title: Diastolic spontaneous calcium release from the sarcoplasmic reticulum increases beat-to-beat variability of repolarization in canine ventricular myocytes after β-adrenergic stimulation.
abstract: BACKGROUND
  Spontaneous Ca(2+) release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during intense β-adrenergic stimulation, leading to SCR.
  
  
  OBJECTIVE
  We aimed to determine ionic mechanisms controlling BVR under these conditions.
  
  
  RESULTS
  Membrane potentials and cell shortening or Ca(2+) transients were recorded from isolated canine left ventricular myocytes in the presence of isoproterenol. Action-potential (AP) durations after delayed afterdepolarizations were significantly prolonged. Addition of slowly activating delayed rectifier K(+) current (I(Ks)) blockade led to further AP prolongation after SCR, and this strongly correlated with exaggerated BVR. Suppressing SCR via inhibition of ryanodine receptors, Ca(2+)/calmodulin-dependent protein kinase II inhibition, or by using Mg(2+) or flecainide eliminated delayed afterdepolarizations and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring L-type Ca(2+) current (I(CaL)) with and without previous SCR indicated that I(CaL) was increased during Ca(2+)-induced Ca(2+) release after SCR, and this contributes to AP prolongation. Prolongation of QT, T(peak)-T(end) intervals, and left ventricular monophasic AP duration of beats after aftercontractions occurred before torsades de pointes in an in vivo dog model of drug-induced long-QT1 syndrome.
  
  
  CONCLUSIONS
  SCR contributes to increased BVR by interspersed prolongation of AP duration, which is exacerbated during I(Ks) blockade. Attenuation of Ca(2+)-induced Ca(2+) release by SCR underlies AP prolongation via increased I(CaL.) These data provide novel insights into arrhythmogenic mechanisms during β-adrenergic stimulation besides triggered activity and illustrate the importance of I(Ks) function in preventing excessive BVR.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Johnson
authors.forename: Jordi
authors.initials: J
authors.lastname: Heijman
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Bode
authors.forename: David J
authors.initials: DJ
authors.lastname: Greensmith
authors.forename: Henk
authors.initials: H
authors.lastname: van der Linde
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
authors.forename: David A
authors.initials: DA
authors.lastname: Eisner
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Trafford
authors.forename: Paul G A
authors.initials: PG
authors.lastname: Volders
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium