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Genetic suppression of Gαs protein provides rate control in atrial fibrillation

Gene therapy-based modulation of atrioventricular (AV) conduction by overexpression of a constitutively active inhibitory Gα i protein effectively reduced heart rates in atrial fibrillation (AF). However, catecholamine stimulation caused an excessive increase in ventricular rate. We hypothesized tha...

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Main Authors: Lugenbiel, Patrick (Author) , Thomas, Dierk (Author) , Kelemen, Kamilla (Author) , Trappe, Kerstin (Author) , Bikou, Olympia (Author) , Schweizer, Patrick Alexander (Author) , Voss, Frederik (Author) , Becker, Rüdiger (Author) , Katus, Hugo (Author) , Bauer, Alexander (Author)
Format: Article (Journal)
Language:English
Published: 2012
In: Basic research in cardiology
Year: 2012, Volume: 107, Issue: 3, Pages: 265
ISSN:1435-1803
DOI:10.1007/s00395-012-0265-5
Online Access:Verlag, Volltext: http://dx.doi.org/10.1007/s00395-012-0265-5
Verlag, Volltext: https://link.springer.com/article/10.1007/s00395-012-0265-5
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Author Notes:Patrick Lugenbiel, Dierk Thomas, Kamilla Kelemen, Kerstin Trappe, Olympia Bikou, Patrick A. Schweizer, Frederik Voss, Rüdiger Becker, Hugo A. Katus, Alexander Bauer
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Summary:Gene therapy-based modulation of atrioventricular (AV) conduction by overexpression of a constitutively active inhibitory Gα i protein effectively reduced heart rates in atrial fibrillation (AF). However, catecholamine stimulation caused an excessive increase in ventricular rate. We hypothesized that modest genetic suppression of a stimulatory G protein in the AV node would allow persistent rate control in acute AF and would prevent undesired heart rate acceleration during β-adrenergic activation. Atrial fibrillation was induced in 12 pigs by atrial burst pacing via an implanted cardiac pacemaker. Study animals were then assigned to receive either Ad-siRNA-Gαs gene therapy to inactivate Gαs protein or Ad-β-gal as control. Gαs protein inactivation resulted in a 20 % heart rate reduction (P < 0.01). AH and HV intervals were prolonged by 37 ms (P < 0.001) and 28 ms (P < 0.001), respectively, demonstrating atrioventricular conduction delay. Impairment of left ventricular ejection fraction (LVEF) during AF was attenuated by Gαs suppression (LVEF 49 %) compared with controls (LVEF 34 %; P = 0.03). Isoproterenol application accelerated ventricular heart rate from 233 to 281 bpm (P < 0.001) in control animals but did not significantly affect pigs treated with Ad-siRNA-Gαs (192 vs. 216 bpm; P = 0.19). In conclusion, genetic inhibition of Gαs protein in the AV node reduced heart rate and prevented AF-associated reduction of cardiac function in a porcine model. Rate control by gene therapy may provide an alternative to current pharmacological treatment of AF.
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First Online: 29 March 2012
Gesehen am 11.06.2018
Physical Description:Online Resource
ISSN:1435-1803
DOI:10.1007/s00395-012-0265-5

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