Reduced synchrony of Ca2+ release with loss of T-tubules—a comparison to Ca2+ release in human failing cardiomyocytes

Louch, William E.

doi:10.1016/j.cardiores.2003.12.031

Cited by 272 publications

(287 citation statements)

References 39 publications

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“…1 and 2). In contrast, with prolonged T-tubule loss, the cellular region becomes unresponsive to either EC-coupling or the synchronising inotropic effects of ␤-adrenergic stimulation [47,48].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

et al. 2010

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a b s t r a c t Narrow, tubular, inward projections of the sarcolemma ('T-tubules') are an established feature of adult mammalian ventricular myocytes that enables them to generate the whole-cell Ca 2+ transients and produce coordinated contraction. Loss of T-tubules can occur during ageing and under pathological conditions, leading to altered cardiac excitation-contraction coupling. In contrast to adult ventricular cells, atrial myocytes do not generally express an extensive T-tubule system at any stage of development, and therefore rely on Ca 2+ channels around their periphery for the induction of Ca 2+ signalling and excitation-contraction coupling. Consequently, the characteristics of systolic Ca 2+ signals in adult ventricular and atrial myocytes are temporally and spatially distinct. However, although atrial myocytes do not have the same regularly spaced convoluted T-tubule structures as adult ventricular cells, it has been suggested that a proportion of adult atrial cells have a more rudimentary tubule system. We examined the structure and function of these atrial tubules, and explored their impact on the initiation and recovery of Ca 2+ signalling in electrically paced myocytes. The atrial responses were compared to those in adult ventricular cells that had intact T-tubules, or that had been chemically detubulated. We found that tubular structures were present in a significant minority of adult atrial myocytes, and were unlike the T-tubules in adult ventricular cells. In those cells where they were present, the atrial tubules significantly altered the on-set, amplitude, homogeneity and recovery of Ca 2+ transients. The properties of adult atrial myocyte Ca 2+ signals were different from those in adult ventricular cells, whether intact or detubulated. Excitation-contraction coupling in detubulated adult ventricular myocytes, therefore, does not approximate to atrial signalling, even though Ca 2+ signals are initiated in the periphery of the cells in both of these situations. Furthermore, inotropic responses to endothelin-1 were entirely dependent on T-tubules in adult ventricular myocytes, but not in atrial cells. Our data reveal that that the T-tubules in atrial cells impart significant functional properties, but loss of these tubular membranes does not affect Ca 2+ signalling as dramatically as detubulation in ventricular myocytes.

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Section: Discussionmentioning

confidence: 99%

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

et al. 2010

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“…A major deficit in failing myocytes is the reduced Ca 2+ content of the SR, which is related to decreased expression and activity of the SR Ca 2+ -ATPase [84,92,146,153] and an increased Ca 2+ leak of the RyR2 due to hyperphosphorylation [84,94,112,122]. These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184] [17,81,113,115,146,184]. Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na …”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

214

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…(Pieske et al, 2002) Finally, it is possible that other changes associated with abnormal RyR function can impact calcium transient alternans. For example, detubulation, (Louch et al, 2004) disruption of the regular organization of transverse tubules, ) and a leaky RyR. (Lehnart et al, 2006) may desynchronize calcium release in ventricular cells and promote the development of alternans.…”

Section: Mechanisms Of Calcium Transient Alternans: Sr Calcium Releasementioning

confidence: 99%

Cellular mechanisms of arrhythmogenic cardiac alternans

Laurita

Rosenbaum

2008

Progress in Biophysics and Molecular Biology

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Mechanical dysfunction remains as one of the best predictors of sudden cardiac death (SCD), but despite this close association the causal relationships between electrical instability and mechanical dysfunction are not fully understood. (Bigger et al., 1984;Buxton et al., 1984) Even though the effects of electrical instability on mechanical dysfunction of the heart is well appreciated and relatively clear, the reverse effects that mechanical dysfunction have electrical instability, or mechano-electrical feedback (MEF), are not. (Kohl et al., 2006;Lab, 1996) Stretch activated channels, for example, are one way mechanical activity can directly influence electrical activity at the cellular level under physiologic and pathophysiological conditions. (Hu et al., 1997) Alternatively, intracellular calcium, which regulates mechanical contraction, can significantly influence electrical function of the heart as well. The mechanisms by which intracellular calcium governs electrical instability of the heart is the main focus of this manuscript. Traditionally, calcium mediated arrhythmogenesis is associated with delayed after depolarizations and abnormal impulse formation. (Katra et al., 2007;Liu et al., 2006;Rosen, 1985;Ter Keurs et al., 2006;Wehrens et al., 2003) However, in this manuscript we focus on how cardiac alternans, a mechanisms of reentrant excitation, is another significant way mechanical dysfunction and arrhythmogenesis are causally related.Cardiac alternans can refer to either mechanical (contractile) or electrical (repolarization) oscillations that occur on an every other beat basis. Cardiac alternans has been recognized for more than 100 years. Shown in Figure 1 (Panel A) is a very early record of arterial pressure measured during a steady state heart rate, where pulse magnitude alternates on every other beat (arrows). (Traube, 1872) At this time, the ECG had not been invented; however, soon after its introduction electrical alternans was reported as well. Shown in Panel B (Figure 1) is an early example of electrical alternans as evidenced by oscillations of the ECG T-wave (arrows) and QRS. (Lewis, 1910) Soon after cardiac alternans was first reported, it was associated with a poor prognosis. (Windle, 1913) Surprisingly, at this same time several important characteristics of cardiac alternans were observed, such as alternans occurring in a structurally normal heart and appearing at faster heart rates. Subsequently, Twave alternans was more directly related to coronary artery occlusion and shown to be highly reproducible. (Hellerstein et al., 1950)

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Reduced synchrony of Ca2+ release with loss of T-tubules—a comparison to Ca2+ release in human failing cardiomyocytes

Abstract: Loss of T-tubules reduces the synchrony of SR Ca2+ release. This could contribute to reduced efficiency of excitation-contraction coupling in heart failure, though dyssynchrony in human failing cells appears to be modest.

Cited by 272 publications

References 39 publications

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

Excitation-contraction coupling and mitochondrial energetics

Cellular mechanisms of arrhythmogenic cardiac alternans

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