Cellular arrhythmogenic effects of congenital and acquired long-QT syndrome in the heterogeneous myocardium

Background - Certain alterations by mutations or drugs of the potassium currents I(Ks) and I(Kr) and the sodium current I(Na) give rise to several types of the long-QT syndrome. I(Ks) is heterogeneously distributed across the ventricular wall. Methods and Results - We investigated the effects of reducing I(Ks) or I(Kr) or enhancing late I(Na) (to simulate the 3 forms of long-QT syndrome) on action potential duration (APD) in the context of I(Ks) heterogeneity. We introduced I(Ks) heterogeneity in the Luo-Rudy dynamic cell model to simulate epicardial, endocardial, and midmyocardial (M) cells. Results demonstrated higher susceptibility of M cells to the development of arrhythmogenic early afterdepolarizations (EADs) in isolated cells and poorly coupled tissue. An important observation is that I(Kr) block or late I(Na) acts to increase APD differences between the cell types, whereas I(Ks) block minimizes such differences. Also, for normal transverse coupling, EADs develop in the endocardial region rather than in the M region as the result of strong electrotonic interaction. Conclusions - I(Ks) heterogeneity and intercellular coupling strongly influence EAD development during interventions or disorders that prolong APD. M cells in isolation or in poorly coupled tissue are more susceptible to EAD development than epicardial or endocardial cells. In well-coupled myocardium, EAD formation in the subendocardium can be the source of focal arrhythmias or provide the trigger for reentrant excitation. The efficacy of I(Ks) block in minimizing APD dispersion could have important implications for antiarrhythmic therapy.