Inverse remodelling of K(2P)3.1 K(+) channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy

Constanze Schmidt, Felix Wiedmann, Xiao-Bo Zhou, Jordi Heijman, Niels Voigt, Antonius Ratte, Siegfried Lang, Stefan M. Kallenberger, Chiara Campana, Alexander Weymann, Raffaele De Simone, Gabor Szabo, Arjang Ruhparwar, Klaus Kallenbach, Matthias Karck, Joachim R. Ehrlich, Istvan Baczko, Martin Borggrefe, Ursula Ravens, Dobromir DobrevHugo A. Katus, Dierk Thomas*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

56 Citations (Web of Science)

Abstract

Aims Atrial fibrillation (AF) prevalence increases with advanced stages of left ventricular (LV) dysfunction. Remote proarrhythmic effects of ventricular dysfunction on atrial electrophysiology remain incompletely understood. We hypothesized that repolarizing K(2P)3.1 K+ channels, previously implicated in AF pathophysiology, may contribute to shaping the atrial action potential (AP), forming a specific electrical substrate with LV dysfunction that might represent a target for personalized antiarrhythmic therapy.

Methods and results A total of 175 patients exhibiting different stages of LV dysfunction were included. Ion channel expression was quantified by real-time polymerase chain reaction and Western blot. Membrane currents and APs were recorded from atrial cardiomyocytes using the patch-clamp technique. Severely reduced LV function was associated with decreased atrial K(2P)3.1 expression in sinus rhythm patients. In contrast, chronic (c) AF resulted in increased K(2P)3.1 levels, but paroxysmal (p) AF was not linked to significant K(2P)3.1 remodelling. LV dysfunction-related suppression of K(2P)3.1 currents prolonged atrial AP duration (APD) compared with patients with preserved LV function. In individuals with concomitant LV dysfunction and cAF, APD was determined by LV dysfunction-associated prolongation and by cAF-dependent shortening, respectively, consistent with changes in K(2P)3.1 abundance. K(2P)3.1 inhibition attenuated APD shortening in cAF patients irrespective of LV function, whereas in pAF subjects with severely reduced LV function, K(2P)3.1 blockade resulted in disproportionately high APD prolongation.

Conclusion LV dysfunction is associated with reduction of atrial K(2P)3.1 channel expression, while cAF leads to increased K2P3.1 abundance. Differential remodelling of K(2P)3.1 and APD provides a basis for patient-tailored antiarrhythmic strategies.

Original languageEnglish
Pages (from-to)1764-1774
Number of pages11
JournalEuropean Heart Journal
Volume38
Issue number22
DOIs
Publication statusPublished - 7 Jun 2017

Keywords

  • Arrhythmia
  • Atrial fibrillation
  • Electrical remodelling
  • Electrophysiology
  • Heart failure
  • K(2P)3.1 channel
  • HEART-FAILURE
  • UP-REGULATION
  • MODEL
  • SUPPRESSION
  • TACHYCARDIA
  • MECHANISMS

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