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European Journal of Heart Failure 2002 4(4):439-444; doi:10.1016/S1388-9842(02)00092-2
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© 2002 European Society of Cardiology

Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy

Bodo Schwartzkopff*, Michael Fassbach, Beate Pelzer, Michael Brehm and Bodo E. Strauer

Department of Cardiology, Angiology and Pneumology Heinrich-Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany

* Corresponding author. Tel.: +49-211-81-18813; fax: +49-211-81-19520 E-mail address: schwartzkopff{at}med.uni-duesseldorf.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Background and aims: Left ventricular (LV) dilation and myocardial remodelling are hallmarks of heart failure in idiopathic dilated cardiomyopathy (DCM). Interstitial collagen is essential for LV integrity and function while degradation of collagen by collagenases, especially matrix-metalloproteinases (MMPs), are suggested to contribute to ventricular dilation. In the present study, serological markers of collagen metabolism were investigated.

Methods and results: Serum levels of MMP-1 and its inhibitor (TIMP-1), the markers for collagen degradation type I (collagen carboxyterminal telopeptide (ICTP)) and synthesis (carboxyterminal propeptide of type I procollagen (PICP)) were quantified by ELISA and RIA of 43 patients with DCM and 47 age-matched control subjects. Free MMP-1 serum concentration was significantly increased in the DCM group (5.29±0.83 vs. 2.22±0.29 ng/ml; P=0.01) as well as the free TIMP-1 concentration (206.54±12.65 vs. 181.44±8.55 ng/ml; P=0.05). The free MMP-1/TIMP-1-ratio was higher in DCM than in the control group (0.030±0.005 vs. 0.012±0.001; P=0.01). ICTP was significantly increased (7.60±1.21 vs. 3.44±0.19 µg/l; P<0.001). PICP was not significantly increased (125.29±8.93 µg/l vs. 113.11±5.47 µg/l; P=n.s.). Free MMP-1 and MMP-1/TIMP-1-ratio correlated with LV end diastolic diameter [cm/m2 body surface area (BSA)] (r=0.28; P=0.03 and r=0.34; P=0.01, respectively) as well as with cardiac index (CI) (r=–0.32; P=0.04 and r=–0.33; P=0.04, respectively) in patients with DCM.

Conclusion: Serum markers of collagen degradation are elevated and might be valuable markers for progression of LV dilation in patients with DCM.

Key Words: Collagenases • Matrix-metalloproteinases • Ventricular remodelling • LV dilation • Dilated cardiomyopathy

Received May 29, 2001; Revised November 23, 2001; Accepted February 5, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Dilated cardiomyopathy (DCM) is defined by ventricular enlargement with thin ventricular walls and impaired systolic function. In spite of new therapeutic concepts and medication, prognosis is still poor [1]. DCM may be idiopathic or caused by infective, toxic, or metabolic factors. The myocardial extracellular matrix (ECM) is supposed to play an important part in the pathogenesis of ventricular dilation. The fibrillar ECM is mainly composed of type I and III fibrillar collagens forming a three-dimensional framework, providing stability of ventricular geometry and preserving alignment of cardiomyocytes which is important for normal left ventricular function [2]. Topographically, cardiomyocytes are surrounded by a collagenous weave with collagen struts bridging the lateral surface of cells. This framework allows an effective transmission of force in systole as well as in diastole. Ventricular wall thinning in DCM is partly explained by rupture and dehiscence of type I collagen fibers and tethers leading to a side-to-side slippage of cardiomyocytes [3–5].

Matrix metalloproteinases (MMPs) are an endogenous family of zinc-dependent enzymes which are responsible for extracellular collagen degradation and ECM remodelling in several states of heart failure [6,7]. So far, more than 16 different subtypes of MMP are known [8,9]. MMPs are regulated at different levels, endogenous extracellular signals play an important role as well as the specific inhibition and regulation by tissue inhibitors of matrix metalloproteinases (TIMPs) [10,11].

Physiologically, MMP-1 and TIMP-1 are co-expressed and are tightly regulated for maintaining the architecture of the ECM [12]. In normal myocardial tissue, a balance between collagen synthesis and degradation exists. It is supposed that any imbalance in the proteinase/proteinase-inhibitor-system with relative or absolute predominance of MMP may disturb intramyocardial tissue architecture. In hearts with DCM, an increase of the intramyocardial activation system of MMPs [13], as well as an increase in MMP itself [14], has been reported.

Up to now, comprehensive data about circulating MMP-1, its inhibitor TIMP-1 in combination with the markers of collagen degradation (ICTP) or synthesis (PICP) in dilated cardiomyopathy are still rare.

As MMP-1 and TIMP-1 provide useful information about cardiac remodelling and collagen turnover [15,16], the aim of this study was to clarify if there are serological markers indicating a disturbed balance of collagenases and its inhibitors, indicating an abnormal collagen metabolism in patients with DCM.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Statistical analysis
 4. Results
 5. Discussion
 References
 
2.1. Subjects
Blood samples from 43 patients with a clinical diagnosis of DCM (37 men, six women) aged 55±2 (31–83) years, who were all in a compensated status without congestion, were investigated. Functional class was evaluated according to the NYHA-class. All patients had undergone routine cardiac catheterization to exclude coronary artery disease, aortic and stenotic peripheral atherosclerosis. Hemodynamic and functional data of the ventricle were evaluated using a Siemens Cathcor system. An angiographically determined ejection fraction (EF) of <45% was required for entry. Left-ventricular end-diastolic diameter (LVEDD, cm)/(BSA, m2) was determined by two-dimensional real-time echocardiography (Toshiba Powervision 5000) that was calculated to body surface area and was ≥2.9 cm/m2 body surface area (LVEDD-BSA) in patients with DCM, according to Val-HeFT-trial criteria [17].

At the time the blood samples were taken, all patients had been receiving heart failure therapy [ACE inhibitors (n=43), diuretics (n=43), glycosides (n=43), beta-blockers (n=43)] for different times.

None of the patients had elevated liver enzymes or suffered from liver cirrhosis or fibrosis, there were no clinical signs of: osteoporosis; multiple myeloma; osteolytic metastases; systemic glucocorticoid treatment; rheumatoid arthritis; or cancer and creatinine was <1.2 mg/100 ml.

The control group consisted of 47 subjects (29 men, 18 women) aged 50±2 (22–80) years (P=0.143) with no history of cardiac complaints, myocardial infarction or valvular failure. Electrocardiogram showed normal findings and chest X-ray gave normal heart silhouette.

2.2. Serum parameters
Peripheral venous blood samples were taken and centrifuged, within 5 min of sampling, at 3000 rev./min for 10 min at 4 °C. Native serum was then stored at –80 °C until use.

According to the study performed by Laviades et al. [16], MMP-1 and TIMP-1 were chosen for this study. MMP-1 is mainly secreted by fibroblasts and is able to initialise type I collagen degradation. It has a strong affinity to type I and III collagen. Active forms of MMP can be inhibited by interaction with TIMP or unspecific inhibitors.

Circulating serum markers of type I collagen metabolism (ICTP=marker for type I collagen degradation, PICP=marker for type I collagen synthesis) and of MMP-1 and TIMP-1 were quantified in patients with DCM and clinically healthy subjects.

Total serum MMP-1 was determined by a two-step sandwich immunoassay (Chemicon International, USA) using enzyme-labelled antibodies, directed against different antigenic sites on the same MMP-1 molecule representing active MMP-1 and its precursor. This antibody does not interfere with {alpha}2-macroglobulin. The inter- and intra-assay variations for MMP-1 determination were 6.1 and 3.7%, respectively. The sensitivity (lower detection limit) was 0.16 ng MMP-1/ml.

Total serum concentration of human-TIMP-1 was determined by a solid phase enzyme immunoassay (Chemicon International, USA) which utilises plate-bound antibodies in combination with enzyme-labelled antibodies directed against different antigenic sites on the same TIMP-1 molecule. The inter- and intra-assay variations for TIMP-1 determination were 6.4 and 4.3%. The sensitivity (lower detection limit) was 0.05 ng of total TIMP-1/ml.

To determine the circulating levels of free MMP-1 and TIMP-1, the MMP-1-/TIMP-1-complex (Chemicon International, USA) was determined by a solid phase enzyme immunoassay based on a two-step immunoreaction using anti-MMP-1 monoclonal antibodies immobilised on a microplate and enzyme-labelled anti-TIMP-1 antibodies.

The inter- and intra-assay variations for this kit were 5.6 and 3.2%. The sensitivity (lower detection limit) was 0.02 ng/ml.

The serum levels of free MMP-1 and TIMP-1 were calculated as described by Laviades et al. [16] by subtracting the value of MMP-1-/TIMP-1-complex from the values of total MMP-1 and total TIMP-1.

Serum PICP was determined by radioimmunoassay (Orion Diagnostica, Finland).

The inter- and intra-assay variations for PICP were 5.1 and 2.8%. The sensitivity (lower detection limit) was 1.2 µg PICP/l.

Circulating ICTP was determined by radioimmunoassay (Orion Diagnostica, Finland).

The inter- and intra-assay variations for ICTP were 5.7 and 4.8%. The sensitivity (lower detection limit) was 0.5 µg ICTP/l.


   3. Statistical analysis
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
4. Results
 5. Discussion
 References
 
For statistical analysis, a SPSS software package was used. Values are expressed as mean±S.E.M. To describe differences between patients with DCM and the control group, the Mann–Whitney U-test was used. Correlation analysis between clinical and angiographic parameters and markers of collagen metabolism were done by one-tailed Spearman's test only in patients with DCM.

Statistical significance was designated at P≤0.05.


   4. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
5. Discussion
 References
 
4.1. Clinical data
The 43 patients (37 male/6 female) were aged 55±2 years and had an average NYHA class of 2.6±0.1; EF of 31±2% and cardiac index (CI) of 2.55±0.17 l/min/m2 BSA. Mean LVEDD was 68±1 mm and LVEDD-BSA 3.47±0.07 cm/m2 BSA. In the patients with DCM, LV-dilation (LVEDD-BSA) did not correlate with NYHA-class (r=0.057; P=0.39), whereas NYHA-class correlated with EF (r=–0.454; P=0.02) and CI (r=–0.430; P=0.03). The average left ventricular end diastolic pressure (LVEDP) was 22.9±2.2 mm Hg.

4.2. Biochemical markers of collagen metabolism
Serum concentrations of total MMP-1 were elevated in patients with DCM compared to control subjects (5.99±0.92 vs. 2.43±0.37 ng/ml; P=0.006). Serum concentrations of free MMP-1 were significantly higher in DCM than in the control group (5.29±0.83 vs. 2.22±0.29 ng/ml; P=0.01).

Serum concentrations of total and free TIMP-1 were increased in patients with DCM (207.25±12.72 vs. 181.67±8.58 ng/ml; P=0.05 and 206.54±12.65 vs. 181.44±8.55 ng/ml; P=0.05).

Serum concentrations of MMP-1/TIMP-1-complex were increased in DCM as well (0.71±0.13 vs. 0.23±0.12 ng/ml; P<0.001).

The ratio of free MMP-1/TIMP-1 showed a 2.5-fold increase in DCM (0.030±0.005 vs. 0.012±0.001; P=0.01).

The circulating serum level of ICTP was significantly elevated in DCM (7.60±1.21 vs. 3.44±0.19 µg/l; P<0.001). In DCM, there was a trend to increased PICP levels (125.29±8.93 vs. 113.11±5.47 µg/l) but the differences were not statistically significant (Fig. 1).


Figure 1
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  		Fig. 1 Serum concentrations of markers for collagen degradation and synthesis (mean±S.E.M.); (a) free MMP-1-concentration [ng/ml]; (b) free TIMP-1 [ng/ml]; (c) ICTP serum concentration [µg/l]; (d) PICP serum concentration [µg/l].

 
No significant differences in circulating MMP-1, TIMP-1, ICTP, or PICP levels were found between male and female patients.

4.3. Correlation of serum markers of collagen metabolism with clinical data in patients with DCM
LVEDD-BSA had a significant correlation with free MMP, with the free MMP-1/TIMP-1-ratio (r=0.284; P=0.03 and r=0.341; P=0.01) and with ICTP (r=0.332; P=0.02). CI showed a significant correlation with free MMP-1 (r=–0.32; P=0.04) and the free MMP-1/TIMP-1-ratio (r=–0.33; P=0.04).

The free MMP-1/TIMP-1-ratio did not significantly correlate with ICTP (r=0.206; P=0.1). There were no significant correlations between the free MMP-1/TIMP-1-ratio and age (r=0.218; P=0.09), NYHA-class (r=0.131; P=0.25), EF (r=0.047; P=0.40), or LVEDP (r=–0.145; P=0.22). Furthermore, no correlations were found between the free MMP-1/TIMP-1-ratio and PICP (r=0.230; P=0.07). There were no correlations between the age of patients and ICTP (r=–0.022; P=0.45) or PICP (r=0.180; P=0.13), respectively.


   5. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
References
 
Various clinical and experimental studies have shown that the development of systolic heart failure is accompanied by ventricular remodelling with LV dilation [11,18,19].

MMPs and TIMPs are essential for a physiological composition of ECM that is characterised by a high turnover of collagen in the normal heart [10,13].

Several studies have examined MMP activity within failing hearts. In experimental heart failure following rapid pacing, MMP activity was found to be increased [3,4,14,20–23]. On the other hand, pharmacological inhibition of MMP with a MMP inhibitor during the pacing period prevented LV dilation as well as impairment of LV pump function, thus supporting the concept of the relevance of MMP inhibition on LV remodelling in vitro [14].

Human LV-tissue samples from hearts with heart failure revealed increased mRNA abundance and increased zymographic MMP activity [21,22].

In this study we found elevated serum markers of collagen metabolism (ICTP) in combination with elevated MMP-1- and TIMP-1-concentrations in peripheral venous blood samples in patients with mild to moderate heart failure due to DCM.

It is known that a balance between MMP and TIMP concentrations exists in the normal myocardium. Any imbalance was supposed to induce a pathologic remodelling of the heart [13]. We found increased MMP-1 and TIMP-1 serum concentrations and more importantly an increased MMP-1/TIMP-1-ratio indicating a disturbed balance with a predominace of collagenolytic activity. This relative predominance of MMP-1 over TIMP-1 may be one cause for an increased type I collagen degradation. Consistently with this, the degradation marker of type I collagen (ICTP) was elevated in our patients. Furthermore, we found a significant correlation between the free MMP-1/TIMP-1-ratio and the degree of LV dilation as well as a negative correlation with cardiac index. On the other hand, in mild to moderate NYHA stages, symptoms poorly correlate with LV-diameter [24]; this is also supported by our data.

It is well known that the incidence for DCM in males is 2.5-fold increased [25]. According to this, only 14% of our patients were female. It is known that sex hormones have effects on cardiac mass [26] and female sex steroids were reported to inhibit MMPs [27]. We found no differences in circulating serum levels of collagen metabolism between male and female patients. Up to now, it is unknown if female patients with DCM may represent a group of patients in whom protective mechanisms such as hormone patterns are altered.

It is to be considered that collagen synthesis and interstitial fibrosis is increased in DCM [28,29]. Myocyte death due to apoptosis, metabolic, viral, toxic, or ischemic factors may all contribute to focal collagen accumulation (replacement fibrosis). This process of replacing myocytes by functionally unfavourable collagen could be sporadic in its amount and its time course. This might explain the significantly increased concentration of TIMP, the inhibitor of collagenolysis, and the slightly elevated marker of type I collagen synthesis. Thus, it has to be considered that focal accumulation of functionally unfavourable collagen and collagen with fewer cross-links [3] are predominant, while on the other hand, the functionally relevant architecture of perimysial and endomysial collagen is degraded.

Our study patients had mild to moderate heart failure according to their symptoms. In mild to moderate heart failure, LV myocardial MMP zymographic activity has been reported to be elevated [14]. On the other hand, with end-stage DCM, LV myocardial concentration of MMP-1 was found to decrease again [13,14,20,21]. Also in experimental DCM a time-dependent change in MMP activity was found with increased zymographic activity of MMP-1 at the beginning and lower activity in end-stages [4].

Thus, the serum marker MMP-1 might give some information about the course of LV dilation in the disease.

Furthermore it is known that MMP- and TIMP-regulation is dependent on extracellular stimuli such as cytokines, hormones and growth factors (IL-1β, TGF-β, TNF-{alpha}, IL-6, IL-10 and epidermal growth factor) which all occur in the progression of DCM [30–32]. Thus, the prevalence and extent of the regulating stimuli of collagen metabolism may also have an independent influence.

Up to now it has been unclear whether the activation of the collagenolytic system has a primary or secondary part in the progression of LV dilation. Our data indicate that increased MMP-1 activity with an imbalance in the free MMP-1/TIMP-1-ratio play an important role in the LV remodelling and enlargement in early stages of heart failure due to DCM.

5.1. Limitations of the study
Abnormal collagen metabolism of the bone could be one cause for elevated MMP-1 or ICTP, but in this study neither MMP-1, PICP nor ICTP significantly correlated with age or NYHA class which could be associated with osteoporosis [33,34]. Furthermore, patients suffering from hepatic diseases or osteoporosis were excluded from the study.

Since all patients were receiving medication for treatment of heart failure, this medication might have had some influence. For ethical reasons, the medication was not interrupted. There are only a few reports marginally investigating the influence of standard medication for heart failure in respect to MMP-1 and TIMP-expression [16,35–38] and no final conclusions can be drawn from these data up to now.

Although our data confirm the findings in recent studies of human tissue from failing hearts, further investigations are necessary to characterise the circulating markers of type I collagen metabolism, to identify their clinical, functional and topographical significance.


   Acknowledgements
 
This study was supported by the Forschungskommission der Heinrich-Heine-University, Düsseldorf and by the Alfried Krupp von Bohlen- und Halbach-Stiftung.


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

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