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 (I(K,ACh) → I(K,ACh-c)), which is associated with ECV failure. This study investigated the role of I(K,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,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,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,ACh-c) blockade. Whole-heart mapping confirmed our findings showing a 60% increase in ECV success rate after I(K,ACh-c) blockade. This study provides new mechanistic insight into failing ECV of AF and identifies I(K,ACh-c) as possible atrium-specific target to increase ECV effectiveness, while decreasing its harmfulness.