title: Restitution slope is principally determined by steady-state action potential duration.
abstract: OBJECTIVE
  The 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.
  
  
  RESULTS
  Experiments 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Division, King's College London, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shattock
authors.affiliation: Cardiovascular Division, King's College London, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Kyung Chan
authors.initials: KC
authors.lastname: Park
authors.affiliation: NHLI, ICTEM Building, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.|Department of Surgery, Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Hsiang-Yu
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Biomedical Engineering, King's College London, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Angela W C
authors.initials: AWC
authors.lastname: Lee
authors.affiliation: Biomedical Engineering, King's College London, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Niederer
authors.affiliation: NHLI, ICTEM Building, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: MacLeod
authors.affiliation: Cardiovascular Division, King's College London, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: James
authors.initials: J
authors.lastname: Winter
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D065096:Calcium Chelating Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D000067268:Isolated Heart Preparation; D007700:Kinetics; D008297:Male; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D012307:Risk Factors; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D002120:Calcium Channel Agonists; D065096:Calcium Chelating Agents; D002118:Calcium
keywords: Action potential duration; Cardiac memory; Electrical restitution; Restitution