Cardiovascular Research

Cardiovascular Research 2003 57(4):887-896; doi:10.1016/S0008-6363(02)00735-6
© 2003 by European Society of Cardiology

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Copyright © 2003, European Society of Cardiology

Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis

Steven M Pogwizd^a,*, Karin R Sipido^b, Fons Verdonck^c and Donald M Bers^d

^aDepartment of Medicine, University of Illinois at Chicago, 840 South Wood Street, M/C 787, Chicago, IL 60612, USA
^bLaboratory of Experimental Cardiology, University of Leuven, Leuven, Belgium
^cInterdisciplinary Research Center, University of Leuven, Kortrijk, Belgium
^dDepartment of Physiology, Loyola University Chicago, Maywood, IL 60153, USA

^* Corresponding author.

Received 8 July 2002; accepted 17 October 2002

KEYWORDS Arrhythmia (mechanisms); Contractile function; Heart failure; Hypertrophy; Na/H-exchanger; Na/K-pump

	1. [Na]i in hypertrophy and heart failure

Top 1. [Na]i in hypertrophy... 2. Causes of [Na]i... 3. Functional consequences of... 4. Changes in Ca... 5. Na and arrhythmogenesis... 6. Conclusion References

 
Myocardial hypertrophy (Hyp) and heart failure (HF) are pathologic states characterized by altered intracellular Ca handling [1,2] that can contribute to diastolic and/or systolic dysfunction and arrhythmias [1,3]. However, there is an important interplay between intracellular Na ([Na]_i) and Ca handling, so that altered levels of [Na]_i and Na transporters can have profound effects on both contractile function and arrhythmogenesis. Both intracellular [Ca] ([Ca]_i) and intracellular pH (pH_i) in cardiac myocytes depend strongly on [Na]_i [1]. This is because Na/Ca exchange (NCX) and Na/H exchange (NHE) are powerful transport mechanisms that use the energy stored in the transmembrane [Na] electrochemical gradient to extrude Ca and protons from the cell. Thus, when [Na]_i rises it can limit the ability of NCX and NHE to extrude Ca and protons from myocytes. This could slow relaxation and recovery of pH_i from acid loads (e.g. during ischemia). First let us consider whether [Na]_i is altered in hypertrophy and HF.

Numerous reports indicate that [Na]_i is increased in hypertrophy [4–7]. The magnitude of [Na]_i elevation (4–6 mM) in hypertrophied guinea pig hearts (induced by aortic banding) was consistent, whether measured by ion-sensitive electrodes (ISE) [4] or nuclear magnetic resonance [5]. Additionally, myocytes from hypertrophied rat hearts (induced by isoproterenol infusion) exhibit a 6 mM increase in [Na]_i assessed by ISE [6]. Dogs with hypertrophy induced by chronic AV block (cAVB) demonstrate a 4 mM increase in subsarcolemmal [Na] compared to controls [7]. However, Baudet et al. [8] detected no change in intracellular Na activity in hypertrophied ferret heart using ISE.

Data regarding [Na]_i in heart failure are more limited. In an arrhythmogenic non-ischemic HF rabbit model (induced by aortic insufficiency and aortic constriction), Despa et al. [9] measured [Na]_i with sodium benzofuran isophthalate (SBFI) and found that [Na]_i is 3 mM higher in HF (both at rest and during stimulation at 1–3 Hz) (Fig. 1A). In this same rabbit HF model, Baartscheer et al. [10] noted a similar increase in [Na]_i. Data in human HF using SBFI suggests a comparable increase in [Na]_i [11]. An exception to this trend is in myocytes from rabbits with pacing-induced HF, where [Na]_i was slightly decreased (measured with SBFI) [12]. This latter HF model differs from the former because the NCX current density was not enhanced, but decreased. Indeed many, but not all, studies of HF models report enhanced NCX expression and function [1,2,13].

View larger version (28K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Increased [Na]i due to increased Na influx in HF rabbit versus control (Ctl). (A) Average [Na]i (measured by SBFI) at rest and during stimulation in control and HF myocytes. (B) [Na]i dependence of Na efflux due to Na/K pump in control and HF. The rate of [Na]i decline (–d[Na]i/dt) was obtained in the absence of strophanthidin (representing Na/K pump plus passive Na efflux) or in the presence of 100 µM strophanthidin (passive Na efflux), and the difference is the Na efflux due to the Na/K pump. (C) Representative data from rabbit HF myocyte where Na influx is taken as the initial rate of rise of [Na]i on abrupt inhibition of the Na/K pump with 200 µM strophanthidin, in the absence and presence of 30 µM tetrodotoxin (TTX). (D) Average data for control and HF rabbit myocytes with the TTX-sensitive component of Na influx accounting for the majority of the difference between HF and control vs. that sensitive to block by HOE-642 (NHE blocker) or Ni (NCX blocker). Data taken from Despa et al. [9] are replotted here.

 

	2. Causes of [Na]i elevation in heart failure

Top 1. [Na]i in hypertrophy... 2. Causes of [Na]i... 3. Functional consequences of... 4. Changes in Ca... 5. Na and arrhythmogenesis... 6. Conclusion References

 
There are two possible explanations for the higher [Na]_i in hypertrophy and HF: (1) decreased Na efflux (i.e. reduced Na/K-ATPase activity), and (2) increased Na influx (by one or more mechanisms). There are multiple mechanisms of Na influx including Na channels, NCX, NHE, Na-bicarbonate cotransport, Na/Mg exchange, and NaK₂Cl cotransport (see Ref. [14] for review). Other than Na channels, all of these transport mechanisms bring Na in using the energy in the Na electrochemical gradient to facilitate the uphill energetic movement of other ions. The main mechanism of Na extrusion in myocytes is the Na/K-ATPase. Na can also be extruded by NCX, which can work in the ‘reverse’ mode (using the energy in the transmembrane [Ca] electrochemical gradient). However, throughout the cardiac cycle there is net Na influx via NCX (and net Ca efflux to extrude Ca which entered via Ca channels). It is unclear whether any other mechanisms contribute significantly to Na extrusion.

So which mechanisms are responsible for the elevated [Na]_i in Hyp and HF? There have been several studies showing decreased expression levels of Na/K-ATPase in Hyp [15,16] and HF [17–20] including human Hyp [21] and HF [22–24]. There are also Na/K-ATPase isoform shifts that could significantly affect activity and affinity of the pump. The Na/K-ATPase is comprised of an -subunit with three isoforms (1, 2, 3) having different affinities for Na (and ouabain), and a β-subunit with two isoforms (β1 and β2, although nearly all of the β subunit in heart is β1). The isoform data in Hyp and HF (including human) have been conflicting. Decreased 2 isoform mRNA and protein levels have been reported in hypertrophied rat [25–29] and infarcted rat hearts [30]. Increased 3 isoform mRNA and protein was noted in hypertrophied rat hearts but accounts for only 5% of total isoform mRNA [29]. Kim et al. [18] reported the absence of 2 isoform in adult canine hearts and that dogs with pacing-induced HF exhibit decreased 3 protein levels. In contrast, in human myocardium, Schwinger et al. [23] found decreased protein levels of 1, 3 and β1 isoforms in HF, while Allen et al. [31] found no significant change in any of the and β isoforms at the mRNA level in human HF. These disparate findings may reflect differences in species and HF models as well as differences in the human HF patient population. Moreover, since all of these studies were performed in tissue homogenates, the results could reflect contributions from nonmyocytes or changes in the total pool of immunoreactive subunits that might not represent the density of Na pumps in the ventricular myocyte sarcolemma. As such, functional assessment of Na pump activity is critical.

Despite the considerable expression data, there is limited functional data available, and results are equivocal. Myocytes from dogs with chronic AV block and hypertrophy demonstrate unchanged maximal pump current (I_p) and decreased [Na]_i affinity [7], which would increase [Na]_i as Na-pump activity must be maintained in the presence of an unchanged Na influx (decreased Na-pump activity at a given [Na]_i). On the other hand, HF rats following myocardial infarction exhibit decreased V_max and unchanged [Na]_i affinity [30].

Despa et al. [9] recently studied [Na]_iregulation in the pressure and volume overload rabbit HF model using SBFI, and found that the [Na]_i-dependence and V_max of the Na/K-pump were unchanged in HF (Fig. 1B). Thus, in some HF models the rise in [Na]_i cannot be explained by reduced Na/K-ATPase function, In fact the higher [Na]_i in HF vs. control indicates that the rate of Na efflux must be higher in this HF model (dotted lines in Fig. 1B). For the cell to be at steady state the rate of Na efflux must be equal to the rate of Na influx. Thus in the HF case of Fig. 1A, the reason for the increased [Na]_i must be the higher rate of Na influx (with a consequent increase in the rate of Na extrusion until influx equals efflux at a higher level of [Na]_i). The rate of Na influx can be measured as the initial rate of either [Na]_i rise (Fig. 1C) or radioactive Na uptake upon abrupt Na/K-ATPase blockade. Of course as time elapses the rate of net influx could diminish as a consequence of rising [Na]_i; but since Na/K-ATPase is the main mechanism of efflux, [Na]_i can rise relatively linearly for a couple of minutes (Fig. 1C). Our results fulfill the above expectation based on measurements of Na efflux via Na/K-ATPase. That is, in HF Na influx rate was about twice as high as in control (Fig. 1D, Total). This initial rate of [Na]_i rise can also be measured in the presence of blockers of individual Na transport systems. This allows identification of the roles played by individual Na transport systems, as shown in Fig. 1C–D. In this case, we used tetrodotoxin (TTX) to inhibit Na channels, Hoe-642 to inhibit NHE and Ni to inhibit NCX (although HOE-642 and Ni could also affect other systems [9,32]). The higher resting Na influx in HF could be largely attributed to a TTX-sensitive mechanism, such as persistent Na current which has been shown to be increased in a model of HF [33], though not in humans [34]. NHE and NCX clearly play a much smaller role, based on the Ni+HOE-sensitive component. It is worth emphasizing that an increased rate of Na influx would elevate [Na]_i and this must also increase the rate of Na extrusion (due to the [Na]_i-dependence of Na/K-ATPase activity (as indicated in Fig. 1B). Thus, in the cAVB dog hypertrophy model (where [Na]_i and Na-pump current are elevated; [7]), we can infer that Na influx is also increased.

Baartscheer et al. [10] using the same rabbit HF model found a similar increase in [Na]_i and unaltered Na/K-ATPase, but they found that increased Na influx via NHE was the largest contributor to the elevated Na influx rate in paced myocytes. They attributed the increased [Na]_i in HF primarily to NHE, which was upregulated in this model and which has been suggested to play a prominent role in hypertrophy and HF [35]. The upregulation of NHE could potentially lead to altered pH, but as shown by the studies of Cingolani and co-workers [36,37], the interaction with the Cl:HCO₃ exchanger prevents major pH changes.

It will be important to further clarify the primary causes of changes in [Na]_i observed in different Hyp and HF models as well as in human heart. In addition, if Na/K-ATPase protein expression is really reduced in the same cells where Na/K-ATPase function appears normal (Fig. 1B), it will be valuable to understand how the myocyte attains the same Na extrusion rate with fewer total Na/K-ATPase molecules. For example, this could result from altered Na/K-ATPase regulation, membrane trafficking, or downregulated Na pumps working at a higher activation state [38].

	3. Functional consequences of elevated [Na]i

Top 1. [Na]i in hypertrophy... 2. Causes of [Na]i... 3. Functional consequences of... 4. Changes in Ca... 5. Na and arrhythmogenesis... 6. Conclusion References

 
If [Na]_i is elevated in Hyp and HF, it is important to consider the cellular consequences, particularly with respect to Ca regulation and contraction. At the simplest level we expect that increased [Na]_i will have the same sort of functional consequences as does Na/K-ATPase inhibition by cardiac glycosides. In general, this is expected to limit Ca extrusion via NCX (and could even favor Ca entry via NCX). Slowing Ca extrusion via NCX will tend to elevate diastolic [Ca]_i especially at high heart rates, thereby contributing to diastolic dysfunction. This is because NCX is the main route by which Ca is extruded from cardiac myocytes [1]. The slowed [Ca]_i decline and elevated diastolic [Ca]_i will tend to increase SR Ca content, which is a major determinant of cardiac contractility. In this case, one would expect greater SR Ca release for any given trigger.

The enhancement of SR Ca content secondary to elevated [Na]_i can occur even at very low heart rates. This has direct implications for the force–frequency relationship. Normally, human, rabbit and canine ventricular muscle demonstrates a clear positive force–frequency relationship, and a major reason for this is a progressive increase in SR Ca content. This rise in SR Ca content with frequency occurs because: (a) there is greater Ca influx per unit time, (b) there is less time for Ca extrusion between beats, and (c) [Na]_i rises with frequency for the same reason and this further limits Ca extrusion by NCX. If the SR is already nearly maximally loaded with Ca at very low frequency (because of the aforementioned effects of the elevated [Na]_i), then there may be little or no further increase in SR Ca as frequency increases. This will result in a flat or even a negative force–frequency relationship [1,13,39,40]. A limiting factor in the positive force–frequency relationship is that there is refractoriness of E–C coupling which accumulates as frequency is increased. At low to moderate frequencies the normal progressive increase in SR Ca content is more than enough to offset this negative effect. However, after the maximal SR Ca content is attained at high frequencies in normal conditions, further increases in frequency result in a negative phase of the force–frequency relationship. In the case of elevated [Na]_i, this occurs at a much lower frequency and can result in a predominantly negative force–frequency relationship. Slower [Ca]_i decline and elevated diastolic Ca may also slow the recovery of Ca channels between beats, and this could further limit the extent of enhancement of systolic function described above at higher heart rates [41].

Increased [Na]_i could also affect the distribution of other ions. For example, [K]_i might fall by 3 mM in the setting of HF (offsetting the rise in [Na]_i), although there are no data on this. However, this reduction in [K]_i would be <3%, and this small [K]_i would have even less impact on the electrochemical [K] gradient (E_K). Elevated [Na]_i could also affect pH_i in hypertrophy or HF by limiting the ability of Na/H exchange to extrude protons. Again, there are limited direct data on this point, but there have been suggestions of increased Na/H exchange functional expression [35].

	4. Changes in Ca handling in hypertrophy and heart failure

Top 1. [Na]i in hypertrophy... 2. Causes of [Na]i... 3. Functional consequences of... 4. Changes in Ca... 5. Na and arrhythmogenesis... 6. Conclusion References

 
In addition to an increase in [Na]_i in Hyp and HF, there have been numerous studies which have characterized changes in the functional expression of many Ca transporters and ion channels. It is not practical to comprehensively review all of the many studies (e.g. see Refs. [1,2,13]). We will first discuss some findings with respect to key systems that have been generally (but not unanimously) observed. Then we will discuss the more integrated cellular consequences of these changes in the context of our own data in animal Hyp and HF models.

Many (but not all) studies in Hyp and HF (both human and animal models) have demonstrated increased expression and function of NCX [42–49]. This NCX upregulation may occur rather rapidly in the course of Hyp [50] and is often increased by 100%, even when measured at the functional level in cells (as NCX current I_NCX or the rate of [Ca]_i decline when SR Ca uptake is inhibited) [42,45]. Doubling the amount of functional NCX in a heart cell has the potential to have tremendous impact on [Ca]_i especially when [Na]_i is also altered. However, as we will see below, the complex dependence of NCX function on [Ca]_i, [Na]_i and membrane potential (E_m) make it difficult to make simple predictions based on protein expression levels until these parameters are placed in the proper context. Most studies in Hyp and HF have shown that action potential duration (APD) is prolonged, and many have shown reductions in outward K currents [46,51–53] that may contribute.

There are also many reports of reduced expression and function of the SR Ca-ATPase [54,55]. Again this is not universally agreed upon, even if widely accepted [44,56], and there may also be variations at different stages of Hyp and HF. For example, Feldman et al. [57] have reported that in rats, SERCA2 downregulation does not occur during compensated hypertrophy, but only at the transition to overt HF. One simple expectation of reduced SERCA2 expression would be a slowing of twitch [Ca]_i decline and relaxation that would contribute to diastolic dysfunction. Another consequence of lowered SR Ca-ATPase activity is that it would reduce SR Ca content and may also create a limiting SR Ca load at higher frequency [58]. This would reduce the amount of Ca available for release during a twitch. In addition to this direct effect, reduced SR Ca load also reduces the fractional SR Ca release for any given level of Ca current trigger. These properties can synergize to produce profound depression of systolic function.

Not all studies in Hyp or HF show both elevated NCX function and reduced SERCA2 function, but most studies that have measured both parameters (especially in HF) have shown at least one of these central functional alterations. This raises an important point about these two transport systems. The SR Ca-ATPase and NCX are competing with each other during relaxation and [Ca]_i decline. Thus if there is a small decrease in SR Ca-ATPase function, a large increase in NCX function could offset the slowing of twitch [Ca]_i decline and relaxation, thereby minimizing diastolic dysfunction [44–46]. On the other hand, both of these functional changes would tend to reduce SR Ca content available for release and thus would work synergistically to depress systolic function. Indeed, a reduction in SR Ca content has been clearly demonstrated in several models of HF [46,59] and in the failing human heart [54]. In relatively compensated Hyp there is often no reduction in contraction or Ca transient amplitude, and increases in Ca transients and SR Ca load have often been seen at this stage [48,61–63].

To shift from these attempts to generalize among heterogeneous models, let us consider two individual models that our groups have studied in some detail. One is a canine model of compensated chronic hypertrophy, induced by complete chronic atrio-ventricular block (cAVB dog) [48,53,64–66]. The second is a rabbit HF model induced by sequential aortic insufficiency and aortic constriction (HF rabbit) [9,45,46,67]. In both animal models there is an increase in [Na]_i of 3 mM (at rest and during stimulation) and an increased APD (Fig. 2A). In both models there is a large increase in NCX functional expression at any given [Ca]_i (Fig. 2C,D). Indeed, in the rabbit HF model there is approximately a doubling of NCX expression at the level of mRNA, protein and I_NCX density (measured either at constant [Ca]_i or dynamic Ca transients) and also a comparable acceleration of the rate of [Ca]_i decline due to NCX during relaxation of caffeine-induced Ca transients [45,46]. In neither model is there a change in Ca current density (Fig. 2B) and no major alteration in SR Ca-ATPase function was apparent (although a modest 24% functional reduction was seen in the rabbit HF model).

View larger version (32K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Action potential duration at 95% repolarization (APD95), Ca current (ICa) density and NCX current density in HF rabbit and cAVB dog myocytes. (A). Increased APD in HF rabbit myocytes (1 Hz, 37 °C) and in cAVB dogs (0.25 Hz, 37 °C). (B) Average ICa density at 0 mV was unchanged in HF rabbit and cAVB dog myocytes (measured during square voltage clamp pulses). (C) Representative Na/Ca exchange current (INCX) evoked by caffeine application in HF rabbit myocyte plotted as a function of [Ca]i (25 °C). (D) Average slopes of INCX versus [Ca]i (at mean [Ca]i near 500 nM) for HF rabbit and cAVB dog myocytes reveals a greater INCX for a given [Ca]i. Data are taken from Pogwizd and co-workers [45,46], Volders et al. [53] and Sipido et al. [48].

 
Despite these relatively parallel changes, there were dramatic differences in how Ca transients, SR Ca load and ventricular contractile function changed in Hyp vs. HF (Fig. 3). In the HF rabbit twitch Ca transients, contractions and SR Ca content were all reduced (by roughly 40%) and at all frequencies studied. In sharp contrast in the hypertrophic cAVB dog, twitch Ca transient amplitude and SR Ca load were both increased. This was especially true at low frequency, but note that after cAVB the ventricular heart rate in these dogs is very low (40 beats/min) [64]. So why is there such a major difference in Ca transients, despite relatively similar quantitative changes in many related fundamental properties?

View larger version (27K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Comparison of twitch [Ca]i and SR Ca load in HF rabbit and cAVB dog myocytes. (A) Representative Ca transients for control and HF rabbit myocytes (1 Hz) and control and cAVB dog myocytes at low stimulation frequency (0.25 Hz), both at 37 °C. Average data for (B) twitch [Ca]i and (C) SR Ca load for HF rabbit and cAVB dog myocytes compared to controls. SR Ca loads were based on either caffeine-induced Ca transient amplitudes (for rabbit) or INCX integrals (for dog). These were converted to common units (µmol/l cytosol) using conventions in Bers [1]. Data are from Pogwizd et al. [46] and Sipido et al. [48].

 
A major part of the answer probably lies in the fine details of [Na]_i elevation and how this alters Ca fluxes by NCX during the cardiac cycle. Keep in mind that the major factors that determine the magnitude and direction of Ca flux are [Na]_i, [Ca]_i and E_m (all of which will affect both the NCX reversal potential and NCX flux magnitude). Fig. 4 shows analysis of this scenario with some reasonable assumptions for heuristic purposes. Shown are simulations of how NCX current (I_NCX) and net integrated Ca transport by NCX ( I_NCX) vary during steady state APs in HF vs. control rabbit myocytes (Fig. 4A–D), and in hypertrophic cAVB vs. control dog myocytes (Fig. 4E–H). Values for [Na]_i during steady state stimulation were those measured in rabbit (8.0 and 11.3 mM in control and HF; [9]), and slightly lower values (6 and 9 mM) were used in control and cAVB dog, based on slightly lower resting values and the lower ventricular frequency in the cAVB dog [7]. I_NCX was calculated according to the equation of Weber et al. [68]. Because NCX senses submembrane [Ca] ([Ca]_sm) which can differ from free cytoplasmic [Ca]_i, [Ca]_sm was approximated by the methods of Weber et al. [68] using global twitch [Ca]_i as in Fig. 3 and Despa et al. [9]. Note that in the rabbit HF case the reduction of [Ca]_i is roughly paralleled by reduced [Ca]_sm peak. In the cAVB dog the peak [Ca]_sm is not much different from control, despite a higher peak [Ca]_i. This effect is due to the matching rate of initial [Ca]_i rise between cAVB and control and the continued slower rise in [Ca]_i in cAVB (where the [Ca]_sm inferred is especially sensitive to the rate of [Ca]_i rise; [68]).

View larger version (32K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Changes in INCX expected during HF rabbit (A–D) and hypertrophic cAVB dog (E–H). (A,E) Typical APs for control, HF rabbit (at 1 Hz) and cAVB dog (0.25 Hz). (B,F) [Ca]sm in control and HF calculated from [Ca]i (inset), based on the method of Weber et al. [68] using =110 and 55 ms and =92 and 50 ms for rabbit and dog, respectively. (C,G) INCX calculated in control, HF and cAVB based on the equation of Weber et al. [68] using data from A and B, and the [Na]i values indicated. For rabbit, parameter values were from Despa et al. [9]. For dog INCX, the value of was changed from 0.35 to 0.5 to improve fits to Em-dependence of INCX and the Vmax values for control dog (6.2 A/F) and cAVB dog (12.9 A/F) were similar to values used for rabbit control vs. HF (6 vs. 11 A/F). (D,H) Cumulative INCX Ca flux based on INCX integral (assuming surface:volume ratio of 6.44 pF/pL cytosol). Raw data used were from Pogwizd et al. [46], Despa et al. [9], and Sipido et al. [48].

 
In both HF and Hyp (Fig. 4) the elevated [Na]_i shifts I_NCX during the AP in the outward direction (producing more Ca entry). In the control (both models) there is only a very brief phase of Ca influx via I_NCX at the upstroke of the AP, and this occurs because E_m exceeds the NCX reversal potential. As [Ca]_sm rises and E_m falls I_NCX reverses and is inward, extruding Ca throughout the remainder of the AP. In the control dog example I_NCX happens to be almost zero throughout most of the AP plateau. This may be serendipitous in this particular case, but it emphasizes that very small changes in [Ca]_i, [Na]_i or E_m during the AP markedly influence both the direction and magnitude of Ca flux via NCX. If we make all of the HF changes for the rabbit except the elevated [Na]_i (i.e. increased APD, reduced Ca transient amplitude and enhanced NCX expression level) I_NCX is still inward throughout almost the entire AP (dotted curve in Fig. 4C). However, increasing [Na]_i (as measured) to 11.3 mM shifts I_NCX to be predominantly outward, bringing Ca in during the AP (Fig. 4C, top curve), but the rate of Ca extrusion upon repolarization is very similar to control. The total Ca entry via NCX during the rabbit HF AP is 6 µmol/l cytosol. This is only slightly less than the integrated Ca influx via Ca current (6–12 µmol/l cytosol; [69]). This increases the total amount of Ca entering the cell during an AP, which must all be extruded by NCX prior to the next steady state beat. Thus, the enhanced NCX expression may be required to ensure adequate Ca extrusion between beats (where Ca extrusion via NCX still occurs). In the rabbit HF model SR Ca load and twitch Ca transients are reduced. In this context the Ca entry via NCX during the AP would tend to limit the mechanical dysfunction in HF (by limiting the decline in Ca transients and SR Ca load). It would hence be expected that if [Na]_i did not rise in HF the contractile dysfunction would be even worse. With reduced SR Ca load and release, and also the greater Ca influx via NCX and Ca current (since Ca-dependent inactivation will be less), the balance of fluxes between the sarcolemma and SR in HF shifts toward the former. Three factors contribute to the shift toward more outward I_NCX in HF: (1) longer APD, (2) lower Ca transient amplitude, and (3) elevated [Na]_i with the latter being perhaps most important [9].

In the cAVB dog there is a comparable rise in [Na]_i and at least as much APD prolongation, but the Ca transient amplitude is elevated. The high [Ca]_i (and [Ca]_sm) and more prominent early AP repolarizing notch limit early Ca entry via NCX, such that there is little change in I_NCX early in the APD (Fig. 4G, cAVB vs. control). However, as [Ca]_sm declines while E_m stays depolarized in the long cAVB dog AP, Ca influx via NCX occurs late in the AP. This Ca influx (6 µM from nadir to peak in Fig. 4H) may serve to load the SR and may directly contribute to the increased SR Ca content in the cAVB vs. control, an effect most prominent at lower frequencies where the APD is especially prolonged. At higher frequencies in dog cAVB there is less difference from control for APD (as with HF rabbit [46,75]) and Ca transient amplitude [48]. This may be in part due to a loss of the late phase of Ca entry via I_NCX (as in Fig. 4G,H) with shorter APD. Indeed, as APD gets shorter at higher frequency in cAVB dog, the more active NCX may extrude Ca from the cell more efficiently and limit further increases in SR Ca content. As the CAVB dog in vivo has low heart rates, an increase in SR content at lower frequencies is particularly adequate in maintaining cardiac output. However, one can also ask why the increased NCX activity doesn’t deplete the SR during the longer diastole, at resting potential. Preliminary experiments show that the SR indeed is not depleted (Sipido, Volders and Vos, unpublished data). Again the high [Na]_i may prevent this depletion. Eisner and colleagues [70,71] showed that with high [Na]_i, Ca gain occurs predominantly in diastole. Likewise, spontaneous activity with high [Na]_i is seen at rest, and related to high SR content in the absence of stimulation [72].

So in the HF rabbit why doesn’t the high [Na]_i and Ca influx during the AP lead to enhanced SR Ca load. Part of this could be timing, in that the always shorter rabbit APD allows higher NCX levels to extrude Ca better upon repolarization, while the SR is still filling. This could create a net unloading of Ca from the cell (and SR) in the steady state, despite more Ca influx via I_NCX and I_Ca during the AP (vs. control). However, changes in SR Ca transport properties in HF probably also contribute. As stated above, we saw a 24% reduction in the functional Ca transport rate of the SR in the rabbit HF model. This would also allow NCX to compete more favorably with SR Ca-ATPase during [Ca]_i decline and could account, at least in part, for the failure of SR Ca load to increase at high stimulation frequency. There could also be an increased diastolic Ca leak from the SR [73], which would effectively weaken the SR Ca-ATPase in its competition with NCX and contribute to SR Ca loss in the rabbit HF cells. Indeed, preliminary results in the rabbit HF model indicate enhanced SR Ca leak. Moreover, we find that stimulation of SR Ca-ATPase by isoproterenol in the HF rabbit can raise steady state SR Ca content to levels comparable to control (and also result in spontaneous SR Ca release, see below). Together these factors can explain how the rabbit HF myocyte reaches a lower steady state SR Ca content, twitch Ca transient and contractile function.

	5. Na and arrhythmogenesis in hypertrophy and heart failure

Top 1. [Na]i in hypertrophy... 2. Causes of [Na]i... 3. Functional consequences of... 4. Changes in Ca... 5. Na and arrhythmogenesis... 6. Conclusion References

 
There is considerable evidence from studies in experimental models of Hyp and HF [46,64,67,74,75] that ventricular tachycardia (VT) can initiate by a nonreentrant mechanism such as early (EADs) or delayed afterdepolarizations (DADs). In cAVB dogs with hypertrophy, VT may arise from EADs and DADs [64,65], and DADs have also been demonstrated in hypertrophied rat myocytes (from chronic isoproterenol infusion) [6]. EADs arise from reactivation of the inward Ca current in the setting of prolonged APD [76,77] resulting from decreased outward K currents including the delayed rectifier I_K [53] and the transient outward current I_to [47,78]. DADs arise from increased SR Ca load in association with spontaneous SR Ca release that activates a transient inward current (I_ti) that is carried primarily by NCX [46,64,76].

In heart failure, EADs have been proposed as a potential mechanism of VT [45,78] because of an increased APD (also arising from decreased outward K currents) [51]. However, increased APD is more evident at low stimulation frequencies and the differences between HF and control disappear at physiological stimulation rates [46,75]. DADs, from activation of I_ti, have been demonstrated in HF myocytes [46,75]. Yet HF myocytes exhibit a decreased SR Ca load [46,59,60]. Here lies a paradox where HF myocytes with low diastolic SR Ca load can activate I_ti and trigger an AP by DADs that tend to occur only with SR Ca overload [76]. Perhaps the difference lies in the threshold level of SR Ca for spontaneous release. This was assessed in rabbit HF myocytes and the threshold SR Ca load for spontaneous SR Ca release was unchanged in HF versus controls [46]. The resolution of this paradox is that preserved β-adrenergic responsiveness of the HF myocytes can raise SR Ca load to a level at which there is spontaneous SR Ca release, and activation of an I_ti (mediated by I_NCX). This preserved β-adrenergic responsiveness may explain why there are more arrhythmic deaths in moderate HF versus end-stage HF (when there is significant β-adrenergic unresponsiveness) [79,80] and why β-adrenergic blockers decrease sudden death in HF [81].

So how does [Na]_i play a role in arrhythmogenesis? In both hypertrophy and HF, increased [Na]_i shifts the reversal potential of the NCX to less negative E_m, and by doing so increases Ca influx via reverse NCX (Fig. 4). While the increased SR Ca load from the increased [Na]_i could have a positive inotropic effect (which would be especially beneficial in HF), it would come at the expense of greater arrhythmogenicity by increasing the propensity for spontaneous SR Ca release, activation of I_ti and the development of DADs and nonreentrant VT (especially in the setting of β-adrenergic stimulation) [46]. In the dog with AVB, DADs and VT can be evoked during specific pacing protocols which result in a critical increase in contractility [65], supporting the role of the high SR content in this model. Ouabain will also induce arrhythmias more easily in AVB than in control [65]. Once a spontaneous SR Ca release occurs, having higher NCX expression in Hyp or HF will result in greater I_ti for any [Ca]_i, and downregulation of I_K1 also allows greater DAD amplitude for a given amount of I_ti [46].

The effects of increased [Na]_i on EAD-mediated arrhythmias in Hyp and HF would be more complex and would relate to the specific mechanisms underlying the EADs. EADs in cAVB dogs induced by APD prolongation with antiarrhythmic agents appear to be unrelated to spontaneous SR Ca release [66]. However, EADs induced by β-adrenergic stimulation in the canine heart were shown to involve a common ionic mechanism with DADs that involves SR Ca overload and spontaneous Ca release [82]. As such, increased [Na]_i would be expected to enhance the particular β-adrenergic-induced EADs by enhancement of SR Ca load as discussed above. Thus enhanced [Na]_i may play a similar role in mediating an enhancement of arrhythmogenicity in the setting of Hyp or HF, though in each condition specific additional and modulating factors are present.

	6. Conclusion

Top 1. [Na]i in hypertrophy... 2. Causes of [Na]i... 3. Functional consequences of... 4. Changes in Ca... 5. Na and arrhythmogenesis... 6. Conclusion References

 
Hypertrophy and HF are characterized by alterations in both Ca and Na handling. NCX plays an important central role in cellular Ca handling in both settings, where it can contribute to enhanced or diminished SR Ca load (depending on conditions such as the amplitude of the Ca transient, APD and the altered expression of ion channels and membrane transporters). Na/Ca exchange can play a dual role by mediating I_ti that ultimately leads to DADs and nonreentrant arrhythmias. In this regard, alterations in [Na]_i can have profound effects on cardiac function and arrhythmogenesis. There is increasing evidence that [Na]_i is increased in HF as well as in hypertrophy. While decreased expression of Na/K ATPase and altered pump isoforms have been known to occur in both Hyp and HF, recent evidence suggests that increased Na influx (rather than decreased Na efflux) may underlie this increase in [Na]_i in HF (and possibly in Hyp). The effects of elevated [Na]_i on Ca handling and I_NCX are complex, such that it could lead to enhanced SR Ca load in Hyp and SR Ca unloading in HF. Nonetheless, increased [Na]_i would be expected to enhance arrhythmogenesis (from DADs and/or EADs) both in Hyp and HF because of effects on SR Ca load. With further understanding of the role of Na influx mechanisms such as TTX-sensitive slowly-inactivating Na channels, Na/H exchanger and other Na co-transporters, and how modulation of [Na]_i can affect contractile function and arrhythmogenesis, we may find important new targets for therapeutic approaches for patients with ventricular hypertrophy and HF.

Time for primary review 26 days.

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