Constitutively Active Acetylcholine-Dependent Potassium Current Increases Atrial Defibrillation Threshold by Favoring Post-Shock Re-Initiation.
Electrical cardioversion (ECV), a mainstay in atrial fibrillation (AF) treatment, is unsuccessful in up to 10-20% of patients. An important aspect of the remodeling process caused by AF is the constitutive activition of the atrium-specific acetylcholine-dependent potassium current (IK,ACh → IK,ACh-c), which is associated with ECV failure. This study investigated the role of IK,ACh-c in ECV failure and setting the atrial defibrillation threshold (aDFT) in optically mapped neonatal rat cardiomyocyte monolayers. AF was induced by burst pacing followed by application of biphasic shocks of 25-100 V to determine aDFT. Blocking IK,ACh-c by tertiapin significantly decreased DFT, which correlated with a significant increase in wavelength during reentry. Genetic knockdown experiments, using lentiviral vectors encoding a Kcnj5-specific shRNA to modulate IK,ACh-c, yielded similar results. Mechanistically, failed ECV was attributed to incomplete phase singularity (PS) removal or reemergence of PSs (i.e. re-initiation) through unidirectional propagation of shock-induced action potentials. Re-initiation occurred at significantly higher voltages than incomplete PS-removal and was inhibited by IK,ACh-c blockade. Whole-heart mapping confirmed our findings showing a 60% increase in ECV success rate after IK,ACh-c blockade. This study provides new mechanistic insight into failing ECV of AF and identifies IK,ACh-c as possible atrium-specific target to increase ECV effectiveness, while decreasing its harmfulness.
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Brian O
BO
Bingen
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Saïd F A
SF
Askar
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Zeinab
Z
Neshati
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Iolanda
I
Feola
Department of Physics and Astronomy, Ghent University, Ghent, Belgium.
Alexander V
AV
Panfilov
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Antoine A F
AA
de Vries
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Daniël A
DA
Pijnappels
D000109:Acetylcholine / Q000378:metabolism*; D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D004554:Electric Countershock / Q000009:adverse effects*; D055785:Gene Knockdown Techniques; D006325:Heart Atria / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D051381:Rats
C092387:Kcnj5 protein, rat; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000109:Acetylcholine