Relationship Between Na
            <sup>+</sup>
            -Ca
            <sup>2+</sup>
            –Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium

Hasenfuß, Gerd; Schillinger, Wolfgang; Lehnart, Stephan E.; Preuß, Michael; Pieske, Burkert; Maier, Lars S.; Prestle, J.; Minami, Kazutomo; Just, Hanjörg

doi:10.1161/01.cir.99.5.641

Cited by 376 publications

(299 citation statements)

References 31 publications

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“…This is an obvious departure from previously published studies of HF in human patients21 or animal studies, of which large animal models utilizing dogs or rabbits have been thought to provide the most clinically useful replacements 11. Nonetheless, although large animal models present with important similarities to humans, for example, with respect to excitation contraction coupling and contractile mechanisms, they also differ with respect to aetiology and have been reported to differ in aspects of cardiac function and response to injury;52, 53, 54 see also the review by Hasenfuss 11…”

Section: Discussionmentioning

confidence: 99%

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

et al. 2018

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AimsCellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end‐stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post‐myocardial‐infarction (MI) patients at mid‐stage of HF.Methods and resultsNine MI patients and eight control patients without MI (non‐MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non‐MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca2+ handling with more spontaneous Ca2+ release events, increased diastolic Ca2+, lower Ca2+ amplitude, and prolonged time to diastolic Ca2+ removal in MI (P < 0.01). Significantly reduced transverse‐tubule density (−35%, P < 0.01) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) function (−26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine‐16 and threonine‐17 in MI provides further mechanisms to the reduced function.ConclusionsDepressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid‐stage of post‐MI HF.

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Section: Discussionmentioning

confidence: 99%

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

et al. 2018

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“…Furthermore, β-adrenergic activation decreases the energetic economy of contraction in human failing myocardium [83]. An elevation of stimulation frequency increases diastolic tension (and reduces systolic force) in failing myocardium with decreased SR Ca 2+ -ATPase expression and a lack of upregulation of the NCX [85]. Diastolic force development, however, is occurring at the same energy expenditure as systolic force generation in human failing myocardium [132].…”

Section: Discussionmentioning

confidence: 99%

“…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], lead to a smaller and more dyssynchronous SR Ca 2+ release during an AP, resulting in slower rates of increase and decay of [Ca 2+ ] c , but higher diastolic [Ca 2+ ] c compared to normal cardiac myocytes [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], since pronounced forward mode I NCX may maintain diastolic function [85] by removing Ca 2+ to the extracellular space. On the other hand, this pronounced forward mode I NCX may further aggravate SR Ca 2+ depletion, since inhibition of I NCX with an inhibitor peptide (XIP [118]) restored SR Ca 2+ load in failing myocytes [91].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

218

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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“…While it is correct that NCX upregulation is interpreted as a compensatory mechanism, there are consequences to it that are not beneficial at all. Upregulation of NCX is one of the mechanisms in heart failure that reduces the SR content and thus contractility [21,22]. Upregulation of NCX is also seen as one of the major mechanisms contributing to the increased susceptibility to arrhythmias in heart failure [23,24].…”

Section: Does An Increase In Ncx Activity Have a Positive Inotropic Amentioning

confidence: 99%

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

Antoons

Sipido

2009

Cardiovasc Drugs Ther

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Relationship Between Na ⁺ -Ca ²⁺ –Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium

Cited by 376 publications

References 31 publications

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

Excitation-contraction coupling and mitochondrial energetics

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

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Relationship Between Na + -Ca 2+ –Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium

Cited by 376 publications

References 31 publications

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

Excitation-contraction coupling and mitochondrial energetics

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

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Product

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Relationship Between Na ⁺ -Ca ²⁺ –Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium