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(Circulation. 1999;99:641-648.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Relationship Between Na⁺-Ca²⁺–Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium

Gerd Hasenfuss, MD; Wolfgang Schillinger, MD; Stephan E. Lehnart, MD; Michael Preuss, MD; Burkert Pieske, MD; Lars S. Maier, MD; Jürgen Prestle, PhD; Kazutomo Minami, MD; Hanjörg Just, MD

From Zentrum Innere Medizin (G.H., W.S., S.E.L., B.P., L.S.M., J.P.), Abteilung Kardiologie und Pneumologie, Universität Göttingen, Göttingen, FRG; Medizinische Klinik III (M.P., H.J.), Universität Freiburg, Freiburg, FRG; and Klinik für Thorax- und Kardiovascularchirurgie (K.M.), Herzzentrum Nordrhein-Westfalen, Bad Oeynhausen, FRG.

Correspondence to Gerd Hasenfuss, MD, Universität Göttingen, Zentrum Innere Medizin, Abteilung Kardiologie und Pneumologie, Robert-Koch-Straße 40, 37075 Göttingen, FRG. E-mail hasenfus{at}med.uni-goettingen.de

	Abstract

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Background—In the failing human heart, sarcoplasmic reticulum (SR) calcium handling is impaired, and therefore, calcium elimination and diastolic function may depend on the expression of sarcolemmal Na⁺-Ca²⁺ exchanger.

Methods and Results—Force-frequency relations were studied in ventricular muscle strip preparations from failing human hearts (n=29). Protein levels of Na⁺-Ca²⁺ exchanger and SR Ca²⁺-ATPase were measured in the same hearts. Hearts were divided into 3 groups by discriminant analysis according to the behavior of diastolic function when stimulation rate of muscle strips was increased from 30 to 180 min^-1. At 180 compared with 30 min^-1, diastolic force was increased by 160%, maximum rate of force decline was decreased by 46%, and relaxation time was unchanged in group III. In contrast, in group I, diastolic force and maximum rate of force decline did not change, and relaxation time decreased by 20%. Na⁺-Ca²⁺ exchanger was 66% higher in group I than in group III. Na⁺-Ca²⁺ exchanger was inversely correlated with the frequency-dependent rise of diastolic force when stimulation rate was increased (r=-0.74; P<0.001). Compared with nonfailing human hearts (n=6), SR Ca²⁺-ATPase was decreased and Na⁺-Ca²⁺ exchanger unchanged in group III, whereas Na⁺-Ca²⁺ exchanger was increased and SR Ca²⁺-ATPase unchanged in group I. Results with group II hearts were between those of group I and group III hearts.

Conclusions—By discriminating failing human hearts according to their diastolic function, we identified different phenotypes. Disturbed diastolic function occurs in hearts with decreased SR Ca²⁺-ATPase and unchanged Na⁺-Ca²⁺ exchanger, whereas increased expression of the Na⁺-Ca²⁺ exchanger is associated with preserved diastolic function.

Key Words: heart failure • calcium • myocardium • sarcoplasmic reticulum • diastole • proteins

	Introduction

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Frequency potentiation of contractile performance is an important mechanism for cardiovascular function.¹ As was shown recently, frequency potentiation of contractile performance is blunted or absent in the failing human heart.^{2 3 4} Studies in isolated myocardium indicated that altered force-frequency relation results from disturbed calcium handling, with decreased instead of increased calcium transients as the stimulation frequency rises.^{5 6} This may result from decreased sarcoplasmic reticulum (SR) Ca²⁺-ATPase protein levels or function with decreased SR calcium uptake.^{7 8 9 10} As a consequence, reduced time for calcium transport at higher frequencies would result in decreased SR calcium accumulation and availability for release for systolic activation of contractile proteins. On the other hand, the frequency-dependent deterioration of SR calcium uptake would cause diastolic calcium accumulation, activation of contractile proteins, and therefore disturbed diastolic function.¹¹ Under those circumstances, the sarcolemmal Na⁺-Ca²⁺ exchanger could serve as an alternative mechanism to eliminate calcium from the cytosol.^{11 12 13} The sarcolemmal Na⁺-Ca²⁺ exchanger was shown to be increased at the level of mRNA and protein in failing human myocardium.^{14 15} However, there is great variability in the degree by which diastolic function is altered in patients with heart failure as well as in isolated failing myocardium.^{7 16} Accordingly, the present study was performed to test the hypothesis that differences in diastolic function in end-stage failing human myocardium are related to differences in Na⁺-Ca²⁺–exchanger protein levels.

	Methods

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Patients
Studies were performed in ventricular myocardium from 29 end-stage failing human hearts obtained from patients undergoing cardiac transplantation (see Table 1). For comparison, myocardium was taken from 6 nonfailing hearts that were obtained from brain-dead organ donors and could not be used for transplantation for technical reasons. The study was reviewed and approved by the Ethical Committee of the University Clinics of Freiburg.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Patients With End-Stage Heart Failure

Muscle Strip Preparation
Immediately after cardiectomy, a portion of the left or right ventricle was excised and submerged in "protective" solution at room temperature and oxygenated by bubbling with 95% O₂-5% CO₂.¹⁷ Thin trabeculae or muscle strips were prepared in a dissection chamber,^{17 18} mounted in the muscle chamber, and connected to the force gauge (OPT1L, Scientific Instruments). Muscles were submerged in normal Krebs-Ringer solution (Ca²⁺ 2.5 mmol/L) at 37°C and stimulated (25% above threshold voltage; 5 ms duration). After an equilibration period of 30 to 60 minutes, the muscle was stretched gradually to the length at which maximum steady-state twitch force was reached (l_max). Force-frequency relation was obtained at 37°C by recording and measuring the twitch after stimulation for 5 minutes at each frequency (30, 60, 90, 120, 150, and 180 min^-1). Developed force is the active force developed during the isometric twitch. Diastolic force is the lowest force value during each stimulus interval. Systolic force is the sum of diastolic and developed force. Time to 50% relaxation is the time from peak isometric force to 50% of systolic force. If 50% relaxation of systolic force did not occur at high stimulation rates, the time from peak force to the next stimulus was used. Average cross-sectional area, calculated as the ratio of blotted muscle weight to muscle length (l_max), was 0.34±0.04 mm² (no differences between groups). Measurements were performed in 12 left ventricular and 9 right ventricular muscle strips from 21 hearts with dilated cardiomyopathy and in 3 left ventricular and 5 right ventricular muscle strips from 8 failing hearts with ischemic cardiomyopathy (Table 1). Failing hearts were separated into 3 groups by means of discriminant analysis according to the change of diastolic force after an increase in stimulation rate from 30 to 180 min^-1. Group I includes muscle strips (n=13) with a frequency-dependent decline in diastolic force or a maximum rise in diastolic force of 30%. Group II muscles (n=6) had an increase in diastolic force of 44% to 98% (68% mean rise), and group III muscles (n=10) had an increase of 125% to 238% (160% mean rise).

Quantification of Na⁺-Ca²⁺ Exchanger and SR Ca²⁺-ATPase Protein Levels
Preparation of Cardiac Tissue Homogenates
Samples of the left or right ventricular free wall were taken immediately after explantation, quickly frozen in liquid nitrogen, and stored at -80°C until use.

Approximately 100 mg of myocardium was thawed in a 9-fold volume of an ice-cold solution of 20 mmol/L Na-HEPES, pH 7.4, 4 mmol/L EGTA, and 1 mmol/L DTT containing 0.1 mmol/L leupeptin, 0.3 mmol/L PMSF, and 0.15 µmol/L aprotinin. Homogenization was performed at 4°C for 8x15 seconds by use of a Polytron Homogenizer PT-K (Brinkman Instruments), followed by 15 strokes of a glass homogenizer. The protein concentrations were determined in triplicate according to Lowry et al.¹⁹ The yield of protein per gram of wet weight was 129±7, 128±4, and 134±5 mg/g in myocardium from group I, group II, and group III muscles, respectively, and 111±7 mg/g in myocardium from nonfailing hearts (no significant differences between groups). In addition, there were no differences in protein yields between left and right ventricular myocardium. Aliquots of the homogenates were frozen in liquid nitrogen and stored at -80°C until use.

Western Blot Analysis
Equal amounts of protein from all samples were subjected to SDS-PAGE according to Laemmli²⁰ and blotted to nitrocellulose.²¹ The blots were blocked in 5% nonfat milk dissolved in TBS (20 mmol/L Tris-Cl, pH 7.4, 150 mmol/L NaCl), then probed for 2 hours with an antibody to Na⁺-Ca²⁺ exchanger²² diluted 1:3000 in TBS containing 1% bovine serum albumin and 0.1% Tween 20, or with antibodies to SR Ca²⁺-ATPase (1:10 000)²³ and calsequestrin (1:2000),²⁴ respectively. Then, the membranes were incubated for 1 hour with a peroxidase-labeled antibody (Amersham Buchler Ltd). Immunoreactive bands were visualized by use of a chemoluminescence kit (Amersham Buchler Ltd) and exposure to a Kodak x-ray film. Specific bands were seen at 120, 70, and 40 kDa with the Na⁺-Ca²⁺–exchanger antibody, at 105 kDa with the SR Ca²⁺-ATPase antibody, and at 53 kDa with the calsequestrin antibody.^{8 14 22}

Quantification of Immunoreactive Bands
Band densities were evaluated by use of a 2202 Ultrascan laser densitometer (LKB). Densitometric units of bands obtained with the Na⁺-Ca²⁺–exchanger antibody were added.^{14 22} Because several blots had to be performed to determine levels of each protein in all samples, 1 heart was used as a reference on all blots. Na⁺-Ca²⁺ exchanger and SR Ca²⁺-ATPase protein levels were normalized to calsequestrin protein levels to account for differences in connective tissue content. Each individual value represents the mean of 2 independent determinations. We plotted different amounts of proteins to corresponding densitometric units to check linearity of the assay before each series of blots.

Statistical Analysis
Data are expressed as mean±SEM. Comparisons of force values at different stimulation rates were performed by repeated-measures ANOVA, followed by Student-Newman-Keuls test. Differences between protein levels or force values of the different groups were tested for significance by 1-way ANOVA, followed by Student-Newman-Keuls test, or by Kruskal-Wallis 1-way ANOVA on ranks, followed by the Dunn test. Correlations were examined by linear or nonlinear regression analysis or by multiple regression analysis, if appropriate. A value of P<0.05 was accepted as statistically significant.

	Results

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Mechanical Parameters
In the failing human myocardium, developed force was maximal at the lowest stimulation rate of 30 min^-1 (19.1±1.6 mN/mm²) and was decreased by 59% at 180 min^-1. This resulted from a decrease in systolic force by 6.3±1.1 mN/mm² and a rise in diastolic force by 4.8±0.9 mN/mm² (Figure 1). Hearts were divided into 3 groups by discriminant analysis according to the behavior of diastolic force after an increase in stimulation rate from 30 to 180 min^-1 (Figure 2). In group I, developed force was decreased by 49% at 180 min^-1 compared with 30 min^-1; in groups II and III, it was decreased by 61% and 67%, respectively (Figure 3; Table 2). In group I, diastolic force was slightly but significantly reduced at 120 min^-1; it was not significantly changed at 180 min^-1. Relaxation time was decreased by 20% at 120 and 180 min^-1, and maximum rate of force decline did not change. In group II, diastolic force was increased by 22% at 120 min^-1 and by 68% at 180 min^-1. There was a frequency-dependent decrease in relaxation time by 15%, and maximum rate of force decline was reduced by 25% from 30 to 180 min^-1. In group III, diastolic force was increased by 69% at 120 min^-1 and by 160% at 180 min^-1. Relaxation time did not change, and maximum rate of force decline was reduced by 29% and 46% at 120 and 180 min^-1, respectively (Figure 3; Table 2). The median stimulation frequency at which diastolic force was minimum differed between groups (120 min^-1 in group I, 60 min^-1 in group II [P<0.05 versus group I], and 30 min^-1 in group III [P<0.05 versus group I]). Aftercontractions were observed in 2 muscles from group I and in 1 muscle each from groups II and III. There was no significant correlation between cross-sectional areas of the muscle strip preparations and the rise of diastolic force after an increase in the stimulation frequency.

View larger version (17K): [in this window] [in a new window]   Figure 1. Influence of stimulation frequency on isometric force development in failing human myocardium (n=29). *Significantly different from lowest stimulation frequency of 30 min-1.

View larger version (15K): [in this window] [in a new window]   Figure 2. Original recordings of isometrically contracting failing human myocardium. Top, Muscle strip representative of group I hearts showing slight decrease of diastolic force at 120 vs 30 min-1 (cross-sectional area was 0.25 mm2). Middle, Muscle strip representative of group II hearts showing moderate increase in diastolic force from 30 to 180 min-1 (cross-sectional area was 0.16 mm2). Bottom, Muscles strip representative of group III hearts exhibiting pronounced rise of diastolic force from 30 to 120 and 180 min-1 (cross-sectional area was 0.16 mm2).

View larger version (23K): [in this window] [in a new window]   Figure 3. Influence of stimulation frequency on developed force (top) and diastolic force (bottom). Frequency-dependent rise of diastolic force and fall of developed force are most pronounced in group III. Differences in statistics compared with Table 2 result from the fact that calculations are done with absolute values in Table 2 and with percentage values in Figure 3. *P<0.05 vs 30 min-1; #P<0.05 vs group I.

View this table: [in this window] [in a new window]   Table 2. Mechanical Parameters of Muscle Strip Preparations

Relationship Between Diastolic Function and Protein Levels of Na⁺-Ca²⁺ Exchanger and SR Ca²⁺-ATPase
Protein levels of SR Ca²⁺-ATPase and Na⁺-Ca²⁺ exchanger were normalized to calsequestrin protein levels, which were not significantly different between groups (6.2±0.4, 6.5±0.9, and 7.8±0.6 densitometric units per milligram of protein in groups I, II, and III, respectively). In group I, Na⁺-Ca²⁺–exchanger protein levels were 39% higher than in group II and 65% higher than in group III myocardium (Figure 4). There was a significant inverse correlation between Na⁺-Ca²⁺–exchanger protein levels and the change in diastolic force after a rise in the stimulation frequency from 30 to 180 min^-1 (Figure 5). Furthermore, there were significant linear inverse correlations between Na⁺-Ca²⁺–exchanger protein levels and relaxation times at 120 min^-1 (r=-0.61; P<0.005) and 180 min^-1 (r=-0.57; P<0.005).

View larger version (13K): [in this window] [in a new window]   Figure 4. Protein levels of Na+-Ca2+ exchanger normalized to calsequestrin protein levels, both in arbitrary densitometric units per milligram of protein (therefore, ratio has no unit). *P<0.05 vs nonfailing myocardium; #P<0.05 vs group I.

View larger version (18K): [in this window] [in a new window]   Figure 5. Relationship between protein levels of Na+-Ca2+ exchanger (normalized to calsequestrin) and change in diastolic force after an increase in stimulation frequency from 30 to 180 min-1, given in percent of diastolic force value at 30 min-1. When nonlinear regression analysis was performed, r=-0.74; P<0.0001. Linear regression analysis yielded r=-0.66; P<0.001. Multiple regression analysis including SR Ca2+-ATPase as a second independent variable did not result in a relevant change of the correlation coefficient. Values from 1 nonfailing human heart, which was not included in regression analysis, are also shown ().

SR Ca²⁺-ATPase protein levels tended to be higher in group I than in group II and III hearts, with no statistically significant difference between groups (Figure 6). There was no significant correlation between SR Ca²⁺-ATPase protein levels and diastolic function of the failing hearts. The ratios of Na⁺-Ca²⁺ exchanger to SR Ca²⁺-ATPase protein levels were similar in all groups of failing myocardium (Figure 7).

View larger version (12K): [in this window] [in a new window]   Figure 6. Protein levels of SR Ca2+-ATPase normalized to calsequestrin protein levels, both in arbitrary densitometric units per milligram of protein (therefore, ratio has no unit). *P<0.05 vs nonfailing myocardium.

View larger version (13K): [in this window] [in a new window]   Figure 7. Ratio of Na+-Ca2+ exchanger to SR Ca2+-ATPase protein levels. *P<0.05 vs nonfailing myocardium (ANOVA followed by Student-Newman-Keuls test); #P<0.05 vs group I (ANOVA followed by Student-Newman-Keuls test); §P<0.05 vs nonfailing myocardium (paired t test).

Comparison of Protein Levels Between Failing and Nonfailing Myocardium
Calsequestrin protein levels in nonfailing myocardium were 6.4±0.6 densitometric units per milligram of protein, which was not different from failing hearts. Compared with nonfailing hearts, Na⁺-Ca²⁺–exchanger protein levels were increased in group I hearts by 80% but were not significantly changed in group II and III hearts (Figure 4). In contrast, SR Ca²⁺-ATPase protein levels were significantly decreased by 48% in group III hearts but were not significantly changed in group I and group II hearts (Figure 6).

As a consequence, compared with control, the ratio of Na⁺-Ca²⁺ exchanger to SR Ca²⁺-ATPase was increased by 241% in group I and by 139% and 189% in groups II and III, respectively (Figure 7). There were no significant differences between protein levels from right and left ventricles of the different disease groups (Table 3).

View this table: [in this window] [in a new window]   Table 3. Protein Levels in Left and Right Ventricular Myocardium

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study demonstrates the following: (1) Na⁺-Ca²⁺–exchanger protein levels are significantly higher in failing hearts that exhibit no frequency-dependent rise of diastolic force (group I); (2) the degree of rise in diastolic force is inversely related to protein levels of Na⁺-Ca²⁺ exchanger; (3) comparison with nonfailing myocardium identifies 2 extreme phenotypes of failing hearts at both ends of the spectrum (group I is characterized by increased Na⁺-Ca²⁺ exchanger and unchanged SR Ca²⁺-ATPase protein levels, whereas in group III, SR Ca²⁺-ATPase levels are significantly decreased and Na⁺-Ca²⁺–exchanger levels are unchanged); and (4) the ratio of Na⁺-Ca²⁺ exchanger to SR Ca²⁺-ATPase is similarly increased in all groups of failing hearts (by a factor of 2 to 4) compared with nonfailing myocardium.

Diastolic function of the heart depends on passive elastic properties of the myocardium as well as on active diastolic force generation due to calcium activation of contractile proteins.^{25 26 27} Beat-to-beat regulation of diastolic calcium occurs predominantly by SR calcium uptake and transsarcolemmal Na⁺-Ca²⁺-exchange.¹¹ In addition, calcium uptake by mitochondria may contribute to control of diastolic calcium.²⁸

The present finding of higher Na⁺-Ca²⁺–exchanger protein levels in group I than in groups II and III or in nonfailing hearts supports the hypothesis that an increase in protein levels of Na⁺-Ca²⁺ exchanger represents an important mechanism for regulation of diastolic calcium elimination and diastolic function in the failing human myocardium.

We were concerned that the frequency-dependent rise of diastolic force in group II and III hearts may have been the consequence of calcium overload due to damage of the muscle strip. However, this is unlikely because diastolic force tended to be even lower in group III at low stimulation rates, and the ratio of developed to diastolic force tended to be higher in group III than in group I muscles. Hypoxia as a cause of disturbed diastolic function is also unlikely because cross-sectional areas were similar in all groups and were below the critical cross-sectional areas above which hypoxia may occur under experimental conditions in human myocardium.^{4 17 18} Furthermore, there was no significant correlation between the cross-sectional areas of the individual muscle strip preparations and the rise of diastolic force at 180 min^-1.

Interpretation of the data is more complex when SR Ca²⁺-ATPase protein levels are taken into account. In group III, SR Ca²⁺-ATPase levels tended to be lower than in groups I and II and were significantly reduced by 48% compared with nonfailing control myocardium. Thus, in addition to lower Na⁺-Ca²⁺–exchanger levels, lower SR Ca²⁺-ATPase levels in group III versus group I may contribute to disturbed diastolic function. Interestingly, the ratio of Na⁺-Ca²⁺ exchanger to SR Ca²⁺-ATPase levels was similar in group I, group II, and group III myocardium but was considerably increased (by a factor of 2 to 4) compared with control. This shows that in all groups, levels of Na⁺-Ca²⁺ exchanger are increased relative to SR Ca²⁺-ATPase. If protein levels reflect transport function, this suggests that calcium elimination across the sarcolemmal membrane is increased relative to calcium uptake by the SR. Because there is evidence that the activity of SR Ca²⁺-ATPase is depressed in failing myocardium by increased phospholamban inhibition of the pump or other mechanisms, the functional consequence of the increased Na⁺-Ca²⁺ exchanger to SR Ca²⁺-ATPase ratio may be even more relevant.^{8 10}

Both mechanisms for cytosolic calcium elimination work in concert with respect to preserve diastolic function. However, the Na⁺-Ca²⁺ exchanger, which eliminates calcium from the myocyte, is the competitor of SR Ca²⁺-ATPase regarding SR calcium uptake and thus SR calcium content and availability for systolic activation of contractile proteins. In light of this, the shift toward a more pronounced transsarcolemmal calcium elimination may be the cause of depressed systolic performance in group I myocardium, in which increased expression of the Na⁺-Ca²⁺ exchanger predominated and SR Ca²⁺-ATPase protein levels were not significantly decreased. This would be consistent with recent observations²⁹ in pressure-volume–overloaded rabbit myocardium with reduced systolic function, in which increased expression of Na⁺-Ca²⁺ exchanger without a significant change in SR Ca²⁺-ATPase levels was observed.

On the other hand, the more pronounced decline of developed force at higher stimulation frequencies (steep inversion of the force-frequency relation) in group III myocardium (Figure 3) may predominantly be the consequence of decreased SR Ca²⁺-ATPase protein levels. This is consistent with previous findings that the degree of inversion of the force-frequency relation changes in parallel with the degree of reduction of SR Ca²⁺-ATPase protein levels.⁷ At a low stimulation frequency of 30 min^-1, calcium accumulation into the SR may still be sufficient for low diastolic calcium concentrations and adequate calcium availability for systolic release in group III. However, at high stimulation frequencies with decreased time for calcium transport, reduced SR calcium accumulation may be the cause of decreased calcium release and force development as well as of increased diastolic force.

The present findings raise the question of which molecular changes may be responsible for the different phenotypes in the failing human myocardium. Differences are not related to different etiologies of the underlying diseases. The finding of a relative increase in Na⁺-Ca²⁺ exchanger over SR Ca²⁺-ATPase protein levels in failing compared with nonfailing human myocardium is in accordance with a previous study on mRNA levels.¹⁴ This may suggest that the changes occur at a transcriptional level. Increased expression of Na⁺-Ca²⁺ exchanger and decreased expression of SR Ca²⁺-ATPase compared with normal adult myocardium reflect the fetal type of expression of calcium cycling proteins in different animal species.^{30 31 32} Both changes result in reduced SR calcium content and calcium availability for systolic activation of contractile proteins. Although decreased expression of SR Ca²⁺-ATPase was observed in many models of myocardial hypertrophy and failure, the finding of increased expression of Na⁺-Ca²⁺ exchanger is less consistent (reviewed in References ³³ and ³⁴ ). This may suggest that regulation of expression of both calcium transporters occurs by different and independent signals. Accordingly, it was recently shown that expression of SR Ca²⁺-ATPase but not that of Na⁺-Ca²⁺ exchanger decreases from the epicardial to the endocardial region of the human heart.³⁵

In summary, discrimination of failing human myocardium according to differences in diastolic function results in subgroups with considerable differences in expression of calcium-regulatory proteins, which suggests that 2 different phenotypes exist at both ends of the spectrum: (1) end-stage failing hearts with increased protein levels of the Na⁺-Ca²⁺ exchanger and unchanged SR Ca²⁺-ATPase levels and (2) end-stage failing hearts with markedly decreased SR Ca²⁺-ATPase protein levels and unchanged Na⁺-Ca²⁺–exchanger levels. Although both types may be associated with decreased systolic calcium availability and impaired systolic function, only the latter type is associated with combined systolic and diastolic dysfunction.

	Acknowledgments

 
This study was supported by DFG grant HA 1233/3-3. We are very grateful to Christine Hoffmann, Dipl. Psych., from the Institut für Sozialpsychologie, Universität Freiburg, FRG, for excellent suggestions in statistical analysis.

Received May 14, 1998; revision received October 8, 1998; accepted October 22, 1998.

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