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


Koenen,  Michael
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Soucek, R., Thomas, D., Kelemen, K., Bikou, O., Seyler, C., Voss, F., et al. (2012). Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go-related gene mutant. Heart Rhythm, 9(2), 265-272. doi:10.1016/j.hrthm.2011.09.008.

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/IKr currents or green fluorescent protein (AdGFP) as control. Adenoviruses were applied using a novel hybrid technique employing atrial virus injection followed by 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 to 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 to 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 (LVEFCERG−G627S = 62.1 ± 4.0% vs. LVEFGFP = 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