title: Genetic suppression of Gαs protein provides rate control in atrial fibrillation.
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-Gα(s) gene therapy to inactivate Gα(s) protein or Ad-β-gal as control. Gα(s) 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 Gα(s) 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-Gα(s) (192 vs. 216 bpm; P = 0.19). In conclusion, genetic inhibition of Gα(s) 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.
authors.affiliation: Department of Cardiology, University of Heidelberg, Medical University Hospital, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lugenbiel
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Kamilla
authors.initials: K
authors.lastname: Kelemen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Trappe
authors.forename: Olympia
authors.initials: O
authors.lastname: Bikou
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.forename: Frederik
authors.initials: F
authors.lastname: Voss
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Becker
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Alexander
authors.initials: A
authors.lastname: Bauer
mesh_terms: D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D001283:Atrioventricular Node / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004562:Electrocardiography; D005355:Fibrosis; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics*; D007545:Isoproterenol / Q000008:administration & dosage; D010138:Pacemaker, Artificial; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D013318:Stroke Volume; D034421:Sus scrofa; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D000318:Adrenergic beta-Agonists; D034741:RNA, Small Interfering; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol