title: Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.
abstract: BACKGROUND
  The Ca(2+) sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. Ca(2+) sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown.
  
  
  OBJECTIVE
  To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility.
  
  
  RESULTS
  Using hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca(2+) sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca(2+) sensitization. To detect ATP depletion and thus energy deprivation, we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 and AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Connexin 43 isoform P0 occurred within minutes in all Ca(2+)-sensitized hearts, in vivo after isoproterenol challenge and in isolated hearts after rapid pacing. Lucifer yellow dye spread demonstrated reduced gap junctional coupling in areas with Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca(2+) desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity slowing, and the reentrant ventricular arrhythmias.
  
  
  CONCLUSIONS
  Myofilament Ca(2+) sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel proarrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may, therefore, contribute to sudden cardiac death in diseases with increased myofilament Ca(2+) sensitivity.
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA. sabine.huke@vanderbilt.edu
authors.forename: Sabine
authors.initials: S
authors.lastname: Huke
authors.forename: Raghav
authors.initials: R
authors.lastname: Venkataraman
authors.forename: Michela
authors.initials: M
authors.lastname: Faggioni
authors.forename: Sirish
authors.initials: S
authors.lastname: Bennuri
authors.forename: Hyun S
authors.initials: HS
authors.lastname: Hwang
authors.forename: Franz
authors.initials: F
authors.lastname: Baudenbacher
authors.forename: Björn C
authors.initials: BC
authors.lastname: Knollmann
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology*; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000378:metabolism / Q000503:physiopathology*; D004562:Electrocardiography; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005260:Female; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009210:Myofibrils / Q000187:drug effects / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology; D013829:Thiadiazines / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D018031:Connexin 43; D006576:Heterocyclic Compounds, 4 or More Rings; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; C472645:blebbistatin; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D002118:Calcium
keywords: Connexin 43; conduction velocity dispersion; familial hypertrophic cardiomyopathy; myofilament Ca2+ sensitivity; sudden cardiac death; ventricular arrhythmias