Abstract
AimsThe steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF.Methods and resultsExperiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM – to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope.Conclusion(s)Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death.
Highlights
Action potential duration (APD) restitution, the process of ratedependent adaptation of the cardiac action potential, has been proposed as a mechanistic determinant of the stability of re-entrant arrhythmia
P < 0.05 are underlined. *Accurate assessments of effective refractory period (ERP) could not be made in ischaemic conditions owing to the induction of ventricular fibrillation (VF) at short coupling intervals
We found no net effect of flecainide but it is conceivable that in the case of substantive post-repolarization refractoriness the maximum slope could be reduced
Summary
Action potential duration (APD) restitution, the process of ratedependent adaptation of the cardiac action potential, has been proposed as a mechanistic determinant of the stability of re-entrant arrhythmia. The original restitution hypothesis, first described in 1968 by Nolasco and Dahlen, suggests that steep restitution relationship will promote ventricular fibrillation (VF).[1,2] In this model, a slope >1 acts to amplify oscillations in APD (alternans) resulting in conduction block and wavebreak. Flattening of the electrical restitution curve—that results in a gradual decrease in alternans towards a steady-state APD—was proposed as a potential target for anti-arrhythmic therapy. Subsequent research showed that the steepness of the restitution curve is not a function of the DI, and of the previous pacing history (i.e. of short-term ‘cardiac memory’), and, different values for restitution slope are generated by different pacing protocols.[3] It was
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