Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-gorelated gene mutant

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Gene therapydependent 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-gorelated 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). Conclusion: 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.