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

Background-Certain alterations by mutations or drugs of the potassium currents 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.