TREK-1 (K2P2.1) K+ channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control

• Verfasst von: Lugenbiel, Patrick [VerfasserIn]
• Verfasst von: Wenz, Fabian [VerfasserIn]
• Verfasst von: Syren, Pascal [VerfasserIn]
• Verfasst von: Geschwill, Pascal [VerfasserIn]
• Verfasst von: Govorov, Katharina [VerfasserIn]
• Verfasst von: Seyler, Claudia [VerfasserIn]
• Verfasst von: Schweizer, Patrick Alexander [VerfasserIn]
• Verfasst von: Franke, Jennifer [VerfasserIn]
• Verfasst von: Weis, Tanja [VerfasserIn]
• Verfasst von: Bruehl, Claus [VerfasserIn]
• Verfasst von: Schmack, Bastian [VerfasserIn]
• Verfasst von: Ruhparwar, Arjang [VerfasserIn]
• Verfasst von: Karck, Matthias [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Thomas, Dierk [VerfasserIn]
• Titel: TREK-1 (K2P2.1) K+ channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control
• Verf.angabe: Patrick Lugenbiel, Fabian Wenz, Pascal Syren, Pascal Geschwill, Katharina Govorov, Claudia Seyler, Derk Frank, Patrick A. Schweizer, Jennifer Franke, Tanja Weis, Claus Bruehl, Bastian Schmack, Arjang Ruhparwar, Matthias Karck, Norbert Frey, Hugo A. Katus, Dierk Thomas
• Jahr: 2017
• Jahr des Originals: 2016
• Umfang: 14 S.
• Fussnoten: First online: 22 December 2016 ; Im Titel ist 2P tiefgestellt und + hochgestellt ; Gesehen am 18.06.2018
• Titel Quelle: Enthalten in: Basic research in cardiology
• Ort Quelle: [Darmstadt u.a.] : Steinkopff, 1937
• Jahr Quelle: 2017
• Band/Heft Quelle: 112(2017,1) Artikel-Nummer 8, 14 Seiten
• ISSN Quelle: 1435-1803
• DOI: doi:10.1007/s00395-016-0597-7
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1576445801

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Concomitant heart failure (HF) poses a particular therapeutic challenge and is associated with prolonged atrial electrical refractoriness compared with non-failing hearts. We hypothesized that downregulation of atrial repolarizing TREK-1 (K2P2.1) K+ channels contributes to electrical remodeling during AF with HF, and that TREK-1 gene transfer would provide rhythm control via normalization of atrial effective refractory periods in this AF subset. In patients with chronic AF and HF, atrial TREK-1 mRNA levels were reduced by 82% (left atrium) and 81% (right atrium) compared with sinus rhythm (SR) subjects. Human findings were recapitulated in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function. TREK-1 mRNA (−66%) and protein (−61%) was suppressed in AF animals at 14-day follow-up compared with SR controls. Downregulation of repolarizing TREK-1 channels was associated with prolongation of atrial effective refractory periods versus baseline conditions, consistent with prior observations in humans with HF. In a preclinical therapeutic approach, pigs were randomized to either atrial Ad-TREK-1 gene therapy or sham treatment. Gene transfer effectively increased TREK-1 protein levels and attenuated atrial effective refractory period prolongation in the porcine AF model. Ad-TREK-1 increased the SR prevalence to 62% during follow-up in AF animals, compared to 35% in the untreated AF group. In conclusion, TREK-1 downregulation and rhythm control by Ad-TREK-1 transfer suggest mechanistic and potential therapeutic significance of TREK-1 channels in a subgroup of AF patients with HF and prolonged atrial effective refractory periods. Functional correction of ionic remodeling through TREK-1 gene therapy represents a novel paradigm to optimize and specify AF management.