期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 91, 期 -, 页码 42-51出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.12.013
关键词
Hypertrophic cardiomyopathy; T-tubules; Excitation-contraction coupling; Imaging; Non-linear microscopy
资金
- European Union Seventh Framework Programme [241577, 241526, 284464]
- National Institutes of Health (NIH) [R01 EB001963]
- Italian Ministry for Education, University and Research
- Italian Ministry of Health [WFR GR-2011-02350583]
- Telethon-Italy [GGP13162]
Abnormalities of cardiomyocyte Ca2+ 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 Delta 160E cTnT mouse model that expresses a clinically-relevant HCM mutation. Contractile function of intact ventricular trabeculae is assessed in Delta 160E mice and wild-type siblings. As compared with wild-type, Delta 160E 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 Ca2+ transient in terms of rise and duration are also observed in Delta 160E trabeculae and isolated cardiomyocytes. Confocal imaging in cells isolated from Delta 160E 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 Ca2+ release in isolated cardiomyocytes. In Delta 160E cardiomyocytes, a significant number of T-tubules (>20%) fails to propagate action potentials, with consequent delay of local Ca2+ release. At variance with wild-type, we also observe significantly increased variability of local Ca2+ transient rise as well as higher Ca2+-spark frequency. Although T-tubule structural remodelling in Delta 160E myocytes is modest, T-tubule functional defects determine non-homogeneous Ca2+ release and delayed myofilament activation that significantly contribute to mechanical dysfunction. (C) 2015 The Authors. Published by Elsevier Ltd.
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