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

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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.

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Abbreviations

AERP:

Atrial effective refractory period

AF:

Atrial fibrillation

cAF:

Chronic atrial fibrillation

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HF:

Heart failure

K2P :

Two-pore-domain K+ channel

LVEF:

Left ventricular ejection fraction

SR:

Sinus rhythm

TREK:

TWIK-related potassium channel

TWIK:

Tandem of P domains in a weak inwardly rectifying K+ channel

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Acknowledgements

We thank Nadine Weiberg, Jennifer Gütermann, Kai Sona, and Bianca Menrath for excellent technical assistance, and the operating room team at the Department of Cardiac Surgery of Heidelberg University for supporting our work. We are grateful to Jochen Keil for providing technical support. This work was supported in part by research grants from the University of Heidelberg, Faculty of Medicine (Postdoctoral Fellowship to P.L.), from the German Cardiac Society (Fellowship to P.L.), from the DZHK (German Centre for Cardiovascular Research; column B project to D.F. and N.F.), from the German Cardiac Society and the Hengstberger Foundation (Klaus-Georg and Sigrid Hengstberger Scholarship to D.T.), from the German Heart Foundation/German Foundation of Heart Research (Project F/08/14 to D.T.), from the Else Kröner-Fresenius-Stiftung (2014_A242 to D.T.), from the Joachim Siebeneicher Foundation (to D.T.), and from the Ministry of Science, Research and the Arts Baden-Wuerttemberg (Sonderlinie Medizin to D.T.). F.W. was supported by the Cardiology Career Program of the Department of Cardiology, University of Heidelberg, and by the Otto-Hess-Scholarship of the German Cardiac Society. K.G. received support from the German Heart Foundation/German Foundation of Heart Research (Kaltenbach Scholarship). P.A.S was supported by the Heidelberg Research Center for Molecular Medicine (Senior Career Fellowship).

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Authors and Affiliations

  1. Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Patrick Lugenbiel, Fabian Wenz, Pascal Syren, Katharina Govorov, Claudia Seyler, Patrick A. Schweizer, Jennifer Franke, Tanja Weis, Hugo A. Katus & Dierk Thomas

  2. Institute for Physiology and Pathophysiology, Heidelberg, Germany

    Pascal Geschwill & Claus Bruehl

  3. DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany

    Claudia Seyler, Patrick A. Schweizer, Tanja Weis, Hugo A. Katus & Dierk Thomas

  4. Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Kiel, Germany

    Derk Frank & Norbert Frey

  5. DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, University Medical Center Schleswig-Holstein, Kiel, Germany

    Derk Frank & Norbert Frey

  6. Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany

    Patrick A. Schweizer

  7. Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany

    Bastian Schmack, Arjang Ruhparwar & Matthias Karck

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  1. Patrick Lugenbiel
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  2. Fabian Wenz
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Correspondence to Dierk Thomas.

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Ethics statement

The study involving human tissue samples was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the Ethics Committee of the University of Heidelberg (Germany; institutional approval number S-390/2011). Written informed consent was obtained from all patients. Animal experiments have been carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the U.S. National Institutes of Health (NIH publication No. 86-23, revised 1985) and with EU Directive 2010/63/EU, and the current version of the German Law on the Protection of Animals was followed. Experiments involving pigs (institutional approval number G-165/12), mice (institutional approval number T-19/14), and rats (institutional approval number V312-7224-121-4) have been approved by the respective local animal welfare authorities.

Conflict of interest

P.L., P.A.S., H.A.K., and D.T. have filed a patent application for the use of K2P potassium channels for altering cardiac electrophysiology. The remaining authors have reported that they have no relationships relevant to the content of this paper to disclose.

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Lugenbiel, P., Wenz, F., Syren, P. et al. TREK-1 (K2P2.1) K+ channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control. Basic Res Cardiol 112, 8 (2017). https://doi.org/10.1007/s00395-016-0597-7

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