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Cardiovascular Research 2007 75(4):813-820; doi:10.1016/j.cardiores.2007.05.003
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Copyright © 2007, European Society of Cardiology

Matrix metalloproteinase-3 and coronary remodelling: Implications for unstable coronary disease

Anthony J. White, Stephen J. Duffy, Anthony S. Walton, Jer Fuu Ng, Gregory E. Rice, Swati Mukherjee, James A. Shaw, Garry L. Jennings, Anthony M. Dart and Bronwyn A. Kingwell*

Baker Heart Research Institute and The Department of Cardiovascular Medicine, Alfred Hospital, Melbourne, Australia

* Corresponding author. Baker Heart Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria, 8008, Australia. Tel.: +61 3 8532 1518; fax: +61 3 8532 1160. bronwyn.kingwell{at}baker.edu.au

Received 7 January 2007; revised 1 April 2007; accepted 7 May 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Objectives Matrix metalloproteinases (MMPs) are plausible candidates for prediction of unstable coronary syndromes. We hypothesised that the MMP-3 polymorphism (– 1171, 5A/6A) would relate to coronary plaque characteristics and unstable clinical presentation.

Methods and results Forty patients with de novo presentation of coronary artery disease (CAD) were classified into unstable coronary syndrome (n=19) or stable angina pectoris (n=21). On coronary intravascular ultrasound, patients with unstable disease had a greater plaque burden, more positive (outward) coronary remodelling, and all but one were MMP-3 6A allele carriers (p=0.027 compared with stable). The relationship between the 6A allele and unstable presentation was substantiated in a validation cohort of 161 CAD patients (58 stable and 103 unstable) and in the total population of 201 CAD patients (79 stable and 122 unstable, p=0.007), and was independent of conventional risk factors. Furthermore, 6A allele carriers had a higher plasma MMP-3 concentration (15.8±12.5 versus 11.7±7.2 ng/mL, p=0.01), maximum coronary stenosis on angiography (89±15% versus 80±23%, p=0.02), plaque area (12.0±5.2 versus 7.5±3.6 mm2, p=0.03), percentage plaque burden (82±7 versus 71±13%, p=0.003), and remodelling ratio (1.03±0.23 versus 0.83±0.12, p=0.003).

Conclusions The MMP-3 6A allele promotes positive coronary remodelling, greater plaque burden, and increased susceptibility to unstable coronary syndromes in humans.

KEYWORDS Matrix metalloproteinase; Acute coronary syndrome; Vulnerable plaque; Arterial remodelling

Abbreviations: EEL, External elastic lamina • IVUS, Intravascular ultrasound • LSD, Least significant difference • MMPs, Matrix metalloproteinases • PCR, Polymerase chain reaction • RR, Remodelling ratio • SNP, Single nucleotide polymorphism


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Accurate identification of patients at risk for unstable coronary syndromes is still not possible. Worldwide, more than 19 million people experience a sudden cardiac event annually [1]. A large proportion of these individuals have no prior symptoms [2] because the underlying coronary lesion upon which thrombus has formed was not previously flow-limiting [3]. These data emphasise that prevention of sudden cardiac events is essential to further reduce coronary artery disease-related morbidity and mortality. Better predictors of individual vulnerability (or risk) are required. This is driving the search for new biomarkers of susceptibility to coronary plaque rupture or surface erosion, the most frequent precipitating events [4].

Arterial remodelling plays an important role in plaque vulnerability [5]. Positive or expansive remodelling in response to atheroma development was initially described as a compensatory phenomenon that preserves the lumen and delays the point at which a given volume of atheroma in the vessel wall becomes flow-limiting [6]. However, more recently, the effects of positive remodelling have been considered more controversial after association with adverse characteristics including increased inflammation [7,8] and unstable clinical presentation [9–11]. The matrix metalloproteinases (MMPs) appear to play an integral role in both remodelling and plaque rupture/erosion, making them attractive candidates as biomarkers for unstable coronary syndromes. Collectively MMPs are capable of degrading all components of the extracellular matrix [12,13] and have been implicated in both positive remodelling and plaque instability [14]. Due to the complex biology of coronary atherosclerotic plaques, a causal role for MMPs in coronary plaque instability remains to be unequivocally established [15]. MMP-3 (stromelysin-1) may be particularly significant to plaque stability and coronary remodelling owing to its broad substrate spectrum and its role in activation of other MMPs including, interstitial collagenase (MMP-1) and gelatinase B (MMP-9) [16,17]. We sought to provide novel mechanistic insight into the role of MMP-3 in unstable coronary disease by comprehensive examination of the relationships between a common functional genetic polymorphism in MMP-3 (– 1171 5A/6A) and coronary plaque and remodelling characteristics assessed using intravascular ultrasound (IVUS). These relationships were further explored in a larger validation cohort (total CAD population n=201) with reference to a healthy control population (n=158) [18]. We focused our primary analysis on MMP-3 genotype as the key marker as it would not be influenced by the acute phase response in unstable patients.

We hypothesised that MMP-3 genotype would relate to coronary plaque characteristics, coronary remodelling, as well as clinical presentation as stable or unstable coronary artery disease.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
2.1 Participants and study design
Patients attending The Alfred Hospital cardiac catheterisation laboratory with a de novo presentation of coronary artery disease (CAD) were recruited between April 2003 and May 2005. A total of 201 patients (age 64±11 years, 79% male) undergoing coronary angiography gave written informed consent to participate in the study, which was approved by the Ethics Committee of The Alfred Hospital and complied with the Declaration of Helsinki (2000). The 201 participants consisted of 40 consecutive consenting patients who underwent IVUS (as described below) and a validation cohort of 161 patients. Patients were excluded if they had undergone previous coronary revascularisation. A fasting blood sample was drawn from the femoral arterial sheath prior to heparinization for DNA, measurement of MMP-3 and routine hematological, lipid and biochemical parameters. Data from these patients were compared with data from healthy controls [18].

All CAD patients were classified independently by two cardiologists (A.J.W. and S.M.) as either (i) unstable coronary syndrome or (ii) stable angina, on the basis of symptoms, 12-lead ECG and cardiac troponin I measurements, according to Braunwald criteria [19,20]. If there was disagreement in classification, a senior cardiologist adjudicated (S.J.D.). The degree of stenosis was estimated as a percentage of the lumen diameter compromised by atheroma with respect to the proximal reference segment by the treating cardiologist who was blinded to all other analyses.

2.2 Intravascular ultrasound
Pre-intervention IVUS images were obtained in 21 stable and 19 unstable patients. Following administration of 100 µg of intra-coronary glyceryl-trinitrate, an IVUS catheter (Atlantis 40MHz or UltraCross 30MHz, Boston Scientific/SciMed, MN) was placed beyond the culprit lesion in a distal reference segment of coronary artery. There was no difference in the use of the two types of probes between the groups (p=0.58). A recording was made during catheter withdrawal at a constant rate of 0.5 mm s–1 through the stenosis and into a proximal reference segment using an automated pull-back device. The images were digitized at 25 frames s–1 for later analysis in a planimetry software package (ImagePro Plus, Media Cybernetics Inc, MD). Standard definitions were used for intimal border, external elastic lamina (EEL) border, minimal lumen diameter, proximal and distal reference segments [21]. From these parameters, measurements of plaque cross-sectional area, percentage plaque burden and remodelling ratio were derived, as described previously [21]. Plaque area (or intima-plus-media area) was calculated as the EEL area minus the lumen area. Percentage plaque area was calculated as (plaque area/EEL area)x100. These measurements were made at the minimum lumen frame. The remodelling ratio (RR) was calculated as EEL area at the minimum lumen frame/([EEL area at distal reference frame+EEL area at proximal reference frame]/2). The ACC consensus document on IVUS measurements suggests that a remodelling ratio of >1.0 represents positive remodelling, and <1.0 represents negative remodelling [21]. Patients were also stratified into three groups based on a coronary remodelling ratio suggested by Schoenhagen and colleagues: negative (RR<0.95), neutral (0.95–1.05) and positive (RR>1.05) [9,22]. All measurements were performed by a cardiologist blinded to the clinical presentation.

2.3 Genotyping
Genomic DNA was prepared from whole blood using routine procedures. 100 ng of genomic DNA was amplified by the polymerase chain reaction (PCR). MMP-3 was genotyped by size with sequence verification in a subset (n=30) (ABI Prism Genescan 337, PE Biosystems, CA). The primers used for PCR and sequencing were as follows (GeneWorks Pty Ltd, SA, Australia), Forward 5'-GAT TAC AGA CAT GGG TCA CG-3', Reverse 5'-GAA TTC ACA TCA CTG CCA CC-3'.

2.4 Biochemistry
Total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were measured in whole blood using an enzyme based assay (Cholestech L.D.X, Cholestech Corporation, Hayward, CA). Troponin I (Architect assay, Abbott, IL; normal range <0.03 µg/L) and high sensitivity C-reactive protein (hsCRP, turbidimetric assay, Roche, Basel, Switzerland) were also assessed. Automated platforms were used to measure hematological (hemoglobin concentration, white cell and platelet counts) (Cell-Dyn 3700, Abbott Laboratories, IL) and renal parameters (Architect, Abbott Laboratories, IL).

MMP-3 protein was measured in heparinized plasma using antibody-coated microparticles (Fluorokine® Multianalyte Profiling kits, R&D systems, MN. Catalog No. LMP513) on a multiplex platform (BioPlexTM, Bio-Rad Laboratories, CA). Each plasma specimen was tested in duplicate. Plasma was unavailable for seven of the 201 participants. The average intra-assay co-efficient of variation between the duplicates was 4.2±4.0%. The limit of detection of the assay is 1.37 pg/mL.

2.5 Statistics
All data were analysed using SPSS for Windows 12.0 (Chicago, IL). Continuous variables were compared by Student's t-tests or ANOVA with least significant difference (LSD) post hoc testing, and categorical variables by Chi-square analysis as appropriate. hsCRP and MMP-3 concentrations were log-transformed to achieve a normal distribution for statistical analysis. Discriminant analysis was performed to determine predictors of unstable clinical presentation. Data are presented as mean±standard deviation, except where indicated. A p value of <0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
3.1 Patient characteristics
The self-identified ancestry of the CAD population was 93% Caucasian, 3.5% South Asian, 0.5% Indigenous Australian and 3.0% other. Patient characteristics are presented according to clinical category (stable angina versus unstable coronary syndrome) for both the IVUS and the validation cohorts in Table 1. For both cohorts, the stable and unstable groups did not differ in age, gender distribution or conventional cardiovascular risk factors, except for the higher proportion of current smokers in the unstable group of the validation cohort (Table 1). Consistent with their diagnosis, the unstable group had a higher white cell count, plasma troponin I and serum hsCRP, and a lower proportion with normal ECG ST segments or normal T waves than the stable group (Table 1). The majority of unstable patients were troponin I positive (i.e. >0.03 µg/L; IVUS cohort, 79%; validation cohort, 83%; total population, 82%).


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  		Table 1 Clinical characteristics

 
The medication profile of the total CAD population was determined at the time of presentation to the catheterisation laboratory. More unstable patients were medicated with statins (84% versus 56%, p<0.0001), heparin (either unfractionated or low-molecular weight) (31% versus 1%, p<0.0001), ACE inhibitors (53% versus 38%, p=0.03) and intravenous GTN infusions (5% versus 0%, p=0.05). On the other hand, the unstable group had a lower proportion taking angiotensin receptor antagonists (13% versus 24%, p=0.05) and calcium channel blockers (17% versus 32%, p=0.02) than the stable group.

3.2 MMP-3 genotype, plaque characteristics and clinical presentation (IVUS cohort)
In the IVUS cohort, the unstable group tended to smaller minimum lumen cross-sectional areas, greater EEL cross-sectional area and plaque area at the minimum lumen frame (Table 2). This translated to a greater cross-sectional plaque burden (p=0.05) and a higher remodelling ratio (p=0.001, Table 2) in the unstable group. Unstable patients were much more likely to have positive remodelling and nearly all stable patients had negative remodelling (p=0.001, Table 2).


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  		Table 2 Plaque characteristics (IVUS) by clinical presentation (IVUS cohort)

 
All but one unstable patient was a 6A allele carrier (95% of the IVUS cohort) and this frequency was significantly greater than in the stable group (67%, p=0.027, Table 3).


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  		Table 3 MMP-3 genotype by clinical presentation

 
6A allele carriers had greater plaque area (p=0.03), plaque burden (p=0.003, Fig. 1, upper panel) and remodelling ratio (p=0.003, Table 4). Arterial remodelling was neutral or positive in 6A carriers, but 5A homozygotes had negative remodelling (p=0.003, Table 4) [21]. To further examine the relationship between genotype and remodelling, patients were stratified into three groups: negative (RR<0.95), neutral (0.95–1.05) and positive (RR>1.05) on the basis of their remodelling ratio [9]. In support of our finding that 6A carriers tend to have positive remodelling (with associated higher plaque volume), we found that all positively remodeled culprit lesions (RR>1.05) were in 6A carriers. This was significantly different from the genotype frequency in the negative remodelling group (p=0.03).


Figure 1
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  		Fig. 1 Plaque burden measured by IVUS (n=40; upper panel) and severity of maximum coronary stenosis on angiography (n=201 lower panel) stratified by MMP-3 – 1171 5A/6A genotype. EEL, external elastic lamina. Data are mean±SEM. * denotes p<0.05, ** denotes p<0.01 (ANOVA with LSD post hoc testing).

 

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  		Table 4 Plaque characteristics (IVUS) by MMP-3 genotype (IVUS cohort)

 
3.3 MMP-3 genotype and clinical presentation (validation cohort)
The validation cohort substantiated the findings of the IVUS cohort with a greater proportion of 6A allele carriers in the unstable group (p=0.047, Table 3). When the IVUS and validation cohorts were combined the 6A allele was more prevalent in the unstable group whether assessed by individual genotype (p=0.03) or by a 6A dominant model (p=0.007, Table 3). 6A allele carriers were also more prevalent in the unstable group (84%) compared to a sub group of a previously reported healthy population (73%) selected to be age and sex matched (p=0.02, n=158, Table 5) [18].


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  		Table 5 Genotype frequencies, total unstable population versus healthy controls

 
To determine whether MMP-3 genotype was an independent predictor of unstable presentation a discriminant analysis was performed. Those parameters which were measurable prior to presentation and differed between the stable and unstable groups in the total CAD population (p<0.1) were entered into this analysis (sex, smoking, hypertensive status, and MMP-3 genotype). Factors which differed between the groups, but were measured after clinical presentation, and therefore potentially a consequence, were not entered into the analysis. When MMP-3 genotype was entered as three possible genotypes (5A5A, 5A6A or 6A6A), then current smoking (p=0.007), MMP-3 genotype (p=0.02) and female sex (p=0.05) were all independent determinants of clinical presentation. If the MMP-3 genotype was entered as a 6A dominant model (5A/5A or 6A carrier), then current smoking (p=0.007) and MMP-3 genotype (p=0.007) were equally strong discriminators of clinical presentation with female sex (p=0.05) as the only other significant independent predictor.

3.4 MMP-3 genotype and patient characteristics
To validate the relationship between genotype and unstable presentation, it is important to eliminate any sources of bias by examining patient characteristics in relation to genotype. The frequency of the 6A allele in the total CAD population was 0.53, with genotype frequencies of 22% (n=44), 50% (n=100) and 28% (n=57) for 5A/5A, 5A/6A and 6A/6A respectively. These frequencies are consistent with Hardy–Weinberg equilibrium. There were no significant differences in age, sex ratio, body mass index (Table 6), lipid levels, hematologic or renal parameters between the MMP-3 genotypes. 6A carriers had a lower proportion with a family history of coronary artery disease than 5A homozygotes. Cigarette smoking and hypertension were in similar proportions in the MMP-3 genotype groups. Proportions of patients on various classes of medication were also similar in the MMP-3 genotype groups. Consistent with the IVUS cohort, 6A carriers had a greater maximum stenosis (i.e. plaque burden) on coronary angiography in both the validation cohort (80±24 versus 89±16%, p=0.01) and in the total CAD population (p=0.02, Table 6; Fig. 1, lower panel).


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  		Table 6 Patient characteristics by MMP-3 genotype (total population)

 
Plasma MMP-3 concentrations were higher in 6A allele carriers whether analysed by individual genotype (p=0.001) or by a 6A dominant model (p=0.01, [Table 6, Fig. 2]). Plasma MMP-3 concentrations were not, however, different between clinical presentations (total population: stable, 14.3±9.0 versus unstable, 15.3±13.1 ng/mL, p=0.98, Table 1). This likely relates to the fact that MMP-3 concentration is transiently reduced in the acute phase of myocardial infarction [23].


Figure 2
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  		Fig. 2 MMP-3 plasma concentration measured by bead-based multiplex immunoassay. Data are stratified by MMP-3 – 1171 genotype (5A/5A n=43; 5A/6A n=95; 6A/6A n=55.) Data are mean±SEM. ** denotes p≥0.01, *** denotes p<0.001 (ANOVA with LSD post hoc testing).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Acknowledgments
 References
 
This study provides new mechanistic insight into how MMP-3 may influence clinical presentation of patients with coronary artery disease. It provides a plausible mechanistic link between MMP-3 genotype, MMP-3 plasma concentrations, plaque and vessel morphology, and susceptibility to unstable coronary disease. Our observation was made initially in a small cohort undergoing invasive IVUS studies and then validated in a larger population. This is the first study to report a potential genetic mechanism connecting positive arterial remodelling associated with increased plaque burden to unstable clinical presentation. Our observations indicate that MMP-3 6A allele carriers have higher circulating plasma concentrations of MMP-3. MMP-3 plays a pivotal role in coronary remodelling as a result of its broad substrate spectrum and its ability to activate other MMPs [16,17]. The data are consistent with the hypothesis that the MMP-3 6A allele promotes positive remodelling, [21] which is associated with higher plaque burden, susceptibility to plaque disruption and unstable clinical presentation [5]. MMP-3 genotype can be assessed prior to clinical presentation and may be a useful component of a risk prediction model for unstable coronary disease. However, this requires confirmation in a prospective study.

A series of recent human pathological and IVUS studies have demonstrated that while positive remodelling may be an appropriate early compensatory mechanism in the setting of coronary atheroma, [6] this lesion type is associated with increased inflammation and plaque instability [5,7,9,10]. It is unclear why some individuals might develop positive remodelling, increased plaque burden and present with unstable symptoms, rather than developing a fibrocalcific, negative remodelling phenotype when exposed to similar environmental risk factors. Our 5A and 6A groups were generally well matched for traditional risk factors, so it is possible that the presence of the 6A allele and the resultant increased production of MMP-3 may have influenced coronary remodelling and plaque vulnerability [24].

Consistent with the current study, the 6A allele has been associated with higher circulating MMP-3 concentrations [25]. Prospective data have linked plasma concentrations of MMP 3 with future adverse cardiovascular disease outcomes amongst a cohort with stable coronary artery disease [26]. However, in the current study, although MMP-3 genotype was associated with unstable clinical presentation and with plasma MMP-3 concentration, the MMP-3 concentration itself was not a determinant of clinical presentation. This likely relates to the fact that MMP-3 concentration is transiently reduced in the acute phase of myocardial infarction [23]. While our unstable group did not have ST elevation myocardial infarctions, myocardial necrosis was present as evidenced by elevation in troponin I (82% of unstable patients were troponin I positive) and this may have obscured differences in plasma MMP-3 between groups. It is also possible that the higher proportion of patients in the unstable group treated with statins and with heparin may have reduced plasma MMP-3 levels [27,28]. However, MMP-3 genotype, which is unaffected by the acute phase response, was highly predictive of clinical presentation, while also establishing a plausible mechanistic link.

The high frequency of the 6A allele (0.53) makes the findings of the current study potentially relevant to approximately 50% of Caucasian populations. This allele frequency is aligned with that reported in Australian [18], British [29] and Swedish [25] populations. Consistent with the current study, the 6A/6A genotype has previously been associated with more rapid angiographic progression of coronary artery disease [30–33] and with carotid disease [34–36]. The mechanism may include higher MMP-3 expression in the arterial wall promoting plaque growth through repeated episodes of subclinical plaque rupture and thrombus formation and incorporation into the plaque [37–39]. In addition, in individuals without a history of myocardial infarction, the 6A/6A genotype has been associated with a greater number of vessels with a stenosis >50% [40]. The current study is the first to report a relationship between MMP-3 genotype and unstable versus stable clinical presentation.

Previous work investigating the frequency of the 5A/6A MMP-3 polymorphism in myocardial infarction relative to healthy controls has been conflicting. Large candidate gene studies have associated the 6A allele with increased risk of myocardial infarction in both Caucasian men [29] and Japanese women [41] relative to healthy individuals. In the current study, 6A allele carriers were also more prevalent in the unstable group compared with healthy controls. Interestingly, the frequency of the 6A allele is higher (between 0.7 and 0.88) in Asian populations [41–45]. In people of Asian descent the MMP-3 5A/6A polymorphism generally appears to be either neutral, [45] or the 5A allele has been associated with elevated coronary risk in both Japanese [42,43] and Chinese [44] populations. Environmental influences such as diet and smoking [29] appear to have an important interaction with MMP-3 genotype and may be particularly important in explaining ethnic differences in the MMP-3 genotype relationship to coronary artery disease [29]. Therefore, the results of the current study in Australians of predominantly European origin cannot necessarily be generalised to other ethnic populations. Importantly, none of these previous studies reported a mechanistic basis for their observations.

4.1 Limitations
The IVUS cohort was relatively small (n=40), although it is notable that these studies were performed prospectively. Given the invasive nature of IVUS investigations, the sample size was determined to provide adequate power (>80%) to detect a clinically significant, approximately 8% difference in plaque burden between stable and unstable presentations. The current findings clearly warrant confirmation in a larger population. In particular, a retrospective analysis of established IVUS databases could be informative.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Acknowledgments
 References
 
The current study establishes a plausible mechanistic link between the common MMP-3 – 1171 6A allele variant and unstable coronary syndromes in a predominantly Caucasian population. The mechanism appears to include elevation of MMP-3 expression, positive coronary remodelling related to greater plaque burden and increased susceptibility to plaque instability. The high frequency of the 6A variant increases the importance of this finding for risk assessment in Caucasian populations. MMP-3 genotype can be assessed prior to clinical presentation and may be a useful component of a risk prediction model for unstable coronary disease.

Time for primary review 32 days


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
References
 
Dr White was supported in 2003 by a scholarship from the Cardiac Society of Australia and New Zealand, and in 2004–2005 by a scholarship from the National Heart Foundation of Australia, and is a PhD candidate at The Alfred Department of Medicine, Monash University. Professor Dart, Associate Professors Kingwell and Gregory Rice are all Research Fellows supported by the National Health and Medical Research Council (NHMRC) of Australia. Dr. Duffy is supported by an NHMRC Centre for Clinical Research Excellence Grant to the Alfred and Baker Medical Unit. This work was supported by grants from the NHMRC of Australia. The authors gratefully acknowledge the technical assistance of Lovisa Dousha and Gillian Barker.


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

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