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FOCUS ISSUE: ATRIAL FIBRILLATION: STATE-OF-THE-ART PAPER

Atrial-Selective Approaches for the Treatment of Atrial Fibrillation

Joachim R. Ehrlich, MD^_*,1,_*, Peter Biliczki, MD, PhD^_*,2, Stefan H. Hohnloser, MD, FACC^_*,3 and Stanley Nattel, MD, FACC^,4

^_* Division of Cardiology, Section of Electrophysiology, J.W. Goethe-University, Frankfurt, Germany
Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.

Manuscript received June 22, 2007; revised manuscript received July 27, 2007, accepted August 13, 2007.

^_* Reprint requests and correspondence: Dr. Joachim R. Ehrlich, J. W. Goethe-University, Theodor Stern Kai 7, 60590 Frankfurt, Germany. (Email: j.ehrlich{at}em.uni-frankfurt.de).

Atrial-selective pharmacologic approaches represent promising novel therapeutic options for the treatment of atrial fibrillation (AF). Medical treatment for AF is still more widely applied than interventional therapies but is hampered by several important weaknesses. Besides limited clinical efficacy (cardioversion success and sinus-rhythm maintenance), side effects like ventricular proarrhythmia and negative inotropy are important limitations to present class I and III drug therapy. Although no statistically significant detrimental survival consequences have been documented in trials, constitutional adverse effects might also limit applicability. Cardiac targets for novel atrial-selective antiarrhythmic compounds have been identified, and a large-scale search for safe and effective medications has begun. Several ionic currents (I_KACh, I_Kur) and connexins (Cx-40) are potential targets, because atrial-selective expression makes them attractive in terms of reduced ventricular side-effect liability. Data on most agents are still experimental, but some clinical findings are available. Atrial fibrillation generates a specifically remodeled atrial milieu for which other therapeutic interventions might be effective. Some drugs show frequency-dependent action, whereas others target structurally remodeled atria. This review focuses on potential atrial-selective compounds, summarizing mechanisms of action in vitro and in vivo. It also mentions favorable interventions on the milieu in terms of conventional (such as antifibrotic effects of angiotensin-system antagonism) and innovative gene-therapy approaches that might add to future AF therapeutic options.

Abbreviations and Acronyms   AF = atrial fibrillation   AP = action potential   APD = action potential duration   Cx = connexin   DPO = diphenylphosphine oxide   ERP = effective refractory period   IKACh = acetylcholine-regulated potassium current   IKr = rapid delayed-rectifier potassium current   IKur = ultrarapid delayed-rectifier potassium current   INa = sodium current   SAC = stretch-activated channel

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