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Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts
Joseph D. Powers, … , Jennifer Davis, Farid Moussavi-Harami
Joseph D. Powers, … , Jennifer Davis, Farid Moussavi-Harami
Published September 15, 2020
Citation Information: JCI Insight. 2020;5(20):e142446. https://doi.org/10.1172/jci.insight.142446.
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Research Article Cardiology

Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts

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Abstract

Dilated cardiomyopathy (DCM) is often associated with sarcomere protein mutations that confer reduced myofilament tension–generating capacity. We demonstrated that cardiac twitch tension-time integrals can be targeted and tuned to prevent DCM remodeling in hearts with contractile dysfunction. We employed a transgenic murine model of DCM caused by the D230N-tropomyosin (Tm) mutation and designed a sarcomere-based intervention specifically targeting the twitch tension-time integral of D230N-Tm hearts using multiscale computational models of intramolecular and intermolecular interactions in the thin filament and cell-level contractile simulations. Our models predicted that increasing the calcium sensitivity of thin filament activation using the cardiac troponin C (cTnC) variant L48Q can sufficiently augment twitch tension-time integrals of D230N-Tm hearts. Indeed, cardiac muscle isolated from double-transgenic hearts expressing D230N-Tm and L48Q cTnC had increased calcium sensitivity of tension development and increased twitch tension-time integrals compared with preparations from hearts with D230N-Tm alone. Longitudinal echocardiographic measurements revealed that DTG hearts retained normal cardiac morphology and function, whereas D230N-Tm hearts developed progressive DCM. We present a computational and experimental framework for targeting molecular mechanisms governing the twitch tension of cardiomyopathic hearts to counteract putative mechanical drivers of adverse remodeling and open possibilities for tension-based treatments of genetic cardiomyopathies.

Authors

Joseph D. Powers, Kristina B. Kooiker, Allison B. Mason, Abigail E. Teitgen, Galina V. Flint, Jil C. Tardiff, Steven D. Schwartz, Andrew D. McCulloch, Michael Regnier, Jennifer Davis, Farid Moussavi-Harami

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Figure 4

L48Q cTnC prevents contractile abnormalities in cardiac tissue isolated from hearts containing D230N tropomyosin.

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L48Q cTnC prevents contractile abnormalities in cardiac tissue isolated ...
(A) Steady-state T as a percentage of the maximum value (at pCa 4.0) of demembranated cardiac muscle measured over a range of extracellular Ca2+ concentrations (pCa = –log([Ca2+]). The data are fit with the Hill equation (see Methods section) shown by the solid lines. (B) The pCa at half-maximal T (pCa50) of cardiac preparations from D230N hearts is significantly less than all other groups, whereas the pCa50 of preparations from L48Q plus D230N DTG hearts is not different from WT. Error bars represent SD. Black lines above the bars indicate P < 0.05 between groups using a 1-way ANOVA and a Tukey’s post hoc test of significance. (C) Average twitch T-time traces (in % WT Tpeak) of intact trabeculae for each genotype (same color scheme as panel A). The WT T-time trace is shown as a dashed green trace against each variant twitch for comparison. (D) The area under the T-time trace (left ordinate) for each genotype and the resulting TI (right ordinate). See Supplemental Table 2 for numerical values. T, tension; cTnC, cardiac troponin C; Ca2+, calcium; Tpeak, peak twitch tension; DTG, double-transgenic.

Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

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