title: Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome.
abstract: BACKGROUND
  Both phase 2 and phase 3 early afterdepolarizations (EADs) occur in long-QT syndromes, but their respective roles in generating arrhythmias in intact cardiac tissue are incompletely understood.
  
  
  RESULTS
  Intracellular Ca (Ca(i)) and membrane voltage (V(m)) were optically mapped in a quasi 2-dimensional model of cryoablated Langendorff-perfused rabbit ventricles (n=16). E-4031 (an I(Kr) blocker) combined with reduced extracellular K ([K(+)](o)) and Mg ([Mg(2+)](o)) prolonged action potential duration heterogeneously and induced phase 2 and phase 3 EADs. Whereas phase 2 EADs were Ca(i)-dependent, phase 3 EADs were not. The origins of 47 triggered activity episodes were attributed to phase 2 EADs in 12 episodes (26%) and phase 3 EADs in 35 episodes (74%). When phase 2 EADs accompanied phase 3 EADs, they accentuated action potential duration heterogeneity, creating a large V(m) gradient across the boundary between long and short action potential duration regions from which triggered activity emerged. The amplitude of phase 3 EADs correlated with the V(m) gradient (r=0.898, P<0.001). Computer simulation studies showed that coupling of cells with heterogeneous repolarization could extrinsically generate phase 3 EADs via electrotonic current flow. Alternatively, reduced I(K1) caused by low [K(+)](o) could generate intrinsic phase 3 EADs capable of inducing triggered activity at the boundary zone.
  
  
  CONCLUSIONS
  Phase 3 EADs can be extrinsic as the result of electrotonic current across steep repolarization gradients or intrinsic as the result of low I(K1) and do not require spontaneous sarcoplasmic reticulum Ca release. Reduction of I(K1) by low [K(+)](o) strongly promotes ventricular arrhythmias mediated by phase 3 EADs in acquired long-QT syndrome caused by I(Kr) blockade.
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Xie
authors.forename: Su-Kiat
authors.initials: SK
authors.lastname: Chua
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung
authors.forename: Seongwook
authors.initials: S
authors.lastname: Han
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Shinohara
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shen
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D003198:Computer Simulation; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology; D008133:Long QT Syndrome / Q000209:etiology* / Q000503:physiopathology*; D023421:Models, Animal; D015221:Potassium Channels / Q000502:physiology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D015221:Potassium Channels; D002118:Calcium