High serum matrix metalloproteinase-9 level predict increased risk of in-hospital cardiac events in patients with type 2 diabetes and ST segment elevation myocardial infarction

doi:10.1016/j.atherosclerosis.2006.11.012

Atherosclerosis

Volume 196, Issue 1, January 2008, Pages 365-371

https://doi.org/10.1016/j.atherosclerosis.2006.11.012 Get rights and content

Abstract

Introduction

The purpose of this study was to compare serum matrix metalloproteinase (MMP)-9 levels in a population of type 2 diabetic versus non-diabetic patients hospitalized with ST-segment elevation myocardial infarction (STEMI) and to examine the relationship between serum MMP-9 levels and the incidence of in-hospital cardiac events, including death and cardiogenic shock.

Methods

We recruited 120 patients with STEMI, of whom 48 were type 2 diabetic and 72 non-diabetic. Serum MMP-9 levels were measured on admission, using a commercially available ELISA. The primary study endpoint was cardiac death in-hospital and cardiogenic shock.

Results

Mean serum MMP-9 levels were significantly higher in type 2 diabetic patients compared to non-diabetic patients (240 ± 52 ng/mL versus 185 ± 47 ng/mL; P < 0.0001). In multivariable analysis, type 2 diabetes was an independent factor for mortality [OR: 1.75 (1.40–2.30); P = 0.005] and cardiogenic shock [OR: 1.55 (1.20–1.70); P = 0.03] when the variable MMP-9 level was not introduced into the model, but it was less significantly associated with mortality [OR: 1.60 (1.40–2.10); P = 0.01] and no longer associated with cardiogenic shock when MMP-9 was in the model.

Conclusion

After STEMI, type 2 diabetes is independently associated with high serum MMP-9 levels. This elevated MMP-9 is strongly associated with the increased incidence of in-hospital mortality and cardiogenic shock observed in type 2 diabetes. Our findings clearly indicate that serum MMP-9 provides a highly valuable prognostic information on in-hospital outcome after STEMI, in particular in type 2 diabetic patients.

Introduction

Matrix metalloproteinases (MMPs) are part of an endogenous family of enzymes responsible for extracellular collagen degradation and remodelling [1]. Among the known MMPs, MMP-2 is distributed throughout the cardiac myocytes and fibroblasts, whereas MMP-9 is mainly expressed in infiltrating inflammatory cells such as neutrophils and macrophages [2], [3]. Results of previous studies have shown that serum MMP-9 levels are higher in patients with acute myocardial infarction (AMI) [4], [5]. Similarly, values of MMP-9 have shown to provide valuable prognostic information on short- and long-term mortality in patients with AMI [6].

Patients with diabetes mellitus have an increased risk of cardiovascular morbidity and mortality [7]. After AMI, diabetic patients have a significantly higher risk of heart failure and cardiogenic shock and therefore a worse outcome, in both short- and long-term [8]. Arteriosclerotic lesions in patients with diabetes mellitus are more unstable than those of nondiabetic subjects [9]. So far, no studies have yet been conducted concerning serum MMP–9 levels after AMI and their relationship with short-term outcomes in diabetic patients. Thus, the aim of our present study was to compare serum MMP-9 levels in a population of type 2 diabetic versus non-diabetic patients hospitalized for ST segment elevation myocardial infarction (STEMI) and to examine the relationship between serum MMP-9 levels and the incidence of in-hospital cardiac events, including death and cardiogenic shock.

Section snippets

Patients

During a period of 18 months, we enrolled 120 consecutive patients with STEMI who were admitted to our institution and fulfilled all of the following criteria: (1) typical, prolonged (>30 min) chest pain at rest; (2) ST-segment elevation ≥0.2 mV at the J point in two or more contiguous precordial leads or ≥0.1 in two or more adjacent limb leads on the standard 12-lead electrocardiogram; (3) presentation in the first 6 h since the onset of chest pain. Diagnosis of AMI was confirmed by increased

Statistical analysis

Results for normality distributed continuous variables are expressed as the mean value ± standard deviation. Analysis of normality of the continuous variables was performed with the Kolmogorov–Smirnov test. Comparisons of continuous variables between type 2 diabetic and nondiabetic patients were performed either by unpaired Student's t-test. Analysis of covariance was used to compare serum MMP-9 mean values between type 2 diabetic and non-diabetic patients after adjustment for potential

Results

Baseline clinical characteristics result in the 120 patients included in the study, are shown in Table 1. They were treated in our hospital with percutaneous coronary intervention. The procedure was performed successfully with re-establishment of TIMI 3 flow in the artery responsible for the infarction. Thus, 120 patients fulfilled the inclusion criteria, of whom 48 of them (40%) were type 2 diabetic, 45 of them (37.5%) had previously known type 2 diabetes, and 3 of them (2.5%) had newly

Discussion

We have shown in the present study, from a cohort of patients hospitalized with STEMI, that type 2 diabetic patients have significantly higher serum MMP-9 levels and that elevated MMP-9 is strongly associated to the increased incidence of in-hospital mortality and cardiogenic shock.

The best of our knowledge, MMP-9 has never been studied in population of type 2 diabetic patients after STEMI. In the present study, we found a significant increase in serum MMP-9 in type 2 diabetic patients compared

Acknowledgement

The authors wish to express their gratitude to Ines Abreu-Afonso for the liguistic aids preparing the manuscript.

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Subjects included in the study were 184 patients with AMI and 180 controls. Genotyping of MMP-9-1562C > T polymorphism was carried out by PCR-based restriction digestion method. Serum MMP-9 was measured using ELIZA assay. All patients were followed for AMI complications during their hospitalization and 6 months later on.
MMP-9-1562 T allele was more frequent in patients than in controls (OR = 1.65, 95%CI 1.09–2.15, P = 0.011). the frequency of CT + TT genotypes were higher in patients with morbidity (OR = 2.85, 95%CI 1.29–6.29, P = 0.008) and with mortality (OR = 3.21, 95%CI 1.28–8.02, P = 0.012) than in those without MI complications. Serum MMP-9 levels were significantly elevated in AMI as compared to controls and more associated with TT genotype. The impairment of LV function (ΔEF, ΔLAD, ΔE/A) was more observed in the TT genotype compared with CC genotype.
Our data suggest that MMP-9 (TT genotype) and its serum level are associated with the risk of suffering AMI in Egyptians. In addition, MMP-9 polymorphism and its level might be useful clinical biomarkers for predicting the outcome of AMI.
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Several biomarkers reflecting inflammatory or proteolytic activity have been known to represent plaque vulnerability. Moreover, a recent study confirmed that contrast-enhanced ultrasound (CEUS) can visualize intraplaque neovascularization (IPN) and demonstrate plaque vulnerability. In this study, we tried to demonstrate that IPN detected by CEUS was correlated with several well-known biomarkers and clinical outcome in patients with coronary artery disease (CAD).
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Among consecutive 89 patients fulfilled the inclusion criteria, 30 patients without IPN (group 1) and 59 patients with IPN (group 2) were analyzed. There were no significant difference in baseline characteristics except for mean age (62.9 ± 10.1 yrs versus 68.4 ± 9.6 yrs, p = 0.015). On multivariate analysis, only MMP-9 (p = 0.021, 95% CI 1.002–1.027) showed a significant association with IPN. But patients with IPN showed only trend for a history of cardiovascular disease (CVD) (44% versus 30%, p = 0.19) and one-year cardiovascular events (CVE) (6.8% versus 3.3%, p = 0.50) compared to group 1. Maximum plaque thickness (p = 0.04, 95% CI 1.230–6.322) showed a significant correlation with the clinical outcome including CVD or CVE.
MMP-9 correlated with IPN on CEUS. For clinical implication, however, large prospective studies are needed.
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However, it remains to be established what determines the decrease of circulating levels of TRAIL in CAD patients [1–3]. In this respect, following AMI, many proteolytic enzymes are released, including matrix metalloproteinases (MMPs) [9–12]. Several studies have demonstrated correlations between MMP2 and/or MMP9 levels, the severity of coronary lesions and the survival rate following AMI in both animal and human studies [9–12].
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In AMI patients the serum levels of TRAIL showed a significant inverse correlation with the MMP2/TIMP2 ratio. In vitro MMP2 induced the cleavage of recombinant TRAIL and inactivated its ability of inducing apoptosis. Moreover, exposure of endothelial cells to TNF-α increased the MMP2/TIMP2 ratio in the culture supernatant.
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Genetic polymorphism c.1562C>T of the MMP-9 is associated with macroangiopathy in type 2 diabetes mellitus
2010, Biochemical and Biophysical Research Communications
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Type 2 diabetes mellitus (T2DM) is strongly associated with elevated mortality and morbidity from atherosclerotic vascular disease manifesting as coronary heart disease, cerebrovascular disease, and peripheral vascular disease [1,2].
To determine whether the matrix metalloproteinase-9 (MMP-9) c.1562C>T polymorphism has an effect on the plasma MMP-9 levels and the macroangiopathic complications in type 2 diabetes mellitus (T2DM).
The genotypes and allelic frequencies of the MMP-9 c.1562C>T were examined with polymerase chain reaction and restriction fragment length polymorphism in 320 patients with T2DM and 160 unrelated healthy subjects. The plasma concentrations of MMP-9 were determined in all subjects.
The mean plasma concentrations of MMP-9 of patients with T2DM were significantly higher than that of controls and the plasma levels of MMP-9 were higher in diabetic patients with macroangiopathy than in patients without macroangiopathy (P < 0.05). The genotype (CC, CT, and TT) distribution of c.1562C>T polymorphism of the MMP-9 gene was 60.0%, 31.3%, and 8.8% in diabetic patients with macroangiopathy, 76.3%, 21.3%, and 2.5% in patients without macroangiopathy, and 77.5%, 21.3%, 1.3% in controls, respectively, a significant difference was found between diabetic patients with and without macroangiopathy (P < 0.05). The frequency of the allele T was higher in patients with macroangiopathy than in patients without macroangiopathy (24.4% vs 13.1%; P < 0.05). Moreover, the plasma MMP-9 levels were markedly higher in patients with TT genotype than those with CC or CT genotype in patients with macroangiopathy (P < 0.05).
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High serum matrix metalloproteinase-9 level predict increased risk of in-hospital cardiac events in patients with type 2 diabetes and ST segment elevation myocardial infarction

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Section snippets

Patients

Statistical analysis

Results

Discussion

Acknowledgement

J Am Coll Cardiol

Am Heart J

Am J Cardiol

J Am Coll Cardiol

Lancet

Clin Chim Acta

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

Am J Med

Lancet

Atherosclerosis

Atherosclerosis

Emerging role of metalloproteinases in the pathophysiology of cardiac diseases

Eur J Clin Invest

Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart

Circulation

Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion

Circulation