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An important aspect of the remodeling process caused by AF is the constitutive activition of the atrium-specific acetylcholine-dependent potassium current (I<jats:sub>K,ACh<\/jats:sub>\u2009\u2192\u2009I<jats:sub>K,ACh-c<\/jats:sub>), which is associated with ECV failure. This study investigated the role of I<jats:sub>K,ACh-c<\/jats:sub> 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\u2013100\u2009V to determine aDFT. Blocking I<jats:sub>K,ACh-c<\/jats:sub> by tertiapin significantly decreased DFT, which correlated with a significant increase in wavelength during reentry. Genetic knockdown experiments, using lentiviral vectors encoding a <jats:italic>Kcnj5<\/jats:italic>-specific shRNA to modulate I<jats:sub>K,ACh-c<\/jats:sub>, yielded similar results. Mechanistically, failed ECV was attributed to incomplete phase singularity (PS) removal or reemergence of PSs (<jats:italic>i.e.<\/jats:italic> 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<jats:sub>K,ACh-c<\/jats:sub> blockade. Whole-heart mapping confirmed our findings showing a 60% increase in ECV success rate after I<jats:sub>K,ACh-c<\/jats:sub> blockade. This study provides new mechanistic insight into failing ECV of AF and identifies I<jats:sub>K,ACh-c<\/jats:sub> as possible atrium-specific target to increase ECV effectiveness, while decreasing its harmfulness.<\/jats:p>","DOI":"10.1038\/srep15187","type":"journal-article","created":{"date-parts":[[2015,10,21]],"date-time":"2015-10-21T08:50:39Z","timestamp":1445417439000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Constitutively Active Acetylcholine-Dependent Potassium Current Increases Atrial Defibrillation Threshold by Favoring Post-Shock Re-Initiation"],"prefix":"10.1038","volume":"5","author":[{"given":"Brian O.","family":"Bingen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sa\u00efd F. 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