title: Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go-related gene mutant.
abstract: BACKGROUND
  Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Gene therapy-dependent modulation of atrial electrophysiology may provide a more specific alternative to pharmacological and ablative treatment strategies.
  
  
  OBJECTIVE
  We hypothesized that genetic inactivation of atrial repolarizing ether-a-go-go-related gene (ERG) K(+) currents using a dominant-negative mutant would provide rhythm control in AF.
  
  
  METHODS
  Ten domestic swine underwent pacemaker implantation and were subjected to atrial burst pacing to induce persistent AF. Animals were then randomized to receive either AdCERG-G627S to suppress ERG/I(Kr) currents or green fluorescent protein (AdGFP) as control. Adenoviruses were applied using a novel hybrid technique combining atrial virus injection and epicardial electroporation to increase transgene expression.
  
  
  RESULTS
  In pigs treated with AdCERG-G627S, the onset of persistent AF was prevented (n = 2) or significantly delayed compared with AdGFP controls (12 ± 2.1 vs. 6.2 ± 1.3 days; P < .001) during 14-day follow-up. Effective refractory periods were prolonged in the AdCERG-G627S group compared with AdGFP animals (221.5 ± 4.7 ms vs. 197.0 ± 4.7 ms; P < .006). Impairment of left ventricular ejection fraction (LVEF) during AF was prevented by AdCERG-G627S application (LVEF(CERG-G627S) = 62.1% ± 4.0% vs. LVEF(GFP) = 30.3% ± 9.1%; P < .001).
  
  
  CONCLUSIONS
  Inhibition of ERG function using atrial AdCERG-G627S gene transfer suppresses or delays the onset of persistent AF by prolongation of atrial refractoriness in a porcine model. Targeted gene therapy represents an alternative to pharmacological or ablative treatment of AF.
authors: Department of Cardiology, University of Heidelberg, Heidelberg, Germany. radim.soucek@gmail.com
authors: Radim
authors: R
authors: Soucek
authors: Dierk
authors: D
authors: Thomas
authors: Kamilla
authors: K
authors: Kelemen
authors: Olympia
authors: O
authors: Bikou
authors: Claudia
authors: C
authors: Seyler
authors: Frederik
authors: F
authors: Voss
authors: Rüdiger
authors: R
authors: Becker
authors: Michael
authors: M
authors: Koenen
authors: Hugo A
authors: HA
authors: Katus
authors: Alexander
authors: A
authors: Bauer
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000628:therapy*; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000494:pharmacology; D006325:Heart Atria / Q000503:physiopathology; D009154:Mutation; D034421:Sus scrofa
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D049452:Green Fluorescent Proteins