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European Journal of Heart Failure 2005 7(4):689-695; doi:10.1016/j.ejheart.2004.09.011
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© 2005 European Society of Cardiology

Serum markers of angiogenesis and myocardial ultrasonic tissue characterization in patients with dilated cardiomyopathy

Tomoaki Ohtsuka*, Katsuji Inoue, Yuji Hara, Norikatsu Morioka, Kiyotaka Ohshima, Jun Suzuki, Akiyoshi Ogimoto, Yuji Shigematsu and Jitsuo Higaki

The Second Department of Internal Medicine, Ehime University School of Medicine Shigenobu, Onsen-gun, Ehime 791-0295, Japan

* Corresponding author. Tel.: +81 89 960 5302; Fax: +81 89 960 5306. E-mail address: tohtsuka{at}m.ehime-u.ac.jp


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background and aims: It has been proven that a disturbance in angiogenesis contributes to the progression of myocardial interstitial fibrosis in idiopathic dilated cardiomyopathy (DCM). This study was designed to evaluate the relationship between serum activity of angiogenic factors and myocardial ultrasonic tissue characterization in patients with DCM.

Methods and results: We studied 30 patients with DCM and 15 healthy control subjects. Serum levels of vascular endothelial growth factor (VEGF), interleukin (IL)-4 and IL-13 were measured using enzyme-linked immunosorbent assay. We determined calibrated myocardial integrated backscatter (IB) as the value of myocardial interstitial fibrosis using ultrasonic tissue characterization and also quantified the magnitude of cyclic variations in IB (CV-IB). Serum levels of VEGF and IL-13 were significantly higher in patients with DCM than in control subjects (both P<0.05). Calibrated IB was significantly higher and CV-IB was markedly lower in patients with DCM than in control subjects (both P<0.01). In patients with DCM, the levels of IL-13 significantly correlated with calibrated IB (r=0.520, P=0.018). In addition, there was a significant negative correlation between levels of VEGF and CV-IB (r=–0.611, P=0.007).

Conclusion: The increase in serum VEGF and IL-13 may be closely related to alterations in myocardial texture in DCM.

Key Words: Angiogenesis • Dilated cardiomyopathy • Ultrasonic tissue characterization

Received March 31, 2004; Revised July 13, 2004; Accepted September 20, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Angiogenesis, the production and organization of newly formed blood vessels, is implicated in a variety of human pathologies [1,2]. It has been proven that a disturbance in angiogenesis contributes to the progression of myocardial interstitial fibrosis in idiopathic dilated cardiomyopathy (DCM) [3]. A number of factors, including growth factors, cytokines and chemokines, are involved in angiogenesis. Vascular endothelial growth factor (VEGF) is a major angiogenic factor and also plays a key role in myocardial remodeling [4]. Recent reports have demonstrated the aberrant expression of myocardial VEGF isoforms in both experimental and clinical forms of dilated cardiomyopathy [3,5]. However, few clinical studies have been reported on the relation between these angiogenic factors and the pathogenesis of DCM. Interleukin (IL)-4 and IL-13 are unique cytokines with an anti-inflammatory effect, which inhibits the secretion of proinflammatory cytokines. The angiogenic activity of these cytokines in vitro and in vivo has also been demonstrated [6]. However, only a few reports provide the relation between these cytokines and angiogenesis in human pathologies, and thus, the additive effect of IL-4 and IL-13 in angiogenesis on the myocardium of DCM has not yet been determined.

Ultrasonic tissue characterization with integrated backscatter (IB) offers a promising method for the assessment of myocardial texture and intrinsic contractile performance [7,8]. Previous studies have investigated ultrasonic tissue characterization in patients with DCM, and have shown that the analysis of IB has the potential to assess the myocardial interstitial fibrosis and intrinsic myocardial contractility in DCM [9,10]. We have thus hypothesized that a close relationship should exist between the activity of angiogenic factors and alterations in myocardial texture in DCM. To test our hypothesis, we investigated the serum levels of VEGF, IL-4 and IL-13 and myocardial ultrasonic tissue characterization by backscatter analysis in patients with DCM, and further assessed the capability of serum IL-4 and IL-13 as a marker associated with angiogenesis in DCM.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Subjects
We studied 30 consecutive patients with DCM between July 2001 and June 2003. The diagnosis of DCM was based on patient history, physical examination, electrocardiogram, echocardiogram and cardiac catheterization. All patients were subjected to coronary angiography, and those with epicardial coronary artery disease were excluded from this study as well as patients with other secondary dilated cardiomyopathy. We also excluded patients who had clinical or laboratory evidence of neoplasms or autoimmune disease and liver or renal dysfunction. Fifteen age-matched healthy subjects who had no evidence of organic cardiac disease and no cardiac dysfunction were retrospectively selected as the control group. All subjects gave written informed consent and participated in this study. The investigation conforms with the principles outlined in the Declaration of Helsinki and the protocol was approved by the Human Investigations Committee of our institution.

2.2. Blood sampling and immunoassays
After bed rest for at least 30 min, peripheral venous blood samples from all subjects were collected into chilled tubes and immediately centrifuged at 4 °C. The serum samples were stored at –80 °C until assay. Serum levels of VEGF were measured by enzyme-linked immunosorbent assays with a commercial kit (Chemicon International, CA, USA). Serum levels of IL-4 and IL-13 were also measured by enzyme-linked immunosorbent assays (Immunotech, Marseille, France), as previously reported [11]. The average inter-assay and intra-assay coefficients of variation were <10% for all assays. At the same time, plasma levels of norepinephrine and brain natriuretic peptide (BNP) were also measured.

2.3. Conventional echocardiographic study
Echocardiographic studies were performed using a SONOS 5500 ultrasound system (Philips) according to the recommendations of the American Society of Echocardiography [12]. In each patient, a standard parasternal long-axis view was recorded at the basal position, and the LV end-diastolic and end-systolic dimensions (EDD and ESD) were determined using M-mode echocardiography. The LV ejection fraction (EF) was calculated as LV systolic function using the modified Simpson method.

2.4. Ultrasonic tissue characterization
To perform ultrasonic tissue characterization using IB, a SONOS 5500 ultrasound system (Philips) with backscatter software was used. Four regions of interest were chosen throughout the left ventricular myocardium in the following views: mid-septum and mid-posterior walls in the parasternal long axis view and the middle portion of the anterior and inferior walls in the parasternal short axis view. The dynamic range of the IB signal was 60 dB. Power transmission and time-gain compensation were kept constant in each patient. We estimated the following two parameters by IB analysis: (1) the mean value of the IB signal which was calibrated at the left ventricle for normalization among patients (calibrated IB) and (2) the magnitude of cyclic variations in IB (CV-IB).

2.5. Statistical analysis
All values are expressed as means±S.D. Differences between patients and control subjects were compared with the Mann–Whitney U rank-sum test for unpaired data. Correlation coefficients for relations between serum levels of angiogenic factors and clinical variables including parameters by IB analysis were tested by using the Spearman rank test. A P-value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Patient characteristics
Table 1 shows the clinical characteristics of the control subjects and patients with DCM. The patients were 5 women and 25 men ranging in age from 25 to 73 years. Sixteen patients were classified as New York Heart Association (NYHA) functional class II, 11 as class III and 3 as class IV. Heart rate was significantly increased in patients with DCM than in control subjects. The values of EDD and ESD were significantly higher and the value of LVEF was significantly lower in patients with DCM than in control subjects. The level of plasma BNP was significantly higher in patients with DCM than in the controls. Twenty-three patients were treated with spironolactone, 6 with digitalis, 27 with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers, and 18 with β-blockers.


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  		Table 1 Patient characteristics

 
3.2. Serum levels of VEGF, IL-4 and IL-13
Fig. 1 shows the serum levels of VEGF, IL-4 and IL-13 in control subjects and patients with DCM. Serum VEGF and IL-13 levels were significantly higher in patients with DCM than in control subjects (VEGF, 41.7±15.3 vs. 29.0±7.0 ng/ml, P=0.032; IL-13, 4.4±2.9 vs. 1.7±1.4 pg/ml, P=0.019), whereas no elevation was found for IL-4.


Figure 1
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  		Fig. 1 Graphs showing serum levels of VEGF, IL-4 and IL-13 in 15 age-matched control subjects and in 30 patients with DCM.

 
3.3. Parameters by IB analysis
All patients showed increased calibrated IB and reduced CV-IB in the four regions of interest compared with controls. The mean value of calibrated IB was significantly higher (17.4±4.6 vs. 12.9±2.7 dB, P=0.008) and the value of CV-IB was significantly lower in patients with DCM than in control subjects (4.2±1.0 vs. 6.7±0.7 dB, P<0.0001) (Fig. 2).


Figure 2
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  		Fig. 2 Graphs showing values of calibrated IB and CV-IB in 15 age-matched control subjects and in 30 patients with DCM.

 
3.4. Relations between VEGF, IL-4 or IL-13 and clinical variables in patients with DCM
In patients with DCM, there was a significant correlation between the serum levels of IL-13 and EDD (r=0.456, P=0.016). However, there were no significant correlations between serum levels of IL-13 and NYHA class and LVEF. In addition, neither plasma norepinephrine nor BNP levels significantly correlated with the levels of IL-13. There were no significant correlations of serum levels of VEGF and IL-4 with NYHA class, plasma norepinephrine, plasma BNP, LV dimensions or LVEF. In addition, there were significant correlations of calibrated IB with EDD (r=0.748, P=0.0002) and ESD (r=0.768, P<0.0001) (Fig. 3). However, neither plasma norepinephrine nor BNP levels significantly correlated with calibrated IB. There were no significant correlations between calibrated IB and NYHA class and LVEF. Moreover, there were no significant correlations of CV-IB with NYHA class, plasma norepinephrine, plasma BNP, LV dimensions or LVEF in patients with DCM.


Figure 3
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  		Fig. 3 Correlations of calibrated IB with the EDD and ESD in patients with DCM.

 
3.5. Relations between VEGF, IL-4 or IL-13 and parameters by IB analysis in patients with DCM
There was a significant positive correlation between serum levels of IL-13 and calibrated IB in patients with DCM (r=0.520, P=0.018) (Fig. 4), although no correlations were found between the levels of VEGF or IL-4 and calibrated IB. In addition, the levels of VEGF significantly correlated with CV-IB in patients with DCM (r=–0.611, P=0.007) (Fig. 4). However, neither IL-4 nor IL-13 levels significantly correlated with CV-IB.


Figure 4
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  		Fig. 4 Correlations of serum IL-13 levels with calibrated IB, and between serum VEGF levels and CV-IB in patients with DCM.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
The present study is the first to demonstrate the relationship between serum levels of angiogenic factors and altered myocardial ultrasonic tissue characterization in DCM. Our results showed a significant correlation between increased serum levels of IL-13 and the increased calibrated IB in patients with DCM, and also indicated that the increased calibrated IB was closely related to LV enlargement in DCM. In addition, we demonstrated a close association between increased serum levels of VEGF and diminished CV-IB in DCM.

The development of quantitative echocardiographic techniques, such as IB and tissue Doppler imaging, has enhanced the ability to assess myocardial tissue characterization. Recently, the analysis of IB and strain rate imaging have been used to detect myocardial structural and functional abnormalities in various cardiac conditions, and it has been shown that IB analysis has a higher ability to assess myocardial fibrosis in comparison with strain rate imaging [13]. Previous studies have demonstrated that the analysis of IB has the potential to assess myocardial interstitial fibrosis and intrinsic myocardial contractility in DCM [9,10]. These clinical observations have revealed an increased calibrated IB and a reduced CV-IB in patients with DCM, and it has been reported that both parameters correlate with a histologic estimate of myocardial fibrosis in the biopsy specimen of DCM patients [14]. In the present study, we demonstrated both increased calibrated IB and reduced CV-IB in our patients as well as a close association between calibrated IB and LV size in DCM. Myocardial extracellular matrix is composed of a complex network of structural protein, mainly collagen types I and III, and degradation of the extracellular matrix during the remodeling process reportedly occurs within the LV myocardium in DCM [15]. Matrix metalloproteinases (MMPs) have been shown to exist in the myocardium, and to be involved in degrading collagen. Thus, a progressive activation of MMPs results in degradation of the fibrillar collagen matrix, and can lead to increased LV wall thinning and LV enlargement [15]. Recent clinical reports have demonstrated alterations in both myocardial and circulating activities of MMPs in patients with DCM [16–18]. Spinale et al. [18] have reported a decreased myocardial activity of the interstitial collagenase, or MMP-1, which degrades the fibrillar collagen such as collagen types I and III, as well as increased activities of gelatinases, or MMP-2 and MMP-9, in DCM. This reduction in MMP-1 activity may result in an increased deposition of collagen types I and III. Indeed, Pauschinger et al. [19] demonstrated increased mRNA abundances of collagen types I and III in the myocardium of human DCM. They also found a significant shift in the collagen type I/type III ratio on both the mRNA and protein levels. Collagen type I represents a stiff fibrillar protein providing tensile strength, whereas collagen type III forms an elastic network storing kinetic energy as an elastic recoil. Therefore, an increased collagen type I/type III ratio may contribute to increasing myocardial stiffness, resulting in both increased calibrated IB and reduced CV-IB in patients with DCM, and it would seem reasonable to conclude that an association existed between increased calibrated IB and LV enlargement, one which was in fact seen in the present study.

IL-4 and IL-13 are multifunctional cytokines whose anti-inflammatory effect downregulates the function of monocytes by inhibiting the secretion of inflammatory cytokines such as tumor necrosis factor (TNF)-{alpha} [11]. Several studies have investigated the enhancement and activity of IL-4 in DCM patients, and clarified the absence of detectable IL-4 in both myocardium and circulation of DCM patients [20,21]. Although IL-13 is a novel cytokine sharing a number of biological properties with those of IL-4, the differential functions of IL-13, but not of IL-4, have been recently reported in various inflammatory disease. However, reports documenting the enhancement and function of IL-13 in DCM have been scarce. In the present study, we first showed the presence of an increase in serum IL-13 in patients with DCM, although no elevation of IL-4 was found. It is known that IL-13 has the ability to selectively induce vascular cell adhesion molecule (VCAM)-1 expression in human endothelial cells [22]. Previous studies have demonstrated that VCAM-1 is closely associated with angiogenesis and have indicated increases in the activities of both myocardial and circulating VCAM-1 in patients with DCM [23,24]. Thus, IL-13 may contribute to angiogenic activity by the induction of VCAM-1 in DCM. More importantly, the present study demonstrated significant correlations of the levels of IL-13 with LV size and calibrated IB. The increased myocardial expression of inflammatory cytokines has recently been found in DCM [25], and experimental studies have documented that myocardial TNF-{alpha} overexpression can lead to a degradation of the fibrillar collagen matrix by stimulating myocardial MMP activity, which produces increases in both LV dilation and LV wall thinning [26]. Moreover, TNF-{alpha} has been found to inhibit angiogenesis induced by antiangiogenic factors at higher concentrations [27]. IL-13 has the better-known anti-inflammatory effect, which inhibits the secretion of these inflammatory cytokines. Therefore, the increase in serum IL-13 may be closely associated with both a disturbance in angiogenesis and alterations in the structure of the myocardial tissue caused by the increased expression of inflammatory cytokines in DCM. Accordingly, our findings may address the novel and interest function of IL-13 in association with angiogenesis in DCM, but not of IL-4.

One of the important findings of the present study is the close relationship between increased serum levels of VEGF and diminished CV-IB in patients with DCM. VEGF is a major angiogenic factor, which has been studied most extensively in pre-clinical and clinical trials of therapeutic angiogenesis for ischemic cardiovascular disease [28]. Since hypoxia is a powerful inducer of angiogenesis, increased myocardial VEGF expression has been demonstrated in patients with myocardial ischemia [4]. Tissue ischemia occurs within the myocardium in DCM, possibly due to a decreased supply caused by microvascular structural and functional abnormalities. Indeed, recent studies have shown that the reduction in myocardial blood flow and volume have been observed in patients with DCM [29,30]. Therefore, it is very likely that the increased serum activity of VEGF in patients with DCM is involved in myocardial perfusion abnormalities. Furthermore, the present study demonstrated reduced CV-IB in patients with DCM and elucidated its relation to increased VEGF levels. CV-IB can be of value in quantifying regional differences in myocardial contractile performance in DCM. Moreover, it is known that the reduction in myocardial blood flow influences attenuation and scattering of myocardial tissue, and could be associated with the deterioration of LV systolic function [29,30]. Accordingly, the increase in serum VEGF may be closely associated with the impaired intrinsic myocardial contractile performance caused by myocardial microvascular abnormalities and myocardial interstitial fibrosis in DCM.

In conclusion, we demonstrated increased serum levels of VEGF and IL-13 in patients with DCM and found a close association between these levels and altered myocardial ultrasonic tissue characterization in DCM. These findings suggest that the increase in serum VEGF and IL-13 may be closely related to alterations in myocardial texture caused by a disturbance in angiogenesis in DCM.

4.1. Limitations of the study
Some limitations of our study merit consideration. First, the cellular source of serum VEGF, IL-4 and IL-13 is not yet known. Since we designed this study to investigate the serum activities of angiogenic factors in patients with DCM, we excluded patients who had clinical or laboratory evidence of malignancy or inflammatory disease and liver or renal dysfunction. Therefore, it is very likely that their source is associated with secretions from the heart. However, our results on serum levels of VEGF partly diverge from those of Abraham et al. [5] in their study on the expression of myocardial VEGF isoforms in patients with DCM. Their study showed the reduced mRNA and protein levels of myocardial VEGF-A in transplant patients with end-stage DCM, whereas elevated both expression levels of VEGF-C have been shown. A previous experimental report has shown that VEGF-C promotes angiogenesis and augments flow to ischemic tissues in the setting of tissue ischemia [31]. Therefore, changes on VEGF levels in serum of DCM patients may result from an increase of myocardial VEGF-C rather than a decrease in VEGF-A. However, the levels of VEGF, which are measured using our immunoassay system, show the total amount of VEGF isoforms in the serum sample. In addition, this study found no evidence of myocardial expression of VEGF isoforms in our patients, showing the lower EDD and the higher EF compared with those in patients of Abraham and colleagues. Thus, to clarify the discrepancy between the levels of VEGF in the serum and in the myocardium, further studies will be required. Second, we could not investigate serum levels of other angiogenic factors such as basic fibroblast growth factor in our patients, and thus this study found no evidence of its relation to altered myocardial ultrasonic tissue characterization in DCM patients. Although serum levels of sVCAM-1 were measured in some patients, the samples were too small for correlations between serum levels of sVCAM-1 and other angiogenic factors and alterations in myocardial texture in DCM to be evaluated. Thus, further studies will be required in a larger number of patients.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
No financial support was received.


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

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