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Ann Thorac Surg 2001;72:2044-2050
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Myocardial tumor necrosis factor–{alpha} expression does not correlate with clinical indices of heart failure in patients on left ventricular assist device support

Peter Razeghi, MDa, Madhuri Mukhopadhyay, BSa, Timothy J. Myers, BSb, Janelle N. Williams, BSa, Christine S. Moravec, PhDc, O. Howard Frazier, MDb, Heinrich Taegtmeyer, MD, DPhil*a,b

a Division of Cardiology, The University of Texas-Houston Medical School, Houston, Texas, USA
b St. Luke’s Episcopal Hospital and Texas Heart Institute, Houston, Texas, USA
c Cleveland Clinic Foundation, Cleveland, Ohio, USA

Accepted for publication July 30, 2001.

* Address reprints requests to Dr Taegtmeyer, Department of Internal Medicine, Division of Cardiology, The University of Texas-Houston Medical School, 6431 Fannin, MSB 1.246, Houston, TX 77030, USA
e-mail: heinrich.taegtmeyer{at}uth.tmc.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Mechanical unloading with a left ventricular assist device (LVAD) can improve clinical indices of heart failure and alter myocardial tumor necrosis factor–{alpha} (TNF{alpha}) expression, but a correlation between clinical and molecular indices has not been established.

Methods. We enrolled 14 patients with end-stage heart failure treated with drugs and mechanical unloading in a protocol including the collection of myocardial tissue samples at LVAD implantation and explantation. Ten nonfailing donor hearts served as controls. TNF{alpha} expression was measured by quantitative reverse transcription polymerase chain reaction. Clinical indices of heart failure were retrospectively analyzed and correlated with myocardial TNF{alpha} expression.

Results. Left ventricular end-diastolic dimension decreased (p < 0.01) and cardiac index (p < 0.001) increased with unloading. Abnormal values of serum sodium, creatinine, blood urea nitrogen, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, and albumin showed a trend toward normalization with mechanical unloading. TNF{alpha} expression was increased in 5 of 14 patients and decreased with mechanical unloading in 4 of them. Surprisingly, there was no correlation between mRNA levels of TNF{alpha} and any of the clinical indices studied.

Conclusions. Although clinical indices of heart failure improve and elevated levels of myocardial TNF{alpha} expression decrease with mechanical unloading, there is no correlation between the two. Thus, clinical and molecular indices of heart failure in LVAD-supported patients do not always correlate.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Mechanical unloading with a left ventricular assist device (LVAD) is used as a bridge to transplantation in patients with end-stage heart failure [1]. Previous studies have reported improved cardiac function with mechanical unloading [2, 3] accompanied by changes in myocardial histology, myocardial contractility, and neurohormone and cytokine levels [4–7]. Cytokines are known to be involved in the pathogenesis of heart failure, and one of them, tumor necrosis factor {alpha} (TNF{alpha}), has received much attention. In one study, antagonism of TNF{alpha} with the soluble TNF{alpha} receptor etanercept improved cardiac function in patients with end-stage cardiomyopathy [8]. In another study, mechanical unloading decreased myocardial TNF{alpha} protein expression in LVAD-supported patients with chronic heart failure [7]. This decrease was especially pronounced in patients who could be successfully weaned from the device, suggesting a potential role of TNF{alpha} as a predictor of myocardial recovery. The aim of the present study was to compare clinical indices of heart failure, to identify those indices that improved with mechanical unloading, and to correlate them with myocardial mRNA levels of TNF{alpha}.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Patient population
The patient cohort consisted of 14 patients treated for heart failure at the Texas Heart Institute between March 1997 and January 2000. From each patient an informed consent was obtained. The patients were predominantly male (12 of 14; 86%) and had a mean age of 39 ± 5 years. Heart failure was due to idiopathic dilated cardiomyopathy (n = 6), ischemic heart disease (n = 5), viral cardiomyopathy (n = 2), or peripartum cardiomyopathy (n = 1). All patients were treated with diuretics, angiotensin-converting enzyme inhibitors, low-dose ß-blockers, and positive inotropic agents. The patients underwent implantation of a HeartMate LVAD (Thermo Cardiosystems, Woburn, MA) as previously described [9]. In the course of this procedure, the HeartMate LVAD is inserted in the upper left portion of the abdominal wall and its drive line connected to an external power source. The inflow conduit is inserted into the left apex of the heart. The outflow cannula is anastomosed to the proximal ascending aorta. Blood circulates from the left ventricle through the inflow cannula into the device and is pumped back through the outflow conduit into the ascending aorta. All patients were supported by an LVAD for a mean of 226 ± 30 days (range, 46 to 437 days) and ultimately had the device explanted before heart transplantation.

As a control, myocardial tissue samples were obtained from 10 organ donors whose hearts initially were considered for cardiac transplantation, but subsequently were deemed unsuitable for transplantation because of unsuspected technical reasons. There were equal numbers men and women, with a mean age of 46 ± 4 years. The mean ejection fraction for the group was 61% ± 3% (range 50% to 85%).

Clinical data analysis
Clinical data covering the period from LVAD implantation to explantation (0 to 7 days) were obtained from the patient’s medical records, entered into a database, and analyzed retrospectively (Table 1).


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  		Table 1. Molecular and Clinical Indices of Heart Failure

 
TNF{alpha} transcript analysis
Because cardiac TNF{alpha} mRNA and protein expression levels do not correlate with serum TNF{alpha} levels [10], we chose to use myocardial biopsy samples. Myocardial tissue samples for TNF{alpha} transcript analysis were obtained from all 14 patients at LVAD implantation and explantation. Patient and control samples were immediately frozen in liquid nitrogen for RNA extraction. RNA was extracted by standard methods [11], reverse transcribed, and analyzed by real-time quantitative polymerase chain reaction (PCR) as described previously [12]. TNF{alpha} and ß-actin expression were measured in triplicates and a nonamplification control was run for each sample. The nucleotide sequences of the probe and the forward and reverse PCR primers used for PCR analysis are shown in Table 2. In all samples, TNF{alpha} expression was normalized to expression of the housekeeping reporter gene ß-actin. Internal RNA standards were prepared using the T7 RNA polymerase method (Ambion, Austin, TX). The normal range of TNF{alpha} expression in the controls was defined as the mean ± 2 SD.


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  		Table 2. Transcript Assays

 
Statistical analysis
Data in the text are expressed as mean ± SEM and in the figures as individual data points. Differences between data obtained from patients at LVAD implantation and explantation were calculated using Student’s t test for paired samples. Correlations between different indices of heart failure were calculated using Pearson’s correlation coefficient. Values of p less than 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Clinical data analysis
Biochemical data
Serum sodium was lower than normal in 10 patients at LVAD implantation but normalized with mechanical unloading (134 ± 1 vs 138 ± 1 mmol/L, p < 0.001, n = 14) (Fig 1A). The blood urea nitrogen (BUN) and creatinine levels were normal or nearly normal in most patients at the time of LVAD implantation, and did not change significantly with mechanical unloading (Fig 1B and 1C). As expected, creatinine and BUN levels correlated positively with each other (r2 = 0.57, p < 0.01). Liver function indices serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) were mildly elevated in 12 patients (Fig 1D and 1E). Only 3 of these 12 patients showed SGOT values of more than 100 IU/L. In all patients, SGOT and SGPT levels either improved or did not change with mechanical unloading. SGOT and SGPT levels correlated positively with each other (r2= 0.94, p< 0.001) and with levels of creatinine and BUN (p< 0.01, for all). Albumin levels were mildly decreased (between 3.0 and 3.9 mg/dL) in 8 patients at LVAD implantation but either increased or showed no significant change with mechanical unloading (Fig 1F). Albumin and cholesterol, the indices of hepatic synthetic function, correlated positively with each other (r2 = 0.66, p < 0.01, data not presented).



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  		Fig 1. General improvement of clinical indices of heart failure from abnormal to normal or near-normal with mechanical unloading. Gray boxes indicate normal ranges. (See Biochemical Data section for description of Fig 1A through H.) Panels A–F, biochemical markers of heart failure; Panel G, echocardiographic marker of heart failure; Panel H, hemodynamic marker of heart failure. (BUN = blood urea nitrogen; GOT = glutamic-oxaloacetic transaminase; GPT = glutamic-pyruvic transaminase; LVDD = left ventricular diastolic diameter.)

 
Echocardiographic and hemodynamic data
Mechanical unloading decreased the size of the left ventricle. LVDD decreased from 7.2 ± 0.3 cm at LVAD implantation to 6.0 ± 0.2 cm at explantation (p < 0.001) (Fig 1G). Cardiac index increased from 1.89 ± 0.18 L · min-1 · m-2 at LVAD implantation to 2.53 ± 0.23 · min-1 · m-2 at explantation (with LVAD off at explantation, p < 0.05) (Fig 1H). There was no correlation between LVDD and cardiac index.

TNF{alpha} gene expression data
Table 3 summarizes the demographic, hemodynamic, and TNF{alpha} expression data. Unexpectedly, only 5 of 14 patients (4 men with idiopathic dilated cardiomyopathy and 1 man with ischemic heart disease) showed elevated mRNA levels of TNF{alpha} (Fig 2). Furthermore, TNF{alpha} gene expression did not correlate with age, ethnicity, or any of the clinical indices of heart failure (Table 1). The lack of correlation between TNF{alpha} expression and SGOT level (Fig 3A) and between TNF{alpha} expression and cardiac index (Fig 3B) is representative of the lack of correlation between TNF{alpha} expression and all other clinical indices of heart failure.


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  		Table 3. Summary of Demographic, Hemodynamic, and TNF{alpha} Expression Data

 


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  		Fig 2. Elevated tumor necrosis factor–{alpha} (TNF{alpha}) expression in myocardial tissue at left ventricular assist device implantation (n = 5) and decreased TNF{alpha} expression during mechanical unloading (n = 4). Myocardial tissue from 10 nonfailing hearts served as control. Gray box indicates normal range of TNF{alpha} expression established in controls (mean ± 2 SD).

 


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  		Fig 3. Lack of correlation between tumor necrosis factor–{alpha} (TNF{alpha}) expression and clinical indices of heart failure. The lack of correlation shown here between (A) TNF{alpha} transcript levels and serum glutamic-oxaloacetic transaminase (GOT) and between (B) TNF{alpha} transcript levels and cardiac index is representative of the lack of correlation between TNF{alpha} expression and clinical indices of heart failure in general.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The three main findings of this study were as follows: (1) mechanical unloading improved clinical (ie, biochemical, echocardiographic, and hemodynamic) indices of end-stage heart failure; (2) myocardial TNF{alpha} expression, if measured by a precise method, is found to increase only in selected patients and to decrease with mechanical unloading when elevated at the time of implantation; and (3) myocardial TNF{alpha} expression does not correlate with clinical indices of heart failure.

General observations on clinical indices
It has already been shown that LVAD treatment improves echocardiographic and hemodynamic factors in heart failure patients [2, 13]. The findings presented here bear this out. We found that the left ventricular chamber size decreased, whereas cardiac index increased. These findings indicate structural and functional improvement of the failing heart.

Previous studies have shown that the severity of hyponatremia is a predictor of survival in end-stage heart failure patients [14]. We found that mechanical unloading reversed hyponatremia, presumably by improving renal perfusion. Dilutional hyponatremia, which is caused by decreased renal perfusion and increased vasopressin release, is a characteristic of chronic heart failure [15].

In addition, we found that other indices of kidney and liver function generally improved with LVAD treatment. This finding is consistent with a previous report of improved kidney and liver function in patients with end-stage heart failure who received LVAD support [13]. Albumin levels were either normal or close to normal at the time of LVAD implantation and increased or remained unchanged in most patients with mechanical unloading. In a previous study, we had shown that serum cholesterol is a predictor of survival in chronic heart failure patients awaiting heart transplantation, and that cholesterol levels of less than 100 mg/dL are associated with a poor prognosis [16]. Cholesterol levels correlated positively with albumin but not with SGOT and SGPT levels (data not presented). This discordance may be explained by the differential regulation of these indices. Although serum levels of SGOT and SGPT mainly depend on the severity of cellular injury, albumin and cholesterol levels depend on hepatic function and nutritional status [17]. We therefore conclude that indices of hepatic injury and hepatic function are abnormal in selected patients with end-stage heart failure at the time of LVAD implantation, and that in most cases they improve with mechanical unloading.

Despite the fact that all clinical indices showed improvement with mechanical unloading when abnormal at the time of implantation, we were unable to establish any correlation between echocardiographic and biochemical markers of heart failure. These findings are consistent with a study that showed a negative correlation between liver function and cardiac index only in those patients with a cardiac index of less than 1.5 L · min-1 · m-2 [18]. When we tried to apply these criteria to our patient population, we found that only 2 patients had a cardiac index of less than 1.5 L · min-1 · m-2, so no meaningful comparison could be made.

General observations on myocardial TNF{alpha} expression
TNF{alpha} has been implicated in the pathogenesis of chronic heart failure. In a mouse model of cardiac-restricted overexpression of TNF{alpha}, TNF{alpha} induced contractile dysfunction [19]. In a study of heart failure patients, immunohistochemistry demonstrated increased myocardial levels of TNF{alpha} and down-regulation of TNF{alpha} with mechanical unloading [7]. The study suggested a role for TNF{alpha} in predicting cardiac recovery in LVAD-supported patients [7]. Here we used a more sensitive method to measure TNF{alpha} transcript levels in myocardial biopsy. Using quantitative reverse transcription polyerase chain reaction (RT-PCR), we found that TNF{alpha} expression was increased only in less than half (5 of 14) of the patients. One explanation for this finding is the heterogeneous composition of our patient population. Four of the 6 patients with idiopathic dilated cardiomyopathy had elevated TNF{alpha} levels, compared with only 1 of the 5 patients with ischemic heart disease. The finding is still consistent with a possible role for myocardial TNF{alpha} expression in the pathogenesis of idopathic dilated cardiomyopathy. However, the correlation is by far not as strong as with the qualitative method of measuring protein stained tissue [10]. Another explanation for our findings may be the stage of disease progression. One recent report noted that TNF{alpha} levels tend to increase in the late stages of chronic heart failure [20]. Unfortunately, the exact duration of heart failure symptoms up to the time of tissue collection could not be determined in all patients. However, in those patients who showed increased myocardial TNF{alpha} expression at LVAD implantation (n = 5), we found that the TNF{alpha} expression decreased in 4 patients and returned to normal in 1. This is consistent with a previous report showing a decrease of TNF{alpha} with mechanical unloading [7]. Thus, TNF{alpha} mRNA levels are less reliable as a marker for heart failure than is its protein expression. This conclusion is consistent with a recent report showing that gene expression of other proinflammatory members of the cytokine family (interleukin 6, glycoprotein 130) are not increased in the failing human heart [21].

The lack of correlation between myocardial TNF{alpha} expression and clinical indices of heart failure is perhaps not surprising in light of the complexity of the cytokine network. The effect of the proinflammatory cytokine TNF{alpha} on cardiac function can be modulated by its receptors and by antiinflammatory cytokines such as interleukin-10 and transforming growth factor-ß [22]. Indeed, one recent study showed that the balance of proinflammatory and antiinflammatory cytokines in the plasma of patients with end-stage heart failure shifted in favor of the proinflammatory cytokines by means of increases in proinflammatory cytokine levels and decreases in antiinflammatory cytokine levels [22].

Conclusions
Although clinical indices of heart failure improve and elevated levels of myocardial TNF{alpha} expression decrease with mechanical unloading, there is no correlation between the two. Thus, clinical and molecular indices of heart failure in LVAD-supported patients do not always correlate. The quest for a reliable molecular marker of left ventricular function is far from complete.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported in part by grant RO1-HL/AG 61483 from the National Institutes of Health. We thank Life Banc of Northeast Ohio, for obtaining the myocardial tissue samples from the nonfailing hearts.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Frazier O.H., Macris M.P., Myers T.J., et al. Improved survival after extended bridge to cardiac transplantation. Ann Thorac Surg 1994;57:1416-1422.[Abstract/Free Full Text]
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  7. Torre-Amione G., Stetson S., Youker K., et al. Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support: a potential mechanism for cardiac recovery. Circulation 1999;100:1189-1193.[Abstract/Free Full Text]
  8. Bozkurt B., Torre-Amione G., Warren M., et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 2001;103:1044-1047.[Abstract/Free Full Text]
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  16. Richartz B., Radovancevic B., Frazier O., Vaughn W., Taegtmeyer H. Low serum cholesterol levels predict high perioperative mortality in patients supported by a left-ventricular assist system. Cardiology 1998;89:184-188.[Medline]
  17. Mahl T. Approach to the patient with abnormal liver tests. Lippincotts Prim Care Pract 1998;2:379-389.[Medline]
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