Focal Energy Deprivation Underlies Arrhythmia Susceptibility in Mice with Calcium-Sensitized Myofilaments
Rationale: The Ca2+ sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy (HCM) and other heart diseases and may contribute to a higher risk for sudden cardiac death (SCD). Ca2+ sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown.
Objective: To investigate how myofilament Ca2+ sensitization creates reentrant arrhythmia susceptibility.
Methods and Results: Using HCM mouse models (troponinT (TNT)-I79N) and a Ca2+ sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca2+ sensitization. To detect ATP depletion and thus energy deprivation we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 as well as AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Cx43-P0 occurred within minutes in all Ca2+ 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 Cx43-P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity (CVT) was slowed and anisotropy increased. Myofilament Ca2+ de-sensitization with blebbistatin prevented focal energy deprivation, CVT slowing and the reentrant ventricular arrhythmias.
Conclusions: Myofilament Ca2+ sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel pro-arrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may therefore contribute to SCD in diseases with increased myofilament Ca2+ sensitivity.
- myofilament Ca2+ sensitivity
- gap junctions
- Connexin 43
- conduction velocity dispersion
- hypertrophic cardiomyopathy
- sudden cardiac death, arrhythmia
- arrhythmia (mechanisms)
- Received January 25, 2013.
- Revision received March 1, 2013.
- Accepted March 26, 2013.