Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice

Franz Baudenbacher, Tilmann Schober, Jose Renato Pinto, Veniamin Y. Sidorov, Fredrick Hilliard, R. John Solaro, James D. Potter, Björn C. Knollmann

Research output: Contribution to journalArticle

160 Scopus citations

Abstract

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 Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)3893-3903
Number of pages11
JournalJournal of Clinical Investigation
Volume118
Issue number12
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Medicine(all)

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    Baudenbacher, F., Schober, T., Pinto, J. R., Sidorov, V. Y., Hilliard, F., Solaro, R. J., Potter, J. D., & Knollmann, B. C. (2008). Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. Journal of Clinical Investigation, 118(12), 3893-3903. https://doi.org/10.1172/JCI36642