Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy

Abstract Abnormalities of cardiomyocyte Ca 2 + homeostasis and excitation–contraction (E–C) coupling are early events in the pathogenesis of hypertrophic cardiomyopathy (HCM) and concomitant determinants of the diastolic dysfunction and arrhythmias typical of the disease. T-tubule remodelling has be...

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Veröffentlicht in:Journal of molecular and cellular cardiology 2016-02, Vol.91, p.42-51
Hauptverfasser: Crocini, C, Ferrantini, C, Scardigli, M, Coppini, R, Mazzoni, L, Lazzeri, E, Pioner, J.M, Scellini, B, Guo, A, Song, L.S, Yan, P, Loew, L.M, Tardiff, J, Tesi, C, Vanzi, F, Cerbai, E, Pavone, F.S, Sacconi, L, Poggesi, C
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Sprache:eng
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Zusammenfassung:Abstract Abnormalities of cardiomyocyte Ca 2 + homeostasis and excitation–contraction (E–C) coupling are early events in the pathogenesis of hypertrophic cardiomyopathy (HCM) and concomitant determinants of the diastolic dysfunction and arrhythmias typical of the disease. T-tubule remodelling has been reported to occur in HCM but little is known about its role in the E–C coupling alterations of HCM. Here, the role of T-tubule remodelling in the electro-mechanical dysfunction associated to HCM is investigated in the Δ160E cTnT mouse model that expresses a clinically-relevant HCM mutation. Contractile function of intact ventricular trabeculae is assessed in Δ160E mice and wild-type siblings. As compared with wild-type, Δ160E trabeculae show prolonged kinetics of force development and relaxation, blunted force-frequency response with reduced active tension at high stimulation frequency, and increased occurrence of spontaneous contractions. Consistently, prolonged Ca 2 + transient in terms of rise and duration are also observed in Δ160E trabeculae and isolated cardiomyocytes. Confocal imaging in cells isolated from Δ160E mice reveals significant, though modest, remodelling of T-tubular architecture. A two-photon random access microscope is employed to dissect the spatio-temporal relationship between T-tubular electrical activity and local Ca 2 + release in isolated cardiomyocytes. In Δ160E cardiomyocytes, a significant number of T-tubules (> 20%) fails to propagate action potentials, with consequent delay of local Ca 2 + release. At variance with wild-type, we also observe significantly increased variability of local Ca 2 + transient rise as well as higher Ca 2 + -spark frequency. Although T-tubule structural remodelling in Δ160E myocytes is modest, T-tubule functional defects determine non-homogeneous Ca 2 + release and delayed myofilament activation that significantly contribute to mechanical dysfunction.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2015.12.013