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

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 P CERG-G627S = 62.1% ± 4.0% vs. LVEF GFP = 30.3% ± 9.1%; P 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.