Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy
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 K2P3.1 K+ channels, previously implicat...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
05 January 2017
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| In: |
European heart journal
Year: 2017, Volume: 38, Issue: 22, Pages: 1764-1774 |
| ISSN: | 1522-9645 |
| DOI: | 10.1093/eurheartj/ehw559 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1093/eurheartj/ehw559 Verlag, Volltext: https://academic.oup.com/eurheartj/article/38/22/1764/2831052 
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| Author Notes: | 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, István Baczkó, Martin Borggrefe, Ursula Ravens, Dobromir Dobrev, Hugo A. Katus, and Dierk Thomas |
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| 245 | 1 | 0 | |a Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation |b implications for patient-specific antiarrhythmic drug therapy |c 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, István Baczkó, Martin Borggrefe, Ursula Ravens, Dobromir Dobrev, Hugo A. Katus, and Dierk Thomas |
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| 520 | |a 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 K2P3.1 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 K2P3.1 expression in sinus rhythm patients. In contrast, chronic (c)AF resulted in increased K2P3.1 levels, but paroxysmal (p)AF was not linked to significant K2P3.1 remodelling. LV dysfunction-related suppression of K2P3.1 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 K2P3.1 abundance. K2P3.1 inhibition attenuated APD shortening in cAF patients irrespective of LV function, whereas in pAF subjects with severely reduced LV function, K2P3.1 blockade resulted in disproportionately high APD prolongation. Conclusion: LV dysfunction is associated with reduction of atrial K2P3.1 channel expression, while cAF leads to increased K2P3.1 abundance. Differential remodelling of K2P3.1 and APD provides a basis for patient-tailored antiarrhythmic strategies. | ||
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