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

152 Citations (Scopus)

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

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Myofibrils
Cardiac Arrhythmias
Troponin T
EMD 53998
Hypertrophic Cardiomyopathy
Cardiomyopathies
Action Potentials
Ventricular Tachycardia
Sudden Death
Hypertrophy
Fibrosis
Heart Rate
Mutation
blebbistatin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Baudenbacher, F., Schober, T., Pinto, J. R., Sidorov, V. Y., Hilliard, F., Solaro, R. J., ... 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

Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. / Baudenbacher, Franz; Schober, Tilmann; Pinto, Jose Renato; Sidorov, Veniamin Y.; Hilliard, Fredrick; Solaro, R. John; Potter, James D.; Knollmann, Björn C.

In: Journal of Clinical Investigation, Vol. 118, No. 12, 01.12.2008, p. 3893-3903.

Research output: Contribution to journalArticle

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', Journal of Clinical Investigation, vol. 118, no. 12, pp. 3893-3903. https://doi.org/10.1172/JCI36642
Baudenbacher F, Schober T, Pinto JR, Sidorov VY, Hilliard F, Solaro RJ et al. Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. Journal of Clinical Investigation. 2008 Dec 1;118(12):3893-3903. https://doi.org/10.1172/JCI36642
Baudenbacher, Franz ; Schober, Tilmann ; Pinto, Jose Renato ; Sidorov, Veniamin Y. ; Hilliard, Fredrick ; Solaro, R. John ; Potter, James D. ; Knollmann, Björn C. / Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 12. pp. 3893-3903.
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