© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Does the loss of transverse tubules contribute to dyssynchronous Ca2+ release during heart failure?
INSERM Unité de Recherche 621, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75013 Paris, France
* Tel.: +33-1-40-25-86-00; fax: +33-1-40-25-86-02. Email address: hatem{at}bichat.inserm.fr
Received 28 January 2004; accepted 30 January 2004
See article by Louch et al. [1] (pages 63–73) in this issue.
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1. Introduction |
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 Top 1. Introduction 2. T-tubules synchronize Ca2+...3. Cellular models to...4. Is there a...5. Conclusion and perspectivesReferences |
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Congestive heart failure (CHF) is the leading cause of death in developed countries. This syndrome is due to the incapacity of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues. Very often CHF is caused by a defect in myocardial contraction. Thereby, a better understanding of the cellular and molecular basis of the altered contractility of failing heart is a major research topic of many laboratories in the hopes of identifying new targets for the treatment of CHF. The manuscript of Louch et al. [1] in the current issue of Cardiovascular Research examines the possibility that alteration of the microarchitecture of cardiac myocytes, specifically of the transverse (T) tubule system, plays a role in the defective excitation–contraction coupling (EC coupling) process of ventricular myocytes from human failing hearts.
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2. T-tubules synchronize Ca2+ release |
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Top1. Introduction2. T-tubules synchronize Ca2+...3. Cellular models to...4. Is there a...5. Conclusion and perspectivesReferences |
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In mammalian cardiac myocytes, contraction is controlled by a sequence of events that includes the activation of the L-type Ca2+ current, which in turn triggers the opening of the Ca2+ release channels [ryanodine receptors of the sarcoplasmic reticulum (SR), RyRs] and the release of Ca2+ from the sarcoplasmic reticulum in keeping with the Ca2+-induced Ca2+ release phenomenon (CICR). The close proximity of the RyRs and the L-type Ca2+ channels in dyadic junctions of the T-tubules provides for privileged Ca2+ cross-signaling between the two sets of proteins and also for the local control of EC coupling. Using confocal microscopy, local and non-propagated variations in [Ca2+]i (Ca2+ sparks) have been observed in ventricular myocytes.[2,3] They are believed to be caused by the activation of a small number of RyRs located in terminal or junctional cisternae of the SR and may represent the elementary release event. The opening of a few Ca2+ channels from T-tubules facing the junctional cisternae can gate the elementary release event [4]. Moreover, it has been possible to localize focal Ca2+ release in the area of dyadic junctions at the Z-line level [5]. The abundant literature on the local control of Ca2+ release points to the major role played by the T-tubule system in the harmonious activation of contraction [6].
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3. Cellular models to study cardiac myocyte T-tubular network |
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Top1. Introduction2. T-tubules synchronize Ca2+...3. Cellular models to...4. Is there a...5. Conclusion and perspectivesReferences |
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Atrial myocytes or Purkinje cells lack T-tubules and therefore have been extensively used to study the relationship between cell microarchitecture and the EC coupling process. In atrial myocytes, a number of terminal cisternae of the SR are not associated with the plasma membrane (corbular or nonjunctional SR) [7]. This distinct microarchitecture is associated with the activation of peripheral and central Ca2+ release during twitch contraction [8]. While the former is gated by the calcium current, the latter is activated by the propagation of Ca2+ release by peripheral or junctional SR independently of the calcium current [9,10]. The respective role of central and peripheral Ca2+ release in the physiology of atrial cells is not yet clear [11].
Several experimental procedures have been used to induce a detubulation of cardiac myocytes, including long-term culture of adult ventricular myocytes [6]. In their study, Louch et al. [1] found that the progressive detubulation of pig ventricular myocytes maintained in culture is paralleled by the lost of synchrony of the SR Ca2+ release process as indicated by the increase in the number and size of the areas showing delayed Ca2+ release. Both the lack of decrease in SR Ca2+ content and of changes in calcium current in this model cannot explain the dyssynchrony of Ca2+ release, which reflects rather the progressive depletion in T-tubules. The authors then used this model of progressive T-tubule loss to address the unresolved question of the mechanisms underlying EC coupling defects in the failing myocardium.
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4. Is there a reduction of T-tubules in the failing human myocardium? |
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Top1. Introduction2. T-tubules synchronize Ca2+...3. Cellular models to...4. Is there a...5. Conclusion and perspectivesReferences |
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In cardiopathies, the EC coupling process is altered, with slow and prolonged Ca2+ transients being the main feature. Although compelling results indicate a depressed SR function in failing myocardium [12], a simple decrease in SR Ca2+ uptake cannot entirely explain the prolongation of the Ca2+ transients in myocytes from failing myocardium [13].
Recently, the role of abnormalities in the cross-signaling between calcium channels and RyRs in the defective EC coupling during CHF has become a focus of particular interest [14–17]. One of the most exciting ideas is that geometric changes in the dyadic cleft could impair the CICR [14]. However, contradictory results exist as to the conditions of the T-tubules in cardiopathies. T-tubule density increases in rat cardiac hypertrophy [18], while it decreases in the model of doxorubicin-induced cardiomyopathy.[19] In canine tachycardia-induced dilated cardiopathy, there is also 
50% T-tubule depletion [20,21]. Data from human hearts are sparse. In dilated and hypertrophied human heart, T-tubules are aberrantly shaped and dilated [22,23], while preliminary studies have found a decrease [24] or no change [25] in T-tubules in failing human hearts. This discrepancy between studies may be explained by species specificities in T-tubule development, the heterogeneity of the cardiopathies studied, and by differences in the approach used to quantify T-tubule density.
An original and alternative approach to address this question is proposed in the manuscript of Louch et al. [1] The authors used the relationship between the degree of detubulation and asynchrony of Ca2+ release in cultured pig myocytes as a scale to characterize the T-tubular network and the SR Ca2+ release process in failing human ventricular myocytes. One advantage of this approach is that it overcomes the difficulty of obtaining human ventricular myocytes from control hearts. They found that T-tubule density and the synchrony of Ca2+ release in failing human ventricles more closely resemble freshly isolated pig myocytes than 2-day cultured cells. Assuming that the pig myocyte is a good model of EC coupling in the human heart, these results suggest that detubulation and asynchronous Ca2+ release is not an important mediator of the defective EC coupling in end-stage heart failure.
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5. Conclusion and perspectives |
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Top1. Introduction2. T-tubules synchronize Ca2+...3. Cellular models to...4. Is there a...5. Conclusion and perspectivesReferences |
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As outlined by the authors, other studies are required to establish the role of changes in T-tubules in EC coupling defects during heart failure. For instance, severe alterations in ventricular myocyte ultrastructure have been observed in only one third of cells from failing human hearts, the remaining being normal [22]. This ratio may be aggravated after enzymatic isolation procedures that may yield predominantly healthy myocytes. Consequently, the few myocytes that can be isolated and studied from a small cardiac specimen may not be representative of the different myocyte populations of the ventricular wall. Moreover, detubulation of cardiac cells may predominate in distinct pathological areas such as the border zone of myocardial infarction or the hibernating myocardium [26]. It is also likely that even a small percentage of myocytes with T-tubule loss and asynchronous Ca2+ release may have a marked impact on cardiac contractility or arrhythmias. Nevertheless, the study of Louch et al. [1] is a significant contribution to the field of local control of EC coupling and provides a means of analyzing the functional consequences of progressive and small alterations of the T-tubular network on EC coupling in cardiac myocytes.
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References |
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Top1. Introduction2. T-tubules synchronize Ca2+...3. Cellular models to...4. Is there a...5. Conclusion and perspectivesReferences |
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