Inhibition of Small-Conductance Ca2+-Activated K+ Channels: The Long-Awaited Breakthrough for Antiarrhythmic Drug Therapy of Atrial Fibrillation?

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See Article by Diness et al There is an urgent unmet need for better treatment of atrial fibrillation (AF) given its strong impact on morbidity and mortality and the expected increase in AF prevalence with the aging of the population.1,2 Current AF management involves antithrombotic therapy to reduce the risk of stroke and normalization of the ventricular response rate (rate control) or restoration and maintenance of normal sinus rhythm (rhythm control).3,4 Although numerous clinical trials have established that both rate and rhythm control produce similar outcomes, rhythm control is often attempted to reduce AF symptoms.3,5 Antiarrhythmic drugs and catheter ablation are the most commonly used approaches for rhythm control therapy. Although ablation is generally more effective in maintaining normal sinus rhythm than antiarrhythmic drugs, it is associated with a significant risk for adverse events3,4 and is not an option for every AF patient, particularly in light of the high costs, the need of specialized skills, and the expected increase in AF prevalence. Moreover, a large fraction of the patients who undergo AF ablation receive additional subsequent treatment with antiarrhythmic drugs.3 Thus, antiarrhythmic drugs still have a major impact on AF management. However, currently available antiarrhythmic drugs have limited efficacy, particularly in longer-lasting forms of AF, and a substantial risk of adverse effects, including ventricular proarrhythmia, which are likely in large part because of their development in the absence of a detailed understanding of AF mechanisms.6,7 Pharmacological AF therapy generally targets the 2 main arrhythmogenic mechanisms: ectopic activity and reentry (Figure [A]).10 Ectopic activity is inhibited by reducing atrial excitability (eg, using class I …