blister and Cardiomyopathy--Hypertrophic

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.. To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility.. 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.. 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.

Topics: Adenosine Triphosphate; Adenylate Kinase; Animals; Arrhythmias, Cardiac; Calcium; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Connexin 43; Disease Models, Animal; Disease Susceptibility; Electrocardiography; Energy Metabolism; Female; Gap Junctions; Heterocyclic Compounds, 4 or More Rings; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Myofibrils; Quinolines; Thiadiazines

Mutations in contractile proteins in heart muscle can cause anatomical changes that result in cardiac arrhythmias and sudden cardiac death. However, a conundrum has existed because mutations in one such contractile protein, a so-called Ca2+ sensor troponin T (TnT), can promote ventricular rhythm disturbances even in the absence of hypertrophy or fibrosis. Thus, these mutations must enhance abnormal electrophysiological events via alternative means. In this issue of the JCI, Baudenbacher et al. report a novel mechanism to explain this puzzle (see the related article beginning on page 3893). They show that a selected TnT mutation in the adult mouse heart can markedly increase the sensitivity of cardiac muscle myofilaments to Ca2+ and enhance the susceptibility to arrhythmia, even in the absence of anatomical deformities. As these same mutations can cause some forms of arrhythmias in humans, these findings are of both basic and translational significance.

Topics: Actin Cytoskeleton; Action Potentials; Animals; Calcium; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cats; Death, Sudden, Cardiac; Disease Models, Animal; Disease Susceptibility; Female; Fibrosis; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Mice; Mice, Mutant Strains; Quinolines; Risk Factors; Tachycardia, Ventricular; Thiadiazines; Troponin T

In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of Ca2+ sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the Ca2+-sensitizing agent EMD 57033 and prevented by myofilament Ca2+ desensitization with blebbistatin. Ca2+ sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament Ca2+ sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of Ca2+ sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.

Topics: Actin Cytoskeleton; Action Potentials; Animals; Calcium; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cats; Death, Sudden, Cardiac; Disease Models, Animal; Disease Susceptibility; Female; Fibrosis; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Mice; Mice, Mutant Strains; Quinolines; Risk Factors; Tachycardia, Ventricular; Thiadiazines; Troponin T