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J Am Coll Cardiol, 2000; 36:208-212
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES: VALVE DISEASE

Elevated circulating levels of serum tumor necrosis factor-alpha in patients with hemodynamically significant pressure and volume overload

Samir R. Kapadia, MDa, Khalid Yakoob, MDa, Simone Nader, MDa, James D. Thomas, MDa, Douglas L. Mann, MD* and Brian P. Griffin, MDa

a Cleveland Clinic Foundation, Cleveland, Ohio, USA
* Winters Center for Heart Failure Research, Baylor College of Medicine and Veterans Affairs Medical Center, Houston, Texas, USA

Manuscript received July 22, 1999; revised manuscript received January 20, 2000, accepted March 27, 2000.

Reprint requests and correspondence: Dr. Brian P. Griffin, The Cleveland Clinic Foundation, 9500 Euclid Avenue, F15, Cleveland, Ohio 44195
Griffib{at}ccf.org


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

We sought to determine whether serum tumor necrosis factor-alpha (TNF-alpha) levels are elevated in patients with hemodynamically significant pressure and volume overload.

BACKGROUND

It has been previously shown that TNF-alpha messenger ribonucleic acid (mRNA) and protein are rapidly expressed in the hearts of animal models subjected to abrupt hemodynamic overloading. The clinical significance of these experimental findings has not been tested in pathophysiologically relevant clinical models in human subjects.

METHODS

We prospectively measured serum TNF-alpha levels and serum TNF receptor 1 and 2 levels in 21 patients with severe aortic stenosis (AS), in 26 patients with 3+ to 4+ mitral regurgitation (MR) and in normal age- and gender-matched control subjects. Patients with AS and MR were either in New York Heart Association (NYHA) functional class I or II and had no significant coronary disease. We compared the cytokine levels among the groups using analysis of variance. We related cytokine levels to the severity of AS using simple regression analysis.

RESULTS

Serum TNF-alpha levels in patients with AS (2.1 ± 1.6 pg/ml, n = 21) and MR (1.3 ± 0.7 pg/ml, n = 26) were significantly higher than those in the control subjects (0.7 ± 0.2 pg/ml, n = 28). Serum TNF receptor 1 and 2 levels were also higher in patients with AS and MR than in control subjects. Cytokine levels were higher in patients in NYHA class II than in those in class I. In patients with a normal ejection fraction (>50%, n = 16), there was a mild positive correlation (r = 0.56, p = 0.025) between serum TNF-alpha levels and the mean gradient across the aortic valve.

CONCLUSIONS

This study demonstrates that serum TNF-alpha is elevated in patients with chronic hemodynamic overloading and early cardiac decompensation. Furthermore, these findings suggest not only that peripheral TNF-alpha levels correlate with the severity of the hemodynamic pressure overload, but also that peripheral TNF-alpha and TNF receptor levels increase in direct relation to deteriorating NYHA functional class.

Abbreviations and Acronyms
  AS = aortic stenosis
  AVA = aortic valve area
  CI = confidence interval
  EF = ejection fraction
  LV = left ventricular
  mRNA = messenger ribonucleic acid
  MR = mitral regurgitation
  NYHA = New York Heart Association
  OR = odds ratio
  TNF-alpha = tumor necrosis factor-alpha

There is increasing evidence that the progressive elaboration of tumor necrosis factor-alpha (TNF-alpha) may play a role in the cardiac decompensation that ensues in a variety of cardiac disease states (1–5). Although TNF-alpha was initially described as a myocardial depressant substance in patients with septic shock, elevation of this cytokine has subsequently been demonstrated in a variety of cardiac disease states, including those of patients with symptomatic heart failure (6,7). When overexpressed, TNF-alpha can exert direct toxic effects on the heart and the peripheral circulation, and thus may potentially explain some of the structural and functional changes that are observed in cardiac decompensation. Indeed, overexpression of TNF-alpha has been shown to lead to left ventricular (LV) dysfunction and LV remodeling in animal models with long-term infusion of TNF-alpha, as well as in transgenic animals with targeted cardiac overexpression (1,2,8).

In the natural history of valvular heart disease, there is a phase of compensatory hypertrophy followed by progressive cardiac decompensation. However, the exact mechanisms that are responsible for the development of cardiac decompensation after hemodynamic overloading remain unknown. Relevant to this discussion is the experimental observation that hemodynamic overloading and myocardial stretch are sufficient to provoke de novo TNF-alpha messenger ribonucleic acid (mRNA) and protein expression in the heart (9,10). However, the clinical significance of these early experimental studies is not known. Accordingly, the purpose of this study was to prospectively study TNF-alpha and TNF receptor levels in patients with clinically significant aortic stenosis (AS) or mitral regurgitation (MR).


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Patient group.   We prospectively enrolled patients with an echocardiographic diagnosis of either significant AS (aortic valve area [AVA] ≤1.0 cm2) or significant MR (3+ to 4+), who had mild symptoms (New York Heart Association [NYHA] functional class I or II). The severity of MR was determined semiquantitatively by using the regurgitant jet length, width and direction on color Doppler echocardiography (11). Every patient had cardiac catheterization within six months of enrollment, and patients with coronary artery stenosis >50% were excluded. Patients with diseases associated with raised serum TNF-alpha, such as recent endocarditis (within six months), active malignancies, infection, connective tissue disorders and fever, were excluded. Patients with complex multivalvular lesions were excluded. For the control group, middle-aged (55 ± 8 years old, n = 28, including 16 [57%] men) normal subjects with no significant illness were used.

Serum cytokine measurements.   Blood was collected in a nonheparinized glass tube from a forearm vein. Blood was stored on ice immediately after collection, and within 15 min serum was separated by standard centrifugation at 1,500 rpm for 10 min. Serum was immediately separated and stored at –70°C until the assay. Cytokine measurements were performed in a core laboratory by scientists who had no knowledge of the clinical information. Commercially available enzyme-linked immunosorbent assay kits (Quantikine HS, R&D Systems) were used for measurement of TNF-alpha and TNF receptors 1 and 2, exactly as described previously (4).

Clinical data collection.   The clinical information was collected prospectively before the assessment of peripheral levels of cytokine and cytokine receptors. The patients’ functional class was determined on the basis of the clinical history, as well as from chart review. Echocardiography was performed in the research echocardiography laboratory at the Cleveland Clinic. M-mode, two-dimensional and Doppler echocardiographic measurements were made on-line by independent observers who had no knowledge of the clinical history. We took end-diastolic measurements of posterior wall and intraventricular septal thickness and end-systolic and end-diastolic measurement of LV diameter, left atrial diameter, ejection fraction (EF) by Simpson’s rule and LV mass measurement by the Penn Convention (12,13). Continuous wave Doppler echocardiography was used to measure the severity of AS. Peak and mean gradients, as well as AVA, using the continuity equation, were calculated for each patient. As previously described, the severity of MR was assessed semiquantitatively by color flow mapping (14) and by analysis of pulmonary venous flow (15–17). Only patients with significant MR (≥3+) were included in the study.

Statistical analysis.   Data are expressed as the mean value ± SD. Continuous variables were compared using the unpaired, two-tailed Student t test. When comparing continuous variables among multiple groups, analysis of variance, with post hoc analysis using the Newman-Keuls test, was employed. Simple linear regression analysis was performed to study the relation between continuous variables. Multiple regression analysis was performed to determine whether the presence of AS and MR was associated with higher TNF-alpha levels independent of age and gender.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Patient group.   We studied 47 mildly symptomatic patients with either AS or MR. Of these 47 patients, 21 had severe AS and 26 had severe MR. The clinical characteristics of these patients are listed in Table 1. Patients with AS were significantly older as compared with patients with MR. The use of angiotensin-converting enzyme inhibitors, digoxin and diuretics for each group are summarized in Table 1. The echocardiographic characteristics are listed in Table 2. The EF was reduced to <50% in five patients with AS and in one patient with MR.


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  		Table 1 Clinical Characteristics

 

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  		Table 2 Echocardiographic Characteristics

 
Circulating levels of TNF-alpha and TNF receptors.   Serum TNF-alpha levels in patients with AS and MR were significantly higher than those levels in the control group (Fig. 1). Patients with AS had significantly higher (p < 0.05) TNF-alpha levels than did patients with MR. Even when patients in NYHA class I were analyzed, the TNF-alpha levels in patients with AS were higher than those in patients with MR (Table 3). In a multiple regression analysis, the presence of AS (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.13 to 1.85) and MR (OR 1.2, 95% CI 1.03 to 1.55) predicted higher TNF-alpha levels, even after adjusting for the age differences. Interestingly, in patients with AS with preserved ventricular function (EF >50%, n = 16), there was a modest positive correlation (r = 0.56, p = 0.025) between peripheral levels of TNF-alpha level and the mean gradient across the aortic valve (Fig. 2).



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  		Figure 1 Serum TNF-alpha levels in normal subjects (0.7 ± 0.2 pg/ml, n = 28), in patients with AS (2.1 ± 1.6 pg/ml, n = 21) and in patients with MR (1.3 ± 0.7 pg/ml, n = 26). Analysis of variance showed significant differences between the groups, and a post hoc comparison demonstrated significant differences between all three groups. Serum TNF-alpha levels of patients with NYHA class I symptoms and control subjects are shown by solid circles, and those levels of patients with class II symptoms are shown by open circles.

 

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  		Table 3 Serum Tumor Necrosis Factor-Alpha Levels in Patients With Aortic Stenosis and Mitral Regurgitation, According to New York Heart Association Functional Class

 


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  		Figure 2 Correlation between the mean gradient across the aortic valve and serum TNF-alpha level in patients with AS and a normal (>50%) LV ejection fraction (n = 16). The central line represents the regression, and the other lines show the 95% confidence levels for the regression.

 
The circulating levels of soluble TNF receptors were also significantly higher in patients with AS than in the control subjects (p = 0.001 for both) (Fig. 3A). However, in patients with MR, TNF receptors 1 and 2 were only minimally elevated and were not statistically different from those in control subjects (p = 0.11 and p = 0.18, respectively) (Fig. 3B). For patients with AS and MR, TNF receptors 1 and 2 were significantly higher in patients in NYHA class II than in patients in NYHA class I (Table 4). Finally, there was a modest correlation between the serum level of TNF receptors 1 and 2 and the mean gradient across the aortic valve (r = 0.44, p = 0.047 and r = 0.43, p = 0.05, respectively).



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  		Figure 3 A Soluble TNF receptor 1 levels in normal subjects (841 ± 361 pg/ml, n = 32), in patients with AS (1,614 ± 884 pg/ml, n = 21) and in patients with MR (1,060 ± 270 pg/ml, n = 26). Soluble TNF receptor 1 levels of patients with NYHA class I symptoms and control subjects are shown by solid squares and those levels of patients with class II symptoms are shown by open squares. B Soluble TNF receptor 2 levels in normal subjects (2,694 ± 884 pg/ml, n = 32), in patients with AS (4,559 ± 2,389 pg/ml, n = 21) and in patients with MR (3,202 ± 838 pg/ml, n = 26). Soluble TNF receptor 2 levels of patients with NYHA class I symptoms and control subjects are shown by solid triangles and those levels of patients with class II symptoms are shown by open triangles.

 

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  		Table 4 Serum Levels of Tumor Necrosis Factor Receptors in Patients With Aortic Stenosis and Mitral Regurgitation, According to New York Heart Association Functional Class

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study shows that circulating levels of TNF-alpha are elevated in patients with clinically significant hemodynamic pressure and volume overload. Moreover, it suggests not only that the peripheral TNF-alpha levels correlate with the severity of the hemodynamic pressure overload (Fig. 2), but also that the peripheral TNF-alpha and TNF receptor levels increase in direct relation to deteriorating NYHA functional classification (Tables 3 and 4). One of the more interesting, albeit unexpected, findings of this study was that patients with chronic pressure overload had higher serum TNF-alpha and TNF receptor (receptors 1 and 2) levels than did patients with chronic volume overload, thus suggesting that pressure overload may serve as a greater stimulus for cytokine production, as compared with volume overload. However, the precise reasons for these differences in cytokines and cytokine receptors in patients with pressure and volume overload are not known at this time.

Circulating levels of TNF-alpha and TNF receptors have consistently been shown to be elevated in patients with heart failure; moreover, the peripheral levels of these proteins have been shown to correlate with the patients’ NYHA functional class (4,18). However, the site and source of cytokine production in heart failure remain unknown. Relevant to this discussion is the observation that both TNF-alpha protein and mRNA are expressed in the hearts of patients with advanced heart failure, whereas neither TNF-alpha protein nor mRNA are expressed in the hearts of normal subjects (5). Although the mechanism for the increase in TNF-alpha mRNA and protein expression is not known, a previous study has shown that TNF-alpha mRNA and protein are rapidly expressed in an animal model of acute pressure overload (9). Accordingly, the positive correlation between peripheral TNF-alpha levels and the mean gradient across the aortic valve in patients with AS suggests not only that chronic pressure overload is a relevant stimulus for TNF-alpha expression, but also that the heart is likely to be an important source for TNF-alpha production. Patients with abnormal LV systolic function were excluded from this analysis, as the pressure gradient in these patients does not accurately reflect the severity of AS and pressure overload.

Although we observed that there was a significant increase in serum TNF-alpha levels in direct relation to deteriorating NYHA class, the results of the present study do not distinguish whether elevated TNF-alpha levels are a cause or effect of increasing cardiac decompensation. Indeed, given the biologic complexity of hemodynamic overloading, it would be naive to suggest that any one molecule was responsible for cardiac decompensation. This statement notwithstanding, it bears emphasis that overexpression of TNF-alpha in the heart has been shown to lead to progressive LV remodeling, as well as progressive LV dysfunction in experimental models (1–3). Moreover, elevated peripheral TNF-alpha levels might be expected to lead to inappropriate vasodilation by increasing endothelial nitric oxide production, which may have overt deleterious consequences in patients with AS. Thus, it is possible that TNF-alpha may be one of a variety of different biologically active molecules that contribute to the progressive cardiac decompensation that occurs in sustained hemodynamic overloading. Apart from the potential pathophysiologic relevance of the present findings, the results of this study suggest that progressively rising TNF-alpha levels may serve as a potentially useful biochemical marker for progressive cardiac decompensation in patients with valvular heart disease. Although it is unlikely that elevated levels of TNF-alpha will ever replace the more traditional indexes that have been used in the timing of surgery for patients with symptomatic valvular heart disease, it is possible that progressive increases in TNF-alpha levels may prove to be useful in the timing of valve replacement in patients with asymptomatic valvular heart disease, in whom a subset of patients experience untoward outcomes (19–23).

One of the major study limitations includes the unavailability of postoperative TNF-alpha levels to verify whether elevated cytokine levels became normalized after surgical correction of pressure or volume overload. Immediate postoperative levels may not be accurate, as the operation itself can lead to elevated cytokine levels. Referring physicians monitor their own patients, which makes it logistically difficult to collect postoperative cytokine levels. Further, the patients with AS are older than patients with MR and the normal control subjects. Although these differences in age between the patient groups does not completely account for the elevated cytokine levels, the impact of aging on cytokine production remains unknown.

Conclusions.   This clinical study directly supports the hypothesis that hemodynamic overloading is a sufficient stimulus for TNF-alpha production in the adult human heart, which is consistent with our previous experimental observations. Moreover, this study suggests that peripheral TNF-alpha and TNF receptor levels increase in relation to the patient’s worsening NYHA functional class. Given the mechanical burden that is imposed by sustained hemodynamic overloading, it is unlikely that modulating TNF-alpha expression will favorably alter the natural history of valvular heart disease. Nonetheless, it is possible that anti-cytokine strategies might be employed as an adjunctive therapy before operation in high risk patients with depressed ventricular performance, in whom sustained ventricular dysfunction may prevent immediate postoperative recovery. Moreover, this study raises the intriguing possibility that serial measurements of TNF-alpha in patients with asymptomatic valvular heart disease may help to identify patients in the earliest stages of decompensation, who are not diagnosed with conventional noninvasive testing. Further studies will be necessary to address these interesting and important possibilities.


   Acknowledgments
 
The authors acknowledge the technical assistance of Lisa Cardon, BS, and Dorellyn Lee-Jackson, BS.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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