Restitution of Action Potential Duration During Sequential Changes in Diastolic Intervals Shows Multimodal Behavior

Abstract

Abstract-Restitution of action potential duration (APD) is thought to be critical in activation instability. Although restitution is used to predict APD during sequential changes in diastolic interval (DI), currently used protocols to determine restitution do not use sequential changes in DI. We explored restitution using a new pacing protocol to change DI sequentially and independently of APD. Transmembrane potentials were recorded from right ventricular endocardial tissue isolated from six dogs. We used three patterns of DIs: oscillatory, to demonstrate differences in APDs depending on previous activation history; random, to minimize effects of previous activation history, each DI preceding an APD had an equal probability of being short or long; and linear, to compare restitution relationship obtained during sequential changes in DI with those obtained using currently used protocols; DIs mimicked those that resulted using currently used protocols, except that they changed in sequence. During oscillatory DIs, restitution showed bimodal trajectory similar to hysteresis. Decrease in APD during decreasing DIs was faster than increase in APD during increasing DIs. When effects of previous activation history were minimized, we observed that for a given DI there were multiple values of APD. Restitution relationship obtained during sequential changes in DI was shallower than those obtained using currently used protocols. Our results show that the new pacing protocol may permit direct evaluation of effects of memory on APD. Sequential and explicit control of DI suggests that use of a unimodal relationship to predict APD when DIs change in sequence may not be appropriate. Key Words: action potential duration Ⅲ electrical restitution Ⅲ arrhythmia Ⅲ fibrillation C ardiac electrical restitution is considered to importantly influence whether an electrical disturbance degenerates into a reentrant activation. 1 Specifically, it is hypothesized that the slope of action potential duration (APD) restitution function, which relates diastolic interval (DI) and following APD, can predict stability of electrical activation. 2-9 The hypothesized mechanism is that a slope equal to or greater than 1 can lead to alternans of APD and block propagation. Activation block, in turn, facilitates reentry, leading to arrhythmia. Conversely, for slopes less than 1, disturbances in APD get smaller, returning to a stable activation. Consistent with this view, in a few animal studies, drugs that decrease the slope of restitution have been shown to have antiarrhythmic properties. 10,11 Therefore, it has been suggested that investigation of restitution relationship may prove helpful during development of treatments for arrhythmia or in evaluation of efficacy of antiarrhythmia drugs. 2 The APD restitution function is widely quantified using one of two pacing schemes. In one scheme, tissue is paced for several tens of beats at constant cycle length (S1) followed by a stimulus (S2) delivered at progressively shorter or longer intervals. The APD resultin...

Restitution Properties During Ventricular Fibrillation in the In Situ Swine Heart

“…This long string of constant cycle lengths removes any effects of short-term cardiac memory associated with variations in cycle length such as occur during VF. 18 Cardiac memory is the phenomenon in which not just the previous DI but also the previous APD, as well as the DIs and APDs of even earlier cycles, influence APD. 19,20 In addition to restitution, cardiac memory may also be important during VF.…”

Electrical Restitution Hysteresis

“…6 -9 The APD observed at any given DI is not unique and depends on the history of activation sequence leading up to that beat. In this issue of Circulation Research, Wu and Patwardhan 10 report on APD restitution in canine isolated ventricular tissue preparations using oscillatory sequences of DI. These investigators made use of a system they previously developed 11 to provide explicit control over DI by starting a timer when the action potential achieved 90% repolarization and stimulating the tissue when the elapsed time reached the prescribed DI for that beat.…”

“…Wu and Patwardhan 10 found that the relationship between APD and preceding DI followed a hysteresis loop rather than a fixed unimodal curve when DI varied sinusoidally. For a given DI, APD was consistently lower when DI was on the rising limb than when DI was falling.…”

Short-Term Memory and Restitution During Ventricular Fibrillation in Human Hearts

“…It is likely that the increase in APD after a short DI (Figure 3) is a result of accumulation of memory due to longer APDs during preceding activations. 16 In a previous porcine study, 5 memory together with restitution showed only 30% contribution to APD variability. That study used a microelectrode on the epicardium of an openchest intubated-ventilated porcine model, and the ␣ level for retention of a variable in the model was 0.25.…”

“…14 Short-term memory is the concept in which APD is determined not only by previous DI but also by APDs from earlier cycles. 15,16 Short-term memory may contribute to APD variance during VF in which the cycle length is not constant. To test these hypotheses, we studied the relative contribution of APD restitution relationship and short-term memory effects on APD variation during early VF in myopathic hearts using the monophasic action potential (MAP) catheter in patients.…”