title: Relative contribution of changes in sodium current versus intercellular coupling on reentry initiation in 2-dimensional preparations of plakophilin-2-deficient cardiac cells.
abstract: BACKGROUND
  Loss of expression of the desmosomal protein plakophilin-2 (PKP2) leads to decreased gap junction-mediated (GJ) coupling, and alters the amplitude and kinetics of sodium current in cardiac myocytes. Whether these modifications, alone or in combination, are sufficient to act as arrhythmogenic substrates remains undefined.
  
  
  OBJECTIVE
  This study sought to characterize arrhythmia susceptibility and reentry dynamics consequent to loss of PKP2 expression, and to assess the relative contribution of cell uncoupling versus alterations in sodium current in generation of reentry.
  
  
  METHODS
  Monolayers of neonatal rat ventricular myocytes were treated with oligonucleotides that either prevented or failed to prevent PKP2 expression. Numerical simulations modeled experimentally observed modifications in I(Na), GJ coupling, or both (models PKP2-Na, PKP2-GJ, and PKP2-KD, respectively). Relative roles of sodium current density versus kinetics were further explored.
  
  
  RESULTS
  Loss of PKP2 expression increased incidence of rotors and decreased frequency of rotation. Mathematical simulations revealed that single premature stimuli initiated rotors in models PKP2-Na and PKP2-KD, but not PKP2-GJ. Changes in sodium current kinetics, rather than current density, were key to reentry initiation. Anatomical barriers led to vortex shedding, wavebreaks, and rotors when I(Na) kinetics, but not GJ coupling or I(Na) density, were altered.
  
  
  CONCLUSIONS
  PKP2-dependent changes in sodium current kinetics lead to slow conduction, increased propensity to functional block, and vortex shedding. Changes in GJ or I(Na) density played only a minor role on reentry susceptibility. Changes in electrical properties of the myocyte caused by loss of expression of PKP2 can set the stage for rotors even if anatomical homogeneity is maintained.
authors: Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48108, USA.
authors: Makarand
authors: M
authors: Deo
authors: Priscila Y
authors: PY
authors: Sato
authors: Hassan
authors: H
authors: Musa
authors: Xianming
authors: X
authors: Lin
authors: Sandeep V
authors: SV
authors: Pandit
authors: Mario
authors: M
authors: Delmar
authors: Omer
authors: O
authors: Berenfeld
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D003198:Computer Simulation; D004195:Disease Models, Animal; D017629:Gap Junctions / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051191:Plakophilins / Q000096:biosynthesis / Q000172:deficiency*; D051381:Rats; D012964:Sodium / Q000378:metabolism*
chemical_list: D051191:Plakophilins; D012964:Sodium