Document Detail


Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans.
MedLine Citation:
PMID:  25082948     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AIMS: We aimed at examining the acetylcholine-dependent inward-rectifier current (IKAch) as a target for the management of atrial fibrillation (AF).
METHODS AND RESULTS: The investigative agents AZD2927 and A7071 concentration-dependently blocked IKACh in vitro with minimal off-target activity. In anaesthetized dogs (n = 17) subjected to 8 weeks of rapid atrial pacing (RAP), the left atrial effective refractory period (LAERP) was maximally increased by 50 ± 7.4 and 50 ± 4.8 ms following infusion of AZD2927 and A7071. Ventricular refractoriness and the QT interval were unaltered. During sustained AF, both drugs significantly reduced AF frequency and effectively restored sinus rhythm. AZD2927 successfully restored sinus rhythm at 10/10 conversion attempts and A7071 at 14/14 attempts, whereas saline converted 4/17 episodes only (P<0.001 vs. AZD2927 and A7071). In atrial flutter patients (n = 18) undergoing an invasive investigation, AZD2927 did not change LAERP, the paced QT interval, or ventricular refractoriness when compared with placebo. To address the discrepancy on LAERP by IKACh blockade in man and dog and the hypothesis that atrial electrical remodelling is a prerequisite for IKACh blockade being efficient, six dogs were studied after 8 weeks of RAP followed by sinus rhythm for 4 weeks to reverse electrical remodelling. In these dogs, both AZD2927 and A7071 were as effective in increasing LAERP as in the dogs studied immediately after the 8-week RAP period.
CONCLUSION: Based on the present series of experiments, an important role of IKACh in human atrial electrophysiology, as well as its potential as a viable target for effective management of AF, may be questioned.
Authors:
Håkan Walfridsson; Ole-Gunnar Anfinsen; Anders Berggren; Lars Frison; Steen Jensen; Gunilla Linhardt; Ann-Christin Nordkam; Monika Sundqvist; Leif Carlsson
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-7-31
Journal Detail:
Title:  Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology     Volume:  -     ISSN:  1532-2092     ISO Abbreviation:  Europace     Publication Date:  2014 Jul 
Date Detail:
Created Date:  2014-8-1     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100883649     Medline TA:  Europace     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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