Cardiac sodium channels: dysregulation meets myocardial failure.

Within the orchestra of cardiac ion channels, voltage–gated Na channels have a key function in the determination of the amplitude and slope of the action potential upstroke. Both are important in the control of impulse conduction velocity and maintenance of appropriate waves of excitation through the workingmyocardium. Themain (α-) subunit of the cardiac sodium channel is encoded by the SCN5A (Nav1.5) gene, and the INa current mediated is responsible for the membrane depolarization. Fast inactivation of sodium channels appears within milliseconds, and the vast majority of sodium channels transit from the open state to a non-conductive state. Gating dysfunction or changes in the number of functional channels of cardiac sodium channels are linked to several cardiac arrhythmias [1–4]. Meanwhile, more than 170 different SCN5A mutations have been reported (currently, 77 for LQT-3, 90 for Brugada syndrome, 10 for conduction disease; see http://www.fsm.it/cardmoc/), and this has enabled evaluation of structure-function relationships of the sodium channel. Analysis of several of these mutations has consistently demonstrated that loss of function is the basic mechanism in Brugada syndrome or conduction disease, which is related to multiple mechanisms that include failure of sodium channel protein expression and, importantly, changes in the voltage-