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European Journal of Heart Failure 2004 6(2):173-180; doi:10.1016/j.ejheart.2003.10.004
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© 2003 European Society of Cardiology

Transcardiac increase in tumor necrosis factor-{alpha} and left ventricular end-diastolic volume in patients with dilated cardiomyopathy{star}

Takayoshi Tsutamoto*, Atsuyuki Wada, Masato Ohnishi, Takashi Tsutsui, Chitose Ishii, Keijin Ohno, Masanori Fujii, Takehiro Matsumoto, Takashi Yamamoto, Tomoyuki Takayama, Tomohiro Dohke and Minoru Horie

Department of Cardiovascular Medicine Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan

* Corresponding author. Tel.: +81-775-48-2215; fax: +81-775-43-5839. E-mail address: tutamoto{at}belle.shiga-med.ac.jp


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Method
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Background: It remains unclear whether tumor necrosis factor (TNF)-{alpha} and interleukin-6 (IL-6) are secreted from the failing heart and whether there is a relationship between the transcardiac gradients of these cytokines and left ventricular (LV) remodeling.

Aims: This study evaluated the relationship between transcardiac gradients of cytokines and LV volume and function in congestive heart failure patients with dilated cardiomyopathy (DCM).

Methods and results: We measured the plasma levels of TNF-{alpha} and IL-6 in the aortic root (Ao) and the coronary sinus (CS) in 60 patients with DCM. There was no difference in plasma IL-6 between the Ao and the CS. However, the plasma TNF-{alpha} level was significantly higher in the CS than that in the Ao. There was a significant correlation between the transcardiac gradient of plasma TNF-{alpha} and the LV end-diastolic volume index (LVEDVI) and LV ejection fraction. According to stepwise multivariate analyses, the transcardiac increase of TNF-{alpha} showed an independent and significantly positive relationship with a large LVEDVI.

Conclusions: These results indicate that the elevated plasma TNF-{alpha} is partly derived from the failing heart in patients with DCM and that TNF-{alpha} plays a potential role in structural LV remodeling in patients with DCM.

Key Words: Interleukin-6 • Tumor necrosis factor-{alpha} • Dilated cardiomyopathy • Ventricular remodeling • Heart failure • Brain natriuretic peptide

Received June 27, 2003; Revised July 10, 2003; Accepted October 8, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Method
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Neurohumoral factors including proinflammatory cytokines are activated and play a role in the pathophysiology and prognosis in congestive heart failure (CHF) [1–5]. Moreover, most of these factors induce cardiac hypertrophy and left ventricular (LV) remodeling which is initially an adaptation to pressure overload and/or volume overload but ultimately leads to CHF.

Expression of the proinflammatory cytokine tumor necrosis factor (TNF)-{alpha} has been described in patients with chronic CHF both in the plasma and the myocardium [4,6–11], and the expression of TNF-{alpha} in myocardium plays an important role in the progression of dilated cardiomyopathy (DCM) [7–10]. Indeed, cardiac-specific overexpression of TNF-{alpha} transgenic mice showed increased LV volume and decreased LV function [12,13]. These results strongly suggest that the failing heart is one source of the elevated plasma TNF-{alpha} in CHF patients with DCM. However, one previous study [14] showed that TNF-{alpha} concentration, which was measured by cytotoxic assay, did not differ between the artery and the coronary sinus (CS). Recently, a sensitive and specific assay system of TNF-{alpha} (enzyme-linked immunosorbent assay) was developed.

Interleukin-6 (IL-6) is also elevated in the plasma of CHF patients, and the level correlates with poor functional status and mortality [15–18]. IL-6 is produced in not only leukocytes but also endothelial cells [19] and vascular smooth muscle cells [20] in vitro. Indeed, we reported that a partial source of elevated circulating IL-6 is the peripheral vascular bed and the pulmonary vascular bed [15,21]. IL-6 is known to cause myocardial depression and LV hypertrophy. IL-6 is also expressed in myocytes, which is induced by hypoxic stress [22]. Recently, both IL-6 mRNA and IL-6 protein were reported to be increased in severe CHF patients including those with DCM [11], suggesting that the increased IL-6 in the myocardium spillover to the circulation.

Therefore, in the present study, we evaluated whether TNF-{alpha} and IL-6 are secreted from the heart and the relationship between the transcardiac gradients of these cytokines and LV remodeling and LV function in CHF patients with DCM.


   2. Method
Top
 Notes
 Abstract
 1. Introduction
 2. Method
3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
2.1. Patients
The study population consisted of 60 consecutive mild to moderate CHF patients (LV ejection fraction (LVEF) <45%) with DCM who were admitted to our institution. The diagnosis of DCM was based on patient history, physical examination, ECG, chest radiography, echocardiography, left ventriculography and coronary angiography. All patients were free of hypertension, ischemic heart disease, valvular heart disease, congenital malformations of the heart or vessels, and intrinsic pulmonary, renal or metabolic diseases. Endomyocardial biopsies were obtained to rule out secondary cardiomyopathies caused by viral or other infectious myocarditis, sarcoidosis, amyloidosis or other metabolic heart disease. Patients with secondary DCM were excluded from the study. We also selected 11 age-matched control subjects (ages, 30–71, mean=52 years) with normal coronary arteries and no coronary spasm by coronary angiography with intracoronary injection of acetylcholine. Informed consent was obtained from all patients before participating in the study, and the protocol was approved by the Human Investigations Committee of our institution.

The subjects were 38 men and 22 women ranging in age from 27 to 78 years old (mean: 55.7 years). Forty patients were classified according to the standards of the New York Heart Association (NYHA) as functional class II, 17 patients as class III and three patients as class IV. At entry into the study, 50 patients were being treated with furosemide, 27 with spironolactone, 37 with angiotensin-converting enzyme (ACE) inhibitors, 38 with digitalis, 33 with β-blockers and 8 with angiotensin type-1 receptor blockers.

2.2. Study protocol
All patients were premedicated with an oral dose of diazepam (5 mg) and rested in bed in the supine position for at least 20 min. Right-sided cardiac catheterization was performed using a 7 F Swan-Ganz catheter. Blood samples for measuring plasma levels of TNF-{alpha}, IL-6, brain natriuretic peptide (BNP), norepinephrine (NE) and angiotensin II were collected simultaneously from the aortic root (Ao) and the CS. A 6Fr catheter (Goodman Co., Ltd, Japan) for blood sampling was positioned in the CS, and the position of the catheter was confirmed by injection of contrast medium just after blood sampling. Left ventriculography was performed using contrast medium after obtaining hemodynamic measurements and blood samples. Patients were classified into two groups: moderately increased LV end-diastolic volume index (LVEDVI) group (Group I) and markedly increased LVEDVI group (Group II), based on the LVEDVI. The cutoff level was the median value (186 ml/m2) for the LVEDVI.

2.3. Measurements of cytokines and neurohumoral factors
Blood for measuring plasma levels of TNF-{alpha} and IL-6 was transferred to a chilled tube containing EDTA (1 mg/ml) and aprotinin (500 kallikrein inactivator units/ml), then centrifuged at 3000 rpm for 15 min at 4 °C. The plasma thus obtained was stored at –30 °C until assayed. Both IL-6 and TNF-{alpha} measurements were performed using commercially available immunoassay (Quantikine HS, R&D Systems, Minneapolis, USA) as previously reported [12]. The intraassay coefficients of variation for IL-6 and TNF-{alpha} are 3.6 and 6.1%, respectively; the intraassay coefficients of variation for IL-6 and TNF-{alpha} are 3.8 and 7.8%, respectively. The minimal detectable values of TNF-{alpha} and IL-6 were 0.12 and 0.094 pg/ml, respectively. The assay system for IL-6 has no cross-reactivity for other cytokines including TNF-{alpha}, and the assay system for TNF-{alpha} has no cross-reactivity for other cytokines including IL-6.

Blood for measurement of the plasma levels of NE and angiotensin II was transferred to a chilled tube containing EDTA (1 mg/ml), centrifuged at 3000 rpm for 15 min at 4 °C, and the plasma thus obtained was stored at –30 °C until assay. The plasma NE concentrations were measured by high-performance liquid chromatography. Plasma angiotensin II levels were measured by radioimmunoassay using specific antibody directed against synthetic angiotensin II (Special Research Laboratory, Tokyo, Japan) as previously reported [17]. Plasma BNP concentrations were measured with a specific immunoradiometric assay kit for human BNP (Shionogi, Osaka, Japan) as previously reported [3].

2.4. Statistical analysis
All results are expressed as the mean±S.E.M. Univariate analysis was performed using Student's t-test. Categorical data were compared against {chi}2 distribution. Comparisons between multiple groups were determined by one-way analysis of variance with Scheffe's test. To evaluate factors regulating the LVEDVI in patients with DCM, univariate and stepwise multivariate analyses were performed using 17 parameters. Linear regression analysis was used to determine the relationship between continuous variables. A P value <0.05 was regarded as significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Method
 3. Results
4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
3.1. Plasma concentrations of neurohumoral factors and cytokines in the Ao and the CS in patients with DCM
In CHF patients with DCM, plasma levels of BNP and NE were significantly higher in CS than that in Ao and increased with the severity of CHF (Fig. 1). There was no difference in angiotensin II between the Ao and the CS in CHF patients with DCM. Plasma levels of TNF-{alpha} and IL-6 were significantly higher in patients with severe CHF than those of control subjects. There was no difference in plasma IL-6 between the Ao and the CS in control subjects or CHF patients. There was no difference in plasma TNF-{alpha} between the Ao and the CS in the control subjects. However, the plasma TNF-{alpha} level in the CS was significantly higher than that in the Ao in CHF patients with DCM (Fig. 2). There was no correlation between the transcardiac increases in TNF-{alpha} and the plasma TNF-{alpha} in the Ao (r=0.136) (Fig. 3).


Figure 1
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  		Fig. 1 Plasma levels of BNP, NE and angiotensin II (Ang II) in control subjects and in CHF patients with DCM. Mild CHF=NYHA functional class II, severe CHF=NYHA functional class III–IV. Ao, aortic root; CS, coronary sinus. *P<0.05 vs. the value in control subjects, #P<0.05 vs. the value in mild CHF patients.

 


Figure 2
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  		Fig. 2 Plasma levels of TNF-{alpha} and IL-6 in control subjects and in CHF patients with DCM. Mild CHF=NYHA functional class II, severe CHF=NYHA functional class III–IV. Ao, aortic root; CS, coronary sinus. *P<0.05 vs. the value in control subjects, #P<0.05 vs. the value in mild CHF patients.

 


Figure 3
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  		Fig. 3 Comparison between plasma TNF-{alpha} in the Ao and the transcardiac gradient of TNF-{alpha} in patients with DCM.

 
3.2. Patients characteristics and neurohumoral and cytokines data (Table 1)
Patients were classified into two groups: mildly increased LVEDVI group (Group I) and very increased LVEDVI group (Group II), based on median value for the LVEDVI (Table 1). LV end-diastolic pressure was significantly higher in Group II than that in Group I. The LVEF was significantly lower in Group II than that in Group I. There were no differences in plasma levels of BNP, NE, angiotensin II and IL-6 in the Ao between the two groups. Plasma TNF-{alpha} level in the Ao was significantly higher in Group II than that in Group I.


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  		Table 1 Patient characteristics

 
3.3. Transcardiac differences of neurohumoral factors and cytokines and LV volume and function in CHF patients with DCM
The transcardiac increases of BNP and TNF-{alpha} were significantly higher in the large LVEDVI group than that in the small LVEDVI group. There was no correlation between the transcardiac increase in BNP and the transcardiac increase in TNF-{alpha}. There was a significant correlation between the transcardiac increase in TNF-{alpha} and the LVEDVI (r=0.574, P<0.0001) and LVEF (r=–0.478, P=0.0001) (Fig. 4). According to stepwise multivariate analyses among hemodynamic and neurohumoral factors, the transcardiac increase in TNF-{alpha} and LVEF showed independent and significant positive relationships with a large LVEDVI in CHF patients with DCM (Table 2). In six patients, we measured TNF-{alpha} in the Ao and the CS before and after 6 months of carvedilol treatment. The plasma level of TNF-{alpha} in the Ao did not change, but a significant decrease of the transcardiac gradient of TNF-{alpha} was observed 6 months after treatment with carvedilol (Fig. 5). In these patients, the LVEDVI was decreased and LVEF was increased with decrease of the transcardiac gradient of TNF-{alpha} 6 months after treatment with carvedilol (Fig. 6).


Figure 4
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  		Fig. 4 Correlation between the transcardiac gradient of TNF-{alpha} and the LVEDVI and LVEF in patients with DCM.

 


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  		Table 2 Univariate and multivariate linear model of the LVEDVI in consecutive 60 patients with DCM

 


Figure 5
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  		Fig. 5 Plasma TNF-{alpha} in the Ao and the transcardiac gradient of TNF-{alpha} before and after 6 months of carvedilol treatment in six patients with DCM. CS, coronary sinus.

 


Figure 6
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  		Fig. 6 Relationship between changes in the transcardiac gradient of TNF-{alpha} and changes in the LV volume and function before and after 6 months of carvedilol treatment in six patients with DCM. Closed circles indicate pre-treatment values and open circles show the values 6 months after carvedilol treatment.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Method
 3. Results
 4. Discussion
5. Conclusions
 Acknowledgments
 References
 
The results of this study demonstrated that (1) elevated plasma TNF-{alpha} is partly secreted from the failing heart in CHF patients with DCM, but plasma IL-6 is not secreted from the heart of DCM patients, (2) plasma TNF-{alpha} in the Ao was not correlated with the transcardiac gradient of plasma TNF-{alpha}, (3) the transcardiac increase in plasma TNF-{alpha} was correlated with the LVEDVI and the LVEF in CHF patients with DCM.

4.1. Source of the elevated plasma TNF-{alpha} and IL-6 in mild to moderate CHF patients with DCM
Both TNF-{alpha} and IL-6 levels are reported to increase in the plasma of patients with CHF. Various cells including myocytes could produce these cytokines, however, the main source of these cytokines has not been fully elucidated. We previously reported that a partial source of elevated circulating IL-6 is the peripheral vascular bed and that TNF-{alpha} is not produced in the peripheral vascular bed in CHF patients [17]. Moreover, we recently reported that a partial source of elevated circulating IL-6 is the pulmonary vascular bed in CHF patients and that TNF-{alpha} is not produced in the lung [21]. In the present study, we showed that a partial source of elevated circulating TNF-{alpha} is the failing heart and that IL-6 is not secreted from the failing heart in mild to moderate CHF patients with DCM. Although most of these elevated cytokines are thought to be derived mainly from leukocytes including macrophages and lymphocytes, IL-6 is secreted from the peripheral and pulmonary vascular bed and TNF-{alpha} is secreted from the failing heart of CHF patients with DCM. These findings suggest that both TNF-{alpha} and IL-6 are increased but the modulation and the sources of these cytokines may differ in CHF patients [12,17].

Although IL-6 mRNA and protein were recently detected in CHF patients with DCM [11], we could not show a significant difference in the plasma IL-6 level between the Ao and the CS in the present study. From the report by Kubota et al. [12], the myocardial TNF-{alpha} level was increased with the severity of CHF. However, the myocardial IL-6 level was increased only in end-stage CHF, and in recent-onset CHF patients, the myocardial IL-6 level was significantly lower than that in non-failing donor hearts. However, non-failing donor hearts may not be appropriate controls because they express elevated IL-6 levels [23]. Torre-Amione et al. [8] reported that myocardial TNF-{alpha} protein was 1.5 times higher in end-stage CHF than that in stable CHF, but myocardial IL-6 protein was 6 times higher in end-stage CHF than that in stable CHF. These findings suggest that myocardial IL-6 expression was more dominant in end-stage CHF rather than myocardial TNF-{alpha} expression. In the present study, most patients had mild to moderate CHF and only three patients had class IV severe CHF. We could not show transcardiac increase in IL-6, however, IL-6 may be increased from the Ao and the CS in end-stage CHF patients.

4.2. Pathophysiological role of TNF-{alpha} in the failing heart in patients with DCM
TNF-{alpha} is a myocardial protein that stimulates cardiac growth, producing cardiac enlargement in experimental animals. Satoh et al. [9] reported that the TNF-{alpha} mRNA and protein which are obtained by endomyocardial biopsies were elevated in DCM patients with large LV volume and low LVEF, and that TNF-{alpha} mRNA and protein level correlate with LV end-systolic volume and LVEF. Torre-Amione et al. [8] reported that TNF-{alpha} was differentially expressed in the LV of the failing heart and that higher levels of TNF-{alpha} are found in the LV apex, followed by the LV septum, LV free wall and right ventricular free wall. They also showed that chronic mechanical circulatory assistance decreased TNF-{alpha} concentration in the failing myocardium, and that the magnitude of the decrease in TNF-{alpha} concentration predicted patients who would recover LV function. These findings suggest a significant and important relationship between the TNF-{alpha} expression in the failing heart and LV remodeling and LV function in patients with DCM.

In the present study, we measured plasma levels of TNF-{alpha} both in the Ao and the CS and found that the failing heart is one source of elevated TNF-{alpha} in CHF patients with DCM. Although a significant increase in plasma TNF-{alpha} was observed in the CS compared to that in the Ao, there was no significant correlation between transcardiac increases in TNF-{alpha} and plasma TNF-{alpha} in the Ao, which is consistent with findings reported by Torre-Amione et al. [6], suggesting that the main source of the increased plasma TNF-{alpha} is not the failing heart. In other words, we could not speculate on the myocardial TNF-{alpha} production (transcardiac increase in TNF-{alpha}) based on the peripheral plasma TNF-{alpha} levels. In the present study, the transcardiac increase in TNF-{alpha} was significantly correlated with LVEDVI and LVEF. Especially, according to stepwise multivariate analyses, among hemodynamic and neurohumoral factors, the transcardiac increase of TNF-{alpha} showed an independent and significant positive relationship with a large LVEDVI in CHF patients with DCM. We recently reported that the local production of TNF-{alpha} in the heart stimulates oxidative stress in the failing heart with DCM [24]. Previous studies reported that myocardial overexpression of TNF-{alpha} causes ventricular dilatation, ventricular dysfunction and interstitial fibrosis like DCM [12,13], suggesting that local expression of TNF-{alpha} in the heart plays a causal role partly via oxidative stress in the pathogenesis of DCM.

4.3. Clinical implication
Our findings suggest the important role of transcardiac increase in TNF-{alpha} in the pathogenesis of CHF patients with DCM, especially in the process of LV remodeling. Previous reports showed that it was important to determine myocardial and not peripheral TNF-{alpha} concentrations, however, the transcardiac increase in TNF-{alpha} may reflect the total amount of myocardial TNF-{alpha}. Moreover, repetitive measurements of myocardial TNF-{alpha} provide an important information for the treatment of CHF. However, it may be difficult to repeatedly measure myocardial TNF-{alpha}, and it may be easier and simpler to perform blood sampling of the Ao and the CS. Endomyocardial biopsies may not reflect total expression of TNF-{alpha}, which differs among the LV apex, septum and free wall [8].

4.4. Limitation
There are several limitations in the present study. In the present study, we did not directly measure myocardial TNF-{alpha} and IL-6 protein levels and had a small number of end-stage severe CHF patients. Moreover, we did not repeatedly measure the transcardiac gradient of plasma TNF-{alpha} before and after CHF treatments. Further studies are needed to clarify these limitations.


   5. Conclusions
Top
 Notes
 Abstract
 1. Introduction
 2. Method
 3. Results
 4. Discussion
 5. Conclusions
Acknowledgments
 References
 
Elevated plasma TNF-{alpha} is partly derived from the failing heart in patients with DCM and a transcardiac increase in TNF-{alpha} is significantly correlated with the LVEDVI and LVEF, suggesting that TNF-{alpha} plays an important role in structural LV remodeling in patients with DCM.


   Acknowledgments
Top
 Notes
 Abstract
 1. Introduction
 2. Method
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
References
 
We wish to thank Ms Ikuko Sakaguchi for excellent technical assistance. We also express thanks to Mr Daniel Mrozek for assistance in preparing the manuscript.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Method
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
{star} Presented in part at the scientific sessions of the American Heart Association, 2002. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Method
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 

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