Genetic suppression of Gαs protein provides rate control in atrial fibrillation

• Verfasst von: Lugenbiel, Patrick [VerfasserIn]
• Verfasst von: Thomas, Dierk [VerfasserIn]
• Verfasst von: Kelemen, Kamilla [VerfasserIn]
• Verfasst von: Trappe, Kerstin [VerfasserIn]
• Verfasst von: Bikou, Olympia [VerfasserIn]
• Verfasst von: Schweizer, Patrick Alexander [VerfasserIn]
• Verfasst von: Voss, Frederik [VerfasserIn]
• Verfasst von: Becker, Rüdiger [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Bauer, Alexander [VerfasserIn]
• Titel: Genetic suppression of Gαs protein provides rate control in atrial fibrillation
• Verf.angabe: Patrick Lugenbiel, Dierk Thomas, Kamilla Kelemen, Kerstin Trappe, Olympia Bikou, Patrick A. Schweizer, Frederik Voss, Rüdiger Becker, Hugo A. Katus, Alexander Bauer
• Jahr: 2012
• Umfang: 12 S.
• Fussnoten: Im Titel ist „s“ tiefgestellt ; First Online: 29 March 2012 ; Gesehen am 11.06.2018
• Titel Quelle: Enthalten in: Basic research in cardiology
• Ort Quelle: [Darmstadt u.a.] : Steinkopff, 1937
• Jahr Quelle: 2012
• Band/Heft Quelle: 107(2012,3) Artikel-Nummer 265, 12 Seiten
• ISSN Quelle: 1435-1803
• DOI: doi:10.1007/s00395-012-0265-5
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1576241394

Abstract

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.