title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Wiedmann
authors.affiliation: DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.|First Department of Medicine, University Medical Center Mannheim, Mannheim, Germany.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhou
authors.affiliation: Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.|Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Jordi
authors.initials: J
authors.lastname: Heijman
authors.affiliation: Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.|Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Göttingen, Germany.|DZHK (German Center for Cardiovascular Research), Göttingen, Germany, partner site.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Antonius
authors.initials: A
authors.lastname: Ratte
authors.affiliation: DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.|First Department of Medicine, University Medical Center Mannheim, Mannheim, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Lang
authors.affiliation: Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Kallenberger
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Chiara
authors.initials: C
authors.lastname: Campana
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Weymann
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Simone
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Gabor
authors.initials: G
authors.lastname: Szabo
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Arjang
authors.initials: A
authors.lastname: Ruhparwar
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.|INCCI Haerzzenter, Institut National de Chirurgie Cardiaque et de Cardiologie Interventionnelle, Luxembourg, Luxembourg.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kallenbach
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.affiliation: Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt, Germany.|Department of Cardiology, St. Josefs-Hospital, Wiesbaden, Germany.
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Ehrlich
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Baczkó
authors.affiliation: DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.|First Department of Medicine, University Medical Center Mannheim, Mannheim, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.affiliation: Institute of Physiology, Medical Faculty, TU Dresden, Dresden, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.affiliation: Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000503:physiopathology*; D015992:Body Mass Index; D000075224:Cardiac Conduction System Disease / Q000209:etiology / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017678:Sex Distribution; D012907:Smoking / Q000009:adverse effects / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D000889:Anti-Arrhythmia Agents; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3
keywords: Arrhythmia ; Atrial fibrillation ; Electrical remodelling ; Electrophysiology ; Heart failure ; K2P3.1 channel