title: TREK-1 (K2P2.1) K+channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control.
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.
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lugenbiel
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Wenz
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Syren
authors.affiliation: Institute for Physiology and Pathophysiology, Heidelberg, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Geschwill
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Govorov
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Seyler
authors.affiliation: Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Kiel, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Derk
authors.initials: D
authors.lastname: Frank
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.|Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Franke
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Weis
authors.affiliation: Institute for Physiology and Pathophysiology, Heidelberg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Bruehl
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schmack
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Arjang
authors.initials: A
authors.lastname: Ruhparwar
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.affiliation: Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Kiel, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. dierk.thomas@med.uni-heidelberg.de.|DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany. dierk.thomas@med.uni-heidelberg.de.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
mesh_terms: D000256:Adenoviridae; D000328:Adult; D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D013552:Swine
chemical_list: D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1
keywords: Atrial fibrillation; Electrical remodeling; Electrophysiology; Gene therapy; TREK-1 channel