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

Abstract

RATIONALE:

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.

METHODS AND 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: Sabine Huke, Raghav Venkataraman, Michela Faggioni, Sirish Bennuri, Hyun S Hwang, Franz Baudenbacher, Björn C Knollmann
• Journal: Circulation research (Circ Res) Vol. 112 Issue 10 Pg. 1334-44 (May 10 2013) ISSN: 1524-4571 [Electronic] United States
• PMID: 23532597 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Connexin 43
• Heterocyclic Compounds, 4 or More Rings
• Quinolines
• Thiadiazines
• EMD 53998
• blebbistatin
• Adenosine Triphosphate
• Adenylate Kinase
• Calcium

Topics

• Adenosine Triphosphate (metabolism)
• Adenylate Kinase (metabolism)
• Animals
• Arrhythmias, Cardiac (metabolism, physiopathology)
• Calcium (physiology)
• Cardiomyopathy, Hypertrophic (metabolism, physiopathology)
• Cardiotonic Agents (pharmacology)
• Connexin 43 (metabolism)
• Disease Models, Animal
• Disease Susceptibility (metabolism, physiopathology)
• Electrocardiography
• Energy Metabolism (drug effects, physiology)
• Female
• Gap Junctions (drug effects, physiology)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Male
• Mice
• Mice, Inbred Strains
• Mice, Transgenic
• Myofibrils (drug effects, physiology)
• Quinolines (pharmacology)
• Thiadiazines (pharmacology)