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.