The Role of Sodium Channel Current in Modulating Transmural Dispersion of Repolarization and Arrhythmogenesis

Ventricular myocardium in larger mammals is composed of three distinct cell types: epicardial, M, and endocardial cells. Epicardial and M cell, but not endocardial cell, action potentials have a prominent I to ‐mediated notch. M cells are distinguished from the other cell types in that they display a smaller I Ks , but a larger late I Na and I Na–Ca . These ionic differences may account for the longer action potential duration (APD) and steeper APD‐rate relationship of the M cell. The difference in the time course of repolarization of phase 1 and phase 3 contributes to the inscription of the electrocardiographic J wave and T wave, respectively. These repolarization gradients are modulated by electrotonic interactions, [K + ] o , and agents or mutations that alter net repolarizing current. An increase in late I Na , as occurring under a variety of pathophysiological states or in response to certain toxins, leads to a preferential prolongation of the M cell action potential, thus prolonging the QT interval and increasing transmural dispersion of repolarization (TDR), which underlies the development of torsade de pointes (TdP) arrhythmias. Agents that reduce late I Na are effective in reducing TDR and suppressing TdP. A reduction in peak I Na or an increase in net repolarizing current in the early phases of the action potential can lead to a preferential abbreviation of the action potential of epicardium in the right ventricle, and thus the development of a large TDR, phase 2 reentry, and polymorphic ventricular tachycardia associated with the Brugada syndrome.