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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 3

Ca2+-sensitizing TnT mutants increase the spatial dispersion of electrical activation during fast pacing and create a substrate for functional reentry.

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Acute challenge with the Ca2+-sensitizing compound EMD 57033 reproduces ...
(A) Examples of isochronal activation maps of mouse hearts at different pacing rates from an R278C and an I79N heart. Hearts were stained with the voltage-sensitive fluorescent indicator di-4-ANEPPS, and epicardial images were obtained from the anterior aspect of the left ventricle at the PCL indicated above each image. (B–D) Effect of TnT mutants on CV and CV dispersion. CVs were calculated along 10 equally spaced radial lines from the stimulus side (red circle) near the apex as shown in B and were averaged for each heart. CV dispersion was quantified as the SD of the 10 CV determinations and expressed as percentage of average CV per heart. (C) Average CV decreased with shorter PCLs (shorter PCLs result in faster pacing) in all groups regardless of genotype. (D) Spatial CV dispersion was significantly increased in Ca2+-sensitized transgenic hearts. *P < 0.05, **P < 0.01 between groups, by 2-way ANOVA with repeated measures; I79N, n = 7; F110I, n = 7; R278C, n = 5. (E) Optically recorded repetitive activation pattern during VT. Fluorescence difference images of successive frames taken from the anterior left ventricle epicardial surface of an I79N heart during sustained VT. The time stamp is referenced to the first image. The activation pattern during VT shows typically a spiral wave rotating around a fixed center, forming a reentrant excitation (see also Supplemental Video 1).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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