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(Circulation Research. 2000;87:275.)
© 2000 American Heart Association, Inc.

Review

Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction

Donald M. Bers

From the Department of Physiology, Loyola University Chicago, Maywood, Ill.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Medical School, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}luc.edu

	Introduction

Top Introduction Ca2+ Requirements for Activation... Ca2+ Removal From the... Ca2+ Influx During the... SR Ca2+ Load and... Restitution and Force-Frequency... References

 
This Review is part of a thematic series on Calcium Cycling in Cardiovascular Cells, which includes the following articles: Ca²⁺ Release Mechanisms, Ca²⁺ Sparks, and Local Control of Excitation-Contraction Coupling in Normal Heart Muscle Interaction Between Ca²⁺ and H⁺ and Functional Consequences in Vascular Smooth Muscle Cardiac Intracellular Calcium Release Channels: Role in Heart Failure

Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction

C. William Balke, Guest Editor

Intracellular Ca²⁺ is the central regulator of cardiac contractility. Moreover, it is becoming increasingly apparent that alterations in myocyte Ca²⁺ regulation may be critically important in both the mechanical dysfunction and arrhythmogenesis associated with congestive heart failure.^{1 2} Thus, it is imperative to have a clear and relatively quantitative understanding of how cellular Ca²⁺ levels are regulated during the normal contraction-relaxation cycle. The scope and relevant references in this field are far too large for this format, so my focus here is narrower and more personal than elsewhere.^{3 4 5} Figure 1A shows the key pathways involved in myocyte Ca²⁺ transport. During the cardiac action potential (AP) L-type Ca²⁺ channels are activated and Ca²⁺ enters the cell via Ca²⁺ current (I_Ca) and also a much smaller amount enters via Na⁺-Ca²⁺ exchange (NCX). Ca²⁺ influx triggers Ca²⁺ release from the sarcoplasmic reticulum (SR) and, to some extent, can also contribute to activation of the myofilaments directly. The Ca²⁺ entry plus the amount released from the SR via Ca²⁺-induced Ca²⁺ release (CICR) raises cytosolic free [Ca²⁺] ([Ca²⁺]_i), causing Ca²⁺ binding to multiple cytosolic Ca²⁺ buffers. One of the most functionally important cytosolic Ca²⁺ buffers is the thin-filament protein troponin C (TnC). When Ca²⁺ binds to TnC, it switches on the myofilaments in a cooperative manner activating contraction. For relaxation and diastolic filling to occur, [Ca²⁺]_i must decline such that Ca²⁺ dissociates from TnC, thereby turning off the contractile machinery. Four Ca²⁺ transporters remove Ca²⁺ from the cytosol: (1) SR Ca²⁺-ATPase, (2) sarcolemmal NCX, (3) sarcolemmal Ca²⁺-ATPase, and (4) mitochondrial Ca²⁺ uniporter. The SR Ca²⁺-ATPase and NCX are most important quantitatively.

View larger version (34K): [in this window] [in a new window]   Figure 1. Ca2+ transport and requirements for activation of myofilament force. A, Schematic diagram of cellular Ca2+ fluxes. B, Ca2+ requirements for contractile activation, based on diastolic [Ca2+]i=150 nmol/L and total cytosolic Ca2+ buffering=244/(1+673/[Ca2+]i)-28. This includes TnC (Ca2+ and Ca2+-Mg2+ sites), myosin, SR Ca2+-ATPase, calmodulin, ATP, creatine phosphate, and sarcolemmal sites. Force is also shown as a function of [Ca2+]i in inset Force=100/(1+{600/[Ca2+]i}4 ). For more details, see Bers.3

Data on Ca²⁺ binding, functional effects, and transport from multiple laboratories and with different experimental approaches allow consideration of Ca²⁺ cycling in relatively quantitative terms. Although these numbers will continue to be refined, they are useful to consider. For consistency, cellular Ca²⁺ will be discussed below in units of µmol/L cytosol (where cytosol is 65% of cell volume and excludes mitochondrial volume that is 30% of cell volume).³

	Ca2+ Requirements for Activation of Myofilaments

Top Introduction Ca2+ Requirements for Activation... Ca2+ Removal From the... Ca2+ Influx During the... SR Ca2+ Load and... Restitution and Force-Frequency... References

 
How much Ca²⁺ is required to activate the myofilaments to produce contraction? Usually myofilament response to Ca²⁺ is shown as a function of free [Ca²⁺]_i (Figure 1B, inset), and the myofilaments respond cooperatively to [Ca²⁺]_i. Indeed, in intact ventricular muscle, the half-activating [Ca²⁺] is 600 nmol/L with a Hill coefficient 4.6.^{6 7} This is very important information, and we know that myofilament Ca²⁺ sensitivity can be decreased by protein kinase A (PKA) phosphorylation of TnI, low pH, and reduced sarcomere length. Indeed, increased myofilament Ca²⁺ sensitivity at longer sarcomere lengths is crucial in Starling’s law of the heart, whereby increased diastolic filling results in stronger ventricular contraction.

The [Ca²⁺]_i dependence of force, however, does not indicate how much total Ca²⁺ is required to activate the myofilaments. This issue is complicated by the fact that there are many other Ca²⁺-binding moieties in the cell that are in dynamic competition with TnC.⁸ Indeed, [Ca²⁺]_i is heavily buffered such that it takes >100 µmol Ca²⁺/L cytosol to raise [Ca²⁺]_i from a diastolic level of 100 nmol/L to a peak systolic level of 1 µmol/L.^{3 9 10 11} Figure 1B incorporates the titration of the other cellular Ca²⁺ buffers (including 70 µmol regulatory TnC and 47 µmol SR Ca²⁺-ATPase sites per L cytosol). This shows the amount of total Ca²⁺ influx plus release that is required for a given level of contractile force, starting from diastolic [Ca²⁺]_i=150 µmol/L. Little force is developed below 30 µmol/L cytosol, but then the curve becomes much steeper. During a typical twitch (at 23°C to 30°C), contractile force reaches 40% of maximum, and this would require 60 µmol Ca²⁺/L cytosol, and [Ca²⁺]_i would be 540 nmol/L. So where does this [Ca²⁺]_i go during relaxation?

	Ca2+ Removal From the Cytosol During Cardiac Relaxation

Top Introduction Ca2+ Requirements for Activation... Ca2+ Removal From the... Ca2+ Influx During the... SR Ca2+ Load and... Restitution and Force-Frequency... References

 
For relaxation and ventricular filling to occur, the Ca²⁺ that activated the myofilaments must be removed from the cytosol by the 4 Ca²⁺ transport systems mentioned above. We analyzed the contributions of each system in quantitative detail by selective inhibition of each transporter during myocyte relaxation and [Ca²⁺]_i decline.^{12 13 14 15} SR Ca²⁺ uptake was prevented by either thapsigargin or 10 mmol/L caffeine, NCX was prevented by complete removal of extracellular Na⁺ and Ca²⁺, sarcolemmal Ca²⁺-ATPase was inhibited by either carboxyeosin or elevated [Ca²⁺]_o, and mitochondrial Ca²⁺ uptake was blocked by rapid dissipation of the electrochemical driving force for Ca²⁺ uptake using the protonophore FCCP. Accounting for Ca²⁺ buffering,^{9 10} [Ca²⁺]_i decline is converted to a rate of [Ca²⁺]_total decline and this Ca²⁺ transport rate (in µmol/L cytosol/sec) is plotted to define Ca²⁺ flux as a function of [Ca²⁺]_i for each system. Then the normal [Ca²⁺]_i transient can be used as a driving function, and Ca²⁺ transport by each system can be calculated. Figure 2A shows that in rabbit ventricular myocytes, the SR Ca²⁺-ATPase removes 70% of the activator Ca²⁺ from the cytosol, whereas the NCX removes 28%, with only 1% each for the sarcolemmal Ca²⁺-ATPase and mitochondrial Ca²⁺ uniporter (referred to collectively as the slow systems). In rat ventricle, the SR Ca²⁺-ATPase activity is higher (presumably due to more pump molecules per unit cell volume¹⁶ ) and Ca²⁺ removal via NCX is less, resulting in a balance of 92:7:1% for SR Ca²⁺-ATPase, NCX, and slow systems (Figure 2B). In mouse ventricle, the situation is quantitatively similar to rat,¹⁷ whereas the balance of Ca²⁺ fluxes in guinea pig, ferret, and human ventricle are more similar to rabbit.^{13 14 15 18 19} The total amount of Ca²⁺ transported during [Ca²⁺]_i decline in both rabbit and rat ventricular myocytes is similar to the 60 µmol Ca²⁺/L cytosol discussed above for Ca²⁺ requirements of contractile activation.

View larger version (24K): [in this window] [in a new window]   Figure 2. Integrated Ca2+ fluxes during twitch relaxation in rabbit and rat ventricular myocytes. Free [Ca2+]i during twitch relaxation was used as a driving function to calculate Ca2+ flux via each system, using the [Ca2+]i dependence of transport rates measured for each system studied in isolation. SR is SR Ca2+-ATPase, and the slow systems are a combination of sarcolemmal (SL) Ca2+-ATPase and mitochondrial Ca2+ uniporter (Mito). Percentages indicate the fraction of the total cytosolic Ca2+ removal attributable to each system when they dynamically interact in the cell. Data in panels A and B are from Bassani et al.12 For panel C, rabbit heart failure (HF), the Vmax for NCX was increased 116% and SR Ca2+-ATPase was reduced by 24% as indicated by Pogwizd et al.2

In failing versus nonfailing human heart, there is also typically a reduction in SR Ca²⁺-ATPase expression^{20 21} and an increase in NCX expression.^{22 23 24} This would shift the balance of Ca²⁺ fluxes during relaxation in favor of Ca²⁺ extrusion via NCX and reduce SR Ca²⁺ uptake. Thus, in the failing human (and rabbit) heart, the SR Ca²⁺-ATPase and NCX may contribute nearly equally to [Ca²⁺]_i decline (Figure 2C) as opposed to a 2- to 3-fold dominance of the SR in the normal heart. This shift in competition from the SR Ca²⁺-ATPase toward NCX will also tend to limit SR Ca²⁺ loading in heart failure. Such a limitation of SR Ca²⁺ loading could also contribute to the mechanical dysfunction in heart failure.²⁴ In addition, the SR Ca²⁺-ATPase transports two Ca²⁺ ions per ATP consumed, whereas extrusion by NCX only pumps one Ca²⁺ per ATP used (indirectly, to pump out the 3 Na⁺ ions via Na⁺-K⁺- ATPase which had entered in exchange for one Ca²⁺ via NCX). Thus, transsarcolemmal Ca²⁺ cycling is energetically more expensive than SR transport.

	Ca2+ Influx During the Cardiac AP

Top Introduction Ca2+ Requirements for Activation... Ca2+ Removal From the... Ca2+ Influx During the... SR Ca2+ Load and... Restitution and Force-Frequency... References

 
If 28% of the activator Ca²⁺ in rabbit is extruded from the rabbit myocyte by NCX at a steady-state twitch, there must be a similar amount of Ca²⁺ entry (eg, via I_Ca) at each beat. Otherwise, there would be progressive loss or gain of cellular Ca²⁺ (ie, this would not be a steady state). Indeed, during an AP in rabbit, there is more Ca²⁺ entry via I_Ca and less SR Ca²⁺ release than in rat.^{3 25} Ca²⁺ influx via I_Ca during a rabbit AP is 10 µmol/L cytosol in cells where SR Ca²⁺ load (based on integration of NCX current; see Figure 4A) was 87 µmol/L cytosol.²⁶ For a fractional SR Ca²⁺ release during the twitch of 43%,²⁷ this indicates an SR Ca²⁺ release of 37 µmol/L cytosol or 77% of activator Ca²⁺ from SR versus 23% for I_Ca. Similar estimations in rat yielded 92% SR Ca²⁺ release and 8% Ca²⁺ entry via I_Ca (with total activator Ca²⁺ 80 µmol/L cytosol).^{25 28} These values agree remarkably well with those for Ca²⁺ removal above (based on [Ca²⁺]_i decline), especially considering differences in methodology and inherent assumptions. Thus, although these quantitative estimates continue to be refined, we are getting an increasingly clear picture of exactly how many Ca²⁺ ions are going where, and when in ventricular myocytes.

View larger version (27K): [in this window] [in a new window]   Figure 4. Measurement of SR Ca2+ content and force-frequency relationship. A, Rapid application of 10 mmol/L caffeine causes release of SR Ca2+ and prevents net reuptake. The difference between total cytosolic Ca2+ ([Ca2+]tot based on [Ca2+]i as in Figure 1B) at rest and peak ([Ca2+]tot) indicates SR Ca2+ released. Almost all of the SR Ca2+ released (93%) is extruded by INa/Ca,12 so the integral of INa/Ca (1.5 pC/pF) multiplied by cell surface to volume ratio (6.44 pF/pL cytosol)60 and divided by 0.93 indicates an SR Ca2+ load similar to that obtained from [Ca2+]tot. B, Force-frequency relationship and SR Ca2+ content (based on RCC amplitude) in human ventricle. Muscles were stimulated (37°C) at various frequencies, and after twitches reached steady-state, RCCs were induced to assess SR Ca2+ load under those conditions (force normalized to that at 0.2 Hz). Data from failing (F) and nonfailing (NF) hearts are from Pieske et al.19

I_Ca is subject to Ca²⁺-dependent inactivation, and this is readily appreciated by the faster current inactivation when Ca²⁺ is the charge carrier versus Ba²⁺ or Na⁺.⁵ Ca²⁺ entering the cell through the channel produces this effect very locally, because it cannot be abolished even by high intracellular Ca²⁺ buffering with EGTA or BAPTA. Recent studies have also shown that calmodulin, which may be bound to the carboxy terminal, mediates Ca²⁺-dependent inactivation.^{29 30 31}

In addition to Ca²⁺ entering the cell, SR Ca²⁺ release can also contribute importantly to this Ca²⁺-dependent inactivation.^{32 33} This is because SR Ca²⁺ is released into the same restricted junctional space where most of the L-type Ca²⁺ channels probably reside (see SR-sarcolemmal junction in Figure 1A). Figure 3A shows how the I_Ca time course during an AP changes when there is no SR Ca²⁺ release (small pulse 1 contraction after SR Ca²⁺ depletion) and as the SR Ca²⁺ release gradually recovers to steady state (pulse 10).³⁴ Kinetic analysis of this difference current (Figure 3B) suggested that the rate of local SR Ca²⁺ release (as sensed by the Ca²⁺ channel) was maximal in 5 ms at 25°C and 2 to 3 ms at 35°C. This is fast compared with fluorescence changes from indicators that are distributed throughout the cytosol. These times are similar to the time to peak I_Ca, which emphasizes that there is very little delay between I_Ca and SR Ca²⁺ release. As the SR refills with Ca²⁺ and contractions approach steady state (from pulse 1 to 10), this SR Ca²⁺ release–dependent inactivation of I_Ca causes the integrated Ca²⁺ influx via I_Ca to decrease by 50% (Figure 3C). Thus, SR Ca²⁺ release creates a negative feedback on Ca²⁺ influx, such that when there is ample SR Ca²⁺ release, further Ca²⁺ influx is turned off. Of course, Ca²⁺ entry via I_Ca also participates in this feedback, and much of the inactivation of I_Ca at pulse 1 is probably due to inactivation that is Ca²⁺ influx–dependent (versus voltage-dependent). Figure 3C also shows that the integrated I_Ca behaves similarly at both 25°C and 35°C. Although at 35°C peak I_Ca is much larger, I_Ca inactivation is also faster, resulting in nearly the same I_Ca integral as at 25°C.

View larger version (29K): [in this window] [in a new window]   Figure 3. Ca2+ influx during AP in rabbit ventricular myocyte. A, APs measured under physiological conditions were used as a voltage-clamp command with all other currents blocked (including INa/Ca). Contraction and ICa were measured during 10 pulses approaching steady state (starting after SR Ca2+ had been depleted by caffeine exposure, 25°C). B, Derivative of the difference current (versus pulse 1 where there was no SR Ca2+ release), indicative of the rate of SR Ca2+ release sensed by the Ca2+ channel (25°C). C, Integrated ICa during APs as the SR reloads at 25°C and 35°C. Inset shows steady-state ICa during AP at both temperatures (data from Puglisi et al).34

The foregoing discussion has not considered Ca²⁺ influx via NCX (ie, outward I_Na/Ca). The direction of I_Na/Ca depends on the concentrations of Na⁺ and Ca²⁺ on both sides of the membrane and also on membrane potential (E_m). Indeed, like ion channels, I_Na/Ca has a reversal potential (E_Na/Ca=3E_Na-2E_Ca, where E_Na and E_Ca are equilibrium or Nernst potentials for Na⁺ and Ca²⁺). At E_Na/Ca, the energy in the [Na⁺] and [Ca²⁺] gradients is exactly balanced such that no net Ca²⁺ transport occurs. In a resting cardiac myocyte, E_Na/Ca is typically -40 mV. When E_m>E_Na/Ca, Ca²⁺ influx via I_Na/Ca is favored thermodynamically. Thus, at the upstroke of the AP, Ca²⁺ entry is thermodynamically favored and outward I_Na/Ca is expected. If one does not consider spatial [Ca²⁺]_i gradients and calculates outward I_Na/Ca with the useful equation described by Luo and Rudy,³⁵ one could infer Ca²⁺ influx of 0.3 to 1 µmol/L cytosol. However, as I_Ca and SR Ca²⁺ release activate rapidly and raise local [Ca²⁺]_i very rapidly (especially near the membrane), this changes E_Ca and E_Na/Ca and greatly limits Ca²⁺ entry via NCX. Inclusion of these local [Ca²⁺]_i considerations might reduce the amount of Ca²⁺ entry expected during a normal AP to 0.2 µmol/L cytosol, concentrated in the first 1 to 3 ms of the AP. This is negligible in comparison to the 10 µmol/L cytosol Ca²⁺ entry via I_Ca.

The amount of Ca²⁺ influx via I_Na/Ca can be increased greatly when [Na⁺]_i is elevated (eg, in response to digitalis glycosides) and also if SR Ca²⁺ release and/or I_Ca is inhibited. Moreover, if the AP is very long and [Ca²⁺]_i declines at plateau potentials, then I_Na/Ca can produce additional late Ca²⁺ influx.³⁶ There is also work that suggests that Ca²⁺ entry via NCX can trigger SR Ca²⁺ release.^{37 38 39 40} Although this may not be important under normal physiological conditions because of the dominant role of I_Ca,^{41 42} it may become more important when [Na⁺]_i is elevated, I_Ca is depressed, or NCX expression is elevated.

	SR Ca2+ Load and Release

Top Introduction Ca2+ Requirements for Activation... Ca2+ Removal From the... Ca2+ Influx During the... SR Ca2+ Load and... Restitution and Force-Frequency... References

 
SR Ca²⁺ load can be raised by increasing Ca²⁺ influx or decreasing Ca²⁺ efflux (eg, elevated stimulation frequency, AP duration, I_Ca, [Ca²⁺]_o, [Na⁺]_i, or reduced [Na⁺]_o). Stimulation of the SR Ca²⁺-ATPase (by phospholamban phosphorylation or gene knockout) also increases SR Ca²⁺ load as well as speeding relaxation and [Ca²⁺]_i decline.⁴³ In heart failure, the combination of reduced SR Ca²⁺-ATPase and elevated NCX may contribute to the lower SR Ca²⁺ load observed,^{2 44} because the SR Ca²⁺-ATPase would compete less effectively with NCX for Ca²⁺ during relaxation and diastole.

High SR Ca²⁺ load increases the amount of Ca²⁺ available for release, but it can also dramatically increase the fraction of SR Ca²⁺ that is released for a given I_Ca trigger.^{27 45} This latter effect may be attributable to a stimulatory effect of high intra-SR [Ca²⁺] on ryanodine receptor open probability.^{46 47} This effect of luminal SR [Ca²⁺] may also contribute to the apparently spontaneous SR Ca²⁺ release observed with cellular Ca²⁺ overload. This is the basis of aftercontractions, transient inward current, and delayed afterdepolarizations that can trigger arrhythmias. At moderately low SR Ca²⁺ load, CICR appears to fail.^{27 45} This property may help the SR reload if it becomes relatively depleted, and it could even contribute dynamically to the turnoff of SR Ca²⁺ release during excitation-contraction coupling (ECC) (see review published earlier in this series⁴⁸ ).

Measuring SR Ca²⁺ load online is less direct than [Ca²⁺]_i, I_Ca, or force. One useful approach is to rapidly apply caffeine (10 to 20 mmol/L), which releases all SR Ca²⁺ and prevents net reuptake because of open SR Ca²⁺ release channels. Then, quantitative measures of SR Ca²⁺ load can be obtained from the amplitude of contraction or [Ca²⁺]_i or by integrating I_Na/Ca (given that most of the SR Ca²⁺ is removed from the cell this way, see Figure 4A). Maximal SR Ca²⁺ content under relatively physiological conditions is 100 µmol/L cytosol or about twice the amount of Ca²⁺ required to activate a twitch.^{26 49 50} Rapid cooling contractures (RCCs) are also useful for assessing SR Ca²⁺, especially in multicellular preparations where slow caffeine diffusion to all the cells limits the utility of the caffeine approach.^{18 19} Cooling to 0°C inhibits Ca²⁺ pumping and also causes rapid SR Ca²⁺ release (presumably due to very long ryanodine receptor openings⁵¹ ). Then, one can measure either [Ca²⁺]_i or contractile force (which develops slowly at 0°C). This technique is less quantitative concerning absolute amounts of Ca²⁺ but is useful for measuring changes in SR Ca²⁺ content under different conditions (Figure 4B).

	Restitution and Force-Frequency Relationship

Top Introduction Ca2+ Requirements for Activation... Ca2+ Removal From the... Ca2+ Influx During the... SR Ca2+ Load and... Restitution and Force-Frequency... References

 
During CICR, SR Ca²⁺ release turns off because the channel either inactivates^{52 53} or adapts to the high local [Ca²⁺]_i.⁵⁴ Thus, recovery from this state requires time and low [Ca²⁺]_i to return to its normal resting Ca²⁺ sensitivity. There is a fast phase of restitution after an AP and twitch (=50 to 300 ms), which is probably due to recovery of I_Ca, availability of Ca²⁺ in the SR, and partial recovery of ryanodine receptors. Some early ECC models included slow diffusion of SR Ca²⁺ from uptake sites to release sites⁵⁵ in explaining rest potentiation, but this diffusion should be very fast (1 to 2 ms), and we now know that longer times are required for Ca²⁺ release channel recovery.^{3 52 53 54 56} There is also a much slower phase of ECC restitution (=5 to 15 seconds), which is largely responsible for post–rest potentiation.^{56 57} Notably, this post–rest potentiation can occur without any increase in SR Ca²⁺ load, I_Ca, or AP duration. Indeed, SR Ca²⁺ content can be declining while twitch SR Ca²⁺ release is increasing for a given I_Ca trigger (ie, increased fractional release).^{19 56} As rest is prolonged, SR Ca²⁺ load decreases in rabbit, guinea pig, ferret, and failing human ventricle. This is because as Ca²⁺ leaks from the SR, some fraction is extruded by NCX rather than being pumped back into the SR. This resting SR Ca²⁺ loss is the basis of rest decay of twitch amplitude in these species and can be prevented by blocking NCX by 0Na-0Ca solution. In fact, blocking NCX produces prominent, long-lasting rest potentiation in rabbit myocytes, a preparation that normally exhibits marked rest decay.⁵⁷ Rat and mouse SR Ca²⁺ content does not decline much with rest, and these species normally exhibit more prominent and longer-lasting rest potentiation (reflecting mainly the increased fractional SR Ca²⁺ release as ECC recovers completely). Thus, for a given I_Ca, the main factors that determine SR Ca²⁺ release are the amount of SR Ca²⁺ available and the fraction of SR Ca²⁺ released (which depends on recent history).

Increasing frequency alters SR Ca²⁺ release in two major ways: (1) It increases SR Ca²⁺ load (due to more frequent I_Ca influx and less time for extrusion by NCX), and (2) there is less time for the ryanodine receptor to recover from inactivated or adapted states. In rat and mouse ventricular muscle, the SR is often found to be relatively full even at very low stimulation frequency, possibly a consequence of relatively high [Na⁺]_i, which limits Ca²⁺ extrusion via NCX.⁵⁸ Thus, increasing frequency in rat or mouse usually causes little or no further increase in SR Ca²⁺, such that the dominant frequency-dependent effect is the encroachment into full recovery time of ECC. Thus, rat and mouse myocytes often show negative force-frequency relationships. If, for some reason, the rat cells start with lower SR Ca²⁺ at low frequency, then a positive force-frequency relationship can also be seen (with increasing [Na⁺]_i and SR Ca²⁺).⁵⁹ In most other species (rabbit, guinea pig, ferret, and nonfailing human), the force-frequency relationship is normally positive and coincides with dramatic increases in SR Ca²⁺ content (Figure 4B). In these cases, the increase in SR Ca²⁺ is more than enough to compensate for a reduction in fractional release at high frequency. In the failing human heart, the SR Ca²⁺ content increases only slightly with increasing frequency, mostly between 0.2 and 1 Hz. Although this is associated with some increase in twitch force, SR Ca²⁺ does not increase further at higher frequency, and so the relationship there is dominated by the intrinsic depressant effect of higher frequency on fractional SR Ca²⁺ release. This results in a flat or negative force-frequency relationship (Figure 4B). This would, of course, limit the functional reserve of the failing human heart and could be a direct consequence of reduced levels of SR Ca²⁺-ATPase and increased levels of NCX expression in the failing heart.¹⁹

In conclusion, Ca²⁺ in cardiac myocytes is in a dynamic yet delicate balance, and the interaction of numerous cellular processes orchestrates many aspects of cardiac function at the cellular level. Many of these systems are also subject to many regulatory influences (not discussed here). The result is a rich variation in functional behavior that allows the heart to function effectively, but this also continues to pose many challenges to understanding this complex system under diverse conditions. Important remaining questions include the molecular mechanism of ECC, how the release channel is regulated physiologically, how alterations in Ca²⁺ handling in disease states lead to mechanical dysfunction and arrhythmias, and what are the best molecular targets for therapeutic strategies.

	Acknowledgments

 
I thank my many collaborators and colleagues who have helped me to learn about Ca²⁺ in heart cells (supported in part by grants from the National Institutes of Health [HL30077 and HL64098]).

Received May 17, 2000; revision received July 3, 2000; accepted July 3, 2000.

	References

Top Introduction Ca2+ Requirements for Activation... Ca2+ Removal From the... Ca2+ Influx During the... SR Ca2+ Load and... Restitution and Force-Frequency... References

 
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