title: Impaired epicardial activation-repolarization coupling contributes to the proarrhythmic effects of hypokalaemia and dofetilide in guinea pig ventricles.
abstract: OBJECTIVE
  Activation-repolarization coupling refers to the inverse relationship between action potential duration and activation time in myocardial regions along the path of ventricular excitation. This study examined whether the activation-repolarization coupling plays a role in coordinating repolarization times between the right ventricular (RV) and left ventricular (LV) chambers, and if impaired coordination contributes to electrical instability produced by hypokalaemia or dofetilide, a blocker of the delayed rectifier K(+) current.
  
  
  METHODS
  In Langendorff-perfused, isolated guinea pig hearts, six monophasic action potential recording electrodes were attached to RV and LV epicardium. Local activation time and action potential duration (APD90 ) were determined during spontaneous beating, regular pacing and extrasystolic excitation.
  
  
  RESULTS
  In regularly beating hearts, the RV epicardial sites had longer APD90 , but exhibited earlier activation times, as compared to LV sites, which minimized the interventricular difference in repolarization time. Upon extrasystolic stimulation, the APD90 was reduced to a greater extent in RV compared with LV, which translated to a reversed slope of APD90 -to-activation time relationship, and increased spatial repolarization gradients. Hypokalaemia and dofetilide prolonged APD90 , with the effect being greater in LV compared with RV. In hypokalaemic hearts, LV activation was delayed. These changes contributed to increased asynchrony in repolarization times in the LV and RV in both regular and extrasystolic beats, and enhanced susceptibility to tachyarrhythmia.
  
  
  CONCLUSIONS
  Impaired RV-to-LV activation-repolarization coupling is an important determinant of electrical instability in the setting of non-uniformly prolonged epicardial APD90 or slowed interventricular conduction.
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark; Department of Health Science and Technology, University of Aalborg, Aalborg, Denmark.
authors.forename: O E
authors.initials: OE
authors.lastname: Osadchii
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D007008:Hypokalemia / Q000150:complications* / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide
keywords: Activation-repolarization coupling; cardiac dysrhythmia; dofetilide; hypokalaemia