Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Constanze Schmidt¹, Felix Wiedmann¹, Niels Voigt¹, Xiao-Bo Zhou¹, Jordi Heijman¹, Siegfried Lang¹, Virginia Albert¹, Stefan Kallenberger¹, Arjang Ruhparwar¹, Gábor Szabó¹, Klaus Kallenbach¹, Matthias Karck¹, Martin Borggrefe¹, Peter Biliczki¹, Joachim R Ehrlich¹, István Baczkó¹, Patrick Lugenbiel¹, Patrick A Schweizer¹, Birgit C Donner¹, Hugo A Katus¹, Dobromir Dobrev¹, Dierk Thomas²

Affiliations

¹ From Department of Cardiology, University of Heidelberg, Germany (C.S., F.W., V.A., P.L., P.A.S., H.A.K., D.T.); Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., X.-B.Z., J.H., S.L., M.B., D.D.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); First Department of Medicine, University Medical Center Mannheim, Germany (X.-B.Z., S.L., M.B.); Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Germany (S.K.); Department of Cardiac Surgery, University Hospital Heidelberg, Germany (A.R., G.S., K.K., M.K.); Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt, Germany (P.B., J.R.E.); Division of Cardiology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany (P.B., J.R.E.); Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary (I.B.); and Department of Cardiology, University of Basel Children's Hospital, Switzerland (B.C.D.).
² From Department of Cardiology, University of Heidelberg, Germany (C.S., F.W., V.A., P.L., P.A.S., H.A.K., D.T.); Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., X.-B.Z., J.H., S.L., M.B., D.D.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); First Department of Medicine, University Medical Center Mannheim, Germany (X.-B.Z., S.L., M.B.); Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Germany (S.K.); Department of Cardiac Surgery, University Hospital Heidelberg, Germany (A.R., G.S., K.K., M.K.); Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt, Germany (P.B., J.R.E.); Division of Cardiology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany (P.B., J.R.E.); Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary (I.B.); and Department of Cardiology, University of Basel Children's Hospital, Switzerland (B.C.D.). dierk.thomas@med.uni-heidelberg.de.

PMID: 25951834
DOI: 10.1161/CIRCULATIONAHA.114.012657

Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Constanze Schmidt et al. Circulation. 2015.

. 2015 Jul 14;132(2):82-92.

doi: 10.1161/CIRCULATIONAHA.114.012657. Epub 2015 May 7.

Authors

Affiliations

¹ From Department of Cardiology, University of Heidelberg, Germany (C.S., F.W., V.A., P.L., P.A.S., H.A.K., D.T.); Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., X.-B.Z., J.H., S.L., M.B., D.D.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); First Department of Medicine, University Medical Center Mannheim, Germany (X.-B.Z., S.L., M.B.); Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Germany (S.K.); Department of Cardiac Surgery, University Hospital Heidelberg, Germany (A.R., G.S., K.K., M.K.); Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt, Germany (P.B., J.R.E.); Division of Cardiology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany (P.B., J.R.E.); Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary (I.B.); and Department of Cardiology, University of Basel Children's Hospital, Switzerland (B.C.D.).
² From Department of Cardiology, University of Heidelberg, Germany (C.S., F.W., V.A., P.L., P.A.S., H.A.K., D.T.); Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., X.-B.Z., J.H., S.L., M.B., D.D.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); First Department of Medicine, University Medical Center Mannheim, Germany (X.-B.Z., S.L., M.B.); Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Germany (S.K.); Department of Cardiac Surgery, University Hospital Heidelberg, Germany (A.R., G.S., K.K., M.K.); Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt, Germany (P.B., J.R.E.); Division of Cardiology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany (P.B., J.R.E.); Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary (I.B.); and Department of Cardiology, University of Basel Children's Hospital, Switzerland (B.C.D.). dierk.thomas@med.uni-heidelberg.de.

PMID: 25951834
DOI: 10.1161/CIRCULATIONAHA.114.012657

Abstract

Background: Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K(2P)3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K+ channel-related acid-sensitive K+ channel-1]) 2-pore-domain K+ (K(2P)) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown.

Methods and results: Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K(2P)3.1 subunits exhibited predominantly atrial expression, and atrial K(2P)3.1 transcript levels were highest among functional K(2P) channels. K(2P)3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared with patients in sinus rhythm. In contrast, K(2P)3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K(2P)3.1 inhibition prolonged APD90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm.

Conclusions: Enhancement of atrium-selective K(2P)3.1 currents contributes to APD shortening in patients with chronic AF, and K(2P)3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K(2P)3.1 as a novel drug target for mechanism-based AF therapy.

Keywords: arrhythmias, cardiac; atrial fibrillation; electrophysiology.

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Comment in

Letter by Olschewski et al Regarding Article, "Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation".
Olschewski A, Chandran N, Olschewski H. Olschewski A, et al. Circulation. 2016 Mar 15;133(11):e439. doi: 10.1161/CIRCULATIONAHA.115.018800. Circulation. 2016. PMID: 26976922 No abstract available.
Response to Letter Regarding Article, "Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation".
Schmidt C, Wiedmann F, Voigt N, Zhou XB, Heijman J, Lang S, Albert V, Kallenberger S, Ruhparwar A, Szabó G, Kallenbach K, Karck M, Borggrefe M, Biliczki P, Ehrlich JR, Baczkó I, Lugenbiel P, Schweizer PA, Donner BC, Katus HA, Dobrev D, Thomas D. Schmidt C, et al. Circulation. 2016 Mar 15;133(11):e440-1. doi: 10.1161/CIRCULATIONAHA.115.020662. Circulation. 2016. PMID: 26976923 No abstract available.

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Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

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Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

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