Positive rate‐dependent action potential prolongation by modulating potassium ion channels

Pharmacological agents that prolong action potential duration (APD) to a larger extent at slow rates than at the fast excitation rates typical of ventricular tachycardia exhibit reverse rate dependence. Reverse rate dependence has been linked to the lack of efficacy of class III agents at preventing arrhythmias because the doses required to have an antiarrhythmic effect at fast rates may have pro‐arrhythmic effects at slow rates due to an excessive APD prolongation. In this report, we show that, in computer models of the ventricular action potential, APD prolongation by accelerating phase 2 repolarization (by increasing I(Ks)) and decelerating phase 3 repolarization (by blocking I(Kr) and I(K1)) results in a robust positive rate dependence (i.e., larger APD prolongation at fast rates than at slow rates). In contrast, APD prolongation by blocking a specific potassium channel type results in reverse rate dependence or a moderate positive rate dependence. Interventions that result in a strong positive rate dependence tend to decrease the repolarization reserve because they require substantial I(K1) block. However, limiting I(K1) block to ~50% results in a strong positive rate dependence with moderate decrease in repolarization reserve. In conclusion, the use of a combination of I(Ks) activators and I(Kr) and I(K1) blockers could result in APD prolongation that potentially maximizes antiarrhythmic effects (by maximizing APD prolongation at fast excitation rates) and minimizes pro‐arrhythmic effects (by minimizing APD prolongation at slow excitation rates).