Novel ion channel targets in atrial fibrillation

ABSTRACT

Introduction: Atrial fibrillation (AF) is the most common arrhythmia in humans. It is progressive and the development of electrical and structural remodeling makes early intervention desirable. Existing antiarrhythmic pharmacological approaches are not always effective and can produce unwanted side effects. Additional atrial-selective antiarrhythmic strategies are therefore desirable.

Areas covered: Evidence for three novel ion channel atrial-selective therapeutic targets is evaluated: atrial-selective fast sodium channel current (I_Na) inhibition; small conductance calcium-activated potassium (SK) channels; and two-pore (K_2P) potassium channels.

Expert Opinion: Data from animal models support atrial-ventricular differences in I_Na kinetics and also suggest atrial-ventricular differences in sodium channel β subunit expression. Further work is required to determine whether intrinsic atrial-ventricular differences in human I_Na exist or whether functional differences occur due to distinct atrial and ventricular action and resting potentials. SK and K_2P channels (particularly K_2P 3.1) offer potentially attractive atrial-selective targets. Work is needed to identify the underlying basis of SK current that contributes to (patho)physiological atrial repolarization and settings in which SK inhibition is anti- versus pro-arrhythmic. Although K_2P3.1 appears to be a promising target with comparatively selective drugs for experimental use, a lack of selective pharmacology hinders evaluation of other K_2P channels as potential atrial-selective targets.

KEYWORDS:

• Atrial fibrillation
• atrial-selective
• fast sodium current
• K_2P
• K_2P3.1
• SK channel
• SK2
• SK3
• two-pore channel

Article highlights

• AF is the most common arrhythmia in humans. Limitations with existing pharmacological treatments drive a search for novel atrial-selective drug targets.

• Preclinical data suggest that atrial-selective fast sodium channel current (I_Na) inhibition may be an attractive approach, due either to intrinsic differences in atrial and ventricular I_Na or to functional differences arising from distinct atrial and ventricular action and resting potentials that affect drug sensitivity.

• SK channel isoforms have been identified in the atria of small and large model species and the human heart. SK2 and SK3 may form heteromultimeric channels with distinct pharmacology. The underlying basis of SK channels in normal and remodeled human atria and settings in which SK inhibition is pro- or antiarrhythmic require further investigation.

• The two-pore channel K_2P3.1 (TASK-1) is preferentially expressed in human atria over ventricles, and K_2P3.1 expression and function are increased in chronic AF. Data with experimental K_2P3.1 inhibitors are suggestive that K_2P3.1 is a promising target.

• Intrinsic differences in human atrial and ventricular I_Na remain to be confirmed. The underlying basis of SK channels in normal and remodeled atria and settings in which SK inhibition is pro- or antiarrhythmic require further investigation. Improved K_2P channel pharmacology is required to determine whether additional K_2P isoforms have significant potential as atrial-selective targets.

This box summarizes key points contained in the article.

Declaration of interest

J Hancox, A James, N Marrion and H Zhang acknowledge research support from the British Heart Foundation. J Hancox, A James, N Marrion also acknowledge research support from the University of Bristol; J Hancox acknowledges support from the University of Bristol International Strategic Fund. The work of D Thomas was supported in part by research grants from the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung – German Centre for Cardiovascular Research) and from the BMBF (German Ministry of Education and Research), from the German Cardiac Society and the Hengstberger Foundation (Klaus-Georg and Sigrid Hengstberger Scholarship), from the German Heart Foundation/German Foundation of Heart Research (project F/08/14 to D.T.), from the Else Kröner-Fresenius-Stiftung (2014_A242 to D.T.), and from the Joachim Siebeneicher Foundation. He also received grant support from MSD Sharp and Dohme and served on advisory boards for and received honoraria for lectures from Sanofi-Aventis. He filed a patent application for the use of K2P potassium channels for altering cardiac electrophysiology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.