Novel feedback based stimulation protocol shows hysteresis in cardiac action potential duration restitution

Short diastolic intervals (DI) produce short action potential durations (APD) due to restitution. Slope of restitution is hypothesized to be critical in initiation of VF. Importance of restitution in mechanisms of VF is recently debated, primarily because of a lack of consistent characterization of restitution. Currently used protocols, standard and dynamic, include pacing at constant S1-S1 intervals for a number of stimuli followed by an S2 or not. In these, DI are a function of both APD (memory effect) and pacing interval (DI=pacing interval - APD). Therefore, restitution functions obtained after variable number of S1 or variable S1-S1 intervals are different. We developed a novel feedback based protocol that permits selection of DI independent of pacing interval and APD. From the instant when transmembrane voltage drops below 90% of repolarization voltage, a stimulus is delivered after predetermined DI. We used DI that oscillated between 0 and 60 msec with periods ranging from 15 sec to 500 msec to quantify effects of short and long term memory on restitution. We used a Luo-Rudy dynamic model of cellular activation. Resulting restitution functions clearly showed multi-modal behavior and hysteresis. When DI increased following a period of decreasing intervals, the APD were shorter than when DI decreased following increasing intervals. Thus, same DI produce different APDs depending on past activation history. Such variation in APD may play a role in increased incidence of VF that is reported after large oscillations in heart rate, i.e. when episodes of bradycardia follow a tachycardic episode.