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 (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.
Highlights
While progression of atrial fibrillation (AF) increases the need for Electrical cardioversion (ECV), it is an independent predictor of ECV failure[9,10]
To improve acute AF treatment it is essential to increase the effectiveness of ECV and decrease the energy required for successful cardioversion, i.e. the atrial defibrillation threshold
To test the hypothesis that IK,ACh-c affects the atrial defibrillation success rate or the atrial defibrillation threshold (aDFT), fibrillating atrial cardiomyocyte cultures were treated with tertiapin before being subjected to electric shocks of 25–100 V in order to determine the DFT
Summary
While progression of AF increases the need for ECV, it is an independent predictor of ECV failure[9,10]. To improve acute AF treatment it is essential to increase the effectiveness of ECV and decrease the energy required for successful cardioversion, i.e. the atrial defibrillation threshold (aDFT). A major aspect of the electrophysiological remodeling process associated with AF progression is the shortening of repolarization caused by (among other factors such as decreased L-type calcium current and increased inward rectifier potassium current) constitutive activity of the acetylcholine-dependent potassium current (IK,ACh → IK,ACh-c)[14,15,16,17]. As anti-arrhythmic drugs targeting ion channels shared between atria and ventricles have been shown to increase the burden of ventricular arrhythmias[19,20], modulation of IK,ACh-c (as a consequence of its atrial specificity) might provide the advantage of decreasing aDFT without risking alteration of ventricular electrophysiology. Selective inhibition of Kir3.x activity was accomplished using tertiapin or by lentiviral vector (LV)-mediated RNA interference (RNAi)
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