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Cardiovascular Research 2003 57(4):921-933; doi:10.1016/S0008-6363(02)00826-X
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Copyright © 2003, European Society of Cardiology

Relevance of Na+–Ca2+ exchange in heart failure

Wolfgang Schillingera, Jan W Fioletb, Klaus Schlotthauera and Gerd Hasenfussa,*

aHerzzentrum Göttingen, Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
bExperimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam and the Interuniversity Cardiology Institute of the Netherlands, Amsterdam, The Netherlands

* Corresponding author. Tel.: +49-551-39-6351; fax: +49-551-39-6389. hasenfus{at}med.uni-goettingen.de

Received 23 September 2002; accepted 27 November 2002

KEYWORDS Arrhythmia (mechanisms); Contractile function; Heart failure; Na/Ca-exchanger; Sarcolemma


   1. Introduction
Top
 1. Introduction
2. Molecular physiology of...
 3. NCX expression and...
 4. NCX and excitation...
 5. NCX and arrhythmias...
 6. Summary
 References
 
Sarcolemmal Na+–Ca2+ exchange plays a pivotal role in ion transport of the myocardium which is crucial for cardiac contractile performance. The driving force of the exchanger molecule depends on sodium and calcium concentrations at either side of the plasma membrane and on the membrane potential. Section 2 of this article aims to review structural and thermodynamic aspects of the Na+–Ca2+ exchanger and its function. Recently, it has been recognized that Ca2+ as well as Na+ homeostasis is impaired in the failing myocardium. Thus, it has been postulated by numerous authors that Na+–Ca2+ exchanger may be altered with respect to expression and function. However, the literature is controversial. Section 3 comments upon a number of recent publications that have been published on this topic. Section 4 summarizes functional consequences of altered expression and function of the exchanger with respect to excitation–contraction coupling which have to be considered with the concomitant changes of other important Ca2+ cycling proteins such as sarcoplasmic reticulum Ca2+-ATPase, phospholamban, and ryanodine receptor. Finally, besides contractile dysfunction in hypertrophy and heart failure, cytoplasmic Ca2+ overload can induce spontaneous SR Ca2+ release. This Ca2+ is partly removed from the cytoplasm by Na+–Ca2+ exchange generating transient inward currents, which were blamed for provoking arrhythmogenic, delayed afterdepolarizations. We have dedicated section 5 to recent literature and clinical studies that may elucidate the role of Na+–Ca2+ exchange in arrhythmogenesis.


   2. Molecular physiology of Na+–Ca2+ exchange
Top
 1. Introduction
 2. Molecular physiology of...
3. NCX expression and...
 4. NCX and excitation...
 5. NCX and arrhythmias...
 6. Summary
 References
 
2.1 Isoforms, expression, structure and regulation
Besides the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA), the sarcolemmal Na+–Ca2+ exchanger (NCX) is the most important Ca2+ transport protein responsible for maintaining the Ca2+ balance of the myocyte. Molecular aspects of its function have been subject to extensive recent reviews [1–5]. We therefore sought to keep the following section short. The exchange protein catalyzes the countertransport of Na+ and Ca2+ ions and can be found in the membranes of many different tissues. The NCX family is comprised of three isoforms [6–8]. The cardiac specific isoform is designated NCX1 which can be abundantly found in the sarcolemma of the heart. NCX proteins have been cloned and the molecular mass of the cardiac NCX1 isoform has been calculated as 110 kDa. NCX1 consists of 970 amino acids [6], 32 amino acids are cleaved off during processing such as the mature protein is 938 amino acids long [9]. In SDS polyacrylamide gels, the exchanger molecule forms diverse bands with apparent molecular weights of 120 and 70 kDa. The latter is believed to consist a proteolytic fragment of the 120-kDa protein. In addition, faint bands in the range of 40, 140 and 160 kDa have been also described [10–12].

Recent topological studies suggested that the exchange protein is comprised of nine transmembrane helices (TMs) with connecting loop regions and a large cytoplasmic hydrophilic domain between TM 5 and 6 [13–15]. Site-directed mutagenesis studies have suggested that TMs 2 and 3 and TMs 7 and 8 together with their connecting loops participate in the formation of the ion translocation pathway in NCX1. These regions contain highly conserved sequences (termed {alpha}-repeats) throughout the whole NCX family [5,14,15]. To date, only few information is available regarding ion-binding and conformational changes of the molecule during ion transport.

The large cytoplasmic loop is believed to contain the regulatory sites of the exchange protein. Regulation is achieved by a variety of extracellular and intracellular factors. However, the exact mechanisms are incompletely understood and require further investigations (for reviews, see Refs. [1–5]). Internal repeat motifs have been identified in the central loop (termed β-repeats) which are highly conserved in the NCX family and were suggested to participate in a high-affinity Ca2+ binding regulatory site. Binding of Ca2+ to this site is important for both the Ca2+ influx and the efflux mode and might involve substantial conformational changes of the protein upon binding or removal of Ca2+ [16]. Regulatory sites have been identified which bind Ca2+ from the cytoplasmic side and Na+ from the external side. These sites are distinct from the transport sites. Thus, Na+ and Ca2+ ions consist both transport substrate and modulator of the exchange activity. In addition, pH and PKC-dependent effects exhibit regulatory action on the exchange activity (reviewed in Refs. [1–5]).

During cardiogenesis, the expression of the NCX occurs early before the onset of ventricular light chain 2 expression and before the heart starts beating [17]. The expression culminates briefly before birth and then continuously decreases until a lower level is reached in the adult heart. In contrast, expression of the sarcoplasmic reticulum Ca2+-ATPase is low in the fetal heart and increases until highest levels are reached in the adult heart. Thus, during normal cardiac development, reciprocal changes in expression of sarcolemmal NCX and SERCA occur [18,19]. As a consequence cyclic changes in [Ca2+]i during contraction–relaxation of the contractile apparatus mainly occur by Ca2+ fluxes via the sarcolemma in fetal hearts and by sarcoplasmic Ca2+ uptake and release in the adult heart. Thyroid hormone seems to consist a regulatory factor in the reciprocal expression of both genes during development changes [20].

2.2 Thermodynamics, flux and beat to beat activity
NCX has been identified for decades as the major pathway for extrusion of calcium from the cardiac cell and recognized for its pivotal role in calcium homeostasis and SR calcium handling on a beat to beat basis [5,21,22]. It catalyzes the transport of calcium across the membrane in exchange for sodium in a reversible manner, depending on the direction of its driving force, by convention called ‘forward’ when sodium is transported inward and calcium outward and ‘reversed’ when ions are transported in the opposite directions. Reversed mode operation might contribute to excitation contraction coupling and is implicated in arrhythmogenesis particularly in pathophysiological conditions.

The driving force of NCX (ENCX) is a function of the trans-sarcolemmal electrochemical potential differences of sodium and calcium and the stoichiometric transport ratio, generally assumed to be 3 Na+:1 Ca2+ [1] although some recent reports indicate 2:1 [23] or 4:1 [24,25]. NCX is electrogenic and carries inward (depolarizing) current in forward mode and outward (repolarizing) current in reversed mode. The magnitude of ENCX follows from thermodynamic evaluation of the respective electrochemical potentials:

Formula
in which ENa (=RT/F ln([Na+]o/[Na+]i) and ECa (=RT/2F ln([Ca2+]o/[Ca2+]i) are the respective Nernst potentials for Na+ and Ca2+, Em the membrane potential and r the stoichiometric ratio.

Maintenance of ENCX in a non-equilibrium steady state requires the continuous input of energy, which builds the electrochemical potential of Na+ by means of the Na/K-ATPase. Therefore, NCX mediated calcium homeostasis ultimately depends on the free energy available from ATP hydrolysis.

Regarding the dependence of ENCX on ion concentrations, it is of importance to note that concentration gradients may extend from a subsarcolemmal ‘fuzzy’ space to the bulk cytoplasm for [Ca2+] [26–31] and for [Na+] [32–35]. The concentrations actually ‘felt’ by NCX are of thermodynamic relevance. To appreciate the impact of spatial concentration gradients on ENCX, it is of importance to realize first, that it is ion activity rather than concentration that thermodynamically matters, and second, that spatial gradients of activity coefficients may be present as well due to sub-membrane abundance of fixed negative charges and the physical properties of ‘structured’ water; such considerations are quantitatively even more pertinent for divalent cations than monovalent cations. It may be speculated that spatial gradients of activity coefficients (partly) compensate for ion concentrations gradients thermodynamically.

The flux through NCX (JNCX) is the product of a ‘conductivity’ (g) and ENCX (JNCX=g·ENCX). This expression stresses the linear dependence of JNCX on ENCX, but does not implicate that NCX behaves as an Ohmic conductor. In fact, the steady state relation between JNCX and ENCX is fundamentally non-linear at either side of the reversal potential [36]. This follows from the fact that the ‘conductivity’ is a complex non-linear function of many variables: binding affinities of reactants at either side of the membrane, Em, regulatory mechanisms such as PKC and PKA dependent signaling, protein phosphorylation, free radicals, ATP, pH and temperature [5]. The affinity for intracellular [Ca2+]i is in the µmolar range, more than two orders of magnitude larger than for [Ca2+]o, while that for intracellular [Na+]i is around 10–20 mmol/l, about 4–5 times less than for [Na+]0. Apart from the substrate binding sites there is rapid (within milliseconds) allosteric regulation by [Ca2+]i with a kd around 125 nmol/l [31] and time dependent inactivation at high [Na+]i [37]. The latter may be of relevance in pathological conditions of much increased [Na+]i such as ischemia or end stage heart failure [38,39].

JNCX, usually measured as membrane current, is a surface related two-dimensional entity (pA/pF). Ion activities are volume related three-dimensional entities. Therefore, the relation between JNCX and the associated change of ion activities not only depends on the level of NCX protein expression, around 300 per µm2 in ventricular myocytes [40], but also on the surface to volume ratio. This is of relevance not only to appreciate the functional effects of the different degree of NCX expression in embryonic and adult cell types, but also of the functional consequences of up-regulation of NCX in over-expression systems [41–43] and in hypertrophy and heart failure with substantially altered cell dimensions [12,44]. Upregulation of NCX would seem to be required to maintain calcium homeostasis when surface to volume ratio decreases.

Steady state considerations require that time averaged [Ca2+]i and [Na+]i are constant, that time averaged ENCX is constant and that time averaged JNCX balances all NCX and L-type calcium channel carried calcium influx. However, on a beat to beat basis substantial dynamic changes of ENCX occur during the cardiac cycle. In steady state, bulk [Na+]i is constant on a beat to beat basis. Therefore, dynamic changes of ENCX during the cardiac cycle mainly result from changing Em during the action potential and from changing [Ca2+]i during SR calcium release, re-uptake and diastole. Little quantitative information is available on the actual change of sub-sarcolemmal activities of Ca2+ and Na+ (intra- and extracellular!) in non-dialyzed cells, and quantification of the dynamic change of ENCX and of the forward and reversed mode contributions to time averaged JNCX is hampered.

Although there is evidence for the existence of subsarcolemmal sodium gradients [45], the dynamic changes of [Na+]i are probably small on a beat to beat basis [46] and bulk [Na+]i data may be conveniently used to calculate ENCX. Regarding calcium the situation is different. Calcium is released from SR in near membrane areas of junctional SR with co-localized NCX, L-type calcium and SR calcium release channels and localized changes of Ca2+activity are more rapid and of larger amplitude than in bulk cytoplasm [28,30,47]. Re-uptake in SR by SERCA2 is de-localized and spatial Ca2+ activity gradients may well persist during steady state. Indeed, studies on single SR calcium release channels indicate that open probability of the channel is regulated by [Ca2+] at the cytoplasmic side in the µmolar range [48] rather than the sub-µmolar range usually measured in bulk cytoplasm during the calcium transient. This implicates uncertainty regarding the dynamic change of ENCX when calculated from dynamic changes of bulk cytoplasmic [Ca2+]i.

Action potential configuration and heart rate affect the relative contributions of reversed and forward mode operation of NCX during the cardiac cycle. Prolongation of action potential duration prolongs reversed mode NCX activity during the plateau phase and shortens forward mode operation during repolarization and diastole (for reviews, see Refs. [47,49]). Increasing heart rate prolongs forward mode during diastole relative to reversed mode during the action potential [50]. Reversed mode ENCX during the action potential implicates a potential contribution of NCX to excitation contraction coupling (CICR). Whether or not the contribution to CICR is of physiological importance depends on the magnitude and duration of reversed mode ENCX. So far there is no consensus on this, at least quantitatively. Recent model studies include larger and more persistent reversed mode NCX current during most of the plateau phase of the action potential [51,52] than older models [53]. In experimental studies, estimates for the contribution of NCX to CICR in ‘normal’ physiological conditions range from negligible [54] to measurable [55] and to 25% or even 100% depending on [Na+]i [56]. [Na+]i substantially modifies the dependence of ENCX on action potential configuration and heart rate. With increasing [Na+]i reversed mode ENCX becomes more prominent during the action potential, and forward mode ENCX becomes reduced during diastole. Reduced forward mode ENCX causes elevation of diastolic [Ca2+]i, which affects SR calcium loading and, consequently, SR release kinetics [48,57] and in turn the dynamic changes of ENCX during the cardiac cycle. All of this is most relevant to the pathophysiology of heart failure in which [Na+]i is substantially elevated [38,39,58] and ENCX is shifted to more positive values [59].


   3. NCX expression and function in hypertrophy and failure
Top
 1. Introduction
 2. Molecular physiology of...
 3. NCX expression and...
4. NCX and excitation...
 5. NCX and arrhythmias...
 6. Summary
 References
 
The expression and function of the NCX in hypertrophy and heart failure have been extensively investigated, but are still controversial. The first early studies in the human heart by Studer et al. [11] investigated myocardial samples from patients with end-stage heart failure and found a ~2-fold increase in mRNA and protein levels compared to healthy control subjects. Increased expression and function have also been reported by other groups [60,61]. In contrast, with respect to SERCA for which reduced protein levels and reduced activity have been reported [11,62–66]. Thus, reciprocal expression of the two most important myocardial Ca2+ transport proteins may occur in the course of heart failure which apparently induce regression to a fetal gene program.

However, some authors analyzing myocardial samples of transplant recipients doubted the overexpression of the NCX in terminal heart failure [67]. Moreover, a study by Piper et al. analyzing myocardial biopsies from different stages of heart failure could not find a significant correlation between NCX mRNA and the clinical stage of heart failure [68]. After all, the concept of just overexpression of the NCX as a general feature in end-stage heart failure may be over-simplified as well as the concept of re-expression of a fetal gene program.

Recently, analyzing protein expression and function of isolated myocardial trabeculae from end-stage failing human hearts we could demonstrate a relationship between overexpression of the NCX and prevention of diastolic dysfunction in end-stage heart failure [12]. This observation lead to the concept of distinct phenotypes in heart failure regarding expression of NCX and to the question what kind of stimuli may underly the differential expression of Ca2+ regulatory proteins. Hypertrophy mostly is a response to mechanical stretch leading to induction of an early gene program and protein synthesis [69]. Kent and McDermott [70] demonstrated that passive stretch of unstimulated adult cat cardiomyocytes induced protein synthesis and increased the mRNA levels of the NCX. The authors demonstrated that this response could not be reproduced by treatment of the cells with angiotensin II and the stretch effect could not be blocked by AT1 receptor antagonists suggesting that induction of NCX overexpression occurred independently from autocrine stimulation by angiotensin II. In failing human myocardium, wall stress has been proposed to consist a major determinant for the expression of the SERCA whereas NCX may be expressed independently from wall stress [71].

Recently, our group identified sympathetic activation as a potential stimulus in the regulation of NCX expression in end-stage failing human hearts [72]. We investigated plasma norepinephrine levels in 23 patients suffering from end-stage heart failure that were scheduled for cardiac transplantation. NCX protein levels analyzed by Western immunoblot after cardiectomy exhibited a significant correlation with norepinephrine. This correlation seemed special and did not only reflect the severity of heart failure since other neurohumoral parameter (e.g. plasma renin activity, aldosterone, ANP, tumor necrosis factor-{alpha}) were not significantly correlated with NCX expression. Moreover, no correlation was found for SERCA with any other parameter (Fig. 1). The functional phenotype of hearts with increased NCX expression and elevated plasma norepinephrine was characterized by the occurrence of malignant ventricular arrhythmia (see Section 5). In accordance with our data, previous work had demonstrated that chronic stimulation with norepinephrine induced an overexpression of the NCX in the rat in vitro and in vivo [73–75]. Moreover, it has been reported that exposure to high extracellular Ca2+ and Na+ resulted in a significant increase in NCX mRNA levels in adult and neonatal myocytes [74,76].


Figure 1
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  		Fig. 1 Upper panel: plot showing correlation between plasma norepinephrine levels and Na+–Ca2+-exchanger protein levels in myocardial samples from 23 transplant recipients with end-stage heart failure. Lower panel: no significant correlation was found between plasma norepinephrine and myocardial SR Ca2+-ATPase protein levels. Protein levels were normalized to calsequestrin. Reproduced with permission from Ref. [72].

 
Expression and function of the exchanger protein was also investigated in animal models of heart failure. We shall briefly summarize the relevant studies and would like to refer the interested reader to an excellent recent review by Sipido et al. [47]: Studies investigating the effect of left ventricular pressure-overload produced marked left ventricular hypertrophy, but reported controversial results with respect to exchanger expression and activity. In the rat, abdominal aortic banding induced no significant change in mRNA and protein levels [77], whereas banding of the ascending aorta induced an ~2-fold increase in mRNA levels [78]. In mice, banding of the thoracic aorta induced an increase of mRNA and protein in two studies [79,80]. However, in the study by Wang et al. [79] Ni2+-sensitive NCX currents were decreased. An interesting observation was made in the study by Ito et al. [80]. The first 4 weeks of aortic banding in mice produced a hypertrophy stage without signs of heart failure. In this stage NCX expression was upregulated, but SERCA and phospholamban expression were unchanged. At week 7, when clinical signs of heart failure occurred NCX expression was still high, but now SERCA and phospholamban expression were downregulated.

Other authors investigated the effect of volume-overload. Ventricular tachycardia pacing with implanted pace-makers leads to heart failure without clear phase of functionally compensated hypertrophy. In the dog, this model of heart failure was associated with upregulation of NCX at the mRNA and protein level and downregulation of SERCA which resulted in an increased Ca2+ removal by NCX as a compensatory mechanism [81]. In contrast, the same methodical approach in the rabbit was associated with downregulation of NCX mRNA and decreased SERCA activity [82] or unchanged NCX mRNA and protein levels (own unpublished data). Pogwizd et al. [44] used combined aortic insufficiency and aortic constriction to induce pressure–volume overload in the rabbit. This model consistently demonstrated upregulation of NCX at the mRNA, protein and current level (see Section 5).

Models investigating post-myocardial infarction hypertrophy and failure reported an increased NCX expression at the mRNA and protein level [83,84], but a decreased Na+-dependent Ca2+ uptake activity in sarcolemmal vesicles [85,86]. Lithwin and Bridge [87] investigating NCX currents in rabbits that underwent ligation of the circumflex branch of left coronary artery reported an increased outward current and an increased contribution of NCX current to SR Ca2+ loading. In these animals SR Ca2+ content was not significantly altered.

Taken together, although not consistently reported in all studies, an increased expression of the NCX is likely to consist a common feature in the course of heart failure. Of course, increased protein levels do not necessarily mean increased exchange activity. The functional consequences depend on multiple factors as discussed in the preceding section. The following sections aim to extrapolate these findings to the cellular level and to the intact beating heart in end-stage heart failure.


   4. NCX and excitation–contraction coupling in heart failure
Top
 1. Introduction
 2. Molecular physiology of...
 3. NCX expression and...
 4. NCX and excitation...
5. NCX and arrhythmias...
 6. Summary
 References
 
During the last decade, there was accumulating evidence that altered calcium homeostasis is of significant relevance for the pathophysiology of myocardial dysfunction and heart failure (for review, see Ref. [88]). First, it was observed that calcium transients and intracellular calcium cycling were considerably altered in the failing human heart. Beuckelmann et al. [89] observed reduced amplitude of calcium transients with reduced systolic calcium concentrations and increased diastolic calcium levels in isolated myocytes from end-stage failing human hearts. At the same time, using myothermal measurements, Hasenfuss et al. [90] observed that the amount and rate of heat liberation of excitation–contraction coupling processes is reduced in myocardial strip preparations from failing human hearts. The latter indicates reduced calcium cycling with decreased rates of sarcoplasmic reticulum calcium uptake in human heart failure [90]. Secondly, it was observed that disturbance of excitation–contraction coupling exaggerates at higher heart rates resulting in inversion of the force–frequency relation: at higher heart rates contractile force and cardiac output increase in nonfailing hearts whereas frequency potentiation of cardiac performance is depressed or inverted in heart failure [91,92].

The altered force–frequency relation in the failing heart was shown to result from altered calcium transients. Using the photoprotein aequorin, it was demonstrated that calcium transients increase with increasing stimulation rate in nonfailing, but decrease in failing human myocardium [93]. Furthermore, it was shown that, lack of frequency-dependent increase in calcium transients were the consequence of disturbed frequency-dependent upregulation of SR calcium load [94]. Thus, disturbed sarcoplasmic reticulum calcium accumulation and handling seem to be the major defect for disturbed excitation–contraction coupling in the failing human heart.

Three major factors seem to contribute to disturbed SR calcium accumulation in human heart failure: (1) increased leak of calcium through ryanodine receptors, (2) reduced SR calcium ATPase activity, and (3) increased transsarcolemmal elimination of calcium by NCX.

A defective regulation of the calcium release channel and increased SR Ca2+ loss in the failing human myocardium was recently suggested by Marx et al. [95]. Using cosedimentation and coimmunoprecipitation, they demonstrated that the calcium release channel complex is containing the ryanodine receptor, protein kinase A, protein phosphatases and the FK 506 binding protein FKBP12.6 [95]. In the failing heart the RyR was hyperphosphorylated by protein kinase A which dissociates FKBP12.6 from the channel resulting in increased sensitivity to Ca2+ induced activation, reduced conductivity and coupled gating, which may result in decreased efficiency of excitation–contraction coupling.

There is however some controversy regarding the functional relevance of RyRs hyperphosphorylation in heart failure. Recent studies using phospholamban knockout mice indicated that PKA-dependent RyR phosphorylation does not induce calcium leak and SR calcium release and that PKA-dependent effects on SR calcium release result from phospholamban phosphorylation with subsequent increased SR calcium load [96].

Calcium accumulation within the SR is a function of calcium availability to the SERCA, activity of the pump, calcium storage in the SR, and calcium leak from the SR. Calcium availability to the pump depends on intracellular calcium concentrations and alternative mechanisms to remove calcium from the cytosol. As a major alternative mechanism to SERCA, the sarcolemmal NCX in its forward mode must be taken into account. In this regard, the exchanger opposes the activity of SERCA to accumulate calcium and therefore, forward mode NCX may reduce SR calcium content, calcium release and systolic activation of contractile proteins (see below). On the other hand, both NCX and SERCA remove calcium from the cytosol for relaxation of the myofilaments. In this regard, both work in concert to facilitate diastolic relaxation of the myofilaments.

SERCA transports two calcium ions per molecule of hydrolyzed high-energy phosphate against a high ion gradient from a free intracellular calcium between 100 nmol/l and 1 µmol/l to a free calcium in the SR of ~1 mmol/l [4]. Sarco-endoplasmic reticulum Ca2+-ATPases are encoded by three genes and five different isoforms are expressed: SERCA2a is the isoform expressed in the heart (for review, see Ref. [97]). No isoform shift has been detected in the failing heart [98].

SERCA is regulated by phospholamban [99,100]. Dephosphorylated phospholamban is an inhibitor of the SERCA activity. It has been recognized that phosphorylation of phospholamban by calcium/calmodulin-dependent protein kinase (CaM kinase; Thr 17) and by protein kinase A (Ser 16) results in stimulation of SERCA [99,101].

Abundance of SERCA expression was studied in various animal models of myocardial failure (for review, see Ref. [102]) with various findings. In failing human myocardium all studies on SERCA mRNA published by now have reported that mRNA levels are reduced in the failing compared to the nonfailing human heart (for review, see Ref. [97]). Consistently, it was shown that SR calcium uptake or SERCA activity are reduced in the failing human myocardium [62,65]. However, some controversy exists whether SERCA expression is also reduced on the protein level (for review, see Ref. [88]). Interestingly, it was shown that SERCA protein levels were significantly reduced in failing but not in compensated hypertrophied human myocardium although mRNA levels of SERCA were reduced both in hypertrophied as well as in failing human hearts [103].

Whether or not protein levels of SERCA and phospholamban were reduced in failing human cardiac tissue, the protein expression of SERCA relative to phospholamban was always diminished [64,104]. Because the stoichiometry of SERCA to phospholamban determines the level of pump inhibition (for review, see Ref. [105]), this finding may indicate that in the basal, low phosphorylated state, PLB-dependent inhibition of SERCA is more pronounced in failing compared to nonfailing human myocardium [106].

Of note, a significant correlation between SERCA protein levels and myocardial function, which was assessed by the force–frequency relation, has been found [63]. This analysis indicated that a wide variation exists in protein levels of SERCA within the group of failing hearts (protein levels differed by a factor of 4) and that this variation in protein levels matches with differences in myocardial function.

SR calcium accumulation depends on the activity of SERCA relative to transsarcolemmal calcium elimination by NCX. Assuming that the forward mode of NCX predominates and that protein levels correlate with activity, we calculated the ratio of NCX to SERCA protein levels in myocardium from endstage failing and nonfailing human hearts. This ratio was increased by a factor of 3 in endstage failing myocardium indicating a relative dominance of Na+–Ca2+ exchange over SR calcium accumulation (Fig. 2). An increase in this ratio could be caused by increased NCX-expression, by decreased SERCA expression, or by both mechanisms. Whether or not the Na–Ca exchange is upregulated in the presence of reduced SERCA activity should have marked impact on diastolic function. Therefore, hearts were differentiated according to their diastolic function [12]. This analysis resulted in identification of different phenotypes: (1) Endstage failing hearts with increased protein levels of NCX and unchanged SERCA levels (designated group I) and (2) endstage failing hearts with markedly decreased SERCA protein levels and unchanged NCX levels (designated group III). In group I, diastolic function is preserved because overall cellular capacity to eliminate cytosolic calcium is high. However, systolic function is impaired because SR calcium accumulation is depressed. In group III, both SR calcium uptake and global cytosolic calcium elimination are significantly reduced and therefore systolic as well as diastolic function is severely compromised (Group II hearts were intermediate with respect to protein expression and contractile function). Enhanced transsarcolemmal, relative to intracellular Ca cycling is most pronounced at high heart rates [94,107].


Figure 2
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  		Fig. 2 Upper panel: graph showing the ratio of Na+–Ca2+ exchanger to SR Ca2+-ATPase protein levels in human myocardial samples from transplant recipients with end-stage heart failure. Nonfailing myocardium from brain-dead organ donors whose hearts could not be used for transplantation due to technical reasons served as a control. According to their contractile function the hearts were divided into subgroups as detailed in the text. It can be seen that in end-stage failing myocardium the ratio of Na+–Ca2+ exchanger to SR Ca2+-ATPase is increased relative to control in all functional groups. Lower panel: graph showing Na+–Ca2+ exchanger protein levels normalized to calsequestrin (no differences between groups for calsequestrin). It is obvious that Na+–Ca2+ exchanger protein levels are significantly upregulated in group I compared to nonfailing myocardium and unchanged in group III. * P<0.05 versus nonfailing (ANOVA followed by Student–Newman–Keul's test); # P<0.05 versus group I (ANOVA followed by Student–Newman–Keul's test); {dagger} P<0.05 versus nonfailing (paired t-test) (Reproduced with permission from Ref. [12]).

 
To prove the concept that overexpression of NCX may depress SR calcium accumulation and systolic function, NCX was overexpressed in adult rabbit ventricular myocytes using adenoviral gene transfer. In these experiments it was shown that overexpression of NCX decreases calcium load of the sarcoplasmic reticulum (Fig. 3), decreases isotonic shortening and depresses the positive shortening frequency relation (Fig. 4), as it is seen in endstage failing hearts [108]. These findings of depressed myocyte performance due to NCX overexpression seem to be in contrast to studies in transgenic mice overexpressing NCX which did not develop signs of heart failure [109–111]. Terracciano et al. [110] showed that even in wild-type mice, there is a significant Ca2+ entry via reverse-mode NCX during rest and during the latter part of the Ca2+ transient. In transgenic NCX-overexpressing mice, reverse-mode Na+–Ca2+ exchange resulted in increased Ca2+ storage of the sarcoplasmic reticulum [110]. Discrepancies between myocytes from transgenic mice that overexpress NCX and NCX-transfected rabbit myocytes can be explained by significant differences in excitation–contraction coupling processes between the two species. Unlike in human, canine and rabbit myocardium, in small mammals with high heart rates (i.e. mice and rats), the action potential is short, the expression of NCX is low, and the [Na+]i concentration is high (see Ref. [4]). In particular, the latter condition favors Ca2+ entry by reverse-mode Na+–Ca2+ exchange in wild type animals, which may become even more pronounced in transgenic animals that overexpress NCX [112]. In accordance, we could demonstrate that the functional consequences of adenoviral overexpression of NCX in rabbit myocytes depends on the activity of the Na+–K+-ATPase, i.e. [Na+]i [113].


Figure 3
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  		Fig. 3 Left panel: original recordings demonstrating the effect of caffeine-‘puffs’ in β-galactosidase (LacZ)- and Na+–Ca2+ exchanger (NCX)-transfected myocytes. Representative experiments are shown. Myocytes were stimulated for 5 min at a stimulation frequency of 120 min–1 to ensure steady-state shortening and SR Ca2+ load. Then, caffeine was ‘puffed’ onto the cells resulting in large contractures. Right panel: bar graphs showing significant depression in fractional shortening of steady-state shortening myocytes and caffeine contractures in NCX- (n=45) compared to LacZ- (n=56) transfected myocytes. Under these conditions, steady-state shortening was 0.042±0.001 in LacZ- and 0.033±0.001 in NCX-transfected myocytes. # P<0.05 vs. LacZ-transfected myocytes. Reproduced with permission from Ref. [108].

 

Figure 4
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  		Fig. 4 Graph showing the influence of stimulation frequency on fractional shortening in isotonically contracting cultured rabbit ventricular myocytes 48 h after transfection of Na+–Ca2+ exchanger (NCX)- (n=27) and β-galactosidase (LacZ)-cDNA (n=26), respectively. In both types of myocytes, there was a frequency-dependent increase in FS up to 120 min–1. While frequency–potentiation in LacZ-transfected control myocytes was steep and FS further increased up to 180 min–1, frequency–potentiation was flat in NCX-transfected myocytes and even reversed at stimulation rates above 120 min. * P<0.05 vs. FS at 30 min–1, # P<0.05 vs. LacZ-transfected myocytes. Reproduced with permission from Ref. [108].

 
Because the sodium level is higher in failing compared to nonfailing human myocardium, NCX is much closer to its reverse mode function promoting calcium influx. Accordingly it has been postulated from experiments in isolated myocytes from endstage failing human hearts that calcium influx via reverse mode NCX during the action potential may significantly contribute to the calcium transient or promote SR Ca loading with enhanced SR Ca release during subsequent depolarizations [114]. In this study by Dipla et al. [114], at low stimulation rates, a second tonic component of isotonic shortening myocytes occurred, associated with a second tonic component of the Ca2+ transient. However, an increase in the stimulation rate from 30 to 90 min–1 caused the action potential duration to decrease and the Ca2+ transients and contractions to shorten. Thus, only at stimulation rates when the action potential is sufficiently long may a tonic component of contraction result from reverse mode Na+–Ca2+ exchange in end-stage failing human myocardium. Furthermore, the recent observation that diastolic function of endstage failing human myocardium is closely related to NCX protein levels supports the hypothesis that under physiological conditions in endstage failing human myocardium the forward Na+–Ca2+exchange mode predominates with favorable effects on diastolic function and unfavorable effects on systolic function.

Because NCX is electrogenic resulting in a net inward current during forward mode calcium elimination, increased expression in endstage failing human myocardium may be associated with increased arrhythmias. Therefore, increased expression of NCX may reflect a link between myocardial dysfunction and increased incidence of arrhythmias in endstage heart failure (see below).

During the last years, several studies indicated that generation of oxygen free radicals is increased in heart failure and that this may be of relevance for the progression of the disease. Free radicals act on various subcellular system, however their action on excitation–contraction coupling processes seems to be of particular relevance. A recent study from our group [115] indicated that hydroxyl radicals induce diastolic dysfunction by calcium-dependent activation of contractile proteins. This could be prevented by inhibition of reversed mode sodium calcium exchange by KB-R 7943 [115] indicating that NCX may be significantly involved in free radical induced myocardial damage. To further investigate this, the effect of hydroxyl radicals were tested in rabbit myocytes overexpressing NCX. It could be shown that diastolic dysfunction is more pronounced in NCX overexpressing cells compared to control myocytes [116]. Furthermore, intracellular sodium was shown to increase following free radical exposure, and inhibition of sodium–proton exchange by cariporide partially reduced radical-induced diastolic dysfunction (own unpublished data). From these data it can be concluded that diastolic dysfunction induced by hydroxyl radicals may result from reverse mode sodium–calcium exchange subsequent, at least in part, to increased intracellular sodium and that increased exchanger levels, as present in failing human myocardium, may increase the sensitivity to free radical damage.


   5. NCX and arrhythmias in heart failure
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 1. Introduction
 2. Molecular physiology of...
 3. NCX expression and...
 4. NCX and excitation...
 5. NCX and arrhythmias...
6. Summary
 References
 
Apart from contractile dysfunction, heart failure is characterized by increased occurrence of ventricular arrhythmias and sudden cardiac death which is a major cause of mortality in heart failure [117]. Using 3-D cardiac mapping it could recently be demonstrated in a model of nonischemic heart failure in rabbits [118] and in human idiopathic dilated cardiomyopathy [119] that ventricular arrhythmias initiated by a non-reentrant mechanism. It has long been known that cytoplasmic Ca2+ overload can induce spontaneous SR Ca2+ release followed by transient inward currents, Iti, which were blamed for provoking arrhythmogenic, delayed afterdepolarizations (reviewed in Ref. [120]). Since the NCX is one of the major Ca2+ handling proteins and an electrogenic transporter by exchanging Na+ for Ca2+ its contribution to the Iti and membrane depolarization by spontaneous SR-Ca2+ release has been subject to several studies with species dependent results.

Pogwizd et al. [121] could demonstrate that the NCX plays a pivotal role in a combined aortic insufficiency and -constriction rabbit heart failure model by promoting on the one hand contractile dysfunction, on the other hand arrhythmogenesis. The increased propensity for triggered arrhythmias was the result of a 2-fold upregulated NCX (current, protein- and RNA-levels), downregulated inward-rectifying K+ current (IK1 by ~50%) and a preserved β-adrenergic responsiveness, allowing sufficient SR-Ca2+ loading to trigger spontaneous SR-Ca2+ release. Spontaneous SR-Ca2+ release evoked an increased inward current, being less opposed by the membrane stabilizing IK1, synergistically promoting action potential prolongation. Sipido and coworkers investigated a canine model of heart failure with chronic complete atrioventricular block. This model is characterized by biventricular hypertrophy and ventricular arrhythmias. The study reported an increased Ca2+ influx by reverse-mode Na+–Ca2+ exchange in isolated myocytes at low stimulation frequencies, which significantly contributes to SR Ca2+ load. This in turn may at the same time increase the propensity to cellular Ca2+ overload and contribute to arrhythmogenesis during spontaneous SR Ca2+ release [122].

In end-stage heart failure intracellular sodium concentrations have been shown to be increased [38,39,58]. This condition may contribute to SR Ca2+ load but may further increase the susceptibility to cellular Ca2+ overload by enhanced reverse-mode or diminished forward-mode Na+–Ca2+ exchange. Interestingly, a recent clinical multicenter study on the long-term effect of the Na+–K+-ATPase inhibitor digoxin on mortality in patients with heart failure had found that patients in the digoxin group had a significant excess of deaths from presumed arrhythmia while total mortality was unchanged because of reduced risk of death due to worsening of heart failure [123].

Recently, we could provide additional data from a clinical study performed with patients suffering from end-stage heart failure who were scheduled for cardiac transplantation [72]. Ca2+ cycling proteins of the explanted failing hearts were measured by Western blot analysis and the collected data were compared to findings in recent Holter ECGs (Fig. 5). We made the intriguing observation that patients with sustained or nonsustained ventricular tachycardia (≥3 consecutive beats, designated ‘high grade’ arrhythmia) had significantly higher Na+–Ca2+-exchanger protein levels compared with patients presenting a maximum of two consecutive ventricular beats (‘low grade’ arrhythmia). Furthermore, Na+–Ca2+-exchanger protein levels in the ‘high grade’ arrhythmia group were significantly higher compared to healthy controls whereas no significant differences were found for patients assigned to the ‘low grade’ arrhythmia group [72]. We were concerned that the relationship of the exchanger expression and the occurrence of arrhythmic events merely reflected the severity of heart failure. In other words, hearts from ‘low grade’ arrhythmia patients might be less severely failed than hearts from ‘high grade’ arrhythmia patients. To exclude this possibility we further measured several clinical and neurohumoral markers of heart failure in the two groups. However, the only significant difference could be found for plasma norepinephrine levels. Furthermore, comparing norepinephrine plasma levels with NCX expression as well as ventricular arrhythmic events revealed a positive correlation. Two conclusions might be drawn from these results: (1) The expression of NCX, norepinephrine plasma levels, and arrhythmia events seemed to be linked and are not simple the result of heart failure severity (see Section 3). (2) Although increased catecholamine levels may by itself increase automaticity of myocardium, induction of increased exchanger expression may at least partly explain the finding of fatal prognosis due to sudden cardiac death that has been associated with increased plasma norepinephrine [124].


Figure 5
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  		Fig. 5 Plots showing individual Na+–Ca2+ exchanger protein levels and plasma norepinephrine levels as well as mean values when patients with end-stage heart failure were divided into subgroups according the occurrence of ventricular arrhythmia in recent 24-h Holter ECGs as detailed in the text. Protein levels were normalized to calsequestrin. * P<0.05, # P<0.001. Reproduced with permission from Ref. [72].

 

   6. Summary
Top
 1. Introduction
 2. Molecular physiology of...
 3. NCX expression and...
 4. NCX and excitation...
 5. NCX and arrhythmias...
 6. Summary
References
 
Altered expression and activity of the sarcolemmal Na+–Ca2+ exchange protein may play a key role for altered contractile function and arrhythmogenesis in hypertrophy and heart failure. To date, a majority of studies reported increased expression and function of the exchanger in human heart failure as well as in animal models. Whether overexpression of the exchanger in heart failure may be beneficial or detrimental is still controversial. This is partially related to the fact that the functional consequences of an altered expression are hard to predict because altered expression does not necessarily mean altered function. Exchanger activity depends on its thermodynamic properties which depend on [Ca]i, [Na]i, and on the action potential predicting the operation mode of the exchanger. Assuming that forward-mode which is believed to be the preferred operation mode in the nonfailing myocyte promoting Ca2+ extrusion and Na+ entry would be increased in failing myocytes with increased NCX abundance in sarcolemmal membranes this might promote SR Ca2+ depletion and induce contractile systolic dysfunction. On the other hand, increased forward-mode activity might prevent cytoplasmic Ca2+ overload and preserve diastolic function. Vice versa, increased reverse-mode Na+–Ca2+ exchange with increased Ca2+ influx may contribute to sarcoplasmic reticulum Ca2+ load and may compensate for decreased expression and activity of SERCA. This in turn may be associated with increased spontaneous SR Ca2+ release followed by arrhythmogenic transient inward currents. Moreover, both operation modes may be increased depending on the phase of the action potential. After all, expression and activity of the exchanger in heart failure have to be considered with the concomitant changes such as alterations in intracellular Na+ or altered expression and activity of the SERCA which strongly impact on cytoplasmic Ca2+. Moreover, since distinct functional phenotypes with respect to NCX expression and function have been described we have to learn more about heterogeneity in heart failure. In this regard, it will be important to identify conditions and external stimuli that lead to induction of specific gene programs which presumably induce distinct functional phenotypes.

Time for primary review 21 days.


   Acknowledgements
 
This work was supported by the Deutsche Forschungsgemeinschaft, grant HA 1233/6-1 to Gerd Hasenfuss and by a grant of the Georg-August-Universität Göttingen to Wolfgang Schillinger.


   References
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 1. Introduction
 2. Molecular physiology of...
 3. NCX expression and...
 4. NCX and excitation...
 5. NCX and arrhythmias...
 6. Summary
 References
 

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