Upregulation of K <sub>2P</sub> 3.1 K <sup>+</sup> Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation
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- Constanze Schmidt
- 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...
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- Felix Wiedmann
- 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...
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- Niels Voigt
- 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...
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- Xiao-Bo Zhou
- 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...
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- Jordi Heijman
- 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...
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- Siegfried Lang
- 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...
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- Virginia Albert
- 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...
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- Stefan Kallenberger
- 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...
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- Arjang Ruhparwar
- 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...
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- Gábor Szabó
- 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...
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- Klaus Kallenbach
- 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...
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- Matthias Karck
- 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...
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- Martin Borggrefe
- 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...
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- Peter Biliczki
- 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...
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- Joachim R. Ehrlich
- 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...
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- István Baczkó
- 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...
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- Patrick Lugenbiel
- 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...
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- Patrick A. Schweizer
- 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...
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- Birgit C. Donner
- 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...
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- Hugo A. Katus
- 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...
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- Dobromir Dobrev
- 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...
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- Dierk Thomas
- 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...
説明
<jats:sec> <jats:title>Background—</jats:title> <jats:p> 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 <jats:sub>2P</jats:sub> 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K <jats:sup>+</jats:sup> channel–related acid-sensitive K <jats:sup>+</jats:sup> channel-1]) 2-pore-domain K <jats:sup>+</jats:sup> (K <jats:sub>2P</jats:sub> ) 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. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> 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 <jats:sub>2P</jats:sub> 3.1 subunits exhibited predominantly atrial expression, and atrial K <jats:sub>2P</jats:sub> 3.1 transcript levels were highest among functional K <jats:sub>2P</jats:sub> channels. K <jats:sub>2P</jats:sub> 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 (APD <jats:sub>90</jats:sub> ) compared with patients in sinus rhythm. In contrast, K <jats:sub>2P</jats:sub> 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K <jats:sub>2P</jats:sub> 3.1 inhibition prolonged APD <jats:sub>90</jats:sub> in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> Enhancement of atrium-selective K <jats:sub>2P</jats:sub> 3.1 currents contributes to APD shortening in patients with chronic AF, and K <jats:sub>2P</jats:sub> 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K <jats:sub>2P</jats:sub> 3.1 as a novel drug target for mechanism-based AF therapy. </jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 132 (2), 82-92, 2015-07-14
Ovid Technologies (Wolters Kluwer Health)