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J Am Coll Cardiol, 2000; 36:233-241
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES: HEART FAILURE

Is myocardial Na+/Ca2+ exchanger transcription a marker for different stages of myocardial dysfunction? Quantitative polymerase chain reaction of the messenger RNA in endomyocardial biopsies of patients with heart failure

Cornelia Piper, MD*, Johannes Bilger, MD{dagger}, Eva-Maria Henrichs{dagger}, Heinz-Peter Schultheiss, MD, FESC{dagger}, Dieter Horstkotte, MD, FESC* and Andrea Doerner, PhD{dagger}

* Department of Cardiology, Heart Center North Rhine-Westphalia, University Hospital of the Ruhr University of Bochum, Bad Oeynhausen, Germany
{dagger} Department of Cardiology, Benjamin Franklin Hospital, Free University of Berlin, Berlin, Germany

Manuscript received May 27, 1999; revised manuscript received December 30, 1999, accepted March 1, 2000.

Reprint requests and correspondence: Dr. Andrea Doerner, Department of Cardiology, Benjamin Franklin Hospital, Free University of Berlin, Hindenburgdamm 30, 12000 Berlin, Germany.
doerner{at}ukbf.fu-berlin.de


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

This study was designed to determine the stage of myocardial dysfunction at which an upregulation of the Na+/Ca2+exchanger (EXCH) transcription takes place.

BACKGROUND

Because EXCH is an important regulator of intracellular calcium homeostasis, alterations in EXCH expression may occur before the onset of end-stage heart failure (HF) to maintain normal intracellular Ca2+ concentrations. We analyzed whether the EXCH transcription level is correlated to the degree of myocardial dysfunction and whether it can be a suitable molecular marker to define the transition to myocardial decompensation early on.

METHODS

By quantitative polymerase chain reaction technique, the level of EXCH transcription was analyzed in myocardial biopsies from 40 patients with various degrees of myocardial dysfunction due to valvular heart disease (VHD; n = 22) or dilated cardiomyopathy (DCM; n = 18). Additionally, biopsies from 7 individuals with excluded heart disease and explanted heart tissue from 13 patients with end-stage HF were investigated.

RESULTS

The level of EXCH transcription of controls (2.6 ± 1.2 attomoles [amol]/ng total RNA) did not differ from that of patients with DCM (2.3 ± 1.5 amol/ng) or VHD (2.1 ± 1.5 amol/ng). No alteration in the EXCH transcription was found in VHD and DCM patients with respect to the severity of myocardial dysfunction. However, patients with end-stage HF showed a four-fold increase in EXCH transcription, amounting to 8.9 ± 1.9 amol/ng (p < 0.05).

CONCLUSIONS

The upregulation in EXCH transcription either occurs very late in human heart failure or is a phenomenon of heart transplantation in end-stage HF. Consequently, myocardial EXCH transcription cannot be used as a marker for early myocardial decompensation.

Abbreviations and Acronyms
  AR = aortic regurgitation
  AS = aortic stenosis
  CI = cardiac index
  DCM = dilated cardiomyopathy
  EF = ejection fraction
  EXCH = Na+/Ca2+ exchanger
  ICM = ischemic cardiomyopathy
  MR = mitral regurgitation
  NYHA = New York Heart Association
  PLaorta = transaortic pressure loss
  RFaorta = transaortic regurgitation
  RFmitral = transmitral regurgitation
  VAD = ventricular assist device

An upregulation of the sarcolemmal Na+/Ca2+ exchanger (EXCH), an important regulator of the intracellular calcium concentration in both mRNA and protein levels, has been demonstrated in end-stage heart failure (HF) (1,2). The electrogenic exchange of one Ca2+ for three Na+ ions across the sarcolemmal membrane by the EXCH maintains low diastolic cytosolic Ca2+ levels and enables diastolic relaxation to take place (3,4). In addition, the EXCH improves cardiac contractility by increasing the systolic influx of Ca2+ ions into the cell (2,5,6). An upregulation of the EXCH may help to compensate abnormally high intracellular Ca2+ concentrations that contribute to the systolic and diastolic functional impairment in the failing heart (7–9).

As diastolic and systolic functions are disturbed long before HF manifests itself, we investigated the stage of myocardial dysfunction at which the EXCH transcription alters, and whether this alteration in the EXCH is a suitable molecular marker for defining the prognostically important transition from adequate to inadequate myocardial adaptation due to chronic pressure and/or volume overload (10–14).

To this end, and for the first time ever, the EXCH transcription level was determined in endomyocardial biopsies from patients with mild to severe myocardial dysfunction and was compared with that measured in hearts explanted from patients with end-stage HF.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   Forty patients (age range 31–85 years, mean 57 ± 13 years; 27 men, 13 women) with chronic pressure overload (aortic stenosis [AS], 11 patients), volume overload (aortic regurgitation [AR], 5 patients; primary mitral regurgitation [MR], 6 patients) or dilated cardiomyopathy (18 patients) were examined. All patients underwent diagnostic right and left heart catheterization including coronary angiography. Significant (>50%) coronary artery disease was excluded in all patients. During right heart catheterization, small biopsies were taken from the interventricular septum, immediately frozen in liquid nitrogen and stored at –80°C. The EXCH expression has been shown to be the same in the interventricular septum and the right and left ventricles in hearts explanted from patients with end-stage HF (15). Biopsies were screened to exclude the presence of myocarditis according to the Dallas classification (16). The study was approved by the ethics committee of the Free University of Berlin, Germany.

The clinical and hemodynamic characteristics of the patients enrolled in the study are listed in Tables 1 The severity of aortic valve obstruction was graded according to the transvalvular pressure loss and Table 2. (PLaorta), the mean transaortic pressure gradient (dp) and effective stroke volume coefficient, which was determined from the simultaneous records of the left ventricular (transseptal technique) and aortic pressure curves. Effective left ventricular stroke volume was determined by the thermodilution method. Hemodynamically relevant AS was defined as PLaorta ≥ 1 mm Hg per ml stroke volume (14). Aortic regurgitation and MR were estimated using the transvalvular regurgitant fraction (RF), which is the difference between total (measured angiographically) and effective left ventricular stroke volume (measured by thermodilution technique). Regurgitant fractions of >30% were considered hemodynamically relevant (13) (Table 1).


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  		Table 1 Clinical, Hemodynamic and Echocardiographic Characteristics of Patients With Valvular Heart Disease

 

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  		Table 2 Clinical, Hemodynamic and Echocardiographic Characteristics of Patients With Dilated Cardiomyopathy

 
In addition to valvular patients, endomyocardial samples were taken from the right ventricular septum of 13 explanted hearts (Table 3) failing because of dilated cardiomyopathy (DCM; n = 2) or ischemic cardiomyopathy (ICM; n = 11). Endomyocardial samples from two healthy donors and from five individuals without myocardial dysfunction, who underwent cardiac catheterization and myocardial biopsies to exclude coronary artery disease and myocarditis, served as controls.


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  		Table 3 Clinical and Hemodynamic Characteristics of Patients Undergoing Heart Transplantation Because of End-Stage HF Caused by Ischemia (End-Stage ICM) or Dilated Cardiomyopathy (End-Stage DCM)

 
Assessment of ventricular function.   Left ventricular ejection fraction (EF) and total stroke volume were determined by cineangiography using the analytic calibration method (17,18). Cardiac index (CI) was calculated as the average of five thermodilution measurements. Hemodynamic data are given in Tables 1 and 2. All patients had transthoracic echocardiography including measurement of left ventricular end-diastolic (LVEDD) and end-systolic (LVESD) dimensions, fractional shortening (FS), end-diastolic left ventricular posterior wall thickness (LVPW) and maximal systolic meridional wall stress (ws) (g/cm2) (Tables 1 and 2). Wall stress was determined according to the Laplace law. Left ventricular radius (LVEDD/2), LVPW and left ventricular peak systolic pressure (LVPRsyst), measured during catheterization, were used to calculate left ventricular wall stress according to the following equation (10):

Quantitative polymerase chain reaction.   The competitive quantitative polymerase chain reaction (q-PCR) was employed to determine the EXCH messenger ribonucleic acid (mRNA) amount in the endomyocardial specimens from the patients described. An internal RNA standard was used, simultaneously reversely transcribed with the target RNA and competitively amplified in the PCR.

Construction of the competitor
A bluescript vector, containing 1.3 kb of the coding and 0.2 kb of the noncoding sequence from guinea pig EXCH complementary deoxyribonucleic acid (cDNA), was used for the synthesis of competitor complementary RNA. An 82-bp fragment was released from the coding region by digestion with Bcll and Hpal. After religation 10 µg plasmid was linearized with Xhol according to the instructions of the manufacturer (Boehringer Mannheim). Transcription was performed in a reaction mixture containing 1 µg plasmid, 5 µl 5x transcription puffer, 5 mmol/liter DTT, 10 U RNAsin-Inhibitor (Boehringer Mannheim) and 4 mmol/liter each of rNTP and 100 U T3-polymerase (Stratagene) at 37°C for 1 h. The transcription mixture was subjected to a 1% low-melting gel electrophoresis. cRNA was extracted with phenol/chloroform and was precipitated with 0.1 vol% sodium acetate pH 5.2 and 2.5 vol% ethanol at –80°C overnight. The RNA was stabilized with tRNA (100 ng tRNA/µl cRNA). The purity of the standard was proved by PCR using nontranscribed standard RNA, which produced no detectable signal.

Quantitative PCR
Total RNA was extracted from the endomyocardial biopsies using the LiCl method (19). The conditions of the reverse transcription and the PCR were optimized, especially in view of the cycles, the amount of isolated total RNA and standard cRNA (data not shown). The following conditions were employed: equal amounts of total RNA (7.5 ng) isolated from the endomyocardial specimens were mixed with increasing amounts of competitor (3.5, 7, 14, 28, 56, 112, 224, and 448 attomoles [amol]) in a reverse transcription (RT) mixture of 12.5 µl, containing 2.5 µl 5 x first strand buffer (GIBCO, Karlsruhe, Germany), 5 U RNAse Inhibitor (Boehringer Mannheim), 0.4 mmol/liter of dNTP mix (Boehringer Mannheim), 8 ng random primer, 8 mmol/liter DTT and 200 U MMLV-Reverse transcriptase (GIBCO).

Sense and antisense primers (5': 5'-AAT GAG CTT GGT TTC ACA-3' and 3': 5'-CCG CCG ATA CAG CAG CAC-3') were chosen to lie in homologous regions of the human (20) and guinea pig (21) cDNA sequences. Competitive PCRs were carried out in a 25-µl reaction mixture containing 10 mmol/liter Tris-HCl, pH 8.3; 50 mmol/liter KCl; 1.5 mmol/liter MgCl2; 200 µmol/liter of each dNTPs; 0.4 µmol/liter of each primer; 5 µl RT mixture and 0.63 U of Taq polymerase (Cetus Perkin Elmer, Weiterstadt, Germany). The denaturation, annealing and extension conditions for the amplification were 45 s at 94°C, 45 s at 60°C and 90 s at 72°C. Thirty amplification cycles were performed with a thermal cycler (Biozyme). Polymerase chain reaction products were subjected to agarose gel electrophoresis and stained with ethidium bromide. Gels were scanned by a computer-based video system (Polaroid, Offenbach, Germany). The intensity of the ethidium–bromide-stained bands of the target and the competitor RNA were evaluated by a computer-based imaging system (NIH image). To correct for differences in the size of the target (861 bp) and the competitor (778 bp) PCR products, the band densities of the respective competitors were multiplied by the specific factor of 1.11. The target/competitor ratio was plotted against the amount of competitor in a log scale. The linear regression was calculated. The amount of competitor corresponding to the log ratio value of 0 is equivalent to the amount of total EXCH-specific RNA in the specimens. The level of EXCH transcription was expressed as amol/ng of total RNA.

Statistical analysis
All data are given as mean ± SD. For statistical analysis nonparametric tests were used; for comparisons of more than two groups the Kruskal Wallis test was applied for testing the global hypothesis. In case of a significant result, the nonparametric Dunn’s test was then used to assess the two-by-two differences. The test of Dunn is based on the comparison in pairs of the mean ranks of the groups. All analyses were performed using SPSS 8.0 software, except for the Dunn’s test (SAS 6.13, Cary, North Carolina).

The p values are given in the following classes: <0.01 and <0.05. A p value of <0.05 was considered significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
This study was designed to clarify whether changes in cardiac function are associated with an altered transcription of the sarcolemmal EXCH in patients with valvular heart disease or DCM. To determine the EXCH mRNA copy number in small endomyocardial biopsy samples, the quantitative PCR technique was employed, using an internal RNA standard as a competitor (Fig. 1).



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  		Figure 1 Total EXCH mRNA quantification by competitive PCR. A constant amount of total RNA (7.5 ng), isolated from an endomyocardial biopsy from a patient suffering from DCM, was mixed with a decreasing amount of competitor cRNA, reverse transcribed and amplified by PCR.

 
The EXCH mRNA level amounted to an average of 2.6 ± 1.2 amol/ng total RNA in the control group. A fourfold increase (8.9 ± 1.9 amol/ng) was found in hearts explanted from patients with end-stage HF due to ischemic or DCM, whereas no differences were seen in patients with AS (1.8 ± 1.4 amol/ng), AR/MR (2.0 ± 1.5 amol/ng) or DCM (2.3 ± 1.5 amol/ng) (Fig. 2).



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  		Figure 2 Plots showing a significant difference (p < 0.05) between the Na+/Ca2+ exchanger mRNA levels of explanted hearts (expl) from patients with end-stage heart failure and those found in endomyocardial tissues of controls (c), of patients with aortic stenosis (AS), aortic or mitral regurgitation (AR/MR), and of dilated cardiomyopathy (DCM).

 
No significant changes in EXCH mRNA amount were found in the group of patients with normal to mildly impaired (EF > 50%) left ventricular EF, with an EF of 30% to 49% or with an EF < 30% (Fig. 3). Similar results were obtained when EXCH amount was correlated to CI, as patients with normal CI (CI > 3.5 liters/min/m2), reduced CI (CI 2.4–3.5 liters/min/m2) or very low CI (CI < 2.4 liters/min/m2) had similar EXCH amounts of 2.0 ± 1.6, 2.0 ± 1.5 or 2.5 ± 1.3 amol/ng total RNA. There was no correlation to other invasively measured hemodynamic parameters and echocardiographic data, nor was there a correlation to the hemodynamic severity of valvular stenosis or valvular regurgitations (Tables 1 and 2).



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  		Figure 3 No significant changes in the Na+/Ca2+ exchanger mRNA transcription level were obtained within patients with chronic heart failure (CHF) irrespective of left ventricular ejection fractions (EFs): EF ≥ 50%, EF = 30%–49% or EF < 30%. But a significant (p < 0.01) difference in EXCH transcription was found between patients with severe CHF (EF < 30%) and explanted hearts (expl), although EF was reduced similarly.

 
Not even patients with severe HF (New York Heart Association [NYHA] grade IV) and a critical hemodynamic condition showed an increase in EXCH transcription, which was found only in tissue from explanted hearts. The EXCH mRNA tended to be lower in patients with heart valve disease and NYHA class I or II than in those with heart valve disease and NYHA class III or IV which was not seen in patients with dilated cardiomyopathy (Fig. 4).



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  		Figure 4 Plots showing a significant difference (p < 0.01) in the EXCH transcription level, even between CHF in NYHA IV and expl, although the clinical situation was similar. Otherwise, a nonsignificant tendency toward lower EXCH mRNA levels was found in NYHA I/II compared with NYHA III/IV for VHD, not seen in DCM.

 
Systolic wall stress, a parameter indicating the state of myocardial adaptation to increased workload, did not induce an increase in the EXCH mRNA level (Fig. 5).



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  		Figure 5 No significant elevation in EXCH transcription level in CHF according to systolic wall stress, a parameter indicating the state of myocardial adaptation to increased workload, is demonstrated.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Transcription and translation of EXCH is known to be upregulated in myocardium of failing hearts. This may be related to changes in calcium homeostasis. The stage of cardiac dysfunction at which upregulation occurs is unknown so far. We therefore examined the EXCH mRNA level in endomyocardial biopsies from patients with mildly, moderately and severely impaired left ventricular function, employing the quantitative PCR technique.

EXCH and calcium homeostasis.   Consistent with earlier findings (1,2), we found a significant increase in the EXCH mRNA amount in explanted human myocardium from patients with end-stage HF. However, we did not see any alterations of EXCH in endomyocardial biopsies from patients with heart failure of varying severity. These findings indicate that the EXCH mRNA level does not change until the myocardium has been finally damaged.

In severe, but not end-stage, HF the intracellular calcium homeostasis seems to be maintained without alteration of the EXCH expression (22). It is likely that the upregulation of the EXCH observed in end-stage HF is necessary to compensate intracellular calcium overload by increasing the calcium efflux across the sarcolemmal membrane (23). Schillinger et al. (24) reported that a subset of patients with end-stage HF had higher levels of EXCH. This study divided the patients into groups with either predominant systolic or predominant diastolic alteration of the force development in isolated muscle strips. Patients with systolic dysfunction showed only slightly increased protein levels of EXCH, whereas EXCH levels doubled in patients with diastolic dysfunction. In the latter group, an inverse relationship between EXCH levels and the severity of diastolic dysfunction was observed, pinpointing the importance of EXCH for diastolic function.

Exch upregulation.   In our study, upregulation of the myocardial EXCH was found to occur only after manifestation of end-stage HF. Whether this upregulation of EXCH occurred shortly before or during heart transplantation is not known. Dipla et al. (25) observed, in favor for EXCH upregulation before heart transplantation, alterations in calcium homeostasis just before heart transplantation was performed. They showed that if patients were put on a ventricular assist device (VAD) before transplantation, contractility, relaxation and catecholamine responsiveness of myocytes isolated from explanted hearts improved, because VAD therapy resulted in higher Ca2+ transportation rates. This indicates an interaction between central hemodynamics and calcium homeostasis. Whether alterations in the EXCH expression were involved in the improvement of calcium transportation rates and of myocardial function remains speculative, although an upregulation of the EXCH expression has been shown to be related to the severity of diastolic dysfunction in failing human hearts (24,26).

Potential mechanisms of EXCH upregulation.   The rise in the EXCH amount may be due to an extremely decelerated relaxation, a reduced response to beta-adrenergic stimulation, decreased force production (25,27) or biochemical changes (acidosis and ATP depletion in endomyocardial ischemia [28], increased levels of circulating cytokines [29] or neurohumoral activation [28,30]) frequently observed in HF.

Otherwise, upregulation of the EXCH mRNA amount is likely to be a phenomenon induced by heart transplantation or perioperative procedures/medications, especially in patients with severely damaged heart tissue (31,32). An alteration in the EXCH expression was shown to occur within 1 to 2 h of acute pressure overload (33), pharmacologically induced increase of Na+ influx (33) or acute ischemia induced in animal models. For example, a significant upregulation of the EXCH expression was seen after adrenergic stimulation with phenylephrine in ventricular cardiocytes of rats, but not if the alpha-receptors had been blocked with prazosin (34). These data demonstrate that, in rats, alpha-adrenergic stimulation induces an increase in EXCH mRNA within 1 h and an increase in protein levels within 24 h. However, in patients with end-stage HF, catecholamines do not seem to influence the upregulation of EXCH transcripts, as elevated EXCH levels were documented even when all patients who had received catecholamines preoperatively were excluded (2).

Volatile anesthetics such as halothane are known to influence EXCH by decreasing the activity of the exchanger, which in turn may induce an elevation of EXCH transcription to compensate for the loss of EXCH activity (35,36).

Myocardial adaptation.   Our data show that alterations in EXCH transcription do not parallel myocardial dysfunction, but occur only in conjunction with end-stage HF. Therefore, EXCH expression is not an early marker for inadequate myocardial adaptation to chronic pressure and/or volume overload (37,38), and timing of surgical intervention may not be directed by this parameter (39,40).

Study limitations.   In this study, the EXCH mRNA levels, but not the EXCH protein levels, were measured in endomyocardial tissue from patients with various degrees of HF. The limited biopsy material forced us to neglect this parameter. However, this parameter is not essential for the assessment of EXCH alterations in patients with myocardial dysfunction, as other groups have shown that an increase in mRNA level is always accompanied by an increase in EXCH protein level.

Conclusion.   Our data indicate that the EXCH transcription level is upregulated in explanted human hearts with end-stage HF, but not in myocardial biopsies from patients with moderate to severe HF. Upregulation of EXCH expression either occurs very late in the natural history of HF as an indication of irreversible myocardial damage or is a phenomenon of hemodynamic, autocrine, endocrine, ischemic and/or drug-induced changes during heart transplantation.


   Acknowledgments
 
We would like to thank Mr. Helmut Drexler and Mr. Hans Reinecke for their technical assistance, and Mr. Rito Bergemann from the Institute of Medical Outcome Research (IMOR) for the statistical analyses.


   Footnotes
 
This study was supported by a grant from the Franz-Loogen Foundation.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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