Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
  • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
  • G01N2333/90—Enzymes; Proenzymes
  • G01N2333/914—Hydrolases (3)
  • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
  • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
  • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
  • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
  • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
  • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
  • G01N2333/96486—Metalloendopeptidases (3.4.24)
  • G01N2333/96491—Metalloendopeptidases (3.4.24) with definite EC number
  • G01N2333/96494—Matrix metalloproteases, e. g. 3.4.24.7
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/32—Cardiovascular disorders
  • G01N2800/324—Coronary artery diseases, e.g. angina pectoris, myocardial infarction
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/54—Determining the risk of relapse

Definitions

• the present invention relates to methods and kits for predicting the survival time of a post acute myocardial infarction patient.
• LV remodelling after myocardial infarction is characterized by progressive LV dilatation 1 , and is associated with an increased risk of heart failure and cardiovascular death 2 .
• MI myocardial infarction
• Recent studies have shown that LV remodelling remains relatively frequent after MI, despite a high rate of acute reperfusion and widespread prescription of secondary prevention medications 3 ' 4 .
• MI size has been identified as risk factors 5 ' 6
• LV remodelling is a process that remains difficult to predict in clinical practice.
• the concept that biological markers may accurately predict clinical outcome is an attractive one. There is growing interest in the research of biological markers that could be used for patients risk assessement in many medical fields.
• biomarkers of extracellular matrix (ECM) turnover matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) or collagen peptides 7 .
• ECM extracellular matrix
• MMPs matrix metalloproteinases
• TIMPs tissue inhibitors of metalloproteinases
• MMPs/TIMPs levels were determined using multiplex technology in samples from the REVE-2 study - a study prospectively designed to analyze relationships between circulating biomarkers and LV remodelling in 246 patients after a first anterior MI and in which repeat echo car dio graphic examinations as well as serial blood sampling were performed during the first year post-MI.
• the present invention relates to a method for predicting the survival time of a post acute myocardial infarction patient comprising i) determining the level of MMP-8 in a blood sample obtained from the patient, ii) comparing the level determined at step i) with a predetermined reference value and iii) providing a bad prognosis when the level determined at step i) is higher than the predetermined reference level and a good prognosis when the level determined at step i) is lower than the predetermine reference value.
• MMP matrix metalloproteinases
• TIMP tissue inhibitors of metalloproteinases
• Serum samples for determination of MMP- 1, -2, -3, -8, -9, -13, TIMP-1,-2, - 3, -4 levels were obtained at hospital discharge, 1-month, 3-months, and 1-year and analyzed using multiplex technology.
• the present invention relates to a method for predicting the survival time of a post acute myocardial infarction patient comprising i) determining the level of MMP-8 in a blood sample obtained from the patient, ii) comparing the level determined at step i) with a predetermined reference value and iii) providing a bad prognosis when the level determined at step i) is higher than the predetermined reference level and a good prognosis when the level determined at step i) is lower than the predetermined reference value.
• MMP-8 has its general meaning in the art and refers to the metalloproteinase 8.
• the predetermined reference value used for comparison may consist of "cut-of ' value that may be determined as described hereunder.
• Each predetermined reference value ("cutoff) value may be determined by carrying out a method comprising the steps of
• step b) providing, for each blood sample provided at step a), information relating to the actual clinical outcome for the corresponding post acute myocardial infarction patient (i.e. the duration of the disease-free survival (DFS) and/or the overall survival (OS));
• information relating to the actual clinical outcome for the corresponding post acute myocardial infarction patient i.e. the duration of the disease-free survival (DFS) and/or the overall survival (OS)
• step c) classifying said blood samples in two groups for one specific arbitrary quantification value provided at step c), respectively: (i) a first group comprising blood samples that exhibit a quantification value for level that is lower than the said arbitrary quantification value contained in the said serial of quantification values; (ii) a second group comprising blood samples that exhibit a quantification value for said level that is higher than - the said arbitrary quantification value contained in the said serial of quantification values; whereby two groups of blood samples are obtained for the said specific quantification value, wherein the blood samples of each group are separately enumerated;
• this method allows the setting of a single "cut-off value that permits discrimination between a poor and a good prognosis with respect to DFS and OS.
• high statistical significance values e.g. low P values
• high statistical significance values e.g. low P values
• a minimal statistical significance value is arbitrarily set and a range of a plurality of arbitrary quantification values for which the statistical significance value calculated at step g) is higher (more significant, e.g. lower P value) are retained, so that a range of quantification values is provided.
• This range of quantification values includes a "cut-off value as described above.
• a "cut-off value poor or good clinical outcome prognosis can be determined by comparing the level of MMP-8 determined at step d) with the range of values which are identified.
• a cut-off value thus consists of a range of quantification values, e.g. centered on the quantification value for which the highest statistical significance value is found (e.g. generally the minimum P value which is found). For example, on a hypothetical scale of 1 to 10, if the ideal cut-off value (the value with the highest statistical significance) is 5, a suitable (exemplary) range may be from 4-6.
• a patient may be assessed by comparing values obtained by measuring the level of MMP-8, where values greater than 5 indicate a poor prognosis and values less than 5 indicate a good prognosis; or a patient may be assessed by comparing values obtained by measuring the level of MMP-8 and comparing the values on a scale, where values above the range of 4-6 indicate a poor prognosis and values below the range of 4-6 indicate a good prognosis, with values falling within the range of 4-6 indicating an intermediate prognosis.
• the method of the invention comprises comparison steps which include a classification of the quantification values measured for the level of MMP-8 in two groups, respectively: (i) a first group termed "Hi” when the quantification value for the level of MMP-8 is higher than the predetermined corresponding reference value and (ii) a second group termed "Lo" when the quantification value for the level of MMP-8 is lower than the predetermined corresponding reference value. Accordingly if the result of the comparison step consists of a "Hi” value, then a bad prognosis is provided. Conversely, if the result of the comparison step consists of a "Lo” value, then a good prognosis is provided.
• the predetermined reference value may be 27 ng/ml (see figure 2).
• the measure of level of MMP-8 can be performed by a variety of techniques.
• the methods may comprise contacting the sample with a binding partner capable of selectively interacting with MMP-8 in the sample.
• the binding partners are antibodies, such as, for example, monoclonal antibodies or even aptamers as above described.
• the aforementioned assays generally involve the binding of the partner (ie. antibody or aptamer) to a solid support.
• Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like.
• the level of MMP-8 may be measured by using standard immuno diagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays.
• immunoassays such as competition, direct reaction, or sandwich type assays.
• assays include, but are not limited to, agglutination tests; enzyme-labelled and mediated immunoassays, such as ELISAs; biotin/avidin type assays; radioimmunoassays; Immunoelectrophoresis; immunoprecipitation.
• An exemplary biochemical test for identifying specific proteins employs a standardized test format, such as ELISA test, although the information provided herein may apply to the development of other biochemical or diagnostic tests and is not limited to the development of an ELISA test (see, e.g., Molecular Immunology: A Textbook, edited by Atassi et al. Marcel Dekker Inc., New York and Basel 1984, for a description of ELISA tests). It is understood that commercial assay enzyme-linked immunosorbant assay (ELISA) kits for various plasma constituents are available. Therefore ELISA method can be used, wherein the _ wells of a microtiter plate are coated with a set of antibodies which recognize MMP-8.
• ELISA test e.g., Molecular Immunology: A Textbook, edited by Atassi et al. Marcel Dekker Inc., New York and Basel 1984, for a description of ELISA tests. It is understood that commercial assay enzyme-linked immunosorbant assay (ELISA) kits for various plasma constituents
• a sample containing or suspected of containing MMP-8 is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labelled secondary binding molecule added. The secondary binding molecule is allowed to react with any captured sample marker protein, the plate washed and the presence of the secondary binding molecule detected using methods well known in the art.
• Measuring the level of MMP-8 may also include separation of the compounds: centrifugation based on the compound's molecular weight; electrophoresis based on mass and charge; HPLC based on hydrophobicity; size exclusion chromatography based on size; and solid-phase affinity based on the compound's affinity for the particular solid-phase that is used.
• said one or two bio markers proteins may be identified based on the known "separation profile" e. g., retention time, for that compound and measured using standard techniques.
• the separated compounds may be detected and measured by, for example, a mass spectrometer.
• levels of immunoreactive MMP-8 in a sample may be measured by an immunometric assay on the basis of a double-antibody "sandwich” technique, with a monoclonal antibody specific for MMP-8 (Cayman Chemical Company, Ann Arbor, Michigan).
• the antibody has no cross-reactivity with the other types of metalloproteinase such as MMP-9.
• said means for measuring MMP-8 level are for example i) a MMP-8 buffer, ii) a monoclonal antibody that interacts specifically with MMP-8, iii) an enzyme-conjugated antibody specific for MMP-8 and a predetermined reference value of MMP-8.
• the method of the invention may further comprises the steps consisting in a) determining the level of BNP in the blood sample obtained from the patient, b) comparing the level determined at step a) with a predetermined reference value and iii) providing a bad prognosis when the level determined at step a) is higher than the predetermined reference level and a good prognosis when the level determined at step a) is lower than the predetermined reference value.
• the predetermined reference value may be determined by the same as described for MMP8. Typically a predetermined reference value for BNP is 130pg/ml (see EXAMPLE). -
• the method as described here above is particularly suitable for monitoring the effectiveness of treatment of post acute myocardial infarction.
• the efficacy of the treatment will be reflected by changes in the measurements of the MMP-8 levels (or the combined values of MMP-8 and BNP levels).
• an efficient treatment will enable to get MMP-8 levels that will decrease compared to the levels of MMP-8 measured before the treatment, suggesting that the survival time of the patient will be improved.
• the method as described here above is for selecting a treatment _ regimen for a patient diagnosed with a bad prognosis according to the method of the invention.
• a further object of the invention relates to a kit for performing the above described method, said kit comprising means for measuring the level of MMP-8 and optionally means for measuring level of BNP in the blood sample obtained from the patient.
• said means for measuring the level of MMP-8 is an antibody that interacts specifically with MMP-8.
• said means for measuring the level of MMP-8 may be an aptamer or any other binding partner that specifically recognizes MMP-8.
• said kit further comprises means for measuring the level of BNP.
• said means for measuring the level of BNP is an antibody that interacts specifically with BNP.
• said means for measuring the level of BNP may be an aptamer or any other binding partner that specifically recognizes BNP.
• Said binding partner(s) can be tagged for an easier detection. It may or may not be immobilized on a substrate surface (e.g., beads, array, and the like).
• a substrate surface e.g., beads, array, and the like.
• an inventive kit may include an array for predicting the risk of having a cardiovascular event as provided herein.
• a substrate surface e.g. membrane
• an inventive kit for immobilization of the binding partner (e.g., via gel electrophoresis and transfer to membrane).
• kits of the invention generally also comprises at least one reagent for the detection of a complex between binding partner included in the kit and biomarker of the invention.
• the kit may further comprise one or more of: extraction buffer and/or reagents, western blotting buffer and/or reagents, and detection means. Protocols for using these buffers and reagents for performing different steps of the procedure may be included in the kit.
• kits of the present invention may optionally comprise different containers (e.g., vial, ampoule, test tube, flask or bottle) for each individual buffer and/or reagent.
• Each component will generally be suitable as aliquoted in its respective container or provided in a concentrated form.
• Other containers suitable for conducting certain _ steps of the disclosed methods may also be provided.
• the individual containers of the kit are preferably maintained in close confinement for commercial sale.
• a kit comprises instructions for using its components for the prediction of a cardiovascular event in a patient according to a method of the invention.
• Instructions for using the kit according to methods of the invention may comprise instructions for processing the biological sample obtained from the patient and/or for performing the test, or instructions for interpreting the results.
• a kit may also contain a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products.
• FIGURES are a diagrammatic representation of FIGURES.
• FIG. 1 LV volumes at 1 year according to tertiles of serum MMP-8 (A) and serum (B) MMP-9 at baseline.
• Tertile 1 corresponds to low levels of MMPs;
• Tertile 2 to intermediate levels and Tertile 3, to high levels.
• Values are mean ⁇ SEM.
• P values are for linear regression between MMP levels and the variables of interest.
• REVE-2 was a multicenter and prospective study designed to analyze the association of circulating biomarkers with LV remodelling.
• Inclusion criteria were hospitalization within 24 hours after symptom onset, and at least 3 LV segments of the infarct zone that were akinetic at the predischarge echocardiography. Exclusion criteria were inadequate echographic image quality, life-limiting noncardiac disease, significant valvular disease, or prior Q-wave MI.
• the research protocol was approved by the Ethics Committee of the Centre Hospitalier et Universitaire de Lille, and written informed consent was obtained from each patient. The protocol required serial echographic studies at hospital discharge (day 3 to day 7), and 3 months and 1 year after MI; serial blood sampling was performed at hospital discharge (day 3 to day 7), and 1 month, 3 months, and 1 year after MI. Clinical follow-up was achieved at 3 years by contacting patient's cardiologist or general practitioner. The endpoint was a composite of cardiovascular death or hospitalization for heart failure episode during 3 years follow-up.
• a standard echographic imaging protocol was used based on apical 4- and 2-chamber views; 2D echocardiograms of the LV short axis were recorded from the left parasternal region at 3 levels: the mitral valve, mid-papillary muscle, and apex. All echocardiograms were analyzed at the Lille Core Echo Laboratory (Lille, France), as previously described 3 . Left ventricular volumes and ejection fraction (EF) were calculated using a modified Simpson's rule.
• serum and plasma ethylenediaminetetraacetic acid (EDTA) used as anticoagulant
• EDTA ethylenediaminetetraacetic acid
• serum and plasma were collected in glass tubes at the 4 time points indicated above. Serum and plasma were processed within 2 h, and samples were divided into aliquots and stored at - 80°C. Samples underwent no more than two freeze/thaw cycles before analysis in a core laboratory (Lille, France). MMPs and TIMPs were measured in serum samples. Serum levels of MMP-1, -2, -3, -8, -9 and -13 were measured using a multiplex luminex kit for simultaneous quantitative detection of human MMPs, according to the manufacturer's instructions (Human MMP Panel Fluorokine Multi Analyte Profiling (MAP) Kit, R&D Systems, Minneapolis, Minneapolis).
• MAP Human MMP Panel Fluorokine Multi Analyte Profiling
• Serum samples required a 10-fold dilution for MMP-1, - 2, -3, -8 and -13 measurement and a 100-fold dilution for MMP-9 according to the protocol. MMP- 13 was not detected in our samples (concentration was below detection limit of 0.71 ng/ml).
• Serum levels of TIMP-1, -2, -3 and -4 were measured using a multiplex tissue inhibitors of metalloproteinases immunoassay (Human TIMP Fluorokine MAP 4-plex Kit, R&D Systems), samples requiring a 50-fold dilution. TIMP-3 was quantified in one third of samples (detection limit at 7.75 ng/ml).
• Baseline MMP-9 level was also measured in plasma samples in all patients using the Milliplex MAP Human MMP Panel 2 (Millipore Corp, Billerica, MA), plasma samples requiring a 20-fold dilution.
• Milliplex MAP Human MMP Panel 2 Milliplex MAP Human MMP Panel 2
• serum MMP-9 level measured by kit from R&D Systems or Millipore in a subgroup of 60 patients. All the samples were analyzed using the Bio-Plex system (Bio-Rad Laboratories, Hercules, CA) according to the instructions from the manufacturer. Analysis of experimental data was performed using four-parameter logistic curve fitting to the standard analyte curves.
• Results are presented as the mean ⁇ SD, median with 25 th and 75 th percentiles, or frequency expressed as a percentage. Variables with skewed distribution were log- transformed before being used as continuous variables in statistical analyses. Continuous variables were compared with the Student's t-test or with simple linear regression, as appropriate. Discrete variables were compared using ⁇ 2 analysis. Changes in circulating biomarkers over time were assessed by repeated measures ANOVA with post hoc test of Scheffe. Association of MMPs and TIMPs with LV remodelling was studied by linear regression analysis. To adjust for multiple testing, we used the Benjamini & Hochberg procedure to control false discovery rate 13 . MMPs with significant univariate association were entered into a linear regression model with BNP for the prediction of LV remodelling.
• Cox proportional hazard analysis was performed to determine predictors of cardiac events free survival.
• SPSS software version 13 SPPS, Chicago, Illinois was used for the statistical analysis.
• LV remodelling was documented by an increase in end-diastolic volume (EDV) (baseline 52.3 ⁇ 14.0 mL/m 2 , 1 year 62.3 ⁇ 18.4 mL/m 2 , P ⁇ 0.0001) and in end-systolic volume (ESV) (baseline 26.8 ⁇ 10.5 mL/m 2 , 1 year 29.0 ⁇ 14.5 mL/m 2 , P ⁇ 0.001 ) at 1-year follow-up. Clinical follow-up data were obtained for 245 patients at a median of 1098 days: 16 patients were hospitalized for heart failure and 15 patients died (11 from cardiac causes).
• Serum levels of MMP-1, -2, -3, -8, -9, and TIMP-1, -2, -4 obtained at baseline, 1 month, 3 months, and 1 year after MI are summarized in Table 1. Overall, 3 temporal patterns were identified: MMP-1 level remained stable throughout the study; MMP-2, MMP-3, TIMP- 2, and TIMP-4 were significantly lower on the baseline sample and increased thereafter; by contrast, MMP-8, MMP-9 and TIMP-1 were significantly higher at baseline and decreased in the chronic phase.
• TIMP-2 showed significant positive correlation with MMP-2, TIMP-1 and TIMP-4.
• CK peak creatine kinase
• Serum levels of MMP-2 and TIMP-4 were significantly higher in women than men, in contrast with MMP-3. Elevated serum levels of MMP-3 and TIMP-4 were associated with a higher incidence of hypertension. We also found that elevated serum levels of MMP-3, TIMP-2 and TIMP-4 were associated with presence of diabetes. By contrast, serum levels of MMP-1, MMP-8 and MMP-9 were not associated with any baseline characteristics of the study population. Of note, there was no association between any MMPs/TIMPs and infarct size as indicated by the peak CK.
• Type of sample, plasma or serum is known to affect measured concentrations of circulating MMP-9.
• MMP-9 was measured in plasma, to strengthen our data, we also measured MMP-9 in plasma of 246 patients in REVE 2 study.
• the present study is the first to provide an in depth investigation of the temporal pattern of many circulating MMPs and all TIMPs during one-year follow-up after acute MI and their relation with LV remodelling and prognosis in a large cohort of patients.
• our study has clear strengths related to its prospective design: relatively high number of patients, very homogeneous study population with a first anterior ST-elevation MI, high rate of reperfusion, nearly systematic use of secondary prevention treatments, serial blood sampling at pre-specified time points during one-year follow-up, prospective assessment of one-year LV remodelling with core lab analysis.
• Another strength is related to the availability of bead-based multi-analyte profiling technology that can multiplex many MMPs or all TIMPs in a single sample and allowed to study a large panel of biomarkers of ECM turnover.
• MMPs/TIMPs concentrations of MMPs/TIMPs in the peripheral blood is at best an indicator of the localized process that is occurring within the myocardium and that, due to different interactions, certain MMPs or TIMPs may not egress into the circulation 8 .
• Preanalytical conditions are known to affect measured concentrations of circulating MMPs and TIMPs, including the type of sample (plasma or serum), the anticoagulant used to collect plasma and the freeze-thaw cycles.
• type of sample plasma or serum
• anticoagulant used to collect plasma
• freeze-thaw cycles we have found higher MMP-9 concentrations in serum compared with plasma, in agreement with previous studies 17 . The observed difference could be attributed to the different release of this analyte from blood cells during platelet activation or sampling process.
• MMP-8 and -9 are both synthesized by differentiating granulocytes, stored in circulating neutrophils, and released after neutrophil activation, a mutuality that could partially explain their association.
• the present study establishes for the first time a positive association between baseline serum MMP-8 and the extent of LV remodelling after Ml. To date, only one study was reported', finding no association with LV remodelling, probably due to a limited number of patients 13 . Our data are in agreement with experimental studies suggesting that increased MMP-8 activity in the infarct area, caused by a more prominent infiltration of inflammatory cells, contribute to infarct rupture in humans 23 . Regarding MMP-9, our study confirms in serum previous findings of positive relationships of plasma MMP-9 with LV remodelling 15 ' 24" 26 . Size of these studies was however often limited with only one study including > 100 patients 25 .
• TIMP-1, -2, -4 with LV remodelling Our data are consistent with several earlier studies for MMP-2 15 ' 24 ' 27"29 but differ for MMP-3, with two previous studies showing positive associations 20 ' 29 .
• TIMP-1, -2 and -4 the review of the published evidence of relationship with LV remodelling has shown discordant results'. The same group found that TIMP-1 concentration correlated with LV volumes and remodelling in a cohort of 404 MI patients 23 but not in a separate cohort of 100 MI patients 30 . Such discrepancies could be explained by methodological differences between studies.
• MMP-8 _ was identified as a strong predictor of prognosis after MI, with similar predictive value to that of BNP, a peptide with powerful associat ion with outcome after M l ' 1 .
• BNP a peptide with powerful associat ion with outcome after M l ' 1 .
• MMP-8 was associated with cardiovascular outcome.
• higher serum MMP-8 was associated with the worst cardiovascular outcome in patients with atherosclerosis, possibly by involvement of MMP-8 in vascular matrix remodelling and rupture of unstable plaques 33 .
• TIMP-2 81 [71-93] 95 [82-106] 93 [84-110] 91 [83-107]
• TIMP-4 1.20 [0.97-1.62] 1.34 [1.08-1.89] 1.37 [1.08-1.83] 1.42 [1.07-1.88]
• EDV end-diastolic volume
• ESV end-systolic volume
• Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms. Stroke 2006;37:235-239.
• Thrailkill KM Moreau CS, Cockrell G, Simpson P, Goel R, North P, Fowlkes JL, Bunn RC. Physiological matrix metalloproteinase concentrations in serum during childhood and adolescence, using Luminex Multiplex technology. Clin Chem Lab Med 2005 ;43: 1392- 1399.
• Tissue plasminogen activator antigen predicts medium-term left ventricular end-systolic volume after acute myocardial infarction. J Thromb Thrombolysis 2010;29:421-428.

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