Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation. Issue 2 (14th July 2015)

• Record Type: Journal Article
• Authors: Schmidt, Constanze; Wiedmann, Felix; Voigt, Niels; Zhou, Xiao-Bo; Heijman, Jordi; Lang, Siegfried; Albert, Virginia; Kallenberger, Stefan; Ruhparwar, Arjang; Szabó, Gábor; Kallenbach, Klaus; Karck, Matthias; Borggrefe, Martin; Biliczki, Peter; Ehrlich, Joachim R.; Baczkó, István; Lugenbiel, Patrick; Schweizer, Patrick A.; Donner, Birgit C.; Katus, Hugo A.; Dobrev, Dobromir; Thomas, Dierk
• Is Part Of: Circulation. Volume 132:Issue 2(2015)
• Publication Date: 2015-07-14
• Subjects: Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.114.012657
• Languages: English
• ISSNs: 0009-7322

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <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<sub>2P</sub>3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K<sup>+</sup> channel–related acid-sensitive K<sup>+</sup> channel-1]) 2-pore-domain K<sup>+</sup> (K<sub>2P</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.</p> </sec> <sec> <title>Methods and Results—</title> <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<sub>2P</sub>3.1 subunits exhibited predominantly atrial expression, and atrial K<sub>2P</sub>3.1 transcript levels were highest among functional K<sub>2P</sub> channels. K<sub>2P</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<sub>90</sub>) compared with patients in sinus rhythm. In contrast, K<sub>2P</sub>3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K<sub>2P</sub>3.1 inhibition prolonged APD<sub>90</sub> in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm.</p> </sec> <sec> <title>Conclusions—</title> <p>Enhancement of atrium-selective K<sub>2P</sub>3.1 currents contributes to APD shortening in patients with chronic AF, and K<sub>2P</sub>3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K<sub>2P</sub>3.1 as a novel drug target for mechanism-based AF therapy.</p> </sec> </abstract>