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European Journal of Heart Failure 2007 9(4):370-376; doi:10.1016/j.ejheart.2006.09.010
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© 2007 European Society of Cardiology

Residual stress ischaemia is associated with blood markers of myocardial structural remodelling

Anca Radauceanua,b, Frédéric Moulinb,c, Wassila Djaballahd, Pierre Y. Marieb,d, François Allaf, Brigitte Doussete, Jean M. Viriona,f, Josette Capiaumonta,b, Gilles Karcherd, Etienne Aliotc and Façez Zannada,b,c,*

a Centre Investigation Clinique (CIC) CHU-INSERM Nancy, France
b Unité mixte UHP-INSERM U684 "Rigidité, Fibrose et Risque Cardio-Vasculaire", CHU Nancy, France
c Département des Maladies Cardiovasculaires CHU Nancy, France
d Service de Médecine Nucléaire CHU Nancy, France
e Laboratoire Central de Chimie CHU Nancy, France
f Service d'Epidémiologie et Evaluation Clinique CHU Nancy, France

* Corresponding author. Centre d'Investigation Clinique (CIC) CHU-INSERM, Hôpital Jeanne d'Arc, BP 303, 54201 Dommartin-lès-Toul, France. Tel.: +33 3 83 65 66 25; fax: +33 3 83 65 66 19. E-mail address: f.zannad{at}chu-nancy.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations. Future...
 6. Conclusion
 Acknowledgments
 References
 
Background: Long-term prognosis of coronary artery disease (CAD) patients is worsened when stress ischemia persists on treatment, but the relationship with adverse cardiac remodelling had never been investigated.

Aim: To analyze changes in blood markers of fibrosis in patients with chronic CAD exhibiting exercise ischaemia.

Methods: Circulating markers of collagen: (i) turnover (amino-terminal propeptide of collagen-III [PIIINP]) and (ii) degradation (matrix metalloproteinase 1 [MMP-1]), were obtained in 139 CAD patients referred for exercise 201Tl-SPECT.

Results: In the 57 patients who had SPECT-ischaemia, PIIINP was higher (4.3±2.9 µg L–1 vs. 3.1±1.5 µg L–1, p=0.002) and MMP-1 lower (3.8±2.1 µg L–1 vs. 4.7±2.8 µg L–1, p=0.04) than in the 82 patients without SPECT-ischaemia. PIIINP was independently related to LV volume, SPECT-ischaemia and age, whereas MMP-1 was related to current treatment with ACEI and β-blockers (p<0.05).

In the 104 patients with a normal LV ejection fraction, only PIIINP was related to SPECT-ischaemia (4.1±2.2 µg L–1 vs. 3.1±1.5 µg L–1, p=0.01).

Conclusion: In patients with chronic CAD, exercise ischaemia is associated with increased collagen-III turnover, independently of concomitant medications and even when LV ejection fraction is normal. Long-term, this increase might relate to adverse cardiac remodelling even when cardiac function is not clearly affected at baseline.

Key Words: Coronary artery disease • Exercise ischaemia • SPECT • Remodelling • Collagen • Fibrosis

Received November 23, 2005; Revised June 8, 2006; Accepted September 25, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Study limitations. Future...
 6. Conclusion
 Acknowledgments
 References
 
Although it is now well recognized that heart failure (HF) is a progressive disorder initiated following a precipitating event, little is known about how and why the transition to symptomatic heart failure occurs [1]. The potential central contribution of left ventricular (LV) remodelling to the overall development of heart failure seems to rely on the various components of the remodelling process, from structural remodelling including alterations in myocytes and subcellular remodelling [2] to the geometric remodelling including changes in the geometry and architecture of the LV chamber [3].

Extracellular collagen matrix turnover is the main determinant of cardiac structural remodelling in hypertension, heart failure and after myocardial infarction [4-6], and can be assessed from circulating markers of collagen synthesis and degradation [7,8]. These markers have been analyzed after myocardial infarction [9,10] and in advanced ischaemic cardiomyopathy [11,12], and have been shown to predict a poor outcome and increased myocardial fibrosis. To date, no analysis of collagen biomarkers in patients with chronic and stable coronary artery disease (CAD) has been reported.

We have previously reported that the long-term prognosis in patients with chronic and stable CAD is worsened when exercise-SPECT-ischaemia is documented despite current medications [13]. It is possible that progressive cardiac remodelling might be a cause of this worsening prognosis. Indeed, in advanced stage coronary heart disease, severely ischaemic areas exhibit enhanced fibrosis [14,15]. Furthermore, fibrosis and remodelling are known to progressively affect cardiac function [16,17] and to enhance the propensity for re-entry arrhythmias [6], which are two of the main mechanisms of disability and death [4,18].

The aim of this study was therefore to determine whether serum markers of collagen synthesis or degradation indicate signs of active remodelling in chronic CAD patients with exercise-SPECT-ischaemia despite current medications.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Study limitations. Future...
 6. Conclusion
 Acknowledgments
 References
 
2.1. Patient selection and study design
Patients, who were referred to the Department of Nuclear Medicine for routine assessment by exercise-SPECT, were included on the basis that: 1) they had a proven history of CAD, defined by a previous coronary angiogram showing at least one >50% coronary stenosis and/or a documented history of myocardial infarction, 2) they did not stop their current medications on the day of the test and 3), they gave informed consent to participate.

Exclusion criteria were: 1) recent (≤6 months) myocardial infarction, 2) congenital or valvular heart disease, 3) hypertrophic or idiopathic dilated cardiomyopathy, 4) unstable cardiac or coronary insufficiency, 5) uncontrolled systemic hypertension, 6) physical inability or contra-indication to perform exercise-SPECT, 7) atrial fibrillation, frequent (>20%) ectopic beats or pace maker, 8) any known non-cardiac disease that might lead to inflammation and/or fibrosis such as all chronic inflammatory disorders, infectious disease, liver disease, cancer, any recent surgery (≤6 months) or coronary angioplasty (≤3 months), any recent episode of acute vascular peripheral disease (≤6 months), or symptomatic arthritis.

The study was performed in accordance with the principles of the Declaration of Helsinki and informed consent was obtained from all subjects on the day of the test. The study was approved by the local Ethics Committee. Just before exercising, a 5 mL venous blood sample was drawn via a catheter inserted in the antecubital vein. Patients were seated during blood sampling. This study was a cross-sectional, observational study and all variables were assessed once.

2.2. Biomarker measurements
Blood samples were collected into polystyrene tubes, centrifuged at 3000 x g and plasma was stored at –20 °C prior to analysis.

Two markers of collagen turnover: procollagen type III amino-terminal peptide [PIIINP] and procollagen type I amino-terminal peptide [PINP], and one marker of collagen degradation: carboxy-telopeptide collagen type I [ICTP], were determined using commercially available radioimmunoassay kits (Orion Diagnostica, Espoo, Finland). The sensitivities of these kits (lowest concentration different from zero) were: 0.3 µg/L for PIIINP, 2.0 µg/L for PINP and 0.4 µg/L for ICTP.

One enzyme involved in the extracellular breakdown of collagen, total matrix metalloproteinase 1 (MMP-1), and its natural inhibitor, total tissue inhibitor of metalloproteinase (TIMP-1), were determined using enzyme linked immunosorbent assays (ELISA) from Amersham Biosciences (Orsay, France). Sensitivities of these kits were 1.7 µg/L for MMP-1 and 1.25 µg/L for TIMP-1. To assess the final proteolytic activity of the enzyme, we calculated the MMP-1/TIMP-1 ratio.

Inter- and intra-assay coefficients of variation ranged from 3% for PINP to 13% for PIIINP.

2.3. Exercise 201Tl SPECT imaging
The procedure used to perform and analyse exercise 201Tl-SPECT has been described previously [13]. Briefly, exercise was performed on a bicycle ergometer, the protocol was started at 20 W and increased by 20 W every 2 min. At peak exercise, 37 MBq of 201Tl per 25 Kg body weight were injected intravenously and a 201Tl activity, corresponding to one third of that given at exercise, was injected 10 min before rest imaging. As previously described, a gated-SPECT acquisition was recorded at rest [19].

Myocardial 201Tl uptake was scored using a 17-segment division of the left ventricle (LV) [13,19]: (i) total extent of exercise defects was determined as the percentage of segments showing moderate to severe reduction of 201Tl uptake at exercise-SPECT, (ii) extent of predominantly scarred myocardium (non-viable myocardium), as the percentage of segments showing fixed defects with <50% uptake after rest-reinjection and (iii) extent of ischaemia (ischaemic and viable myocardium), as the percentage of segments with either reversible defects or fixed defects with >50% uptake after rest-reinjection.

Only the SPECT abnormalities which involved at least 10% of the LV (≥2 segments), were considered to be significant for the definitions of: (i) abnormal exercise-SPECT (exercise-defects≥10% of LV), (ii) myocardial ischaemia (ischaemic and viable area≥10% of LV) and (iii) area with predominantly necrotic myocardium (non-viable area≥10% of LV).

On rest gated-SPECT acquisitions, LV end-diastolic and end-systolic volumes and LV ejection fraction were determined automatically using QGS software [19,20]. Cut-off values defining the limit of normal results were: 45% for LV ejection fraction, 120 mL for end-diastolic volume and 70 mL for end-systolic volume [20].

2.4. Statistical analysis
Continuous variables were reported as mean±SD and discrete variables, as percentages. Biomarkers whose blood levels were significantly related to an exercise-SPECT-ischaemia were initially selected by using ANOVA. For each selected biomarker: (i) all univariate predictors of blood concentrations were determined from the variables listed in Tables 1 and 2 and using Pearson correlation for continuous variables and ANOVA for discrete variables and (ii), best independent predictors of blood concentrations were determined by stepwise ascending regression multivariate analyses of variables showing a P value<0.1 at univariate analyses. Variables were entered in the model and further removed at P value<0.05 and >0.1, respectively.


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  		Table 1 Baseline characteristics of the study population (n=139)

 


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  		Table 2 Exercise-SPECT and rest gated-SPECT: main results

 
All computations were carried out using SAS statistical software version 8.2. A P value<0.05 was considered to be indicative of a significant difference.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Study limitations. Future...
 6. Conclusion
 Acknowledgments
 References
 
3.1. Characteristics of the study population
A total of 139 patients were included, 88% were men, 54% had a history of myocardial infarction, 50% had hypertension, 27% were diabetics and mean age was 64±10 years (Table 1). According to the inclusion criteria, all patients continued their medications on the day of the test (Table 1).

Mean LV ejection fraction, determined on rest gated-SPECT, was 53±14% and was abnormal (<45%) in 24% of patients (Table 2). Exercise-SPECT was abnormal in 55% of patients and exercise test was positive in 25%. Ischaemic myocardium was documented by SPECT in 41% of patients and predominantly necrotic myocardium (non-viable myocardium), in 27% (Table 2).

The mean and range values for all biomarker concentrations are given in Table 3.


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  		Table 3 Plasma concentrations of each biomarker in the overall population

 
3.2. Comparison of blood marker concentrations between patients with and those without SPECT-ischaemia
Patients with SPECT-ischaemia had higher concentrations of PIIINP (4.3±2.9 µg L–1 vs. 3.1±1.5 µg L–1, p=0.002) and lower concentrations of MMP-1 (3.8±2.1 µg L–1 vs. 4.7±2.8 µg L–1, p=0.04), when compared with those without SPECT-ischaemia. By contrast, there was no significant difference between the two groups for PINP (34±13 µg L–1 vs. 31±10 µg L–1), TIMP1 (831±439 µg L–1 vs. 773±419 µg L–1), ICTP (2.8±1.6 µg L–1 vs. 2.4±1.9 µg L–1) and MMP-1/TIMP-1 ratio (0.0041±0.0090 vs. 0.0040±0.0092).

When these comparisons were restricted to the 105 patients with a normal LV ejection fraction (35 with and 70 without SPECT-ischaemia), the significant difference persisted for PIIINP (4.1±2.2 µg L–1 vs. 3.1±1.5 µg L–1, p=0.01), but not for MMP-1 (4.1±2.3 µg L–1 vs. 4.7±2.9 µg L–1).

Of the 57 patients with SPECT-ischaemia, 21 also had SPECT-necrosis, whereas 36 did not. As illustrated in Fig. 1, PIIINP concentrations were not significantly different between these two groups.


Figure 01
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  		Fig. 1 Comparisons in plasma levels of PIIINP between patients with neither SPECT-necrosis nor SPECT-ischaemia (N–I–), those with only SPECT-necrosis (N+I–) or SPECT-ischaemia (N–I+) and those with both SPECT-necrosis and SPECT-ischaemia (N+I+).

 
3.3. Uni- and multivariate predictors of plasma levels of PIIINP and MMP-1
Univariate predictors are listed in Table 4. Higher PIIINP and lower MMP-1 concentrations, were not only associated with SPECT-ischaemia, but also with larger LV volumes and with lower LV ejection fractions.


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  		Table 4 P value for univariate predictors (p<0.1 at univariate analysis) of the plasma concentrations of either PIIINP or MMP-1

 
An abnormal (>120 mL) LV end-diastolic volume was associated with higher plasma levels of PIIINP (4.2±2.9 µg L–1 vs. 3.2±1.7 µg L–1, p=0.04) and with lower levels of MMP-1 (3.7±1.9 µg L–1 vs. 4.6±2.7 µg L–1, p=0.01). Similarly, significant differences in circulating levels of collagen markers were found for patients with an abnormal (>70 mL) as compared with a normal (≤70 mL) LV end-systolic volume (PIIINP: 4.4±3.4 µg L–1 vs. 3.3±1.6 µg L–1, p=0.01; MMP-1: 3.3±1.7 µg L–1 vs. 4.6±2.6 µg L–1, p=0.01).

In contrast, patients with an abnormal (<45%) LV ejection fraction did not exhibit different levels of collagen markers as compared to those with a normal LV ejection fraction (PIIINP: 4.0±3.2 µg L–1 vs. 3.4±1.9 µg L–1, NS; MMP-1: 3.7±1.8 µg L–1 vs. 4.5±2.7 µg L–1, NS).

MMP-1 was also lower in patients who had had a myocardial infarction (3.7±1.7 vs. 5.0±3.1, p=0.004) and in patients treated with ACEI (3.6±1.9 vs. 5.1±2.9, p=0.002) or beta-blockers (3.9±2.1 vs. 5.1±3.0, p=0.03). A trend towards an ascending relationship was also found for age and PIIINP (p=0.09).

No other associations between circulating levels of either PIIINP or MMP-1 with the variables listed in Tables 1 and 2 were found, including the presence or absence of hypertension (for PIIINP: 3.7±2.3 µg L–1 vs. 3.5±2.2 µg L–1, NS; for MMP-1: 4.4±2.6 µg L–1 vs. 4.2±2.5 µ.L–1, NS) or of diabetes (for PIIINP: 3.3±1.9 µg L–1 vs. 3.6±2.4 µg L–1, NS; for MMP-1: 4.2±2.4 µg L–1 vs. 4.3±2.6 µg L–1, NS).

By multivariate analysis, the best independent predictors of PIIINP level were: end-diastolic LV volume (p=0.03), SPECT-ischaemia (p=0.04) and age (p=0.05), and when SPECT-ischaemia was excluded: end-diastolic LV volume (p=0.03) and age (p=0.05). Fig. 2 illustrates the combined influence of SPECT-ischaemia and LV volume showing that in the population with the largest LV volumes, SPECT-ischaemia was associated with the highest PIIINP concentrations.


Figure 02
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  		Fig. 2 Comparisons in plasma levels of PIIINP between patients classified according to: (i) the presence or absence of SPECT-ischaemia (I+ and I–, respectively) and (ii) a LV end-diastolic volume higher or lower than the median value of study population (V+ and V–, respectively).

 
For MMP-1, concomitant treatments with ACEI (p=0.002) and beta-blockers (p=0.02) were independent predictors of MMP1 level. When these variables were excluded, a history of myocardial infarction remained the only predictor of MMP1 (p=0.004).

Fig. 3 illustrates the influence of both ACEI and beta-blockers treatments on the plasma level of MMP-1.


Figure 03
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  		Fig. 3 Comparisons in plasma levels of MMP-1 according to concomitant medical treatment: (i) presence or absence of ACEI (ACEI+ and ACEI–, respectively) and (ii) presence or absence of beta-blockers (BB+ and BB–, respectively).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Study limitations. Future...
 6. Conclusion
 Acknowledgments
 References
 
For the first time, serum markers of collagen synthesis and degradation have been obtained in a general population of patients with stable and chronic CAD and have been shown to correlate with stress perfusion and cardiac function assessed on current medications and thus, in daily-life conditions. The main finding was that CAD patients had higher serum PIIINP levels when persistent ischaemia on treatment was detected during exercise. This suggests that persistent ischaemia is associated with myocardial structural remodelling. Further investigation is needed to confirm these results and to explore their potential prognostic and therapeutic implications.

Changes in serum collagen biomarkers have previously been reported in CAD patients after acute myocardial infarction [9,10,21,22] and in ischaemic dilated cardiomyopathy [11,12]. However, our population of mildly symptomatic patients with stable and chronic CAD is definitely different: LV ejection fraction was normal in as many as 76% of cases and only 29% had angina. Short-term outcome in such clinically stable patients is generally excellent, but longer term outcome is much more variable and clearly affected when stress ischaemia is present despite current medication [13]. This point is strengthened by the beneficial prognostic effects provided by myocardial revascularisation, when silent ischaemia may be documented in such patients [23].

We hypothesized in our study that stress ischaemia may act as a stimulus for myocardial structural remodelling, therefore we analysed the univariate and multivariate determinants of serum collagen biomarkers.

Exercise-SPECT-ischaemia was observed in 41% of our patients who had higher concentrations of PIIINP, a marker of collagen-III global turnover, and lower concentrations of MMP-1, a marker of collagen degradation compared to non-ischaemic patients. By multivariate analysis, however, SPECT-ischaemia was an independent predictor of PIIINP but not of MMP-1.

MMP-1 was related to a history of myocardial infarction in univariate analysis, as well as in multivariate analysis. However, when concomitant medications were introduced in step by step regression, this relationship was lost and MMP-1 become significantly associated only to concomitant medications (ACEI and beta-blockers).

Available evidence supports differential time-dependent extracellular matrix (ECM) degradation after acute myocardial infarction. Very early after MI (first 24 h), collagen degradation clearly exceeds synthesis as shown by increased MMP1 [24,25]. In the later stages after MI (2 weeks to 1 year or more) healing and scarring processes to actively repair the damaged site [5] exceed ECM degradation, as shown by decreased MMP and increased TIMP or decreased MMP/TIMP ratio [24,25]. In our study, only patients who had had MI≥6 months were included. Consequently, the findings that MMP-1 levels were lower in these patients as compared with those with no MI (3.7 vs. 5 µg/l) are in accordance with previous reports.

On the other hand, ACE inhibition has been shown to prevent collagen deposition and fibrosis in experimental studies [26]. Together with decreased collagen synthesis, proMMP1 and MMP-1 activity also decreased probably in relation to decreased ECM turnover [27]. Although blockade of the renin-angiotensin system and sympathetic system have been reported to produce beneficial effects on cardiac remodelling, the effect of different drugs on subcellular remodelling have not been examined extensively [2].

We found in our study decreased MMP-1 levels after ACEI and beta-blocker treatments (3.6 vs. 5.1 and 3.9 vs. 5.1 µg/l, respectively). Our results are in accordance with the relatively few published data on the effects of ACEI and beta-blocker treatments on MMP1. In human and experimental models, both medications have been shown to decrease the myocardial concentration and activity of MMP, together with a slowing down of LV remodelling [5,6,28,29]. A marked decrease in the blood level of MMP1 together with minimal changes in end-diastolic diameter was shown when patients with acute MI were given ACEI [29]. In addition, beta-blockers may act by antagonizing angiotensin II-induced sympathetic stimulation and thus act through a pathway similar to that of ACEI [28].

In the present study, SPECT-ischaemia was not associated with signs of enhanced collagen-I turnover (no increase in PINP level). Collagen-I is generally involved in thick collagen fibers showing numerous cross-links and associated with high tensile strength, whereas collagen-III is mainly observed in much thinner and elastic fibers [24]. Collagen-I is, therefore, more efficient for structural support and is much more abundant in the healthy heart, as well as in the mature infarct scar [5,24] and in hypertensive heart disease [30].

In contrast, collagen-III seems to be the main component of "reactive" ischaemic-related fibrosis, since it can be synthesized in a more rapid and reactive way and could play an important role in the development of new areas of myocardial fibrosis in different clinical settings. After myocardial infarction [24] new collagen is mostly thin type III, whereas subsequent collagen maturation involves a conversion to thick type I that provides an increased resistance to distension. In patients with persistent exercise ischaemia, we found in our study higher PIIINP levels than in patients with no ischaemia, suggesting an increased type III collagen global turnover leading to a "reactive" fibrosis.

Synthesis of collagen-III has been shown to be predominantly enhanced in severe and/or uncompensated cardiomyopathies of various origins, as well as in acute or chronic severe ischaemia as occurs: (i) in the days following an acute myocardial infarction [9,10], especially when revascularization is unsuccessful [9], and (ii) in ischaemic cardiomyopathies where an enhanced collagen-III synthesis is observed within viable myocardium, outside infarct areas [24].

By determining plasma levels of PIIINP, the present study confirms this relation between increased collagen-III turnover and ischaemia in patients with stable and chronic CAD. Furthermore, this relation persists when analysing only patients with normal LV ejection fraction, giving evidence of an onset at an early stage of ischaemic heart disease as a potential mechanism of transition to clinical heart failure.

On multivariate analyses, PIIINP level was related to residual SPECT-ischaemia, aging and LV volume, but not to concomitant treatment with ACEI and beta-blockers, which were associated with MMP1 level. Aging and LV volume are known to be strongly associated with adverse cardiac remodelling: older patients exhibit enhanced cardiac fibrosis, whatever the cardiac disease, and LV dilation is commonly associated with fibrosis development during LV ischaemic remodelling [24].

Finally, the relationship between PIIINP level and residual SPECT-ischaemia suggests that revascularization to alleviate myocardial ischaemia might be the treatment of choice for lowering plasma PIIINP levels. This hypothesis should be investigated in further studies.


   5. Study limitations. Future directions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations. Future...
6. Conclusion
 Acknowledgments
 References
 
Although blood markers of fibrosis are not specific for myocardial tissue, it is likely that our results and, especially, the relation between PIIINP level and ischaemia, truly reflect changes occurring within myocardium. Firstly, our patients were carefully selected to exclude any extra-cardiac cause of fibrosis or remodelling. Secondly, in patients with idiopathic or ischaemic dilated cardiomyopathy, serum levels of PIIINP have been shown to correlate to the amount of collagen within the myocardium [12].

Biomarker measurements were not performed in an age- and sex-matched healthy population, and this is a limitation of our study.

Further studies should be conducted in order to define the clinical significance of ischaemia-related increase in PIIINP level in patients with chronic and stable CAD, namely the relationship of PIIINP level to outcome and to further deterioration of LV function or the impact of myocardial revascularization on PIIINP. We are currently following our study population in a prospective survey.

It should be noted that following myocardial infarction or in advanced ischaemic cardiomyopathies, high plasma levels in PIIINP have been consistently associated with worsened outcome [11,22], further deterioration in LV function [10] and enhanced myocardial fibrosis [12].


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations. Future...
 6. Conclusion
Acknowledgments
 References
 
In patients with chronic and stable CAD, exercise-SPECT-ischaemia on treatment is associated with an increase in blood marker of collagen-III turnover (PIIINP), independently of concomitant medications and even when LV ejection fraction is normal. This result suggests that long-term, this increase in PIIINP level might relate to adverse cardiac remodelling even when cardiac function is not clearly affected at baseline. This hypothesis needs to be confirmed in large prospective studies.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations. Future...
 6. Conclusion
 Acknowledgments
References
 
The authors thank the association of ARISC (Association de Recherche et Information Scientifique en Cardiologie, CHU Nancy) for financial support.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations. Future...
 6. Conclusion
 Acknowledgments
 References
 

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W. Iraqi, P. Rossignol, M. Angioi, R. Fay, J. Nuee, J. M. Ketelslegers, J. Vincent, B. Pitt, and F. Zannad
Extracellular Cardiac Matrix Biomarkers in Patients With Acute Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure: Insights From the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) Study
Circulation, May 12, 2009; 119(18): 2471 - 2479.
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