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Constitutively active acetylcholine-dependent potassium current increases atrial defibrillation threshold by favoring post-shock re-initiation

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Abstract
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 (I-K,I-ACh -> I-K,I-ACh-c), which is associated with ECV failure. This study investigated the role of I-K,I-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 I-K,I-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 I-K,I-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 I-K,I-ACh-c blockade. Whole-heart mapping confirmed our findings showing a 60% increase in ECV success rate after I-K,I-ACh-c blockade. This study provides new mechanistic insight into failing ECV of AF and identifies I-K,I-ACh-c as possible atrium-specific target to increase ECV effectiveness, while decreasing its harmfulness.
Keywords
cardiac arrhythmias, atrial fibrillation, cardioversion, VENTRICULAR-FIBRILLATION, ELECTRICAL CARDIOVERSION, CARDIAC TISSUE, CLINICAL IMPLICATIONS, WAVE-FORM, MECHANISM, TERMINATION, TRIAL, RISK, MYOCARDIUM

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Chicago
Bingen, Brian O, Saïd FA Askar, Zeinab Neshati, Iolanda Feola, Alexander Panfilov, Antoine AF de Vries, and Daniël A Pijnappels. 2015. “Constitutively Active Acetylcholine-dependent Potassium Current Increases Atrial Defibrillation Threshold by Favoring Post-shock Re-initiation.” Scientific Reports 5.
APA
Bingen, B. O., Askar, S. F., Neshati, Z., Feola, I., Panfilov, A., de Vries, A. A., & Pijnappels, D. A. (2015). Constitutively active acetylcholine-dependent potassium current increases atrial defibrillation threshold by favoring post-shock re-initiation. SCIENTIFIC REPORTS, 5.
Vancouver
1.
Bingen BO, Askar SF, Neshati Z, Feola I, Panfilov A, de Vries AA, et al. Constitutively active acetylcholine-dependent potassium current increases atrial defibrillation threshold by favoring post-shock re-initiation. SCIENTIFIC REPORTS. 2015;5.
MLA
Bingen, Brian O et al. “Constitutively Active Acetylcholine-dependent Potassium Current Increases Atrial Defibrillation Threshold by Favoring Post-shock Re-initiation.” SCIENTIFIC REPORTS 5 (2015): n. pag. Print.
@article{7054182,
  abstract     = {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 (I-K,I-ACh -> I-K,I-ACh-c), which is associated with ECV failure. This study investigated the role of I-K,I-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 I-K,I-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 I-K,I-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 I-K,I-ACh-c blockade. Whole-heart mapping confirmed our findings showing a 60% increase in ECV success rate after I-K,I-ACh-c blockade. This study provides new mechanistic insight into failing ECV of AF and identifies I-K,I-ACh-c as possible atrium-specific target to increase ECV effectiveness, while decreasing its harmfulness.},
  articleno    = {15187},
  author       = {Bingen, Brian O and Askar, Saïd FA and Neshati, Zeinab and Feola, Iolanda and Panfilov, Alexander and de Vries, Antoine AF and Pijnappels, Daniël A},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keywords     = {cardiac arrhythmias,atrial fibrillation,cardioversion,VENTRICULAR-FIBRILLATION,ELECTRICAL CARDIOVERSION,CARDIAC TISSUE,CLINICAL IMPLICATIONS,WAVE-FORM,MECHANISM,TERMINATION,TRIAL,RISK,MYOCARDIUM},
  language     = {eng},
  pages        = {15},
  title        = {Constitutively active acetylcholine-dependent potassium current increases atrial defibrillation threshold by favoring post-shock re-initiation},
  url          = {http://dx.doi.org/10.1038/srep15187},
  volume       = {5},
  year         = {2015},
}

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