CARDIOMYOPATHY
Relationship between plasma level of cardiotrophin-1 and left ventricular mass index in patients with dilated cardiomyopathy
Takayoshi Tsutamoto, MD*,*,
Atsuyuki Wada, MD*,
Keiko Maeda, MD*,
Naoko Mabuchi, MD*,
Masaru Hayashi, MD*,
Takashi Tsutsui, MD*,
Masato Ohnishi, MD*,
Masanori Fujii, MD*,
Takehiro Matsumoto, MD*,
Takashi Yamamoto, MD*,
Xinwen Wang, MD*,
Shigeru Asai, PhD ,
Tetsuo Tsuji, PhD,
Hitoshi Tanaka, PhD,
Yoshihiko Saito, MD ,
Koichiro Kuwahara, MD,
Kazuwa Nakao, MD and
Masahiko Kinoshita, MD*
* First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan
Diagnostic Department, Shionogi & Co., Osaka, Japan
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
Manuscript received March 26, 2001;
revised manuscript received June 19, 2001,
accepted July 13, 2001.
* Reprint requests and correspondence: Dr. Takayoshi Tsutamoto, First Department of Internal Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, 520-2192, Japan
tutamoto{at}belle.shiga-med.ac.jp
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Abstract
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OBJECTIVES
The study evaluated the relationship between plasma cardiotrophin-1 (CT-1) concentration and left ventricular (LV) mass in dilated cardiomyopathy (DCM) patients with congestive heart failure (CHF).
BACKGROUND
Cardiotrophin-1 is a newly identified member of the interleukin-6 (IL-6) family of cytokines and one of the endogenous ligands for gp130 signaling pathways in the heart, and it has potent hypertrophic and survival effects on cardiac myocytes. However, the clinical significance of CT-1 is poorly understood.
METHODS
We measured the plasma CT-1 level in 51 consecutive patients with DCM. Patients were classified into two groups: small LV mass index group and large LV mass index group, based on the median level of LV mass index.
RESULTS
The plasma CT-1 level was increased in DCM patients with the severity of CHF and was significantly higher in the large LV mass group than in the small LV mass group, despite the absence of a difference in LV ejection fraction between the two groups. In addition, there was a significant positive correlation between the plasma CT-1 level and the LV mass index (r = 0.627, p < 0.0001). According to stepwise multivariate analyses among hemodynamic and neurohumoral factors, a high plasma CT-1 level showed an independent and significant positive relationship with a large LV mass index in patients with DCM.
CONCLUSIONS
These results indicate that the plasma CT-1 level is increased in patients with DCM and is significantly correlated with the LV mass index, suggesting that CT-1 plays an important role in structural LV remodeling in patients with DCM.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | BNP | = brain natriuretic peptide | | CT-1 | = cardiotrophin-1 | | CHF | = congestive heart failure | | DCM | = dilated cardiomyopathy | | IL-6 | = interleukin-6 | | LV | = left ventricular | | LVEF | = left ventricular ejection fraction | | NYHA | = New York Heart Association |
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Neurohumoral factors including cytokines are activated and play an important role in the pathophysiology and the prognosis in congestive heart failure (CHF) (1–10). In addition, most of these factors induce cardiac hypertrophy, which is initially an adaptation to pressure overload and/or volume overload but ultimately leads to CHF.
Cardiotrophin-1 (CT-1), is a member of the interleukin-6 (IL-6) family of cytokines, which was originally discovered as a factor that can induce hypertrophy of cardiac myocytes (11–13). The CT-1 mRNA is widely expressed in various tissues including the heart, kidney, skeletal muscle, and liver (14), and CT-1 is increased in plasma in patients with CHF (15). Cardiotrophin-1 binds with the gp130/leukemia inhibitory factor receptor heterodimer and induces ventricular hypertrophy in vivo and in vitro (16,17). Moreover, the augmented expression of CT-1 has been detected in the ventricle of genetically hypertensive rats where it may contribute to ongoing hypertrophic response (18). Similarly, overexpression has been reported of both CT-1 and gp130 in the rat ventricle after myocardial infarction and during experimental acute Chagasic cardiomyopathy (19,20). Moreover, CT-1-induced cardiomyocyte hypertrophy in vitro resembles the hypertrophic pattern observed in volume overload hypertrophy in human CHF (17,21,22). Taken together, CT-1 plays an important role in structural remodeling that characterizes CHF related to volume overload such as dilated cardiomyopathy (DCM).
Talwar et al. (15) reported that plasma CT-1 levels are increased in patients with CHF; however, the plasma CT-1 concentration in patients with DCM, which is characterized by volume overload, remains unknown. Recently, we developed a sensitive and specific radioimmunoassay for human CT-1 (23). Therefore, in the present study, we evaluated the relationship between plasma CT-1 level and the left ventricular (LV) mass index and neurohumoral factors such as norepinephrine and angiotensin II, which can stimulate CT-1 production in vitro, in patients with DCM.
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Methods
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Patients.
The study population consisted of 51 consecutive CHF patients with dilated cardiomyopathy (DCM) (left ventricular ejection fraction [LVEF] <45%). The diagnosis of DCM was based on patient history, physical examination, electrocardiogram, 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. Among the 51 patients with DCM, there were no patients with diabetes mellitus or hyperlipidemia. The subjects were 33 men and 18 women ranging in age from 17 to 78 years (mean: 55 years). Thirty-three patients were classified according to the standards of the New York Heart Association (NYHA) as functional class II, 14 patients as functional class III, and four patients as class IV. At entry into the study, 44 patients were being treated with furosemide, 23 with spironolactone, 32 with angiotensin-converting enzyme (ACE) inhibitors, 35 with digitalis, 14 with beta-blockers and 3 with angiotensin type-1 receptor blockers. Most drugs had been administered for more than two months. We also selected 16 control subjects (aged 26 to 75 years; mean, 54 years). Among the 16 control subjects, there were no patients with diabetes mellitus, hyperlipidemia or hypertension. 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.
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 7F Swan-Ganz catheter. Blood samples for measuring plasma levels of CT-1, IL-6, brain natriuretic peptide (BNP), norepinephrine, angiotensin II and endothelin-1 were collected from the femoral artery. Left ventriculography performed by contrast medium was analyzed for LVEF and left ventricular (LV) volume after obtaining hemodynamic measurements and blood samples.
The M-mode echocardiography was also performed with two-dimensional monitoring using a Sonolayer phased-array sector scanner (model SSH-160A, Toshiba, Tokyo, Japan) in a blinded fashion within one week before catheterization. Left ventricular mass was calculated according to the American Society of Echocardiography recommendations (24) but was then corrected according to the suggestions of Devereux et al. (25). Patients were classified into two groups: small LV mass index group and large LV mass index group, based on the LV mass index. The cutoff level was the median value (163 g/m2) for the LV mass index.
Measurements of neurohumoral factors and CT-1.
Blood for measuring plasma levels of CT-1, IL-6, BNP and endothelin-1 was transferred to a chilled tube containing EDTA (1 mg/ml) and aprotinin (500 kallikrein inactivator U/ml) and then centrifuged at 3,000 rpm for 15 min at 4°C. The plasma thus obtained was stored at –30°C until assayed. Plasma CT-1 levels were measured by a sensitive and specific RIA for human CT-1, as previously reported (23). In this RIA, recombinant full-length human CT-1 was used for both the standard and the tracer. The working range of this RIA was 120 to 8,300 fmol/ml. The coefficient of variation (CV) values for within- and between-assay values were 4.1% to 5.6% (n = 10) and 3.3% to 8.4% (n = 5), respectively. This RIA did not cross-react with IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor or oncostatin M (23).
The plasma IL-6 level was determined using a commercially available immunoassay (Quantikine HS, R&D Systems, Minneapolis, Minnesota), as previously reported (10). Plasma BNP concentrations were measured with a specific immunoradiometric assay kit for human BNP (Shionogi, Osaka, Japan), as previously reported (7). The plasma endothelin-1 level was determined using an antibody against synthetic endothelin-1 (Peninsula Laboratories, Belmont, California) and 125I-labeled endothelin-1 (Amersham Japan, Tokyo), as previously reported (3). Plasma angiotensin II levels were measured using an RIA with a specific antibody directed against synthetic angiotensin II, as reported previously (26). The plasma norepinephrine concentration was measured by high-performance liquid chromatography.
Statistical analysis.
All results are expressed as the mean ± SEM. Univariate analysis was performed using the Student t test. Categorical data were compared against a chi-squared distribution. Comparisons between multiple groups were determined by one-way analysis of variance (ANOVA) with the Scheffe’s F test. To evaluate the factors regulating the LV mass index in patients with DCM, univariate and stepwise multivariate analyses were used among the 15 parameters. Linear regression analysis was employed to determine the relationship between continuous variables. A p value <0.05 was regarded as significant.
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Results
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Hemodynamic and neurohumoral data.
Patients were divided into two groups according to symptoms, and they were analyzed for hemodynamic and neurohumoral data (Table 1). Left ventricular end-diastolic pressure was significantly higher in severe CHF patients (NYHA functional class III or IV) than in mild CHF patients (NYHA functional class II). The LVEF was significantly lower in severe CHF than in mild CHF patients. Neurohumoral factors such as plasma levels of BNP, norepinephrine, endothelin-1, IL-6 and CT-1 were significantly higher in severe CHF patients than in mild CHF patients.
Plasma concentration of CT-1 and LV mass index in patients with DCM.
Plasma CT-1 level was increased with the severity of CHF in DCM patients compared with that in control subjects (Fig. 1). There were no differences in heart rate, mean arterial blood pressure, LV end-diastolic pressure and LVEF between the small LV mass index group and the large LV mass index group, and there were also no differences in plasma levels of BNP, norepinephrine and treatments (Table 2). Plasma levels of CT-1, IL-6 and endothelin-1, and LV end-diastolic volume index were significantly higher in the large LV mass group than in the small LV mass group (Fig. 2).
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Figure 1 Plasma cardiotrophin-1 (CT-1) concentrations in control subjects and in congestive heart failure (CHF) patients with dilated cardiomyopathy. Mild CHF = New York Heart Association (NYHA) functional class II; severe CHF = NYHA functional class III–IV. *p < 0.05 versus the value of control subjects; #p < 0.05 versus the value of the mild CHF.
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Figure 2 Plasma cardiotrophin-1 (CT-1) concentrations in patients with dilated cardiomyopathy. Patients were classified into two groups: small left ventricular mass index (LVMI) group and large LVMI, based on the median value of LV mass index. *p < 0.01 versus the value in the small LVMI group.
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Comparison between the plasma CT-1 level and other neurohumoral factors.
In 51 CHF patients with DCM, there was no significant correlation between plasma level of CT-1 and plasma levels of norepinephrine (r = 0.097), angiotensin II (r = 0.035), endothelin-1 (r = 0.036), BNP (r = 0.064), and IL-6 (r = 0.071).
Relationship between the plasma CT-1 level and LV mass index.
Table 3 shows the results of univariate and multivariate analyses assessing the factors regulating the LV mass index in 51 patients with CHF. According to stepwise multivariate analyses, a high plasma CT-1 (p < 0.0001) and LV end-diastolic volume index (p < 0.0001) were significant independent predictors of a large LV mass index in patients with DCM. Figure 3 shows the correlation between the plasma CT-1 concentration and the LV mass index (r = 0.627; p < 0.0001).
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Figure 3 Correlation between the plasma cardiotrophin-1 (CT-1) concentrations and the left ventricular (LV) mass index in patients with dilated cardiomyopathy.
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Discussion
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The results of this study demonstrate that the plasma CT-1 level increases with the severity of CHF in DCM patients compared with that in control subjects. Furthermore, we demonstrate for the first time that the plasma CT-1 level correlates with the LV mass index in patients with DCM, which is characterized by volume overload, suggesting that CT-1 plays an important pathophysiological role of LV remodeling and/or LV hypertrophy in patients with DCM.
Relationship between the CT-1 and structural LV remodeling.
Wollert et al. (17,21) reported that hypertrophic response induced by CT-1 signaling through gp130 is distinct from the hypertrophic response seen after stimulation of G-protein coupled receptors, both on a morphological and a molecular level. Adrenergic agonists, endothelin-1, and angiotensin II induce a rather uniform increase in cardiomyocyte size, but CT-1 induces a predominant increase in cell length with the addition of new sarcomeric units in series but no concomitant increase in cell width. In the present study, although there was no correlation between plasma levels of norepinephrine, endothelin-1, and angiotensin II and LV mass index (data not shown), there was a significant positive correlation between plasma CT-1 level and LV mass in patients with DCM. Therefore, our human data are consistent with the experimental studies including the results by Wollert et al. (17,21). Overexpression has been reported of both CT-1 and gp130 in the rat ventricle after myocardial infarction and during experimental acute Chagasic cardiomyopathy (19,20), suggesting that CT-1 contributes to LV remodeling in patients with myocardial infarction and Chagas’ disease, which are characterized by volume overload. Moreover, there was a positive correlation between ventricular CT-1 mRNA and LV mass index in a canine model of pacing-induced experimental CHF that closely mimics human DCM (27). Therefore, these results (19,20,27) also support our data of a positive correlation between plasma CT-1 level and LV mass in patients with DCM.
Relationship between the plasma CT-1 level and LV mass index in patients with DCM.
The CT-1 mRNA is widely expressed in various tissues, including heart, kidney, skeletal muscle and liver (14), and CT-1 is increased in plasma in patients with CHF (15); however, both the source and the clearance of increased plasma CT-1 remain unknown. It has been shown that gp130, which mediates the action of CT-1, is abundantly expressed in the heart (28), suggesting that elevated circulating CT-1 contributes to LV hypertrophy. However, further studies are needed to clarify the source and clearance of plasma CT-1 in patients with CHF.
Neurohumoral factors such as norepinephrine and angiotensin II, which can stimulate CT-1 production in vitro (29,30), were increased in the present study. However, there was no correlation between plasma CT-1 concentration and plasma levels of these vasoconstrictors. Therefore, these neurohumoral factors may not be the main cause of increased plasma CT-1 in patients with DCM. According to stepwise multivariate analyses, a high plasma CT-1 was a significant independent predictor of a large LV mass index in patients with DCM, suggesting the important role of CT-1 in LV remodeling in patients with DCM. Although the cause and effect of this relationship remain unknown, a previous study has reported ventricular hypertrophy in transgenic models that overexpress IL-6 and IL-6 receptor (31) and the possibility of increased gp130 expression in CHF, suggesting that CT-1 may stimulate myocardial hypertrophy in patients with DCM. Recently, we reported that plasma IL-6 level was an independent prognostic predictor in patients with CHF including DCM (32); however, further studies are needed to evaluate the cause and effect of this relationship and the relation between plasma CT-1 and the prognosis of DCM patients. In addition, further studies are also needed to evaluate the plasma CT-1 and LV mass index in patients with other etiologies such as hypertension, ischemic heart disease and hypertrophic cardiomyopathy.
Conclusions.
The plasma CT-1 level increases with the severity of CHF in DCM patients compared with that in control subjects, and it correlates with the LV mass index in patients with DCM, which is characterized by volume overload, suggesting that CT-1 has an important pathophysiological role in LV remodeling and/or LV hypertrophy in patients with DCM.
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Acknowledgments
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We thank Ms. Ikuko Sakaguchi for her excellent technical assistance. We also express thanks to Mr. Daniel Mrozek for his assistance in preparing the manuscript.
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Footnotes
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This study was partly supported by a Japanese Grant-in-Aid for Scientific Research.
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References
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Abstract
Methods