Upregulation of K2P 3.1 K + Current Causes Action Potential Shortening in Patients with Chronic Atrial Fibrillation

Constanze Schmidt, Felix Wiedmann, Niels Voigt, Xiao Bo Zhou, Jordi Heijman, Siegfried Lang, Virginia Albert, Stefan Kallenberger, Arjang Ruhparwar, Gábor Szabó, Klaus Kallenbach, Matthias Karck, Martin Borggrefe, Peter Biliczki, Joachim R. Ehrlich, István Baczkó, Patrick Lugenbiel, Patrick A. Schweizer, Birgit C. Donner, Hugo A. KatusDobromir Dobrev, Dierk Thomas

Research output: Contribution to journalArticle

86 Citations (Scopus)

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. K2P 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 + (K2P) 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. K2P 3.1 subunits exhibited predominantly atrial expression, and atrial K2P 3.1 transcript levels were highest among functional K2P channels. K2P 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 90) compared with patients in sinus rhythm. In contrast, K2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions - Enhancement of atrium-selective K2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K2P 3.1 as a novel drug target for mechanism-based AF therapy.

Original languageEnglish
Pages (from-to)82-92
Number of pages11
JournalCirculation
Volume132
Issue number2
DOIs
Publication statusPublished - Jul 14 2015

Keywords

  • arrhythmias cardiac
  • atrial fibrillation
  • electrophysiology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Schmidt, C., Wiedmann, F., Voigt, N., Zhou, X. B., Heijman, J., Lang, S., Albert, V., Kallenberger, S., Ruhparwar, A., Szabó, G., Kallenbach, K., Karck, M., Borggrefe, M., Biliczki, P., Ehrlich, J. R., Baczkó, I., Lugenbiel, P., Schweizer, P. A., Donner, B. C., ... Thomas, D. (2015). Upregulation of K2P 3.1 K + Current Causes Action Potential Shortening in Patients with Chronic Atrial Fibrillation. Circulation, 132(2), 82-92. https://doi.org/10.1161/CIRCULATIONAHA.114.012657