Abstract
Both inherited and acquired cardiac arrhythmias are often associated with the abnormal functional expression of ion channels at the cellular level. The complex machinery that continuously traffics, anchors, organizes, and recycles ion channels at the plasma membrane of a cardiomyocyte appears to be a major source of channel dysfunction during cardiac arrhythmias. This has been well established with the discovery of mutations in the genes encoding several ion channels and ion channel partners during inherited cardiac arrhythmias. Fibrosis, altered myocyte contacts, and post-transcriptional protein changes are common factors that disorganize normal channel trafficking during acquired cardiac arrhythmias. Channel availability, described notably for hERG and KV1.5 channels, could be another potent arrhythmogenic mechanism. From this molecular knowledge on cardiac arrhythmias will emerge novel antiarrhythmic strategies.
Highlights
Both inherited and acquired cardiac arrhythmias are often associated with the abnormal functional expression of ion channels at the cellular level
Studies on the genetics of inherited cardiac arrhythmias show that certain loss-offunction (LOF) mutations are associated with altered channel trafficking that are retained in intracellular organelles
Robust evidence of the role of caveolin-3 in long QT cardiac arrhythmias came from the identification of four mutations (F97C, S141R, T78M, and A85T) in patients referred for Long QT syndrome (LQTS)
Summary
Cardiac excitability is generated exclusively by cardiomyocytes. Some of them are able to depolarize spontaneously the pacemaker cells of the sinus node, some others are specialized in the transmission of the electrical impulse (Purkinje cells), whereas the vast majority are involved in the excitation–contraction coupling process. Electrogenic systems are composed mainly of voltage-dependent channels (VOC), some pumps, and exchangers. The second phase of the AP is a plateau phase lasting a few hundreds of msec, during which the excitation–contraction coupling process is activated, which is controlled by the L-type calcium current. A number of potassium currents shape the AP; they belong to voltage-dependent and inward rectifier potassium channel families. In addition to a change in the membrane electrical potential, the continuous variations in free intracellular calcium during the EC coupling process are a master regulator of cardiac excitability mainly via the electrogenic Na+-Ca+ exchanger (NCX); the direct effect of calcium on channel gating (rapid inactivation of the L-type calcium channel); or the activation of a second messenger, such as CaMK-II. There are differences between atrial and ventricular myocytes that are mainly due to the cellular architecture and notably the organization of the t-tubular system, which is highly developed in ventricular myocytes (see for more information [1])
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