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

• Verfasst von: Soucek, Radim [VerfasserIn]
• Verfasst von: Thomas, Dierk [VerfasserIn]
• Verfasst von: Kelemen, Kamilla [VerfasserIn]
• Verfasst von: Bikou, Olympia [VerfasserIn]
• Verfasst von: Seyler, Claudia [VerfasserIn]
• Verfasst von: Voss, Frederik [VerfasserIn]
• Verfasst von: Becker, Rüdiger [VerfasserIn]
• Verfasst von: Koenen, Michael [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Bauer, Alexander [VerfasserIn]
• Titel: Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go-related gene mutant
• Verf.angabe: Radim Soucek, MD, Dierk Thomas, MD, Kamilla Kelemen, MD, Olympia Bikou, MD, Claudia Seyler, PhD, Frederik Voss, MD, Rüdiger Becker, MD, Michael Koenen, PhD, Hugo A. Katus, MD, Alexander Bauer, MD
• Jahr: 2012
• Jahr des Originals: 2011
• Umfang: 8 S.
• Fussnoten: Available online 8 September 2011 ; Gesehen am 02.08.2018
• Titel Quelle: Enthalten in: Heart rhythm
• Ort Quelle: New York, NY [u.a.] : Elsevier, 2004
• Jahr Quelle: 2012
• Band/Heft Quelle: 9(2012), 2, Seite 265-272
• ISSN Quelle: 1556-3871
• DOI: doi:10.1016/j.hrthm.2011.09.008
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Atrial fibrillation
• Sach-SW: Gene therapy
• Sach-SW: HERG
• Sach-SW: Ion channel
• Sach-SW: Rhythm control
• K10plus-PPN: 1578206448

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/IKr 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 (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.