Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy
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Updated: Mar 28, 2026
Analysis of Tubular Membrane Networks in Cardiac Myocytes from Atria and Ventricles
Published on: October 15, 2014
C Crocini1, C Ferrantini2, M Scardigli1
1European Laboratory for Non-Linear Spectroscopy, 50019 Florence, Italy.
Insights
Hypertrophic cardiomyopathy (HCM) involves T-tubule defects that impair cardiomyocyte calcium handling and electrical activity, leading to impaired heart function. These T-tubule abnormalities contribute to the mechanical dysfunction seen in HCM.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Abnormalities in cardiomyocyte calcium (Ca2+) handling and excitation-contraction (E-C) coupling are key early events in hypertrophic cardiomyopathy (HCM) pathogenesis.
- T-tubule remodeling is implicated in HCM, but its specific role in E-C coupling alterations remains unclear.
Purpose of the Study:
- To investigate the role of T-tubule remodeling in the electro-mechanical dysfunction associated with hypertrophic cardiomyopathy (HCM).
- To analyze the spatio-temporal relationship between T-tubular electrical activity and local Ca2+ release in a mouse model of HCM.
Main Methods:
- Assessment of contractile function in ventricular trabeculae from a clinically relevant HCM mouse model (Δ160E cTnT) and wild-type siblings.
- Confocal imaging and two-photon random access microscopy to analyze T-tubule architecture, action potential propagation, and Ca2+ transients in isolated cardiomyocytes.
- Measurement of Ca2+ spark frequency and local Ca2+ transient variability.
Main Results:
- Δ160E trabeculae exhibited prolonged force development/relaxation, blunted force-frequency response, and increased spontaneous contractions compared to wild-type.
- Isolated Δ160E cardiomyocytes showed prolonged Ca2+ transients, significant T-tubule remodeling, and impaired action potential propagation (>20% of T-tubules).
- HCM cardiomyocytes displayed increased variability in local Ca2+ transient rise, higher Ca2+ spark frequency, and delayed local Ca2+ release, indicating non-homogeneous Ca2+ handling.
Conclusions:
- Modest T-tubule structural remodeling in HCM leads to significant functional defects.
- These T-tubule functional defects, including impaired action potential propagation and non-homogeneous Ca2+ release, contribute to delayed myofilament activation and mechanical dysfunction in hypertrophic cardiomyopathy.
- Targeting T-tubule abnormalities may offer a therapeutic strategy for HCM-related electro-mechanical dysfunction.
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.
