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European Journal of Heart Failure 2007 9(10):1032-1037; doi:10.1016/j.ejheart.2007.07.015
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© 2007 European Society of Cardiology

Plasma level of cardiotrophin-1 as a prognostic predictor in patients with chronic heart failure

Takayoshi Tsutamotoa,*, Shigeru Asaib, Toshinari Tanakaa, Hiroshi Sakaia, Keizo Nishiyamaa, Masanori Fujiia, Takashi Yamamotoa, Masato Ohnishic, Atsuyuki Wadac, Yoshihiko Saitod and Minoru Horiea

a Department of Cardiovascular Medicine, Shiga University of Medical Science Seta-Tsukinowa, Otsu, 520-2192, Japan
b Diagnostic Department, Shionogi & Co., Ltd. 2-5-1 Mishima, Settsu-shi, Osaka 566-0022, Japan
c Kusatsu General Hospital Kusatsu, 520-0028, Japan
d First Department of Internal Medicine, Nara Medical University Kashihara, Nara, 634-8522, Japan

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


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Cardiotrophin-1 (CT-1) is a member of the interleukin (IL-6) family of cytokines and is increased in patients with chronic heart failure (CHF).

Aims: To evaluate the prognostic role of CT-1 in patients with CHF.

Methods and results: We measured the plasma levels of CT-1, brain natriuretic peptide (BNP), and IL-6 in 125 patients with CHF. Patients were monitored for a mean follow-up period of 2.9years. Plasma levels of CT-1 increased with severity of CHF. There was a significant negative correlation between plasma CT-1 and left ventricular ejection fraction. There was a significant correlation between plasma CT-1 and log IL-6. During the follow-up period, 37 patients died. High plasma levels of CT-1, BNP, and IL-6 were independent predictors of mortality on stepwise multivariate analysis. The hazard ratio for mortality in patients with plasma BNP>170pg/mL and CT-1>658fmol/mL was 2.48 (95% confidence interval, 1.217–5.060) compared to those with plasma BNP>170pg/mL and CT-1<658fmol/mL (p=0.0124).

Conclusion: These findings indicate that plasma CT-1 measurement provides additional prognostic information and that combined levels of CT-1 and BNP are more accurate at predicting mortality in patients with CHF than either marker alone.

Key Words: Cardiotrophin-1 • Brain natriuretic peptide • Heart failure • Prognosis • Interleukin 6

Received March 26, 2007; Revised June 13, 2007; Accepted July 23, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Cardiotrophin-1 (CT-1) is a member of the interleukin-6 (IL-6) family of cytokines and was originally discovered as a factor that can induce hypertrophy in cardiac myocytes [1-3]. CT-1 mRNA is widely expressed in various tissues including the heart, kidney, skeletal muscle, and liver [4]. CT-1 binds with gp130/leukaemia inhibitory factor receptor heterodimer and induces ventricular hypertrophy in vivo and in vitro [5,6]. It also inhibits apoptosis of the myocardium in vitro, suggesting that CT-1 and the gp130 system are factors that influence myocardial survival under pathological conditions. Zolk et al. [7] suggested that CT-1 contributes to ventricular hypertrophy and remodelling, as well as to protection against apoptosis in the failing heart. Plasma levels of CT-1 and soluble gp130 have been reported to be increased in patients with CHF [8-10]. We previously reported that plasma CT-1 is increased in CHF patients with dilated cardiomyopathy and is significantly correlated with left ventricular (LV) mass index, suggesting that CT-1 plays an important role in structural LV remodelling [10].

Recently, Fritzenwanger et al. [11] reported that CT-1 induced both IL-6 mRNA and protein in a concentration- and time-dependent manner in human umbilical vein endothelial cells. Therefore, CT-1 might be in part responsible for the increased IL-6 plasma concentrations in CHF. Zolk et al. [12] reported that CT-1 significantly depressed contractility, at concentrations comparable to CT-1 plasma levels found in patients with CHF, suggesting that chronically increased synthesis and release of CT-1 may further accelerate contractile dysfunction and disease progression in CHF. A recent study by Khan et al. [13] reported that CT-1 is a prognostic marker of death or heart failure in patients with acute myocardial infarction. However, the prognostic role of CT-1 in patients with chronic heart failure (CHF) remains unknown. The aim of this study was therefore to evaluate the prognostic role of CT-1 in patients with CHF, and to compare the prognostic role of CT-1 with BNP, IL-6, soluble gp130, and TNF{alpha}.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
One hundred and twenty five patients hospitalised with chronic CHF (94 men and 31 women) aged between 22 and 84 years (mean 60), were recruited at our institutions. Informed consent was obtained from all patients for participation in the study, according to a protocol approved by the Committee on Human Investigation at our institutions. The cause of heart failure was dilated cardiomyopathy in 59 patients, ischaemic heart disease in 59 patients, and hypertensive heart disease in 7 patients. All patients had a left ventricular ejection fraction <45% on left ventriculography with radionuclide or contrast medium. Patients with acute myocardial infarction, infection, chronic inflammatory disease, malignancy or renal failure were excluded. Sixty-nine patients were in New York Heart Association (NYHA) functional class II, 32 in class III, and 24 in class IV. One hundred and six patients were clinically stable on constant doses of diuretics; 107 patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and 78 patients were treated with β-blockers. All drugs had been administered for at least 4 weeks (most drugs for over 3 months).

2.2. Study protocol
This was a prospective study and at entry blood samples were drawn from the antecubital vein after at least 30 min of bed rest in a supine position. Left ventriculography was performed by contrast medium or radioisotope at least one week before or after blood sampling. All patients were followed for at least one year (mean follow up period was 2.9 years). Thirty-seven patients died of cardiac causes during the follow-up period.

2.3. Measurement of plasma levels of CT-1 and soluble gp130 and other neurohumoral factors
Blood for measuring plasma levels of CT-1, soluble gp130, TNF{alpha}, IL-6, and BNP was transferred to chilled tubes containing EDTA (1 mg/mL) and aprotinin (500 kallikrein inactivator units/mL), and then centrifuged at 3000 rpm for 15 min at 4 °C. The plasma was then stored at –30 °C until assay. Plasma CT-1 levels were measured by a sensitive and specific RIA for human CT-1, as previously reported [10,14]. In this RIA, recombinant full-length human CT-1 was used for both the standard and the tracer. The working range of this RIA is 120-8300 fmol/mL. The CV values for within- and between-assay were 4.1-5.6% (n=10) and 3.3-8.4% (n=5), respectively. This RIA did not cross-react with IL-6, IL-11, leukaemia inhibitory factor, ciliary neurotrophic factor, or oncostatin M [14]. The mean plasma CT-1 level for the control subjects was 501±12 fmol/mL [10]. Plasma levels of soluble gp130, TNF{alpha}, and IL-6 were determined using a commercially available immunoassay (Quantikine HS, R&D Systems, Minneapolis, USA) as previously reported [15]. Plasma BNP concentrations were measured with a specific immunoradiometric assay kit for human BNP (Shionogi, Osaka, Japan) as previously reported [16]. Plasma norepinephrine concentration was measured by high-performance liquid chromatography.

2.4. Analysis
All values are expressed as the mean±SD. Univariate analyses were performed using the Student's t-test. Categorical data were compared using a chi-squared distribution. Differences in mean levels of BNP, TNF{alpha}, and IL-6 between the two groups were tested by Mann-Whitney U test for unpaired values with two-tailed p values of <0.05 and log BNP, log TNF{alpha} and log IL-6 were used for regression models. Pearson's correlation coefficient and the non-parametric Spearman's correlation methods were used for correlation analysis. The prognostic value of the variables was tested in a Cox proportional hazard regression analysis. Receiver operating characteristic curves of BNP, CT-1 and IL-6 demonstrating mortality risk were constructed. Kaplan-Meier analysis was performed on the cumulative rates of survival in patients with CHF stratified into two groups based on cut-off values of BNP, CT-1 and IL-6, and the differences between survival curves were analyzed by log-rank test. Linear regression analysis was used to determine the relationship between continuous variables. A value of p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Patient characteristics
Thirty-seven patients died during the follow-up period; the mean follow-up period was 2.9 years (interquartile range: 1.8-3.2 years). NYHA functional class differed significantly between survivors and non-survivors (Table 1). There were no differences between survivors and non-survivors in age, sex, aetiology of heart failure or treatment. LVEF was significantly lower in non-survivors than in survivors. Neurohumoral variables such as norepinephrine, BNP, IL-6 and TNF{alpha}, soluble gp130, and CT-1 were significantly higher in non-survivors than in survivors.


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  		Table 1 Patient characteristics and neurohumoral variables according to survival

 
3.2. Comparison between plasma CT-1 concentrations, LVEF and other neurohumoral variables
Plasma levels of CT-1 and soluble gp130 increased with the severity of CHF [CT-1: mild CHF (NYHA class II): 604±10 vs. severe CHF (NYHA class III or IV):655±18 fmol/mL, p<0.01; soluble gp130: mild CHF: 163±10 vs. severe CHF 210±14 ng/mL, p<0.01]. There was a negative correlation between plasma CT-1 and LVEF (r=–0.23, p=0.01, Fig. 1). There were significant correlations between plasma CT-1 and IL-6 (rs=0.268, p=0.0066, Fig. 2) and TNF{alpha} (rs=–0.22, p=0.024). There were no significant correlations between plasma CT-1 concentration and plasma levels of norepinephrine (r=0.052), BNP (rs=0.059) and soluble gp130 (r=0.029).


Figure 01
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  		Fig. 1 Correlation between plasma levels of cardiotrophin (CT)-1 and left ventricular ejection fraction (LVEF) in patients with symptomatic left ventricular dysfunction.

 


Figure 02
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  		Fig. 2 Correlation between plasma levels of cardiotrophin (CT)-1 and interleukin-6 (IL-6) in patients with chronic heart failure.

 
3.3. Univariate and multivariate predictors of mortality
During the follow-up period, 37 patients died. Ten clinical, neurohumoral and haemodynamic variables were analyzed using univariate and stepwise multivariate Cox proportional hazards regression analyses (Table 2). On univariate analyses, ten clinical, neurohumoral and haemodynamic variables were significant predictors of mortality. On stepwise multivariate analyses, only high levels of plasma BNP (p<0.0001), CT-1 (p=0.0003), and IL-6 (p=0.0005) were significant independent predictors of mortality (Table 2).


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  		Table 2 Univariate and multivariable predictors of mortality

 
3.4. Receiver operating characteristic analysis
Receiver operating characteristic curves of BNP, IL-6 and CT-1, demonstrating mortality risks are shown in Fig. 3. The cut-off level for BNP was determined as 170 pg/mL, giving a sensitivity of 86% and specificity of 69% (AUC=0.814; 95% CI:0.726-0.902, p<0.0001). The cut-off level for IL-6 was determined as 2.63 pg/mL, giving a sensitivity of 89% and specificity of 53% (AUC=0.762; 95% CI:0.673-0.851, p=0.002). The cut-off level for CT-1 was determined as 658 fmol/mL, giving a sensitivity of 57% and specificity of 74% (AUC=0.654; 95% CI:0.543-0.765, p=0.0019).


Figure 03
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  		Fig. 3 Receiver operating characteristic curves for the ability of brain natriuretic peptide (BNP), interleukin-6 (IL-6) and cardiotrophin (CT)-1 to predict mortality in CHF patients. AUC = area under the curve.

 
3.5. Kaplan-Meier lifetime analysis
Patients were divided into groups based on cut-off levels for BNP, IL-6 and CT-1, and Kaplan-Meier survival curves were constructed. Patients with higher concentrations than the cut-off levels of BNP, IL-6 and CT-1 had a poor prognosis. Patients were then stratified into four groups based on the cut-off levels for plasma concentrations of CT-1 and IL-6 and cumulative survival curves were constructed by Kaplan-Meier survival methods (Fig. 4A). Patients were also stratified into four groups based on the cut-off levels for plasma concentrations of CT-1 and BNP, and cumulative survival curves were constructed by Kaplan-Meier survival methods (Fig. 4B). The hazard ratio patients with plasma IL-6>2.63 pg/mL and CT-1>658 fmol/mL was 30.1 (95% confidence interval, 4-225) compared to those with plasma IL-6<2.63 pg/mL and CT-1<658 fmol/mL for mortality (p=0.0009). The hazard ratio for mortality in patients with plasma BNP<170 pg/mL and CT-1>658 fmol/mL was 9.56 (95% confidence interval, 1.16-82) compared to patients with plasma BNP<170 pg/mL and CT-1<658 fmol/mL (p=0.0039). The hazard ratio for mortality of patients with plasma BNP>170 pg/mL and CT-1>658 fmol/mL was 2.48 (95% confidence interval, 1.217-5.06) compared to patients with plasma BNP>170 pg/mL and CT-1<658 fmol/mL (p=0.0124).


Figure 04
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  		Fig. 4 Kaplan-Meier survival curves for patients stratified into four groups based on cut-off levels of (A) interleukin-6 (IL-6) and cardiotrophin (CT)-1 and (B) brain natriuretic peptide (BNP) and cardiotrophin (CT)-1.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Recently, Khan et al. reported that CT-1 was a prognostic marker of death or heart failure in patients with acute myocardial infarction [13]. In the present study, we have reported for the first time that plasma CT-1 is a prognostic marker in patients with CHF. However, the reason why and the mechanism by which patients with a high CT-1 level had a poor prognosis, remains unknown. The positive correlation between plasma CT-1 and IL-6 suggests that CT-1 might be responsible for increased IL-6, as previously reported [11], which may depress myocardial contractility and worsen endothelial function. Moreover, chronically increased CT-1 may depress the contractile function of the myocardium [12] and may further accelerate disease progression.

We measured plasma levels of CT-1, soluble gp130, and other neurohumoral variables in 125 patients with symptomatic left ventricular dysfunction, who were followed-up for a long period. Plasma levels of CT-1 and soluble gp130 increased with the severity of CHF, which is consistent with previous reports [8-10]. There were significant correlations between plasma CT-1 concentrations and LVEF, IL-6 and TNF{alpha}. There were no significant correlations between plasma CT-1 and plasma levels of norepinephrine, BNP, and soluble gp130. A high plasma level of CT-1 was shown to be an independent predictor of mortality on stepwise multivariate analysis and the combination of the measurements of BNP and CT-1, or IL-6 and CT-1 was more useful for estimating mortality than a single biomarker measurement. Therefore, our findings suggest that measuring the plasma CT-1 level provides important information that is additional to that obtained from neurohumoral variables previously known to be associated with high mortality in CHF patients. However, the relatively low sensitivity and low predictive value of CT-1 alone compared to those of BNP and IL-6 are limitations.

CT-1, a cytokine of the IL-6 family, induces cardiac hypertrophy through the Janus kinase/transcription 3 (JAK/STAT) cascade. In addition, CT-1 has anti-apoptotic effects in myocytes, mediated through mitogen activated protein kinase. Hirota et al. [17] reported an important role of gp130 in the heart in response to pressure overload. In mice lacking the CT-1 receptor gp130 in the heart, aortic banding-induced pressure overload results in massive cardiac cell apoptosis and death from heart failure. In contrast, control mice demonstrate a hypertrophic response and survive. Hence, CT-1 may exert a protective effect against apoptosis following overload, allowing a compensatory hypertrophy that may initially be beneficial. In the present study, plasma levels of CT-1 and soluble gp130 were increased, which is consistent with previous findings. Although the increase in CT-1 and gp130 may have a cardioprotective effect in human heart failure, as shown in experimental studies, excessive neurohumoral activation, as with BNP one of the cardioprotective neurohumoral factors, is ultimately a maladaptive response to myocardial injury, and eventually contributes to the development of heart failure. We have previously reported that plasma CT-1 is increased in CHF patients with dilated cardiomyopathy and is significantly correlated with the LV mass index [10], suggesting that structural LV remodelling may become maladaptive with the progression of CHF.

CT-1 mRNA is widely expressed in various tissues including the heart, kidney, skeletal muscle, and liver [4]. Although the mechanism of the increase in plasma CT-1 remains unknown, ventricular stretch may be one of the stimulators of CT-1 from the failing heart [18]. Cardiac natriuretic peptides including BNP play a compensatory role in CHF, via diuresis, vasodilatation, and suppression of the renin angiotensin and sympathetic nervous system. In addition, cardiac natriuretic peptides may have a cardioprotective effect on the myocardium, via autocrine and paracrine signalling, as is the case with CT-1. Both BNP and CT-1 have a beneficial effect not only on the myocardium but also on haemodynamic variables [19,20]. Therefore, stimulators such as ventricular wall stress and other local neurohumoral factors and cytokines that increase BNP and CT-1 and promote structural LV remodelling [10] may become maladaptive with the progression of CHF.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
The plasma level of CT-1 increased with the severity of CHF, and a high plasma level of CT-1 was shown to be an independent predictor of mortality in patients with symptomatic left ventricular dysfunction. Although the reason why plasma CT-1 is an independent prognostic predictor remains unknown, stimulators such as ventricular wall stress and other local neurohumoral factors and cytokines that increase BNP and CT-1 may become maladaptive with the progression of CHF.


   Acknowledgements
 
We wish to thank Aoi Murata for excellent technical assistance. We also express thanks to Mr. Daniel Mrozek for assistance in preparing the manuscript.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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