Effect of rapid delayed rectifier current on hysteresis in restitution of action potential duration in swine

Electrical stability in the heart depends on two important factors; restitution of action potential duration (APD) and memory. Repolarization currents play an important role in determining APD and also affect memory. We determined the effects of blocking the rapid component of the delayed rectifier (I_Kr) on a quantifiable measure of memory, i.e. hysteresis in restitution of APD, in swine. Transmembrane potentials were recorded from right ventricular endocardial tissues. Two pacing protocols with explicit control of diastolic interval (DI) were used to change DIs in a sequential and sinusoidal pattern to quantify hysteresis in restitution of APD. E-4031 (5 μM/L) was used to block I_Kr. Measures of memory and restitution were quantified by calculating hysteresis loop thickness, area, overall tilt, and maximum and minimum delays between DIs and APDs. Blocking I_Kr with E-4031 increased the baseline APD, loop thickness, area, and tilt (p<0.05). However, loop thickness did not increase beyond what could be predicted by the increase in baseline APD after block of I_Kr. The substantial change in APD after blocking I_Kr suggests that this current plays a major role in repolarization in the swine. Loop thickness is a measure of memory, an increase in which is predicted by theory to reduce instability in activation. In our study, the substantial increase in loop thickness could be accounted for by an equally substantial increase in APD and therefore does not necessarily indicate increased memory after blocking I_Kr. Our results also suggest that factors based on restitution and memory need to be considered in the context of operating point, i.e. baseline APD, when they are used to explore mechanisms that affect electrical stability in the heart.