Mechanism of repolarization alternans has restitution of action potential duration dependent and independent components

Introduction: Investigation of relationship between diastolic-interval (DI)-dependent restitution of action potential duration (APD) and alternans of APD has produced conflicting results. We used a novel pacing protocol to determine the role of restitution in alternans by minimizing changes in DI preceding each activation. Methods: Transmembrane potentials were recorded from right ventricular endocardial tissue isolated from five dogs. We used three pacing sequences: (i) The tissue was paced at a constant DI for 100 beats. (ii) The DIs were changed randomly between two sequences of constant DI. (iii) Each constant DI trial was followed by constant cycle length trial where pacing cycle length was equal to average cycle length during previous constant DI trial. Results: Alternans of APD occurred even when DIs preceding each activation were invariant. Slopes of restitution during constant DI pacing were both negative and positive and were much larger than unity. Alternans amplitude during constant cycle length pacing was larger than during constant DI, 32.2 ± 12.3 versus 7.5 ± 2.8 msec, P < 0.01. Random perturbation of DI decreased alternans amplitude during constant DI pacing from 14.7 ± 4.8 to 10.5 ± 3.4 msec, P < 0.01. Conclusion: Our results indicate that mechanism of repolarization alternans has restitution-dependent and restitution-independent components. However, our results also provide direct evidence that shows that DI-dependent restitution of APD is not a necessary mechanism for the alternans to exist. Ability to pace with explicit control of DI provides a novel approach to dissect mechanisms of alternans into restitution-dependent and restitution-independent effects.