T-tubule remodeling in human hypertrophic cardiomyopathy
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ORIGINAL PAPER
T‑tubule remodeling in human hypertrophic cardiomyopathy Giulia Vitale1 · Raffaele Coppini3 · Chiara Tesi1 · Corrado Poggesi1 · Leonardo Sacconi2,4 · Cecilia Ferrantini1,2 Received: 11 March 2020 / Accepted: 22 October 2020 © The Author(s) 2020
Abstract The highly organized transverse T-tubule membrane system represents the ultrastructural substrate for excitation–contraction coupling in ventricular myocytes. While the architecture and function of T-tubules have been well described in animal models, there is limited morpho-functional data on T-tubules in human myocardium. Hypertrophic cardiomyopathy (HCM) is a primary disease of the heart muscle, characterized by different clinical presentations at the various stages of its progression. Most HCM patients, indeed, show a compensated hypertrophic disease (“non-failing hypertrophic phase”), with preserved left ventricular function, and only a small subset of individuals evolves into heart failure (“end stage HCM”). In terms of T-tubule remodeling, the “end-stage” disease does not differ from other forms of heart failure. In this review we aim to recapitulate the main structural features of T-tubules during the “non-failing hypertrophic stage” of human HCM by revisiting data obtained from human myectomy samples. Moreover, by comparing pathological changes observed in myectomy samples with those introduced by acute (experimentally induced) detubulation, we discuss the role of T-tubular disruption as a part of the complex excitation–contraction coupling remodeling process that occurs during disease progression. Lastly, we highlight how T-tubule morpho-functional changes may be related to patient genotype and we discuss the possibility of a primitive remodeling of the T-tubule system in rare HCM forms associated with genes coding for proteins implicated in T-tubule structural integrity, formation and maintenance. Keywords Hypertrophic cardiomyopathy · T-tubules · Excitation–contraction coupling
Introduction T-tubules are transverse and deep invaginations of the surface sarcolemma running along the Z-line regions in mammalian ventricular myocytes. Functionally, T-tubules guarantee a rapid propagation of the action potential (AP) towards the cardiomyocyte core. The high concentration of key excitation–contraction (E–C) coupling proteins on T-tubule membrane, such as dihydropyridine receptors (DHPRs) and other membrane channels/transporters * Cecilia Ferrantini [email protected] 1
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
2
European Laboratory for Nonlinear Spectroscopy (LENS), University of Florence, Sesto Fiorentino, Italy
3
Department NeuroFarBa, University of Florence, Florence, Italy
4
National Institute of Optics, National Research Council, Florence, Italy
(Orchard et al. 2009; Pásek et al. 2008; Yang et al. 2002), allows synchronous triggering of Ca2+ release from the sarcoplasmic reticulum (SR) across the entire cardiomyocyte, as well as simultaneous activation of all myof
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