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Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice
Franz Baudenbacher, … , James D. Potter, Björn C. Knollmann
Franz Baudenbacher, … , James D. Potter, Björn C. Knollmann
Published November 20, 2008
Citation Information: J Clin Invest. 2008;118(12):3893-3903. https://doi.org/10.1172/JCI36642.
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Research Article Article has an altmetric score of 1

Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice

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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 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.

Authors

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

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Figure 1

Isoproterenol challenge causes ventricular ectopy in transgenic mice with Ca2+-sensitized myofilaments.

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Isoproterenol challenge causes ventricular ectopy in transgenic mice wit...
(A and B) Effect of different TnT mutations on Ca2+ sensitivity of force development of skinned fiber bundles. (B) Average change in pCa50 of force development (ΔpCa50) of the different groups of transgenic mice studied here. The ΔpCa50 values for R278C, F110I, and I79N were expressed relative to the pCa50 of WT before (control [CON]) and after phosphorylation with the catalytic subunit of protein kinase A. **P < 0.01 compared with WT; §P < 0.01 compared with F110I; n = 16 each. Values for ssTNI are taken from ref. 25. In this and subsequent figures, data from mice or hearts with Ca2+-sensitized myofilaments are presented in color, whereas data from mice or hearts with normal myofilament Ca2+ sensitivity are presented in gray. #P < 0.05 compared with NTg littermates, n = 6. (C–F) Effect of isoproterenol in anesthetized mice. (C) ECG recording from an F110I mouse illustrating isoproterenol-induced PVCs (arrows). (D) Note the significantly higher PVC rate in mice with Ca2+-sensitized myofilaments (F110I, n = 6; I79N, n = 9; ssTnI, n = 5) compared with normal myofilament Ca2+ sensitivity (NTg, n = 14; WT, n = 23; R278C, n = 13). *P < 0.05, †P < 0.005 compared with WT, by Mann-Whitney U test. (E) Example of nonsustained VT recorded in an I79N mouse after isoproterenol injection. (F) VT incidence after isoproterenol injection. *P < 0.05 compared with WT, by Fisher’s exact test; group sizes as in D.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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