Experimentally-Based Computational Investigation into Beat-To-Beat Variability in Ventricular Repolarization and Its Response to Ionic Current Inhibition

Beat-to-beat variability in repolarization (BVR) has been proposed as an arrhythmic risk marker for disease and pharmacological action. Themechanisms are unclear but BVR is thought to be a cell level manifestation of ion channel stochasticity, modulated by cell-to-cell differences in ionic conductances. In this study, we describe the construction of an experimentally-calibrated set of stochastic cardiac cell models that captures both BVR and cell-to-cell differences in BVR displayed in isolated canine action potentialmeasurements using pharmacological agents. Simulated and experimental ranges of BVR are compared in control and under pharmacological inhibition, and the key ionic currents determining BVR under physiological and pharmacological conditions are identified. Results show that the 4-aminopyridine-sensitive transient outward potassium current, I-to1, is a fundamental driver of BVR in control and upon complete inhibition of the slow delayed rectifier potassium current, I-Ks. In contrast, I-Ks and the L-type calcium current, I-CaL, become the major contributors to BVR upon inhibition of the fast delayed rectifier potassiumcurrent, I-Kr. This highlights both I-Ks and I-to1 as key contributors to repolarization reserve. Partial correlation analysis identifies the distribution of I-to1 channel numbers as an important independent determinant of themagnitude of BVR and drug-induced change in BVR in control and under pharmacological inhibition of ionic currents. Distributions in the number of I-Ks and I-CaL channels only become independent determinants of the magnitude of BVR upon complete inhibition of I-Kr. These findings provide quantitative insights into the ionic causes of BVR as a marker for repolarization reserve, both under control condition and pharmacological inhibition.