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(Circulation Research. 2000;87:529.)
© 2000 American Heart Association, Inc.

Editorial

Na⁺-Ca²⁺ Exchange in Failing Myocardium

Friend or Foe?

William H. Barry

From the Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City, Utah.

Correspondence to William H. Barry, MD, University of Utah Health Sciences Center, Division of Cardiology, 50 North Medical Dr, Salt Lake City, UT 84132. E-mail whbarry{at}med.utah.edu

Key Words: myocardium • Na⁺-Ca²⁺ exchange • sarcoplasmic reticulum

	Introduction

Top Introduction References

 
The Na⁺-Ca²⁺ exchanger (NCX) is a cation transporting protein present in the plasma membrane of animal cells. NCX transports three Na⁺ in exchange for one Ca²⁺ and thus is electrogenic; the function of the exchanger is controlled by the gradients for Na⁺ and Ca²⁺ across the cell membrane and membrane potential.¹ In normal cardiac myocytes, NCX plays an important role in Ca²⁺ homeostasis. NCX functions in a forward mode, in which Na⁺ enters the cell and Ca²⁺ is extruded. The rate of Ca²⁺ extrusion by NCX is much greater than by the sarcolemmal Ca²⁺ pump,² and Bridge et al³ have shown that NCX extrudes the amount of Ca²⁺ that enters the cell via the L-type Ca²⁺ channel as Ca²⁺ current, thus maintaining Ca²⁺ homeostasis on a beat-to-beat basis. As NCX extrudes Ca²⁺ and thus lowers Ca²⁺ from its peak, it contributes to relaxation in parallel with Ca²⁺ uptake by the sarcoplasmic reticulum (SR) Ca²⁺-ATPase.⁴ The extent to which NCX contributes to the decline of the Ca²⁺ transient varies between species,⁵ because the relative balance between the activities of these two Ca²⁺ removal systems is influenced by their level of expression, the [Na⁺]_i, and the duration of the action potential. In rats and mice, which have a high level of activity of the SR Ca²⁺-ATPase and a relatively high [Na⁺]_i, NCX is responsible for only 10% of relaxation. In rabbits, which have a lower [Na⁺]_i and SR Ca²⁺-ATPase activity, NCX contributes more significantly to the decline of the Ca²⁺ transient, especially during the terminal phase of the transient.⁶

NCX can also produce Ca²⁺ influx by operating in the reverse mode. Electrochemical considerations indicate that early after the upstroke of the action potential, before a rise in intracellular [Ca²⁺]_i occurs because of Ca²⁺-induced Ca²⁺ release, Ca²⁺ influx on the exchanger will occur.⁷ Ca²⁺ influx can also occur after decline of the [Ca²⁺]_i transient if the duration of the action potential is long. The magnitude of this influx is dependent on the magnitude and rate of rise of the [Ca²⁺]_i transient, the density of NCX in the sarcolemmal membrane, and the [Na⁺] adjacent to NCX in the subsarcolemmal space, which is influenced by the Na⁺ pump activity and I_Na as well as by the bulk cytosolic [Na⁺].⁸ The functional importance of reverse-mode NCX (Ca²⁺ influx) has been debated. This mode of NCX function has been proposed to increase the content of Ca²⁺ in SR,^{9 10 11} modulate the effectiveness of the L-type Ca²⁺ channel current in inducing Ca²⁺ release,^{12 13 14} and directly induce Ca²⁺ release,^{15 16 17 18} although other experimental work does not support a significant role for NCX-induced Ca²⁺ release in excitation-contraction (EC) coupling.^{19 20}

Recent work in which NCX activity has been increased or decreased in isolated myocytes has provided conflicting data regarding the physiological importance of Ca²⁺ influx via NCX. Studies in transgenic murine myocytes that overexpress the exchanger by 2.5-fold have indicated that rather than producing Ca²⁺ depletion, increased activity of NCX produces an increased diastolic Ca²⁺ influx and SR Ca²⁺ loading²¹ or an increase in Ca²⁺ influx during EC coupling, which contributes to the Ca²⁺ transient and can produce a reduced dependence on L-type Ca²⁺ channel current during EC coupling.¹⁴ On the other hand, Satoh et al²² reported that 5 µmol/L KBR-7943, an inhibitor of reverse-mode NCX, had no effect on the magnitude of the Ca²⁺ transient or contraction in rat myocytes. Yang et al²³ have reported that 5 µmol/L KBR-7943 decreases the [Ca²⁺]_i transient in rabbit myocytes. Although KBR effects at concentrations of >1 µmol/L could be attributable to an effect of the drug on L-type Ca²⁺ channels, Yang et al²³ also observed that submicromolar concentrations of KBR inhibited the increase in [Ca²⁺]_i transient induced by endothelin-1 and have suggested that this effect is attributable to inhibition of an endothelin-1–induced increase in reverse-mode NCX. Unpublished work from our laboratory has indicated that 5-µmol/L KBR-7943 also produces a small but significant decrease in the magnitude of the Ca²⁺ transient in mouse ventricular myocytes. Some of these differences in experimental results may relate to species-dependent variations in expression of NCX,²⁴ [Na⁺]_i, and action potential duration, factors that influence reverse-mode NCX. Thus, NCX in cardiac myocytes can function in both forward and reverse modes, although the physiological importance of Ca²⁺ influx on NCX remains somewhat controversial.

A thorough understanding of the mechanisms and importance of NCX function is important, because the activity of this transporter is altered in heart hypertrophy and failure. Experiments in several laboratories have shown that hypertrophy in animals is associated with a switch to a fetal pattern of gene expression,²⁵ including changes in actin and myosin isoforms, an increase in atrial natriuretic factor, a decrease in SR Ca²⁺-ATPase, and an increase in NCX expression. The possible functional importance of increased NCX expression and reduced SR Ca²⁺-ATPase activity has been studied in immature hearts and animal models of hypertrophy and failure. Haddock et al²⁶ and Chin et al²⁷ reported an apparent greater dependence on Ca²⁺ influx via NCX during an action potential and a reduced dependence on SR function for maintenance of the [Ca²⁺]_i transient in newborn versus adult rabbit myocytes. Litwin and Bridge²⁸ showed that in hypertrophied myocytes isolated from a peri-infarct area in a rabbit heart, NCX expression was increased and L-type Ca²⁺ current was decreased by 30% to 40%. In voltage-clamp studies, NCX seemed to provide Ca²⁺ influx to load the SR. The authors proposed that the increased activity of the NCX was maintaining SR Ca²⁺ loading in spite of some decrease in L-type Ca²⁺ current. O’Rourke et al²⁹ found increased NCX and decreased SR Ca²⁺-ATPase expression in myocytes from a pacing-induced failure canine model and showed that forward function of NCX seemed to compensate partially for reduced SR Ca²⁺-ATPase function in reducing [Ca²⁺]_i during a transient. Pogwizd et al³⁰ found increased NCX expression in a rabbit model of left ventricular pressure and volume overload, with no change in SR Ca²⁺-ATPase or Ca²⁺ current density. Twitch amplitude was decreased by 21% and SR Ca²⁺ content was not altered, but the rate of decline of a caffeine-induced [Ca²⁺]_i transient was accelerated. They proposed that increased NCX activity was reducing the amplitude of contraction and that increased NCX-dependent currents contributed to arrhythmias in this model.

In this issue of Circulation Research, Ito et al³¹ report studies of isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) and compensatory hypertrophy of 4 and 7 weeks’ duration. Although protein levels of NCX were increased at both 4 and 7 weeks, the SR Ca²⁺-ATPase to phospholamban protein ratio was depressed only in the 7-week AS myocytes. Under resting conditions, the amplitude of shortening and peak systolic [Ca²⁺]_i were not different from controls in myocytes from animals at 7 weeks, although contraction, relaxation, and the decline of the Ca²⁺ transients were slower in the hypertrophied myocytes. In response to rapid pacing stimulation or exposure to high [Ca²⁺]_o, cell shortening and peak systolic Ca²⁺ increased in controls, but the responses were depressed in 7-week AS myocytes, and SR Ca²⁺ content was reduced during rapid pacing in 7-week hypertrophied myocytes. These abnormalities cannot be ascribed to increased expression of NCX, because they were not present in 4-week AS myocytes. These results suggest that during hypertrophy in mice, reduced SR Ca²⁺-ATPase activity rather than increased NCX is the most important factor producing a functional abnormality during stress.

It is also known that the NCX protein may be increased and SR Ca²⁺-ATPase may be decreased in myocardium patients with heart failure,³² and this may have functional importance. Houser and colleagues^{33 34 35} have reported that in failing human ventricular myocytes isolated from explanted hearts, there is a late tonic component of contraction and [Ca²⁺]_i transient. They suggest that this is attributable to influx of Ca²⁺ on NCX, possibly caused by increased expression of the exchanger and the prolonged action potential duration that is seen in human failing myocardium.³⁶ This late tonic component could be inhibited by exposure to KBR-7943, providing some additional support for this hypothesis.³³ This idea is also consistent with the early observations of Gwathmey et al,³⁷ who noted a delayed secondary increase in the aequorin [Ca²⁺]_i transient in failing myocardium. This was insensitive to ryanodine but was eliminated by verapamil, which could have shortened the prolonged action potential. The work of Flesch et al³⁸ also suggests that enhanced expression of the exchanger could support contraction in failing myocytes by providing an additional source of Ca²⁺ influx to provide activation of the contractile elements and maintain SR Ca²⁺ loading.

On the other hand, studies by Schillinger et al³⁹ and Hasenfuss et al⁴⁰ have shown that failing human myocardium with an increased NCX exchanger but normal SR Ca²⁺-ATPase protein levels develop normal contractile force at rates of 40 to 60 min^-1 but show a negative inotropic response to an increased pacing rate. To test the hypothesis that a reduced contractile force at high frequency of pacing is related to increased NCX activity, Schillinger et al⁴¹ report in this issue of Circulation Research important studies in which adenoviral transfection of the NCX gene in rabbit ventricular myocytes increased the level of expression of protein by 2- to 3-fold. This resulted in no significant change in fractional shortening during stimulation at 30 to 60 min^-1 but caused a reduced positive inotropic response at faster rates of pacing. In support of the hypothesis that this effect was attributable to enhanced extrusion of Ca²⁺ from the myocyte by NCX, Schillinger et al show that SR Ca²⁺ content, as estimated from the contractile response to abrupt exposure to caffeine, was reduced in myocytes overexpressing the exchanger. These data support the hypothesis that increased expression of NCX in failing human myocardium promotes enhanced extrusion of Ca²⁺ from the myocyte, particularly at fast heart rates when action potential durations are relatively short, and suggest that this contributes, along with reduced expression of the SR Ca²⁺-ATPase, to the reduction in SR Ca²⁺ content that has been observed in failing myocardium.^{42 43}

Do these findings, that a reduced Treppe response in rabbit myocardium is caused by an increased expression of NCX, mean that NCX activity, although helpful in maintaining diastolic function, is detrimental to systolic function in failing human myocardium? It is not certain that this is always the case. First, as mentioned previously, the [Na⁺]_i and the action potential duration are of critical importance in determining the balance between Ca²⁺ influx and efflux on the exchanger. In failing human myocardium, the action potential is prolonged,³⁵ especially at slow rates of stimulation,^{35 36 44} and the [Na⁺]_i in failing human myocardium may be elevated. These factors could increase the importance of Ca²⁺ entry via reverse-mode NCX in failing human myocardium and produce a situation in which increased expression of NCX would, in fact, be beneficial rather than detrimental with respect to SR Ca²⁺ loading, especially at slow heart rates. This may explain why systolic function of failing myocardium is relatively normal at slow rates of stimulation³⁹ and account for some of the benefits of ß-blocker therapy, which slows heart rate in patients with heart failure.

In summary, presently data are somewhat conflicting regarding the influence of increased expression of the NCX on myocyte function. The experiments of Schillinger et al⁴¹ are important in that they demonstrate for the first time that increased expression of NCX in rabbit myocytes with a relatively low [Na⁺]_i and longer duration action potential can have a negative inotropic effect and produce depletion of SR Ca²⁺. This effect may be important in impairing contraction of failing human myocardium at rapid rates of contraction, but increased NCX expression may benefit systolic as well as diastolic function at slower rates of contraction, especially in myocardium with reduced activity of the SR Ca²⁺-ATPase.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

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This Article Extract Full Text (PDF) Correction (v87,p953) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barry, W. H. Search for Related Content PubMed PubMed Citation Articles by Barry, W. H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL SODIUM Medline Plus Health Information Heart Diseases Heart Failure Related Collections Contractile function Calcium cycling/excitation-contraction coupling Gene expression Genetically altered mice Heart failure - basic studies Hypertrophy Ion channels/membrane transport