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 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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Authors | 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, Dierk Thomas |
Journal | European heart journal
(Eur Heart J)
Vol. 38
Issue 22
Pg. 1764-1774
(Jun 07 2017)
ISSN: 1522-9645 [Electronic] England |
PMID | 28057773
(Publication Type: Journal Article)
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Copyright | Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: [email protected]. |
Chemical References |
- Anti-Arrhythmia Agents
- Nerve Tissue Proteins
- Potassium Channels, Tandem Pore Domain
- potassium channel subfamily K member 3
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Topics |
- Action Potentials
(physiology)
- Aged
- Anti-Arrhythmia Agents
(therapeutic use)
- Atrial Fibrillation
(drug therapy, physiopathology)
- Body Mass Index
- Cardiac Conduction System Disease
(etiology, physiopathology)
- Cardiomyopathy, Dilated
(physiopathology)
- Down-Regulation
(physiology)
- Female
- Humans
- Male
- Nerve Tissue Proteins
(antagonists & inhibitors, metabolism)
- Potassium Channels, Tandem Pore Domain
(antagonists & inhibitors, metabolism)
- Sex Distribution
- Smoking
(adverse effects, physiopathology)
- Up-Regulation
(physiology)
- Ventricular Dysfunction, Left
(physiopathology)
- Ventricular Remodeling
(physiology)
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