Skip Navigation

European Journal of Heart Failure 2006 8(2):147-153; doi:10.1016/j.ejheart.2005.06.008
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (13)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Alla, F.
Right arrow Articles by Zannad, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alla, F.
Right arrow Articles by Zannad, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2006 European Society of Cardiology

Early changes in serum markers of cardiac extra-cellular matrix turnover in patients with uncomplicated hypertension and type II diabetes

François Allaa, Anna Kearney-Schwartzb, Anca Radauceanub, Sylvie Das Doresc, Brigitte Doussetc,d and Faiez Zannadb,d,*

a Epidemiology Department (EA 3444), University Hospital Nancy, France
b Clinical Investigation Center, INSERM-CHU Nancy, France
c Biochemistry Laboratory, University Hospital Nancy, France
d University Henri Poincaré (EA 3447), Nancy, France

* Corresponding author. Centre d'Investigation Clinique (CIC) INSERM-CHU, Hôpital Jeanne d'pArc, 54 200 Dommartin-les-Toul FRANCE. Tel.: +33 383 65 66 25; fax : +33 383 65 66 19. E-mail address: cic{at}chu-nancy.fr


   Abstract
Top
 Abstract
1. Methods
 2. Results
 3. Discussion
 4. Limitations
 5. Conclusion
 References
 
Aims: Extracellular matrix (ECM) turnover is a major determinant of diastolic dysfunction and pumping capacity, thus potentially contributing to the progression of congestive heart failure (CHF). Patients with both arterial hypertension and diabetes have a high risk of heart failure. Whether these patients have changes in cardiac ECM has not been studied previously. Our objective was to compare blood markers of collagen turnover among patients with CHF, patients with hypertension and type II diabetes (HD), and healthy individuals.

Methods and results: Measurements were performed in 239 CHF patients; 64 HD patients and 92 healthy subjects. We showed by adjusted ANOVA that PIIINP levels were significantly higher in CHF and HD patients than in controls, and higher in CHF patients than in HD patients. MMP1 levels were significantly lower in CHF and HD patients than in controls. Collagen type I markers (PICP and PINP) were not influenced by CHF but were lower in HD patients as compared to controls (p<0.05 for all comparisons).

Conclusion: In heart failure, markers of cardiac collagen synthesis are increased and markers of degradation are decreased, potentially contributing to cardiac fibrosis and thus to poor outcome. Changes in collagen turnover may also occur early in the disease process in high-risk patients before heart failure is clinically detectable.

Key Words: Heart failure • Hypertension • Diabetes mellitus • Remodelling • Collagen • Extracellular matrix

Received March 25, 2005; Revised May 11, 2005; Accepted June 27, 2005

Extracellular matrix (ECM) turnover is an essential process in cardiac remodeling, hypertensive cardiac hypertrophy, dilated cardiomyopathy and following myocardial infarction [1]. Cardiac fibrosis is a major determinant of diastolic dysfunction and pumping capacity, and it may provide the structural substrate for arrhythmogenecity [1], thus potentially contributing to the progression of congestive heart failure (CHF) and to sudden death.

Evaluation of cardiac collagen turnover by measurement of biological markers is a useful tool for monitoring "at a distance" cardiac tissue repair and fibrosis [2], both in experimental models [3] and in clinical conditions [4-9].

In CHF patients with systolic dysfunction, we have previously reported that the serum level of a collagen synthesis marker, the procollagen type III amino-terminal peptide (PIIINP), was significantly associated with mortality [10].

In patients with hypertension, it has been shown that collagen synthesis is increased and degradation decreased [3,11]. Patients with diabetes mellitus have not been well studied and results are less consistent: collagen synthesis markers may decrease or alternatively rise depending on the presence of diabetes complications and/or concomitant arterial hypertension [12,13]. Moreover, in vitro studies have shown different effects of hyperglycemia on collagen I and collagen III synthesis [14].

Arterial hypertension and diabetes individually predispose to CHF; patients with both conditions have an even greater risk of heart failure [15]. Whether these patients have changes in cardiac ECM has not been previously reported. Our hypothesis is that early changes in cardiac ECM, as monitored by serum markers of collagen synthesis and degradation, may occur in high risk patients before heart failure is detectable. Therefore, the aim of our study was to compare ECM turnover markers among patients with heart failure and systolic dysfunction with or without diabetes, patients with arterial hypertension and diabetes mellitus, and healthy individuals.


   1. Methods
Top
 Abstract
 1. Methods
2. Results
 3. Discussion
 4. Limitations
 5. Conclusion
 References
 
1.1. Patients and study design
The study population consisted of three groups, as follows:

- CHF patients. Among the 261 patients randomized in French centers into the RALES trial [10,16], 239 with neither acute nor chronic inflammatory disease participated in this sub-study. RALES included patients with severe CHF and left ventricular systolic dysfunction (history of NYHA IV within 6 months of randomization and NYHA III or IV at randomization and left ventricular ejection fraction less than 35%). Of these patients 23% had type II diabetes.
- Hypertension, type II diabetic patients (HD). Patients in this group had arterial hypertension and type II diabetes. The JNCVI definition of arterial hypertension was used (DBP>85 mm Hg and/or SBP>130 mm Hg) [17]. Only patients who were not receiving any antihypertensive treatment, or who had received treatment for less than 1 year, were included. Type II (non-insulin dependent) diabetes mellitus was defined as two consecutive fasting glycemias >1.26 g/l [18]. Only patients with HbA1c<9% were included.
Patients with clinically significant cardiovascular disease (in particular CHF and coronary disease), inflammatory disease or dyslipidemia were excluded by careful clinical, ECG and biological examinations.
- Healthy subjects. After an extensive examination, healthy subjects without arterial hypertension, diabetes, cardiovascular or inflammatory disease were selected as controls.

HD patients and healthy subjects were recruited through a General Practitioner Network and were included after physical examination and laboratory tests in a single clinical research center. HD patients and healthy subjects were age matched.

Patients or subjects with conditions known to be associated with changes in collagen turnover, such as inflammatory diseases, systemic diseases, hepatic failure or cancer, were excluded.

1.2. Laboratory analysis
Blood samples were drawn at baseline. Serum samples were stored at –20 °C until assay. Concentrations of collagen synthesis markers: procollagen type III aminoterminal peptide (PIIINP), procollagen type I carboxyterminal peptide (PICP) and procollagen type I aminoterminal peptide (PINP), were measured by radioimmunoassay (Orion Diagnostica, Finland). Serum total metalloproteinase 1 (MMP1 [an enzyme implicated in collagen degradation]), and serum total tissue inhibitor of metalloproteinase 1 (TIMP1), were measured by ELISA (Amersham Pharmacia Biotech, UK).

1.3. Data collection
At inclusion: age, sex, systolic and diastolic blood pressure, and body mass index were recorded. For the CHF group, etiology, NYHA class and left ventricular ejection fraction were also recorded at baseline.

1.4. Statistical analysis
Statistical analysis consisted of 1) a description of the three groups and a comparison of their characteristics, with values expressed as mean±SD or percent of the population; 2) a study of the association between patient characteristics and levels of ECM turnover markers; 3) an age and sex adjusted comparison of levels of ECM turnover markers between the three groups.

For inter-group comparisons and the study of associations between patient characteristics and levels of ECM turnover markers, ad-hoc methods (Pearson chi-square, Mann-Whitney test, correlation test, ANOVA) were used.

Normality and homogeneity of variance assumptions (Levene's test) were checked. When significant differences in marker levels were observed between groups, pairwise comparisons adjusting for multiple tests were conducted (Bonferroni-Holm method).

The sample size was calculated on the basis of the following assumption: for each marker the difference between two groups would be at least as important as half of its standard deviation. The power was set at 80% with a two-tailed alpha of 0.05.

All analyses were performed using SAS© software version 8.02. All comparisons were two sided and unpaired. A p-value<0.05 was considered significant.

1.5. Legal and ethical considerations
All patients were informed about the study and gave consent to participate. The protocol was approved by the local ethics committee (CCPPRB).


   2. Results
Top
 Abstract
 1. Methods
 2. Results
3. Discussion
 4. Limitations
 5. Conclusion
 References
 
The study population consisted of 395 subjects (Table 1) aged from 33 to 90 years, 66% were men. The mean age and the proportion of men were higher in CHF patients than in the other groups.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline patient characteristics

 
Patients with CHF were on conventional therapy at the time of the RALES trial (100% on diuretics, 92% on ACE inhibitors, 59% on digitalis, 5% on beta-blockers). Half of the HD patients had been treated for arterial hypertension for less than one year prior to the study (22% were on ACE inhibitors, 17% on angiotensin II receptor inhibitors, 8% on beta-blockers, 6% on diuretics, 3% on calcium channel blockers).

2.1. Levels of ECM turnover markers
In the whole population, blood concentrations (expressed in µg/l) were 4.5±2.2 for PIIINP, 133.7±74.8 for PICP, 42.2±22.7 for PINP, 2.9±2.0 for MMP1, and 688.3±428.7 for TIMP. PIIINP values were higher in men than in women (4.8±2.3 men vs. 4.0±1.9 women; p<0.05) and were negatively correlated with age (r=–0.30; p<0.05). Other tested markers were not affected by age or sex.

In both the HD and control groups, concentrations of markers were not related to body mass index, mean systolic and diastolic blood pressure, or HbA1c. In CHF patients, levels of all markers were not affected by NYHA class or LVEF.

In the CHF group, patients undergoing digitalis therapy had higher levels of PIIINP when compared to other patients (5.4±2.7 µg/l vs. 4.2±2.0 µg; p=0.0002). In the HD group, there was no difference in levels of all markers between patients who were being treated and those who were not being treated for hypertension.

2.2. Intergroup comparisons
Overall comparisons between groups showed a significant difference for all tested markers. The mean PIIINP level was significantly higher in CHF and HD patients than in controls but the change was significantly more important in CHF patients than in HD patients. CHF patients and controls exhibited similar values of PICP and PINP, these were significantly higher when compared to the HD group. Decreased MMP1 was observed in both patient groups, and CHF patients tended to have lower values than HD patients (p=0.07). TIMP1 levels were significantly lower in CHF patients than in either of the other groups (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2 Comparative serum levels of ECM turnover markers between the three groups

 
Within the CHF group, 23% of patients had diabetes mellitus. These diabetic patients had lower procollagen I levels (significant for PINP) and higher concentrations of MMP1 and TIMP1 when compared to the non-diabetic CHF sub-group. The differences in marker levels between diabetic and non-diabetic subjects appeared to be independent of age, sex and presence or absence of ischemic heart disease (Table 3).


View this table:
[in this window]
[in a new window]

  		Table 3 Comparison between diabetic and nondiabetic CHF sub-groups

 

   3. Discussion
Top
 Abstract
 1. Methods
 2. Results
 3. Discussion
4. Limitations
 5. Conclusion
 References
 
In this study, we have confirmed that biological markers of cardiac collagen synthesis are increased and markers of degradation are decreased in heart failure, suggesting a net cardiac collagen accumulation. Interestingly, we have shown for the first time that these changes in ECM markers are present in high-risk patients prior to clinically detectable heart failure. Finally, changes in markers of collagen synthesis are type-specific and selectively influenced by the presence of diabetes.

3.1. Cardiac extra cellular matrix turnover
Changes in ECM matrix turnover may lead to cardiac fibrosis. Both collagen types I and III are present in normal and diseased myocardial tissue, type I is predominant in the myocardium, and type III is more specific to cardiac tissue [19-21]. The proliferation, the phenotypic transformation and/or the stimulation of activity of fibroblasts are associated with variations in metalloproteinase expression and are important processes of ventricular remodeling in the pathophysiology of CHF.

In hypertension, it has been suggested that excessive collagen deposition causes stiffness of the heart during the chronic phase of hypertrophy, especially during the transition to heart failure and subsequent altered cardiac function [20]. Therefore, we hypothesized that changes contributing to collagen accumulation are detectable early in the process of cardiac remodeling and in conditions predisposing to heart failure. Both hypertension and diabetes are conditions predisposing to CHF. Our study population consisted of patients with both risk factors, a condition with an even greater risk of CHF [15].

The usefulness of biological markers as indirect indicators of cardiac ECM turnover has been reported in experimental models [22-24] and in humans. Since PINP, PICP, and PIIINP are released with collagen type I or III molecules in a stoichiometric manner during collagen biosynthesis, they are considered as markers of this process [2,25,26]. These markers are not specific to the myocardium. In particular hypertension and diabetes affect various organs, especially vascular tissues, from which serum procollagen fragments could be released. However, Querejeta et al. showed a correlation between myocardial collagen content and serum concentration of PICP in hypertension [9]. More recently, they have demonstrated that serum PICP was secreted by the heart via the coronary sinus in patients with hypertensive heart disease [27].

Fibrillar collagens within the myocardium are substrates for MMPs. Among the MMPs, MMP1 has the highest affinity for fibrillar collagen and preferentially degrades collagen I and III [21,28-30]. MMP1 accounts for the degradation of up to 40% of the newly synthesized collagen in different tissues [28]. The net level of MMP1 activity is dependent on the relative concentrations of active enzyme and of a family of naturally occurring tissue inhibitors of metalloproteinases, namely TIMPs [31]. Among the four identified TIMPs, TIMP1 has been shown to be as the most abundantly expressed TIMP in the myocardium from patients with heart failure [32]. MMP1 and TIMP1 are co-expressed in cardiac fibroblasts and are tightly regulated for maintaining the architecture of the ECM [33].

3.2. Changes of ECM markers in CHF
When compared to healthy subjects, variations in levels of biological markers of collagen turnover occurred in patients with CHF. We observed a very marked increase in collagen type III production but no change in collagen type I as assessed by PINP and PICP levels. In our study, in patients with CHF, serum PIIINP concentrations were higher than in controls, which is consistent with previous reports [7]. Moreover, serum PIIINP concentrations have been shown to be independent predictors of mortality [10]. In contrast, serum levels of PICP and PINP were not related to mortality [10]. The absence of changes in collagen type I markers in our CHF patients is consistent with the research of Schwartzkopff, who did not observe an increase in PICP levels in patients with dilated cardiomyopathy vs. controls [34]. In the same way, Lombardi showed an increase in PIIINP levels, with no changes in PINP and PICP levels in patients with hypertrophic cardiomyopathy compared to controls [35].

Together with an increase of collagen synthesis markers levels, our results suggest that collagen degradation is slower in patients with CHF, thus potentially resulting in cardiac fibrosis. Results from previous work are inconclusive. A recent clinical study showed increased levels of MMP1, TIMP1 and a very marked elevation of the MMP1/TIMP1 ratio interpreted as a disturbed balance with a predominance of collagenolytic activity in mild to moderate CHF [34]. In the same way, expression of TIMP1 and MMP1 mRNA were increased in patients with deteriorating HF vs. stable HF patients [32]. On the other hand, in severe CHF, as was the case in our patients and consistent with our results, myocardial concentration of MMP1 was found to be decreased [36], and the cardiac expression of TIMP-transcripts and proteins was also significantly reduced [37]. Associated with the reduction in TIMP1 levels in both non-ischemic and ischemic cardiomyopathy, an absolute reduction in MMP1/TIMP1 complex formation was also observed [38]. A recent study has shown that deficiency of TIMP1 exacerbates left ventricular remodeling after myocardial infarction in mice [39]. Furthermore, studies based on experimental heart failure found a time-dependent change in MMP activity during the course of CHF [40]. A single time point cannot fully represent the dynamic changes that occur throughout the development of cardiac dysfunction [21].

The simultaneous decrease of MMP1 and TIMP1 leads to a MMP1/TIMP1 ratio in both subgroups of CHF patients comparable to that of the control group. This may be an adaptive process in order to increase MMP activity [38]. It may also reflect an inability of the myocardium to normalize the elevated wall stress once the heart decompensates [41].

3.3. Changes of ECM markers in hypertension and diabetes
Previous work in this area has included patients with either hypertension or diabetes. To our knowledge, our study is the first to report on ECM biomarkers in patients with both conditions. Mean levels of PIIINP were higher in HD patients than in controls, and mean levels of PINP, PICP and MMP1 were lower in HD patients than in controls. Consistent with our findings, previous studies have shown an increase in serum PIIINP levels in hypertension, which correlate to anatomic and functional alterations of the left ventricle [8].

The observed low level of MMP1 in the HD group was associated with a stable level of TIMP1 (or a nonsignificant increase) and explains the low MMP1/TIMP1 ratio amounting to almost half of the ratio observed in the control group. This finding might result in a stoichiometric imbalance between MMP1 and TIMP1 favouring at least in part MMP1 inhibition and consequently influencing the remodeling process. These results are consistent with the findings of a previous clinical report in arterial hypertension which suggested that cardiac fibrosis in arterial hypertension is not only due to increased collagen synthesis but also results from depressed degradation of collagen as indicated by low levels of MMP1 and high levels of TIMP1. In addition, hypertensive patients with baseline left ventricular hypertrophy exhibited lower levels of MMP1 and higher levels of TIMP1 than hypertensive patients without baseline left ventricular hypertrophy [3]. In the same way, in the Framingham Heart Study, in participants free of heart failure and previous myocardial infarction, plasma TIMP1 was related to indices of left ventricular hypertrophy and systolic dysfunction [42]. Our results are also in agreement with the expression profile of the MMP system noted in diabetes. Indeed, in vitro and in vivo studies on arterial vasculature, have reported that high glucose exposure did not affect TIMP1 expression [43], but decreased proMMP1 levels and total MMP activity [44]. Although serum levels of MMPs and TIMP do not necessarily reflect their activity in the tissues, it may be speculated that they underlie important and specific effects due to hypertension and diabetes in the network of interactions contributing to myocardial fibrosis. Whether the coexistence of diabetes and hypertension may exacerbate this mechanism, remains to be investigated.

3.4. Impact of diabetes on procollagen subtype levels
Our results argue in favour of a fundamental effect of diabetes on collagen turnover: diabetics had specific characteristics whatever the type of cardiac disease (hypertension or CHF). The aetiology of ventricular dysfunction in diabetes is complex [45]. The initiating event may be due to insulin resistance. As shown in experimental models [46,47], hyperinsulinemia and insulin-resistance may alter the cardiac collagen/muscular ratio. On the other hand, dysglycemia plays an important role via the effects of oxidative stress, protein kinase C activation and advanced glycosylation end-products on collagen metabolism [45,48]. Experimental studies with diabetic rats have observed myocardial modifications including a decrease in synthesis and degradation of collagen with prolonged turnover periods that disappeared after early insulin therapy [49]. In addition, in patients with type II diabetes other factors may be involved, especially leptine [50].

Contrary to what we observed with PIIINP, collagen type I, measured with PINP and PICP, was decreased in HD patients. This finding contrasts with the observed increase of PICP in patients with hypertension [8], suggesting that the presence of diabetes may have a selective influence on collagen subtype changes. An immunohistochemical study of myocardial biopsies revealed a significantly higher proportion of type III collagen in diabetics than in nondiabetic patients, while the proportion of collagen type I did not differ between the groups [51]. Serological markers of matrix remodeling in diabetes have not been fully explored and discrepancies characterize the results reported in the literature—in particular in type II diabetes. Inukai et al. showed that PICP concentration was not different in uncomplicated type II diabetic patients vs. controls while it was increased in complicated diabetes and related to the progression of nephropathy [12]. The synthesis of collagen types I and III by fibroblasts varies with glucose concentration, high levels of glucose result in an increase in collagen III synthesis but does not affect collagen I production [14].

Another possible explanation for the decrease of collagen I synthesis markers in diabetics may be related to the effect of diabetes on bone turnover. Diabetes is associated with osteopenia, although this relationship is more controversial for type II than type I. This is due to a deficit of osteoblasts (cellular sources of collagen type I), which may be related experimentally to hyperglycemia [52,53]. Because type I collagen is the most abundant protein of bone, comprising about 85% of the bone matrix, the decrease of osteoblast activity and procollagen I synthesis may lead to a reduction in PINP and PICP concentrations. Since both parameters are markers of collagen formation without tissue specificity, initially used for monitoring the bone collagen synthesis [54], we cannot exclude that the decrease of collagen I synthesis may at least in part reflect the effects of diabetes on bone turnover. Collagen III markers may be more cardiac specific than collagen I markers. Consequently it may be recommended to use PIIINP for monitoring cardiac collagen turnover more specifically.


   4. Limitations
Top
 Abstract
 1. Methods
 2. Results
 3. Discussion
 4. Limitations
5. Conclusion
 References
 
We did not assess left ventricular geometry and function in our patient and control populations. Thus, we cannot comment on the possible influence of left ventricular hypertrophy or diastolic dysfunction on our results.

For obvious reasons, patients in our study did not discontinue their anti-diabetic and anti-hypertensive drugs. Previous reports have shown that anti-hypertensive drugs may regress changes in ECM markers [3,8]. In our study, we did not find a significant interaction between current therapy and the markers under study. In fact, the magnitude of observed changes may have been underestimated by the effect of concomitant therapy.

The three groups were not similar with respect to baseline characteristics. However, the different characteristics of the groups can be explained by the different clinical profiles of the conditions (for example hypertensive diabetics had a greater BMI than controls). We found no relationship between patient characteristics and marker levels. But we cannot rule out the fact that the differences in ECM marker levels between the three groups may have been related in part to these baseline differences.

Remodeling in other organs can influence ECM serum markers. In order to limit this potential bias, we excluded subjects with diseases known to be associated with changes in collagen turnover.


   5. Conclusion
Top
 Abstract
 1. Methods
 2. Results
 3. Discussion
 4. Limitations
 5. Conclusion
References
 
In heart failure, cardiac collagen synthesis markers are increased and degradation markers are decreased, potentially contributing to cardiac fibrosis and thus to poor outcome. Changes in collagen turnover may occur early in the disease process in high-risk patients with diabetes and hypertension before heart failure is clinically detectable. Variations in collagen type I levels may be influenced independently by the presence of type II diabetes. ECM turnover is a dynamic process that can be monitored clinically via assessment of serum markers.


   Acknowledgements
 
This study was supported by the French Society of Arterial Hypertension, the Fondation de France, the University Hospital of Nancy, and the European Section of Aldosterone Council.

The authors would like to thank general practitioners who participate at the Lorraine's region network, Jean-Marc Virion for statistical support, and Meghan Mulrenin for reviewing the manuscript.


   References
Top
 Abstract
 1. Methods
 2. Results
 3. Discussion
 4. Limitations
 5. Conclusion
 References
 

  1. Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev (1999) 79:215–262.[Abstract/Free Full Text]
  2. Weber KT. Monitoring tissue repair and fibrosis from a distance. Circulation (1997) 96:2488–2492.[Web of Science][Medline]
  3. Laviades C., Varo N., Fernandez J., Mayor G., Monreal I., Diez J. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation (1998) 98:535–540.[Abstract/Free Full Text]
  4. Uusimaa P., Risteli J., Niemela M., et al. Collagen scar formation after acute myocardial infarction: relationships to infarct size, left ventricular function, and coronary artery patency. Circulation (1997) 96:2565–2572.[Abstract/Free Full Text]
  5. Sato Y., Kataoka K., Matsumori A., et al. Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponion T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy. Heart (1997) 78:505–508.[Abstract/Free Full Text]
  6. Host N., Jensen L., Bendixen P., Jensen S., Koldkjaer O., Simonsen E. The aminoterminal propeptide of type III procollagen provides new information on prognosis after acute myocardial infarction. Am J Cardiol (1995) 76:869–873.[CrossRef][Web of Science][Medline]
  7. Klappacher G., Franzen P., Haab D., et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol (1995) 75:913–918.[CrossRef][Web of Science][Medline]
  8. Diez J., Laviades C., Mayor G., Gil M., Monreal I. Increased serum concentration of procollagen peptides in essential hypertension—relation to cardiac alteration. Circulation (1995) 91:1450–1456.[Abstract/Free Full Text]
  9. Querejeta R., Varo N., Lopez B., et al. Serum Carboxy-Terminal Propeptide of Procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation (2000) 101:1729–1735.[Abstract/Free Full Text]
  10. Zannad F., Alla F., Dousset B., Perez A., Pitt B. on behalf of the RALES Investigators. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure. Circulation (2000) 102:2700–2706.[Abstract/Free Full Text]
  11. Diez J., Laviades C., Monreal I., Gil M., Panizo A., Pardo J. Toward the biochemical assessment of myocardial fibrosis in hypertensive patients. Am J Cardiol (1995) 76:14D–17D.[CrossRef][Medline]
  12. Inukai T., Fujiwara Y., Tayama K., Aso Y., Takemura Y. Serum levels of carboxy-terminal propeptide of human type I procollagen are an indicator for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract (2000) 48:23–28.[CrossRef][Web of Science][Medline]
  13. Arkkila P., Ronnemaa T., Koskinen P., Kantola I., Seppanen E., Viikari J. Biochemical markers of type III and I collagen: association with retinopathy and neuropathy in type 1 diabetic subjects. Diabet Med (2001) 18:816–821.[CrossRef][Web of Science][Medline]
  14. Benazzoug Y., Borchiellini C., Labat-Robert J., Robert L., Kern P. Effect of high-glucose concentrations on the expression of collagens and fibronectin by fibroblasts in culture. Exp Gerontol (1998) 33:445–455.[CrossRef][Web of Science][Medline]
  15. Ho K., Pinsky J., Kannel W., Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol (1993) 22:6A–13A.[Medline]
  16. Pitt B., Zannad F., Remme W.J., et al. Randomized aldactone evaluation study (RALES) mortality trial. N Engl J Med (1999) 341:709–717.[Abstract/Free Full Text]
  17. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med (1997) 157:2413–2446.[Abstract/Free Full Text]
  18. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care (1997) 20:1183–1197.[Web of Science][Medline]
  19. Bishop J.E., Laurent G.J. Collagen turn-over and its regulation in the normal and hypertrophying heart. Eur Heart J (1995) 16:38–44.[Abstract]
  20. Zannad F., Dousset B., Alla F. Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension (2001) 38:1227–1232.[Abstract/Free Full Text]
  21. D'Armiento J. Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction. Trends Cardiovasc Med (2002) 12:97–101.[CrossRef][Web of Science][Medline]
  22. Varo N., Etayo J., Zalba G., et al. Losartan inhibits the post-transcriptional synthesis of collagen type I and reverses left ventricular fibrosis in spontaneously hypertensive rats. J Hypertens (1999) 17:107–114.[Web of Science][Medline]
  23. Sekita S., Katagiri T., Sasai Y., Takeda K. Studies on collagen in the experimental myocardial infarction. Jpn Circ (1985) 49:171–178.
  24. Melkko J., Niemi S., Risteli L., Risteli J. Radioimmunoassay of the carboxyterminal propeptide of human type I procollagen. Clin Chem (1990) 36:1328–1332.[Abstract/Free Full Text]
  25. Risteli J., Risteli L. Analysing connective tissue metabolites in human serum: biochemical, physiological and methodological aspects. J Hepatol (1995) 22(suppl_2):77–81.[CrossRef][Web of Science][Medline]
  26. Jensen L., Horslev-Petersen K., Toft P., et al. Serum aminoterminal type III procollagen peptide reflects repair after myocardial infarction. Circulation (1990) 81:52–57.[Abstract/Free Full Text]
  27. Querejeta R., Lopez B., Gonzalez A., et al. Increased collagen type I synthesis in patients with heart failure of hypertensive origin. Relation to myocardial fibrosis. Circulation (2004) 110:1263–1268.[Abstract/Free Full Text]
  28. Woessner J.F. Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J (1991) 2145–2154.
  29. Coker M., Thomas C., Clair M., et al. Myocardial matrix metalloproteinase activity and abundance with congestive heart failure. Am J Physiol (1998) 274:H1516–H1523.[Web of Science][Medline]
  30. Visse R., Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res (2003) 92:827–839.[Abstract/Free Full Text]
  31. Denhardt D., Feng B., Edwards D., Cocuzzi E., Malyankar U. Tissue inhibitor of metalloproteinases (TIMP, aka EPA): structure, control of expression and biological functions. Pharmacol Ther (1993) 59:329–341.[CrossRef][Web of Science][Medline]
  32. Barton P., Birks E., Felkin L., Cullen M., Koban M., Yacoub M. Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure. Heart Lung Transplant (2003) 22:738–744.[CrossRef][Web of Science][Medline]
  33. Tyagi S.C., Kumar S.G., Banks J., Fortson W. Co-expression of tissue inhibitor and matrix metalloproteinase in myocardium. J Mol Cell Cardiol (1995) 27:2177–2189.[CrossRef][Web of Science][Medline]
  34. Schwartzkopff B., Fassbach M., Pelzer B., Brehm M., Strauer B. Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy. Eur J Heart Fail (2002) 4:439–444.[Abstract/Free Full Text]
  35. Lombardi R., Betocchi S., Losi M., et al. Myocardial collagen turnover in hypertrophic cardiomyopathy. Circulation (2003) 108:1455–1460.[Abstract/Free Full Text]
  36. Spinale F., Coker M., Heung L., et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation (2000) 102:1944–1949.[Abstract/Free Full Text]
  37. Li Y., Feldman A., Sun Y., McTiernan C. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation (1998) 98:1728–1734.[Abstract/Free Full Text]
  38. Spinale F., Coker M., Bond B., Zellner J. Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target. Cardiovasc Res (2000) 46:225–238.[Abstract/Free Full Text]
  39. Creemers E., Davis J., Parkhurst A., et al. Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice. Am J Physiol Heart Circ Physiol (2003) 284:H364–H371.[Abstract/Free Full Text]
  40. Spinale F., Coker M., Thomas C., Walker J., Mukherjee R., Hebbar L. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function. Circ Res (1998) 82:482–495.[Abstract/Free Full Text]
  41. Janicki J., Brower G., Gardner J., Chancey A., Stewart J.J. The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling. Heart Fail Rev (2004) 9:33–42.[CrossRef][Web of Science][Medline]
  42. Sundström J., Evans J., Benjamin E., et al. Relations of plasma total TIMP-1 levels to cardiovascular risk factors and echographic measures: the Framingham Heart Study. Eur Heart J (2004) 25:1509–1516.[Abstract/Free Full Text]
  43. Death A., Fisher E., McGrath K., Yue D. High glucose alters matrix metalloproteinase expression in two key vascular cells: potential impact on atherosclerosis in diabetes. Atherosclerosis (2003) 168:263–269.[CrossRef][Web of Science][Medline]
  44. Portik-Dobos V., Anstadt M., Hutchinson J., Bannan M., Ergul A. Evidence for a matrix metalloproteinase induction/activation system in arterial vasculature and decreased synthesis and activity in diabetes. Diabetes (2002) 51:3063–3068.[Abstract/Free Full Text]
  45. Watts G.F., Marwick T.H. Ventricular dysfunction in early diabetic heart disease: detection, mechanisms and significance. Clin Sci (2003) 105:537–540.[CrossRef][Web of Science][Medline]
  46. Duerr R., McKirnan M., Gim R., Clark R., Chien K., Ross J.J. Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat. Circulation (1996) 93:2188–2196.[Abstract/Free Full Text]
  47. Anversa P., Kajstura J., Cheng W., Reiss K., Cigola E., Olivetti G. Insulin-like growth factor-1 and myocyte growth: the danger of a dogma: Part II. Induced myocardial growth: pathologic hypertrophy. Cardiovasc Res (1996) 32:484–495.[Free Full Text]
  48. Hayden M.R., Tyagi S.C. Myocardial redox stress and remodeling in metabolic syndrome, type 2 diabetes mellitus, and congestive heart failure. Med Sci Monit (2003) 9:SR35–SR52.[Medline]
  49. Reddi A.S. Collagen metabolism in the myocardium of normal and diabetic rats. Exp Mol Pathol (1988) 48:236–243.[CrossRef][Web of Science][Medline]
  50. Tang M., Potter J.J., Mezey E. Leptin enhances the effect of transforming growth factor beta in increasing type I collagen formation. Biochem Biophys Res Commun (2002) 297:906–911.[CrossRef][Web of Science][Medline]
  51. Shimizu M., Umeda K., Sugihara N., et al. Collagen remodelling in myocardia of patients with diabetes. J Clin Pathol (1993) 46:32–36.[Abstract/Free Full Text]
  52. Balint E., Szabo P., Marshall C., Sprague S. Glucose-induced inhibition of in vitro bone mineralization. Bone (2001) 28:21–28.[CrossRef][Medline]
  53. Spanheimer R.G., Umpierrez G.E., Stumpf V. Decreased collagen production in diabetic rats. Diabetes (1988) 37:371–376.[Abstract]
  54. Parfitt A., Simon L., Villanueva A., Krane S. Procollagen type I carboxy-terminal extension peptide in serum as a marker of collagen biosynthesis in bone. Correlation with Iliac bone formation rates and comparison with total alkaline phosphatase. J Bone Miner Res (1987) 2:427–436.[Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
G. J. Mak, M. T. Ledwidge, C. J. Watson, D. M. Phelan, I. R. Dawkins, N. F. Murphy, A. K. Patle, J. A. Baugh, and K. M. McDonald
Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone.
J. Am. Coll. Cardiol., October 27, 2009; 54(18): 1674 - 1682.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
R. Martos, J. Baugh, M. Ledwidge, C. O'Loughlin, N. F. Murphy, C. Conlon, A. Patle, S. C. Donnelly, and K. McDonald
Diagnosis of heart failure with preserved ejection fraction: improved accuracy with the use of markers of collagen turnover
Eur J Heart Fail, February 1, 2009; 11(2): 191 - 197.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
F. G. Spinale
Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function
Physiol Rev, October 1, 2007; 87(4): 1285 - 1342.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
R. Martos, J. Baugh, M. Ledwidge, C. O'Loughlin, C. Conlon, A. Patle, S. C. Donnelly, and K. McDonald
Diastolic Heart Failure: Evidence of Increased Myocardial Collagen Turnover Linked to Diastolic Dysfunction
Circulation, February 20, 2007; 115(7): 888 - 895.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (13)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Alla, F.
Right arrow Articles by Zannad, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alla, F.
Right arrow Articles by Zannad, F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?