA by direct injection into the myocardium with associated electroporation.…”

Section: Modulation Of Autonomic Effects On Atrial Potassium Current mentioning

confidence: 99%

“…The difference in parasympathetic effect between the atrium and ventricle may be explained by differences in I K-ACh distribution between the atria and ventricles, and thus the effect of parasympathetic stimulation on potassium current and refractory periods in each chamber. Whereas, I K-ACh is abundant in most atrial tissue [46], I K-ACh is expressed to a much lower degree in the ventricle, with ventricular myocytes having little or no I K-ACh [48]. This finding may be responsible for the observed fact that, while parasympathetic stimulation significantly shortens the action potential duration in the atria, it either lengthens the action potential duration [49] or shortens it by a significantly smaller amount in the ventricle [50, 51].…”

Section: Autonomic Control Of Potassium Current In the Ventriclementioning

confidence: 99%

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Modulation of Cardiac Potassium Current by Neural Tone and Ischemia

Tomson

Arora

2016

Cardiac Electrophysiology Clinics

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SYNOPSIS The cardiac action potential is generated by intricate flows of ions across myocyte cell membranes in a coordinated fashion to control myocardial contraction and the heart rhythm. Modulation of the flow of these ions in response to a variety of stimuli results in changes to the action potential. Abnormal or altered ion currents can result in cardiac arrhythmias. Potassium currents are particularly important for determining the cardiac action potential duration and repolarization. The autonomic nervous system plays an important role in the modulation of cardiac electrophysiology and has a particularly important role in modulation of potassium currents. Abnormalities of autonomic regulation of potassium current play a role in the genesis of cardiac arrhythmias, and alterations in acetylcholine-activated potassium channels may play a key role in atrial fibrillation. Ischemia is another important modulator of cardiac cellular electrophysiology that alters cardiac potassium current through effects on ATP-sensitive potassium channels in ways that may result in cardiac arrhythmias, particularly ventricular fibrillation.

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“…Modifying the effect of various neurohumoral factors may also be effective. Targeted Gi protein inhibition, 50) as well as inhibitors of the acetylcholineactivated K + channel, 51,52) was reported to have curative effects against experimental atrial fibrillation. Certain antiarrhythmic drugs, such as pilsicainide, appear to have some selectivity towards the pulmonary vein myocardium probably due to the less negative resting membrane potential.…”

Section: Pharmacological Strategies Against Pulmonary Vein Automaticitymentioning

confidence: 99%

Electrophysiological and Pharmacological Properties of the Pulmonary Vein Myocardium

Namekata

Tsuneoka

Tanaka

2013

Biological & Pharmaceutical Bulletin

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The pulmonary vein contains a myocardial layer extending from the left atrium, which is receiving attention as the source of ectopic electrical activity underlying atrial fibrillation. Electrophysiological and pharmacological analysis of the pulmonary vein myocardium performed in various experimental animal species have revealed characteristics such as presence of intracellular Ca 2+ oscillations and low repolarizing potency. The automaticity of the pulmonary vein myocardium is affected by various neurotransmitters, hormones and pharmacological agents. Clarification of the mechanisms and regulation of pulmonary vein automaticity would lead to the development of novel therapeutic strategies and pharmacological agents for atrial fibrillation.

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

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

Cited by 32 publications

References 45 publications

Constitutive Expression of a Dominant-Negative TGF-β Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate

Constitutive Expression of a Dominant-Negative TGF-β Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate

Modulation of Cardiac Potassium Current by Neural Tone and Ischemia

Electrophysiological and Pharmacological Properties of the Pulmonary Vein Myocardium

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