Mechanisms of termination and prevention of atrial fibrillation by drug therapy

Workman, A.J. , Smith, G.L. and Rankin, A.C. (2011) Mechanisms of termination and prevention of atrial fibrillation by drug therapy. Pharmacology and Therapeutics, 131(2), pp. 221-241. (doi: 10.1016/j.pharmthera.2011.02.002)

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Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I–IV drugs, namely Na+ channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca2+ channel blockers; the “upstream therapies”, e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as “atrial-selective” multiple ion channel blockers, gap junction-enhancers, and intracellular Ca2+-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms. Keywords: Atrial fibrillation; Cardiac arrhythmia mechanisms: reentry, afterdepolarisations; In-vivo animal models; Pathological electrical remodelling; Pharmacological treatment; Anti-arrhythmic drug mechanisms Abbreviations: ACE, angiotensin-converting enzyme; AF, atrial fibrillation; AFCL, AF cycle length; APD, action potential duration; DAD, delayed afterdepolarisation; EAD, early afterdepolarisation; ERP, effective refractory period; ICaL, L-type Ca2+ current; ICaT, T-type Ca2+ current; If, funny current; IK1, inward rectifier K+ current; IKACh, acetylcholine-activated K+ current; IKr, rapid delayed rectifier K+ current; IKS, slow delayed rectifier K+ current; IKur, ultra-rapid delayed rectifier K+ current; INa, Na+ current; INa/Ca, Na+-Ca2+ exchanger current; INa/H, Na+-H+ exchanger current; INaL, late INa; ISKCa, small conductance Ca2+-activated K+ current; ITO, transient outward K+ current

Item Type:Articles
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Rankin, Mrs Aileen and Workman, Dr Antony
Authors: Workman, A.J., Smith, G.L., and Rankin, A.C.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Pharmacology and Therapeutics
Copyright Holders:Copyright © 2011 Elsevier
First Published:First published in Pharmacology and Therapeutics 131(2):221-241
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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