Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments

Abstract

Rationale: The Ca2+ sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. 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 hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca2+ 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 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 Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca2+ desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity 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 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 Ca2+ sensitivity. © 2013 American Heart Association, Inc.