Dynamic Regulation of Sodium/Calcium Exchange Function in Human Heart Failure

Weber, Christopher R.; Piacentino, Valentino; Houser, Steven R.; Bers, Donald M.

doi:10.1161/01.cir.0000095274.72486.94

Cited by 141 publications

(99 citation statements)

References 32 publications

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“…The experimental observations shown in the inset of Figure 2 (panel A) taken from reference [5], show the variability of the APD in failing myocytes from human hearts, which falls within the simulated values of APD observed. Figure 2B depicts an altered [Ca 2+ ] i transient under HF conditions, as has been documented experimentally and is shown in the inset [31]. Indeed, diastolic [Ca 2+ ] i is slightly increased, whereas peak systolic [Ca 2+ ] i is reduced to 41% of the one observed during normal conditions.…”

Section: Introductionsupporting

confidence: 66%

Influence of heart failure on nucleolar organization and protein expression in human hearts

Roselló‐Lletí¹,

Rivera²,

Cortés³

et al. 2012

Biochemical and Biophysical Research Communications

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Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na + current (I NaL ) is relevant and is currently under investigation. In this study we examined the role of I NaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I NaL . A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I NaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I NaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca 2+ transient. A mechanistic investigation of intracellular Na + accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na + / K + pump, the Na + /Ca 2+ exchanger and I NaL . The results of the simulations also showed that in failing myocytes, the enhancement of I NaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I NaL prolong APD and alter Ca 2+ transient facilitating the development of early afterdepolarizations. An enhanced I NaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca 2+ ] i homeostasis of failing myocytes.

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Section: Introductionsupporting

confidence: 66%

Influence of heart failure on nucleolar organization and protein expression in human hearts

Roselló‐Lletí¹,

Rivera²,

Cortés³

et al. 2012

Biochemical and Biophysical Research Communications

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“…Physiological Relevance of Dual Cytosolic Ca 2ϩ and pH Sensing-Our work and that of others suggest that NCX is activated allosterically by Ca 2ϩ as [Ca 2ϩ ] i rises (6,15,20,31). The details of this allosteric process are still not fully resolved.…”

Section: Discussionmentioning

confidence: 64%

“…1) and off-line analysis of the currents (Fig. 2) were based upon the approach of Weber et al (15,20). After break-in and again before any repetition of the protocol, the cells were held at E m of Ϫ100 mV for 3-5 min to facilitate Ca 2ϩ efflux via inward I NCX , resulting in low initial [Ca 2ϩ ] i .…”

Section: Overexpression and Purification Of Cbd1 Cbd2 And Cbd12mentioning

confidence: 99%

Proton-sensing Ca2+ Binding Domains Regulate the Cardiac Na+/Ca2+ Exchanger

Boyman

Hagen

Giladi

et al. 2011

Journal of Biological Chemistry

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“…During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212]. In this context, the elevation of [Na + ] i in cardiac failure and hypertrophy may be regarded as a beneficial and compensatory mechanism [94].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

“…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 [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212] Are defects in EC coupling linked to energy starvation in heart failure?Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”

mentioning

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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Dynamic Regulation of Sodium/Calcium Exchange Function in Human Heart Failure

Abstract: Background-Sarcolemmal

Cited by 141 publications

References 32 publications

Influence of heart failure on nucleolar organization and protein expression in human hearts

Influence of heart failure on nucleolar organization and protein expression in human hearts

Proton-sensing Ca2+ Binding Domains Regulate the Cardiac Na+/Ca2+ Exchanger

Excitation-contraction coupling and mitochondrial energetics

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