© 2008 European Society of Cardiology
Plasma connective tissue growth factor is a novel potential biomarker of cardiac dysfunction in patients with chronic heart failure
a Department of Medicine and Biological Science, Gunma University Graduate School of Medicine Japan
b Department of Laboratory Science, Gunma University School of Health Science Japan
c Division of Cardiology, Gunma Prefectural Cardiovascular Center Japan
d Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Japan
* Corresponding author. Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. Tel.: +81 27 220 8142; fax: +81 27 220 8158. E-mail address: araim{at}showa.gunma-u.ac.jp (M. Arai).
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. Discussion5. ConclusionAcknowledgmentsReferences |
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Background: Connective tissue growth factor (CTGF) has been recently reported as a mediator of myocardial fibrosis; however, the significance of plasma CTGF concentration has not been evaluated in patients with heart failure. The aim of this study was to investigate the clinical utility of plasma CTGF concentration for the diagnosis of heart failure.
Methods and results: We evaluated fifty-two patients with chronic heart failure. The plasma concentration of CTGF and other markers of fibrosis were assessed and compared with clinical and echocardiographic data. Plasma CTGF was significantly elevated in symptomatic patients in proportion to their NYHA classes and was significantly correlated with plasma brain natriuretic peptide (BNP) concentration (r = 0.395, P < 0.01). Plasma CTGF was also correlated with plasma transforming growth factor beta (TGF-β) (r = 0.512, P < 0.01), matrix metalloproteinase (MMP)-2 (r = 0.391, P < 0.05) and tissue inhibitor of MMP (TIMP)-2 (r = 0.354, P < 0.05) concentrations. Interestingly, plasma CTGF was correlated with E/E' value evaluated by tissue Doppler echocardiography (r = 0.593, P = 0.012), but not with systolic function and left ventricular mass.
Conclusion: Our study suggests that plasma CTGF concentration is a novel diagnostic marker for cardiac dysfunction and may provide additional specific information about myocardial fibrosis in chronic heart failure patients.
Key Words: Cytokines • Ventricular remodeling • Extracellular matrix • Natriuretic peptide
Received July 3, 2007; Revised December 14, 2007; Accepted February 20, 2008
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionAcknowledgmentsReferences |
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Heart failure is associated with structural alterations of myocardial tissue, known as myocardial remodeling [1]. Characteristic features of cardiac remodelling include hypertrophy of cardiac myocytes and myocardial fibrosis [1,2]. The latter involves the proliferation of cardiac fibroblasts and increased deposition of extracellular matrix (ECM), as well as altered composition of ECM [2]. Since the pathological significance of fibrosis is an essential part of heart failure, methods for accurately monitoring this process are the subject of considerable research. Several previous studies have shown that circulating markers of ECM synthesis and degradation, mainly degradation products of collagen or intermediates of collagen synthesis, correlate with the degree of cardiac fibrosis and/or cardiac dysfunction [3-5]; however, the correlation of these markers and cardiac fibrosis is very weak.
We and others have previously shown that connective tissue growth factor (CTGF/CCN2) acts as a mediator of myocardial remodelling and fibrosis [6-9]. Further, ctgf expression levels are increased in myocardial samples from patients with cardiomyopathy [8] or diastolic heart failure [6]. Our previous report showed that myocardial ctgf expression is regulated by various neurohumoral factors, such as G-protein coupled receptor ligands, transforming growth factor β (TGF-β), and brain natriuretic peptide (BNP) [6]. BNP is an established marker of cardiac dysfunction, and is known to have an anti-fibrotic function [10]. Interestingly, we showed that predominant myocardial ctgf expression relative to bnp expression was a critical determinant of myocardial fibrosis in an experimental animal model of diastolic heart failure [6]. CTGF is a secreted protein, and plasma CTGF concentration correlates with the severity of several systemic fibrotic disorders [11]. These results suggest that, like BNP, secreted CTGF level may be a candidate plasma marker in cardiac dysfunction. Therefore, the purpose of this study was to establish the plasma concentration of CTGF as a novel diagnostic modality of heart failure by utilizing a recently developed enzyme-linked immunoassay (ELISA) assay system [12]. We measured plasma CTGF concentration in patients with chronic heart failure (CHF) and compared these values with the clinical characteristics of patients, echocardiographic parameters of cardiac function and BNP. In addition, to investigate the significance of the plasma CTGF level, we determined the relationship between plasma CTGF and other markers associated with ventricular remodelling, i.e. neurohumoral factors and cytokines such as TGF-β1 and osteopontin [13], oxidative stress markers such as urinary 8-iso-prostaglandin F2
(8-iso-PGF2) and 8-hydroxydeoxyguanosine (8-OHdG) [14], and ECM markers such as matrix metalloproteinase (MMP) 1, 2, and 9, tissue inhibitor of metalloproteinase (TIMP) 1 and 2, procollagen type I C-terminal propeptide (PICP), carboxy-terminal telopeptide of collagen type I (ICTP), and the amino-terminal propeptide of type III procollagen (PIIINP).
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionAcknowledgmentsReferences |
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The study was approved by the local ethics committee and conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from all patients.
2.1. Patients
We studied 52 Japanese patients with chronic heart failure [40 men and 12 women], aged 32 to 89 years (mean age 64) who were treated at Gunma University Hospital or Gunma Prefectural Cardiovascular Center for heart failure between April 2004 and March 2006. The main demographic and clinical characteristics of the patients included in the study are detailed in Table 1. The prevalence of idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, and ischaemic cardiomyopathy was 46%, 21%, and 13%, respectively. The present study did not include patients with a history of neoplastic, hepatic, infectious, collagen or peripheral atherosclerotic diseases, or any surgical procedure in the preceding 6 months. All patients had stable symptoms and no inflammatory signs at the time of evaluation.
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2.2. Blood sampling and measurement of CTGF
Plasma and serum samples were obtained from peripheral venous blood. Whole blood was withdrawn from the cubital vein with sodium EDTA and kept on ice, and then plasma was separated by centrifugation for 30 min. Plasma and serum samples were stored at –80 °C until analysis. Plasma CTGF concentrations were measured by sandwich enzyme-linked immunosorbent assay (ELISA) as previously described [12]. Cut-off level (3.0 ng/mL) was determined by repeated measurements from five healthy age-matched volunteers. Plasma BNP concentration was measured by immunoradiometric assay (Shionoria BNP assay, Shionogi Pharmaceutical Co). Plasma TGF-β (R&D systems, Minneapolis, MN), Serum MMP1, MMP2 and MMP9 activity (Amersham Biosciences, UK) and serum TIMP1 and TIMP2 concentrations (Daiichi Finechemical Inc. Toyama, Japan) were measured by ELISA. Humoral factors were measured as follows: osteopontin, ELISA (Immuno-Biological Laboratories, Takasaki, Japan); norepinephrine, high-performance liquid chromatography; angiotensin II and aldosterone, radioimmuno assay. Urine (5 mL) was transferred into a tube containing 0.25 mg of indomethacin and centrifuged at 10,000 g for 10 min, and the resulting supernatant was stored at –80 °C until the assay for urinary oxidative stress markers. Urine 8-iso-PGF2
and 8-OHdG concentrations were determined using an enzyme immunoassay kit (8-isoprostane EIA kit; Cayman Chemical, Ann Arbor, MI) and an ELISA kit (Japan Institute for Control of Aging, Fukuroi, Japan), respectively. Serum PICP, ICTP and PIIINP levels were measured by radioimmunoassay (Orion Diagnostica, Oununsalo, Finland).
2.3. Echocardiographic measurement
Two-dimensional imaging examinations were performed according to recommendations of the American Society of Echocardiography [15]. Pulsed Doppler was used to record transmitral flow in the apical four-chamber view [16]. Tissue Doppler velocities were acquired at the septal and lateral annular sites and averaged as previously described [17]. Studies were analyzed by an echocardiographer who was blinded to all clinical data.
2.4. Statistical analysis
Values are expressed as the mean±S.D or median with interquartile range. If the blood test result was below the limit of detectability of a test, the lower limit of detection was recorded. Statistical analyses were carried out using the SPSS version 14.0 (SPSS Inc, Chicago, IL). Plasma CTGF concentration among different NYHA groups was compared by Kruskal Wallis test. The difference of the plasma CTGF concentration between patient groups with or without a past history of heart failure was tested by Mann-Whitney test. Multiple linear regression analysis was performed to evaluate the independent factors predictive of plasma CTGF concentration. Simple linear regression analyses were also applied to determine the correlation between plasma CTGF concentration and biological markers associated with heart failure and echocardiographic parameters. A probability value <0.05 was considered statistically significant.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionAcknowledgmentsReferences |
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3.1. Clinical characteristics and plasma CTGF concentration in the patient population
The clinical characteristics of patients with CHF are summarized in Table 1. Of 52 patients with CHF, 65% patients had a previous history of overt heart failure within the past year. The proportion of patients with New York Heart Association (NYHA) class I and class II symptoms was 46% and 46%, respectively. The median plasma BNP concentration was 126.0 pg/mL (interquartile range 333.8 pg/mL), which was higher than the cut-off level in normal subjects (18.4 pg/mL). The plasma norepinephrine concentration in this patient population was 470±181 pg/mL, which was also significantly higher than the normal cut-off level of 168.4 pg/mL.
Plasma CTGF concentration was compared among patients with different NYHA heart failure classes. The median plasma CTGF concentration in NYHA class I (asymptomatic patients), was 7.25 ng/mL with an interquartile range of 7.52 ng/mL, which was higher than the cut-off level of healthy subjects (3.0 ng/mL). The plasma CTGF concentration increased in proportion to the increase in NYHA class. Overall differences were detected by Kruskal Wallis test (Fig. 1A). In addition, patients with a previous history of overt heart failure had a higher concentration of plasma CTGF than patients without heart failure history (Fig. 1B). There was no significant relationship between drug therapy and plasma CTGF concentration.
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3.2. Relationship between plasma level of CTGF and neurohumoral factors
Multiple linear regression analysis was performed to determine the independent humoral factors predictive of plasma CTGF concentration (Table 2). Among several plasma and urine factors related to heart failure, plasma BNP (β-coefficient, 0.636, P=0.005) and TGF-β (0.617, P=0.004) were independent predictors of plasma CTGF. Simple linear regression analysis was applied to determine the correlation between plasma CTGF and BNP concentrations. Plasma CTGF concentration was positively correlated with the plasma BNP level (r=0.395, P<0.01, Table 3A).
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In addition to BNP and TGF-β, simple linear regression analysis demonstrated that plasma CTGF concentration had significant positive correlations with plasma MMP2 and TIMP2 concentrations; however, there was no significant correlation between the plasma CTGF level and plasma norepinephrine, osteopontin, angiotensin II, MMP1, MMP9, and TIMP1 levels. Plasma CTGF concentration did not correlate with urine oxidative stress marker levels (Table 3A). Biochemical markers of collagen turnover, PICP, ICTP, and PIIINP were also not correlated with plasma CTGF concentration. Plasma CTGF was independent of age, renal function (creatinine), anaemia (haematocrit), and norepinephrine levels (Table 3A). Plasma concentrations of norepinephrine, osteopontin and angiotensin II were not significantly altered for different severities of heart failure. In contrast to CTGF, plasma BNP concentration did not correlate with TGF-β and MMP2 concentrations (Table 3B).
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3.3. Relationship between plasma level of CTGF, BNP, and TGF-β and echocardiographic parameters
Coefficients of correlation are listed in Table 4. Circulating levels of CTGF had a significant positive correlation with E/A and E/E' ratios estimated by transmitral flow velocity and tissue Doppler velocity of the mitral annulus. There were no significant correlations between plasma CTGF and LV mass or LVEF. Plasma BNP was significantly correlated with LV mass, E' and E/E'. TGF-β did not significantly correlate with any echocardiographic parameters.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionAcknowledgmentsReferences |
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In this study, plasma CTGF concentrations were significantly increased in patients with CHF in proportion to their NYHA class and correlated significantly with plasma BNP concentration. To our knowledge, this is the first report demonstrating elevated plasma CTGF concentration in patients with CHF.
4.1. Establishment of plasma CTGF concentration as a novel diagnostic marker of heart failure
It has been shown that CTGF is a possible key determinant of progressive tissue fibrosis, excessive scarring and wound repair in various organs [18]. In cardiac myocytes, ctgf gene expression is regulated by factors that induce cardiac remodelling, such as TGF-β, angiotensin II, endothelin 1, oxidative stress, and cell stretch [6,18]. It has been demonstrated that the mRNA or protein level for ctgf is upregulated in the human failing heart [6,8]; however, the ctgf mRNA level or tissue concentration of CTGF protein in the heart is not an easy diagnostic tool in clinics and community hospitals. As CTGF is a secreted protein, we measured the plasma concentration of CTGF in heart failure patients and determined whether the plasma CTGF concentration can serve as a novel diagnostic modality in heart failure.
Plasma CTGF concentration was significantly correlated with the E/E' ratio but not with LVEF. The E/E' ratio is an estimate of LV filling pressure and thus, in part, reflective of LV diastolic function [17]. Since CTGF is a profibrotic cytokine and an excess fibrosis of the heart is a critical determinant of diastolic dysfunction, the positive correlation between CTGF and E/E' may suggest a causative role of CTGF as an inducer of heart failure through excess fibrosis. In fact, plasma CTGF concentration was positively correlated with NYHA heart failure class and a previous history of heart failure. The plasma concentration of CTGF did not show any correlation with age, serum creatinine, haematocrit, or the presence of atrial fibrillation. These data suggest that the plasma concentration of CTGF is a good marker to compare the degree of heart failure in patients with different clinical conditions.
In this study, we also examined the correlation between BNP and echocardiographic parameters (Table 4). Both CTGF and BNP have a significant correlation with E/E', an index of LV filling pressure at early diastolic phase. On the other hand, although BNP level was correlated with E', an inverse of time constant of early diastolic velocity of the mitral annulus, CTGF level showed a correlation with E/A, an index that represents both early and late diastolic properties. Thus CTGF may indicate different diastolic properties from BNP. As with the NYHA functional class and plasma BNP level, E/E' is a strong prognostic predictor in patients with CHF [19,20]. The association between plasma CTGF level and E/E' may represent the predictive value of the CTGF level in estimating survival of heart failure patients.
4.2. Different roles of CTGF and TGF-β in fibrosis
TGF-β has been demonstrated to mediate cardiac fibrosis [21] as well as fibrosis in other organs. It has been shown that the profibrotic effects of TGF-β are, in part, mediated through ctgf induction in various organs [18]. Sanderson et al. showed that plasma TGF-β levels were elevated in patients with dilated cardiomyopathy [22]; however, analysis of the association between its circulating level and NYHA class, and other humoral factors has not been performed. In this study, we compared CTGF and TGF-β to determine which factor is better correlated with parameters of heart failure. Although plasma CTGF was significantly correlated with NYHA classes, plasma BNP level and E/E', the plasma TGF-β level was not correlated with these parameters (no difference in mean TGF-β levels among different NYHA classes: TGF-β vs. BNP, r=0.068, ns; TGF-β vs. E/E', r=0.2, ns, Table 4). CTGF and TGF-β have common and separate biological effects on target organs. Besides the profibrotic effect, TGF-β is involved in the suppression of growth, inflammation and immune-reaction and other biological processes as well as fibrosis. In fact, circulating levels of TGF-β have been shown to be modulated by smoking, diabetes, obesity, and hypertension [23]. In the failing heart, multiple biological reactions secondary to heart failure could influence the plasma TGF-β level; therefore, even though TGF-β and CTGF are both involved in tissue fibrosis, CTGF may be more specific than TGF-β for fibrosis, and thus cardiac remodelling in heart failure.
4.3. CTGF and extracellular matrix turnover
In this study, the plasma CTGF level was correlated with MMP2 and TIMP2 concentrations. In patients with dilated cardiomyopathy and ischaemic cardiomyopathy, the cardiac content and activity of MMP2 protein (72 kDa, gelatinase-A) have been shown to be elevated [24]. Elevated MMP activity promotes changes in the ECM structure through degradation pathways, and thus results in reduced contractility and progressive ventricular dilatation [25]. TIMP2, which directly binds to a propeptide of MMP2, is an endogenous inhibitor of MMP activity [26]. It has been reported that over-expression of ctgf increases mmp2 expression in vascular smooth muscle cells [27]. Our data demonstrating the positive correlation between CTGF and MMP2 indicate that the interaction between these two factors demonstrated in experimental conditions is also true in failing human hearts. In our study, TIMP2 and MMP2 were increased according to the increase of CTGF. Since TIMP2 counteracts against MMP2, we measured plasma concentrations of collagen metabolites (plasma PICP, ICTP and PIIINP). In our study, concentrations of these metabolites were not significantly correlated with NYHA class. Querejeta et al. demonstrated that the plasma concentration of the propeptide of procollagen type I (PIP) is increased in hypertensive heart disease [3]. The number of patients with hypertension was not sufficient in our study, and further study should be performed to address the discrepancy between these two studies.
4.4. CTGF, the renin-angiotensin-aldosterone system and oxidative stress
Experimental models and clinical studies have shown that the renin-angiotensin-aldosterone system (RAAS) is a critical determinant of cardiac remodelling and myocardial fibrosis including CTGF production [9,28]; however, plasma angiotensin II levels were not associated with CTGF levels or disease severity. Several of our patients were being treated with blockers of the RAAS (N=27: 51.9%) and/or loop diuretics (N=32: 61.5%). These drugs might have affected the results of this study.
Oxidative stress is also an important mediator in cardiac remodeling [29] and ctgf expression [18]; however, we could not show an association between oxidative stress and CTGF in this study. A larger study may be required to examine the association.
4.5. Study limitations
Although we measured plasma CTGF concentration in this study, we did not determine the source of CTGF production. It has been reported that mRNA and protein of CTGF are produced and increase in the failing heart [7,8]. We therefore think that the increased plasma CTGF concentration is due to increased production in the heart. Simultaneous measurement of CTGF in coronary sinus blood and aortic root blood would address this issue.
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5. Conclusion |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionAcknowledgmentsReferences |
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For the first time, we observed that plasma CTGF concentration was increased in patients with chronic heart failure. CTGF level was associated with NYHA functional class, a previous history of congestion, plasma BNP level and E/E' on echocardiography. Plasma TGF-β and BNP were independent predictors of plasma CTGF; however, TGF-β was neither associated with BNP nor echocardiographic parameters. These data suggest that plasma CTGF concentration represents the LV filling pressure and/or diastolic dysfunction. Given that CTGF is an initiator of myocardial fibrosis, plasma CTGF level may have a prognostic value of LV pathological remodelling, especially in diastolic heart failure.
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Acknowledgments |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionAcknowledgmentsReferences |
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We are grateful to Mari Mogi for study coordination. This work was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI B-17390224 and S-15109010) from the Japan Society for the Promotion of Science (JSPS).
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