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Myofilament Ca2+ Sensitization Causes Susceptibility to Cardiac Arrhythmia in Mice

Title: Myofilament Ca2+ Sensitization Causes Susceptibility to Cardiac Arrhythmia in Mice.
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Name(s): Baudenbacher, Franz, author
Schober, Tilmann, author
Pinto, Jose, author
Sidorov, Veniamin, author
Hilliard, Fredrick, author
Solaro, R. John, author
Potter, James, author
Knollmann, Björn C., author
Type of Resource: text
Genre: Text
Issuance: serial
Date Issued: 2008
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_migr_biomed_faculty_publications-0050 (IID), 10.1172/JCI36642 (DOI)
Keywords: actin cytoskeleton, action potentials, calcium, cardiomyopathy, hypertrophic, cardiotonic agents, cats, sudden death, cardiac, disease models, disease susceptibility, fibrosis, heterocyclic compounds with 4 or more rings, mice, mutant strains, quinolines, risk factors, tachycardia, ventricular, thiadiazines, Troponin T
Uncontrolled subjects: Actin Cytoskeleton, Action Potentials, Animals, Calcium, Cardiomyopathy, Hypertrophic, Cardiotonic Agents, Cats, Death, Sudden, Cardiac, Disease Models, Animal, Disease Susceptibility, Female, Fibrosis, Heterocyclic Compounds with 4 or More Rings, Humans, Male, Mice, Mice, Mutant Strains, Quinolines, Risk Factors, Tachycardia, Ventricular, Thiadiazines, Troponin T
Note: Originally published in The'>http://www.jci.org/articles/view/36642">The Journal of Clinical Investigation.
Citation: Baudenbacher F, Schober T, Pinto JR, Sidorov VY, Hilliard F, Solaro RJ, Potter JD, & Knollmann BC. (2008). Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J Clin Invest, 118(12):3893-903. doi: 10.1172/JCI36642.
Subject(s): Amino acids
Peptides
Proteins
Cardiovascular system -- Diseases
Cells
Chemicals -- Physiological effect
Heterocyclic compounds
Inorganic compounds
Investigations
Macromolecules
Medical sciences
Organic compounds
Pathology
Symptoms
Links: http://dx.doi.org/10.1172/JCI36642
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_migr_biomed_faculty_publications-0050
Owner Institution: FSU
Is Part of Series: Department of Biomedical Sciences Faculty Publications.
Is Part Of: The Journal of Clinical Investigation.
Issue: 12, 118

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Baudenbacher, F., Schober, T., Pinto, J., Sidorov, V., Hilliard, F., Solaro, R. J., … Knollmann, B. C. (2008). Myofilament Ca2+ Sensitization Causes Susceptibility to Cardiac Arrhythmia in Mice. Journal Of Clinical Investigation. Retrieved from http://dx.doi.org/10.1172/JCI36642