Effects of rapid and slow potassium repolarization currents and calcium dynamics on hysteresis in restitution of action potential duration

We used a mathematical model to investigate effects of repolarizing currents Ikr and Iks, calcium (Ca) current ICaL, and Ca dynamics in network sarcoplasmic reticulum and junctional sarcoplasmic reticulum (JSR) on hysteresis in restitution of action potential duration. Enhanced Ikr increased slope of restitution, hysteresis loop thickness, and delay between peaks of diastolic intervals and action potential duration. Increase in Iks decreased loop thickness and peak delay. Decrease in ICaL had effects similar to increasing Ikr, except slope of restitution decreased markedly. Uptake of Ca into the network sarcoplasmic reticulum had less effect on hysteresis than transfer of Ca into JSR. Faster transfer of Ca into JSR markedly decreased loop thickness and peak delay. Our results provide insight into mechanisms responsible for this newly identified property of restitution. Such information will be valuable in studies where modification of hysteresis is used to investigate its role in arrhythmogenesis.