title: Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue.
abstract: BACKGROUND
  Delayed afterdepolarizations (DADs) have been well characterized as arrhythmia triggers, but their role in generating a tissue substrate vulnerable to reentry is not well understood.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that random DADs can self-organize to generate both an arrhythmia trigger and a vulnerable substrate simultaneously in cardiac tissue as a result of gap junction coupling.
  
  
  METHODS
  Computer simulations in 1-dimensional cable and 2-dimensional tissue models were performed. The cellular DAD amplitude was varied by changing the strength of sarcoplasmic reticulum calcium release. Random DAD latency and amplitude in different cells were simulated using gaussian distributions.
  
  
  RESULTS
  Depending on the strength of spontaneous sarcoplasmic reticulum calcium release and other conditions, random DADs in cardiac tissue resulted in the following behaviors: (1) triggered activity (TA); (2) a vulnerable tissue substrate causing unidirectional conduction block and reentry by inactivating sodium channels; (3) both triggers and a vulnerable substrate simultaneously by generating TA in regions next to regions with subthreshold DADs susceptible to unidirectional conduction block and reentry. The probability of the latter 2 behaviors was enhanced by reduced sodium channel availability, reduced gap junction coupling, increased tissue heterogeneity, and less synchronous DAD latency.
  
  
  CONCLUSIONS
  DADs can self-organize in tissue to generate arrhythmia triggers, a vulnerable tissue substrate, and both simultaneously. Reduced sodium channel availability and gap junction coupling potentiate this mechanism of arrhythmias, which are relevant to a variety of heart disease conditions.
authors.affiliation: UCLA Cardiovascular Research Laboratory; Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Liu
authors.affiliation: UCLA Cardiovascular Research Laboratory; Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands.
authors.forename: Enno
authors.initials: E
authors.lastname: de Lange
authors.affiliation: UCLA Cardiovascular Research Laboratory; Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California; Department of Integrative Biology and Physiology, University of California, Los Angeles, California.
authors.forename: Alan
authors.initials: A
authors.lastname: Garfinkel
authors.affiliation: UCLA Cardiovascular Research Laboratory; Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California; Department of Integrative Biology and Physiology, University of California, Los Angeles, California; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.affiliation: UCLA Cardiovascular Research Laboratory; Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, California. Electronic address: zqu@mednet.ucla.edu.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D003198:Computer Simulation; D017629:Gap Junctions / Q000378:metabolism; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013615:Tachycardia, Sinoatrial Nodal Reentry / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D002118:Calcium
keywords: Arrhythmia; Computer simulation; Conduction block; Delayed afterdepolarization; Reentry