Received date: June 25, 2017; Accepted date: July 10, 2017; Published date: July 15, 2017
Citation: Guo F, Chai W, Liu M, Yu C, Liu W, et al. (2017) The Relationship between MMP-9 and Infarct Related Artery Reflow in Acute STEMI Patients. J Diabetes Metab 8:749. doi:10.4172/2155-6156.1000749
Copyright: © 2017 Guo F, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Objective: Atherosclerotic plaque rupture leading to coronary artery occlusion is the culprit event which underpins a majority of acute myocardial infarction, and Matrix metalloproteinases (MMPs) contribute to atherosclerotic plaque rupture by involving in extracellular matrix degradation and artificial balloon extrusion. Patients with ST-segment elevation myocardial infarction (STEMI) caused by plaque rupture are at high risk for slow reflow, but the relationship between reflow and MMP-9 remains unclear, especially in the real world of local plaque rupture. We investigated the association between the levels of matrix metalloproteinase-9 (MMP-9) in infarct-related arterial infusion and the risk of slow reflow in STEMI patients following percutaneous coronary intervention (PCI).
Methods: 65 eligible acute STEMI patients undergoing successful PCI were included in the current study. Blood samples were obtained from the extraction catheter placed distal to the lesion during PCI. Plasma MMP-9 levels were determined by immunoassay method.
Results: Using multiple logistic regression analysis, MMP-9 levels (OR 0.881, CI 0.791-0.981; P=0.021) was found to be a significant risk factor of slow flow together with HSCORE (OR=0.085, CI 0.014-0.506; P=0.007). ROC curve with area under the curve (0.740) and 95% confidence interval (0.607-0.872) revealed that lesion MMP-9 changes had an predictive value for no reflow(P=0.002).
Conclusions: The present study indicated that plasma MMP-9 levels in the culprit coronary artery was associated with slow flow in patients with ST-elevation MI following successful primary PCI.
Matrix metalloproteinase; Coronary artery reflow; Atherosclerotic plaque; Percutaneous coronary intervention
Atherosclerotic plaque rupture is the culprit event which underpins a majority of acute myocardial infarction (AMI). Matrix metalloproteinases (MMPs) contribute to atherosclerotic lesion progression by involving in extracellular matrix degradation [1,2]. With the progress of disease, the over-expression of these enzymes lead to thinning of the plaque fibrous cap, resulting in plaque instability, rupture and thrombosis and thus development to acute ischemic in the clinical .
Atherosclerosis of all cells in the vessel wall can secrete several metalloproteinase , but MMP-9 was secreted mainly by the inflammatory cells [5,6]. In atherosclerotic plaque of AMI, MMP-9 is more concentrated in the local of plaque which has more foam cells , early elevated of the level of MMP-9 in plasma in the patients with acute coronary syndrome has relationship with the activity of unstable plaque . Patients with STEMI caused by plaque rupture are at high risk for slow reflow, but the relationship between reflow and MMP-9 remains unclear, especially in the real world of plaque rupture. In this study we investigated the possible relationship between the elevated of the level of MMP-9 in the lesion or peripheral in plaque of acute myocardial infarction with slow blood flow after percutaneous coronary intervention (PCI).
We consecutively recruited 70 eligible STEMI patients, who received successfully primary percutaneous coronary intervention as needed in Yantai Hill Hospital. Inclusion criteria were prolonged chest pain (>30 min) no responding to nitroglycerin infusion, ST-segment elevation ≥ 0.2 mV in two or more adjacent leads on standard electrocardiogram, more than double the upper normal limits of creatine kinase (CK), CK-MB, or relative index, and successful primary PCI performed within 12 h of the onset of chest pain. Stent implantation was successfully performed in all patients.
No significant side-branch occlusion occurred during the procedure. Overall, 5 patients were excluded from the study, due to time from symptom onset ≥ 12 h (n=4) or missing of blood sample for MMP-9 measurement (n=1). Thus, 65 patients (age 62.5 ± 10.5 years, 38 males, mean 1.54 ± 0.53 stent was used per patient) were eventually included in the study. This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of Yantai Hill Hospital. Written informed consent was obtained from all participants.
All patients included in the study were given 300 mg oral aspirin, 300 mg clopidogrel in the emergency room. The patients were transferred to the cardiac catheterization laboratory and primary PCI was then performed. PCI procedures were performed through radial or femoral (n=3) approach with a 6 French guiding catheter. A bolus of 5000 IU of heparin was administered. Selective coronary angiography was performed after the intracoronary administration of nitroglycerin, at least five standardized views of the left coronary artery and three views of the right coronary artery were obtained. After conventional wire crossing, Diver CE (Innovative technologies, Italy) was used in all STEMI patients only if a total occlusion (thrombolysis in myocardial infarction [TIMI] flow 0) existed, then direct stenting implantation was performed whenever possible, preceded by balloon predilatation if necessary.
Blood sampling protocol and determinations
Blood samples were drawn from a brachial vein in all patients at the time of admission. Blood was collected in EDTA tubes or tubes without any anticoagulan and centrifuged. Plasma and serum aliquots were stored at -80 in appropriate cuvettes until assayed. C-reactive protein serum levels were measured using an immune nephelometric high-sensitivity method (DADE Behring, Milan, Italy). Serum cardiac enzymes (creatine kinase [CK] and CK-MB fraction) were measured every 4 h during the first day and every 24 h in the following 3 days using standardized methods.
To detect MMP-9 at the lesion site during PCI, Diver CE, a 6-F compatible rapid exchange clot extraction catheter, was advanced along the guidewire and positioned 10-20 mm distal to the coronary stenosis. Sets of blood samples were drawn from the lesion by extraction catheter before balloon angioplasty. All blood samples were drawn slowly in all cases to minimize factors activation. All samples were immediately put on ice and centrifuged at 3,500 rpm for 10 min at 4°C, then frozen at -80°C until the assays were performed. Levels of serum MMP-9 was determined by ELISA according to the manufacturer's instructions.
Assessment of flow
TIMI flow was assessed according to previous studies . TIMI flow grade was assessed at an angiographic core laboratory as previously defined . The CTFC is the number of cine frames required for contrast to first reach standardized distal coronary landmarks in the culprit artery and is measured with a frame counter on a cine viewer. The CTFC is a measure of time and data were converted when necessary to be based on the most common filming speed used in the United States (30 frames/s).
The CTFC was divided by 30 to calculate the transit time for dye to traverse the length of the artery to the landmark in seconds and multiplied by 1000 to calculate the time in milliseconds. This was used along with the heart rate to calculate the fraction of a cardiac cycle required for dye to traverse the artery: fraction of cardiac cycle=(CTFC/30 seconds)/(60 seconds/heart rate). Calculation of the fraction of a cardiac cycle required for dye to traverse the culprit artery normalizes the CTFC for heart rate. MBG was assessed according to van’t Hof et al. criteria . We defined angiographic no-reflow as a coronary TIMI flow grade ≤ 2 after vessel reopening or TIMI flow 3 with a final MBG ≤ 2 (modified from Gibson et al.) .
Collateral grading was done according to the Rentrop grading system that ranges from 0 (no collateral filling) to 3 (complete vessel opacification by retrograde flow) . Thrombus score was modified from Gibson et al. . Angiographic assessment was always performed by two independent angiographers who were unaware of MMP-9 results, and final agreement was 90%, with discordances being resolved by consensus.
Comparisons between groups were done by t-test or Mann-Whitney U test (as indicated) for continuous variables and by Fisher’s exact test for discrete variables. Correlation analyses were done by Pearson test or Spearman test, as indicated. Multivariable logistic regression analysis was applied to identify whether MMP-9 was independently associated with coronary no-reflow. A receiver operating characteristic (ROC) curve was used to acquire appropriate sensitivity and specificity of MMP-9 to identify the best threshold value for no flow. All statistical analyses were performed using SAS version 9.13 (SAS Institute Inc., Cary, NC, USA). Statistical significance was determined when P<0.05.
Clinical characteristics of patients
The 65 patients who underwent primary PCI on the IRA, 19 (29.3%) developed no-reflow after the procedure. Table 1 shows a comparison of the baseline characteristics of the patients, and blood samples were drawn from a brachial vein in all patients before PCI.
|Reflow (n=46)||No-reflow (n=19)||P value|
|Age, year||61.2 ± 10.1||65.7 ± 11.0||0.114|
|Male gender, %||28||10||0.54|
|BMI, kg/m2||24.7 ± 2.2||25.0 ± 1.5||0.573|
|Diabetes mellitus, n||19||11||0.222|
|Heart rate (bpm)||74.0 ± 10.8||76.6 ± 11.4||0.399|
|Systolic blood pressure (mmHg)||144.8 ± 18.8||134.1 ± 23.8||0.059|
|Diastolic blood pressure (mmHg)||87.0 ± 8.5||84.2 ± 7.9||0.228|
|CK-MB peak (ng/ml)||231.0 ± 83.0||249.7 ± 82.8||0.411|
|Fasting blood glucose (mmol/L)||9.0 ± 3.1||8.6 ± 2.3||0.628|
|Uric acid (mmol/L)||301.5 ± 63.8||303.0 ± 62.7||0.929|
|Total cholesterol (mmol/L)||5.44 ± 1.25||5.40 ± 1.14||0.892|
|HDL cholesterol (mmol/L)||1.19 ± 0.23||1.13 ± 0.23||0.2.72|
|LDL cholesterol (mmol/L)||3.07 ± 0.86||3.22 ± 0.79||0.52|
|Triglycerides (mmol/L)||1.62 ± 0.62||1.87 ± 0.74||0.164|
|MMP (pg/ml)||25.8 ± 6.9||27.8 ± 5.3||0.447|
BMI: body mass index; CK: Creatine kinase; MMP-9: matrix metalloproteinase-9
Note: * Statistically significant
Blood samples were drawn from a brachial vein in all patients before PCI
Table 1: General characteristics of patients.
Angiographic and procedural characteristics
Angiographic and procedural data are listed in Table 2. It was observed that the no-reflow group mainly consisted of patients with lesion length, reference luminal diameter, high thrombus score and lesion MMP-9 levels, which was determined from blood samples taken from lesions before balloon angioplasty. However, the presence of multivessel disease, IRA, target lesion locations and lesion types in subtotal occlusions showed no difference between the two groups (P>0.05).
|Reflow (n=46)||No-reflow (n=19)||P value|
|Time to balloon (h)||6.03 ± 1.45||6.76 ± 1.49||0.072|
|Number of diseased vessels, n, %||2.41 ± 0.78||2.58 ± 0.77||0.435|
|Culprit vessel, n||0.761|
|Initial TIMI 0 flow, n||36||17||0.289|
|Target lesion location, n||0.512|
|Lesion length (mm)||29.0 ± 13.2||35.31 ± 14.9||0.01|
|Reference luminal diameter (mm)||3.97 ± 0.46||4.30 ± 0.57||0.016|
|Thrombus score ≥ 4, n||17||14||0.007*|
|Diver use, n, %||46, 100||19, 100||1|
|Lesion MMP-9||32.6 ± 7.7||42.1 ± 7.1||0.001*|
|Number of stents||1.47 ± 0.51||1.68 ± 0.58||0.158|
Note: * Statistically significant
Blood samples were drawn from the lesion before balloon angioplasty to determine lesion MMP-9
Table 2: Angiographic and procedural findings.
The slow flow of risk factors for P<0.2 (including age, Systolic blood pressure, Triglycerides (mmol/L), Time to balloon (h), Lesion Length, Reference luminal diameter, Thrombus score, Lesion MMP-9 and Number of stents) included in the regression analysis, the observed indicator (Tables 3 and 4).
|Time to balloon||0.728||0.498||1.063||0.1|
|Systolic blood pressure||1.021||0.994||1.049||0.122|
|Reference luminal diameter||0.292||0.097||0.88||0.029*|
Note: * statistically significant
Table 3: Univariate logistic regression analysis of slow reflow.
|Time to balloon||0.777||0.435||1.387||0.394|
|Systolic blood pressure||1.028||0.99||1.068||0.152|
|Reference luminal diameter||0.167||0.031||0.89||0.036*|
Note: * statistically significant
Table 4: Multivariable predictors of angiographic slow reflow.
ROC curve analysis
The receiver operating characteristic curve revealed that a lesion MMP-9 change (ROC area: 0.740, 95% CI: 0.607-0.872, P=0.002) had predictive value for no reflow phenomenon (Figure 1).
We found that the lesion site, rather than peripheral parts of the MMP-9 levels increased, affecting the coronary re-flow after stenting. Accurate diagnosis in patients with coronary heart disease, early risk stratification and effective treatment can significantly reduce the incidence of cardiovascular complications and mortality [13,14]. Recently, elective or primary PCI can significantly benefit to the patient with acute coronary syndrome [15-17]. Although the mortality of PCI perioperative is less than 3%, and gradually reduced, but allcause mortality in patients with coronary heart disease is still high [18,19]. The emergence of drug-eluting stents significantly reduced the risk of stenosis of coronary artery and the ratio of the essential for revascularization of coronary heart disease, but no-reflow or slow reflow of opening the infracted related artery in the post-operative patients weakened the benefit of PCI [20,21].
We found that the level of MMP-9 in the lesion was higher than that in the peripheral coronary artery after PCI, which was closely related to TIMI blood flow after PCI, suggesting that activation of local inflammatory factors may be involved in the activity or slow reflow mechanism. PCI can lead to changes in the level of peripheral MMP-9, suggesting that the intervention itself may also stimulate the body to produce inflammatory response; and the level of lesion MMP-9, although subtle changes, we still believe that preoperative local inflammatory cytokines may be involved in postoperative slow reflow occurs.
Atherosclerosis is the basic process of coronary heart disease, inflammation plays an important role in this process. The process of atherosclerosis including monocytes and T-lymphocyte migration from the blood stream to the vessel wall, and lipoproteins penetrate and gather in the vessel wall by the support of adhesion molecules and growth regulating factors, and subsequently modified of lipoproteins stimulate leukocyte recruitment, bring about inflammation .
Recent studies have found that fragmentation can be induced inflammation associated with the damage by leukocyte recruited in the matrix tissue . The non-specific collagen and elastic peptide fragments can also induce neutrophils, monocytes and fibroblasts to chemotactic response. Glycosaminogly can fragments can cause tissue damage, may be involved in regulating inflammation, hyaluronic acid fragments induce the expression of multiple inflammatory genes by macrophages and endothelial cells , suggest that it may has an important role in the process of regulate inflammation, and hyaluronic acid fragments removed from the injury tissue is required of chronic inflammation disappeared.
This study has also found that lesion MMP-9 was significantly higher than the outer periphery, suggesting their involvement in plaque rupture and acute occlusion. Some scholars have found that MMP-9 levels in vessel is higher than that in the coronary sinus and femoral arteries in the patients with acute myocardial infarction , so we believed that this increase was caused by plaque rupture rather than myocardial infarction.
Although this study was not able to measure the size of the plaque, we found that, after removal of the system level, MMP-9 also involved in the intervention slow reflow, suggesting that fragmentation of the plaque is still persistent inflammatory activity. In addition, IMMP-9 has been reported to have procoagulant activity , indicating that localized inflammatory response may also be a direct result of slow reflow.
In summary, it showed that local but not systemic MMP-9 was higher in patients with no reflow/slow reflow after PCI than in those with successful reperfusion. The results suggest that MMP-9 may be both involved and a prognostic marker of no reflow phenomenon.
All of the authors declare that they have no conflicts of interest regarding this paper.