Emerging concepts in the pharmacogenomics of arrhythmias: ion channel trafficking.
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.
Harkcom
William T
WT
Department of Pharmacology, Weill Medical College of Cornell University, 520 E 70th Street, New York, NY 10021, USA.
Abbott
Geoffrey W
GW
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D016503:Drug Delivery Systems; D006801:Humans; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D010597:Pharmacogenetics
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels