Emerging concepts in the pharmacogenomics of arrhythmias: ion channel trafficking

Abstract

Continuous, rhythmic beating of the heart requires exquisite control of expression, localization and function of cardiac ion channels – the foundations of the cardiac myocyte action potential. Disruption of any of these processes can alter the shape of the action potential, predisposing to cardiac arrhythmias. These arrhythmias can manifest in a variety of ways depending on both the channels involved and the type of disruption (i.e., gain or loss of function). As much as 1% of the population of developed countries is affected by cardiac arrhythmia each year, and a detailed understanding of the mechanism of each arrhythmia is crucial to developing and prescribing the proper therapies. Many of the antiarrhythmic drugs currently on the market were developed before the underlying cause of the arrhythmia was known, and as a result lack specificity, causing side effects. The majority of the available drugs target the conductance of cardiac ion channels, either by blocking or enhancing current through the channel. In recent years, however, it has become apparent that specific targeting of ion channel conductance may not be the most effective means for treatment. Here we review increasing evidence that suggests defects in ion channel trafficking play an important role in the etiology of arrhythmias, and small molecule approaches to correct trafficking defects will likely play an important role in the future of arrhythmia treatment.

Keywords::

• arrhythmia
• atrial fibrillation
• hERG
• KCNQ1
• Kv1.5
• LQTS
• surface expression
• trafficking

Financial & competing interests disclosure

Geoffrey W Abbott is supported by the National Heart, Lung and Blood Institute, National Institutes of Health (R01 HL079275; R01HL101190), the American Heart Association (0855756D), and an Irma T Hirschl Career Scientist Award. William T Harkcom is supported by a National Institutes of Health Predoctoral Training Grant (T32GM073546). 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.

No writing assistance was utilized in the production of this manuscript.