Plasma Matrix Metalloproteinase-9 Research Articles

Significance of phosphorylated epidermal growth factor receptor, matrix metalloproteinases, and E-cadherin in oral cancer

Objective: The most challenging problem in oral cancer is late monitoring and disease spread (metastasis). The study aimed to simultaneously evaluate phosphorylated epidermal growth factor receptor (pEGFR), truncated E-cadherin protein, and matrix metalloproteinases (MMPs) in patients with oral cancer. Methodology: pEGFR and truncated E-cadherin protein were measured from 25 paired tissues by ELISA and Western blot, respectively. Plasma MMPs levels were studied by gelatin zymography from 100 controls and 100 patients with oral cancer. The results revealed significant higher expression of pEGFR and truncated E-cadherin protein in malignant oral cancer tissues as compared to adjacent normal. Plasma MMPs were significantly elevated in patients with oral cancer as compared to the controls. An increase in the levels of pEGFR and truncated E-cadherin protein was observed in advanced and metastatic disease as compared to early and nonmetastatic disease. The levels of MMPs were increased in advanced disease as compared to early disease. Kaplan–Meier's survival analysis indicated that elevated expression of pEGFR, truncated E-cadherin protein, active MMP-2, pro MMP-9, total MMP-2, and total MMP-9 has reduced the overall survival. Conclusion: Simultaneous elevation of pEGFR, truncated E-cadherin protein, and MMPs indicated its role in oral carcinogenesis. Further combination therapies targeting these markers might help in combating oral cancer.

Association of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels with diabetic foot ulcer in Egyptians with type 2 diabetes mellitus

Background The imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may play an important role in impaired healing of diabetic foot ulcer. Aim of the work This study was designed to investigate the association of MMP-9 and TIMP-1 levels in diabetic foot ulcer among Egyptian patients with type 2 diabetes mellitus attending the outpatient clinic of National institute of diabetes and endocrinology. Patients and methods This study was conducted on a total number of 90 participants comprising three groups: group I included 35 type 2 diabetic patients without foot ulcer. Group II included 35 type 2 diabetic patients having various degrees of foot ulcer complications. Group III included 20 apparently healthy participants (as controls). In addition to the routine clinical and laboratory investigations, MMP-9 and TIMP-1 were measured. All patients were randomly taken from the outpatient clinic of National institute of diabetes and endocrinology. Results The study results showed that the higher levels of plasma MMP-9 and the lower levels of TIMP-1 were associated with patients with diabetic foot ulcer. Conclusion The measurement of plasma MMP-9 and TIMP-1 in type 2 diabetic patients may help us to know the patients at most risk to develop diabetic foot ulcer.

Phase 1b Study of the Safety, Pharmacokinetics, and Disease-related Outcomes of the Matrix Metalloproteinase-9 Inhibitor Andecaliximab in Patients With Rheumatoid Arthritis

PurposeAndecaliximab (GS-5745) is a highly selective monoclonal antibody against matrix metalloproteinase-9 (MMP9), a proteolytic enzyme implicated in the pathogenesis of rheumatoid arthritis (RA). This study assessed the safety and pharmacokinetic (PK) parameters of andecaliximab in patients with RA and evaluated the effects of andecaliximab treatment on exploratory disease biomarkers. MethodsIn this double-blind, Phase 1b trial, patients with active RA were randomized (4:1) to receive 400-mg andecaliximab or placebo every 2 weeks for a total of 3 intravenous infusions. The primary and secondary end points were safety and the PK parameters of andecaliximab, respectively. Data were summarized by using descriptive statistics. FindingsA total of 18 patients were randomized; 15 received andecaliximab (participants with confirmed RA diagnosis without current administration of a biologic DMARD a biologic DMARD (disease-modifying antirheumatic drug), aged 18 to 70 years old, weighing >45 to <120 kg). No deaths, serious adverse events, or study discontinuations occurred. All reported adverse events were grade 1 or grade 2 in severity. Mean plasma andecaliximab exposure was 587 d · µg/mL and 878 d · µg/mL at days 1 and 29, respectively, suggesting moderate accumulation. The median terminal t1/2 was 5.65 days; mean volume of distribution at steady state was 4560 mL. Mean MMP9 coverage (the percentage of total plasma MMP9 bound by therapeutic antibody) was maintained at ~80% after the first administration of andecaliximab. ImplicationsAndecaliximab administered as 3 infusions over 29 days was generally safe and well tolerated in patients with RA. The majority of total plasma MMP9 was bound by andecaliximab after the first administration. Clinical studies of increased treatment duration in larger patient cohorts are warranted. ClinicalTrials.gov identifier: NCT02176876. Registered on 25 June 2014.

The platelet phenotype in patients with ST-segment elevation myocardial infarction is different from non–ST-segment elevation myocardial infarction

It is assumed that platelets in diseased conditions share similar properties to platelets in healthy conditions, although this has never been examined in detail for myocardial infarction (MI). We examined platelets from patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) compared with platelets from healthy volunteers to evaluate for differences in platelet phenotype and function. Platelet activation was examined and postreceptor signal transduction pathways were assessed. Platelet-derived plasma biomarkers were evaluated by receiver operator characteristic curve analysis. Maximum platelet activation through the thromboxane receptor was greater in STEMI than in NSTEMI but less through protease-activated receptor 1. Extracellular-signal related-kinase 5 activation, which can activate platelets, was increased in platelets from subjects with STEMI and especially in platelets from patients with NSTEMI. Matrix metalloproteinase 9 (MMP9) protein content and enzymatic activity were several-fold greater in platelets with MI than in control. Mean plasma MMP9 concentration in patients with MI distinguished between STEMI and NSTEMI (area under curve [AUC] 75% [confidence interval (CI) 60-91], P = 0.006) which was superior to troponin T (AUC 66% [CI 48-85, P = 0.08), predicting STEMI with 80% sensitivity (95% CI 56-94), 90% specificity (CI 68-99), 70% AUC (CI 54-86, P < 0.0001), and NSTEMI with 50% sensitivity (CI 27-70), 90% specificity (CI 68-99), 70% AUC (CI 54-86, P = 0.03). Platelets from patients with STEMI and NSTEMI show differences in platelet surface receptor activation and postreceptor signal transduction, suggesting the healthy platelet phenotype in which antiplatelet agents are often evaluated in preclinical studies is different from platelets in patients with MI.

Usefulness of plasma matrix metalloproteinase-9 levels in prediction of in-hospital mortality in patients who received emergent percutaneous coronary artery intervention following myocardial infarction.

The aim of the present study was to investigate the predictive value of the plasma matrix metalloproteinase-9 (MMP-9) level at admission for in-hospital mortality in patients who received emergency percutaneous coronary intervention (PCI) following AMI. A single blood sample was collected at admission from 155 consecutive AMI patients who underwent emergent PCI. The plasma levels of MMP-9 value (528.9±191.6 ng/ml) were significantly higher in the patients who died (n=24) than in the survivors (385.4±236.0 ng/ml) during 14 days of hospitalization (P=0.005). The age, left ventricle wall motion score index (WMIS), Global Registry of Acute Coronary Events (GRACE) score and B-type natriuretic peptide (BNP) levels and GENSINI score at admission were significantly different between the patients who died and those who survived (P<0.001, P=0.004, P<0.001 and P<0.001, respectively). Cut-off concentrations for prediction of death was identified from receiver operator characteristic (ROC) curves. Using the cut-off value (MMP-9 level 398.2 ng/ml) to stratify the patients into two groups, the group with higher MMP-9 levels had a greater rate of in-hospital mortality than the lower level group (P<0.001). With the exception of the GRACE score, among all biomarkers measured, in stepwise multiple logistic regressions, only the MMP-9 level predicted the risk of in-hospital death after adjustment for all other risk factors (odds ratio 5.02, 95% CI 1.44 to 17.55). In conclusion, a higher MMP-9 level is an independent predictor of in-hospital death in AMI patients who received emergency PCI.

Ferulaldehyde Improves the Effect of Methotrexate in Experimental Arthritis.

Methotrexate (MTX) is still the gold standard for treatment of rheumatoid arthritis (RA). The therapeutic efficacy of low-dose of MTX can be increased by its combination with a natural substance, ferulaldehyde (FRA). The aim of this study was to evaluate the effect FRA and MTX administered alone or in combination in adjuvant arthritis. The disease was induced to Lewis male rats by intradermal injection, which contains a suspension of heat-inactivated Mycobacterium butyricum in incomplete Freund’s adjuvant. The experiment of 28 days included: healthy animals, arthritic animals, arthritic animals with administration of FRA at the oral daily dose of 15 mg/kg, arthritic animals with administration of MTX at the oral dose of 0.3 mg/kg twice a week, and arthritic animals administered with FRA and MTX. FRA in monotherapy decreased significantly only the level of interleukin-1β (IL-1β) and matrix metalloproteinase-9 in plasma. Combination of FRA and low-dose MTX was more effective than MTX alone when comparing body weight, hind paw volume, arthritic score, plasmatic levels of IL-1β, activity of γ-glutamyl transferase, and relative mRNA expression of IL-1β in the spleen. Therefore, the combination treatment was the most effective. The obtained results are interesting for future possible innovative therapy of patients with RA.

Effect of acute and chronic exercise on plasma matrix metalloproteinase and total antioxidant levels.

The relationship between acute and chronic exercise and expression of matrix metalloproteinases (MMPs) in muscles is unknown. There happen some alterations in the oxidant-antioxidant balance due to exercise. This study aimed to investigate the levels of MMP-1, tissue inhibitors of metalloproteinases (TIMP-1), hyaluronic acid (HA), total antioxidant status (TAS), and total oxidant status (TOS) following acute and chronic exercising in rats. Twenty-six Wistar Albino male rats were divided in to three groups: control, acute, and chronic groups. In acute group, treadmill exercise was performed 3 days/wk, 10 min/day for 1 week. In chronic group, exercise performed 7 days/wk, 60 min/day for 4 weeks. At the end of the experiment, plasma MMP-1, TIMP-1, HA, TAS, and TOS levels were measured. In current study, the MMP-1, TIMP-1, HA, and TOS levels not observed statistically significant difference among all groups, but in chronic group, there was a significantly difference (P<0.05) between the control and experimental groups in terms of TAS and oxidative stress index (OSI) levels. TAS, TOS, and OSI levels were significantly different between control and chronic exercise group (P<0.01, P<0.05, and P<0.01, respectively). According to these results, we can say acute and chronic exercise does not effect on plasma MMP-1, TIMP-1, and HA levels.

Plasma Glial Fibrillary Acidic Protein, Copeptin, and Matrix Metalloproteinase-9 Concentrations among West African Stroke Subjects Compared with Stroke-Free Controls

Measurement of plasma molecular markers among stroke patients has been proposed as an avenue for improving the accuracy of stroke diagnosis. There is paucity of data on the potential role of these markers in resource-limited settings, where the burden of stroke is greatest. To assess the potential diagnostic and prognostic performance of 3 proposed biomarkers for stroke in a resource-constrained setting. Consecutive stroke subjects presenting at a tertiary medical center in Kumasi, Ghana, with radiologically confirmed diagnosis and etiologic subtype information available were recruited along with age- and gender-matched controls in a 2:1 ratio. Plasma concentrations of glial fibrillary acidic protein (GFAP), copeptin, and matrix metalloproteinase-9 (MMP-9) among stroke patients and stroke-free controls were measured in duplicates using enzyme linked immunoassays. Diagnostic and prognostic correlates were assessed using area-under-the-curve (AUC) measures of receiver operator curves and logistic regression analysis, respectively. There were 156 stroke subjects with a mean age of 61.3 years of which 47.4% were females and 74 age- and gender-matched stroke-free controls. Median (interquartile range) time from symptom onset to hospital presentation for care was 7 days (5-11). Diagnostic accuracy of a single measurement of the 3 biomarkers for stroke using AUC (95% confidence interval) plots were as follows: .84 (.77-0.91), P < .0001, for GFAP; .85 (.79-0.92), P < .0001, for copeptin; and .65 (.56-0.73), P = .0003, for MMP-9. None of the biomarkers was associated with stroke severity or mortality. Plasma concentrations of GFAP and copeptin demonstrated stronger associations with stroke occurrence in this West African cohort compared with controls.

Urinary phthalate metabolite concentrations in relation to levels of circulating matrix metalloproteinases in pregnant women

Phthalate exposure has been shown to be associated with adverse pregnancy outcomes. However, human studies informing relevant mechanistic pathways are lacking. Experimental studies have reported that matrix metalloproteinases (MMPs), which are responsible for extracellular protein degradation, may be upregulated in response to phthalate exposure. In this exploratory study we measured urinary phthalate metabolite concentrations, plasma MMP levels, and relevant covariates among 134 pregnant women. There were statistically significant or suggestive positive relationships between several phthalates, particularly between metabolites of di-(2-ethylhexyl) phthalate, with MMP-1 and MMP-9 levels. Further research is needed to confirm these results and how they may inform the mechanisms involved between phthalate exposure and adverse pregnancy outcomes.

ID:2028 PLASMA LEVELS OF MMPs AND TIMP-1 IN BLADDER CANCER PATIENTS

Background: Urinary bladder cancer (UBC) is a common disease worldwide with high mortality rate [1]. UBC is the ninth most frequently diagnosed cancer worldwide, with highest incidence rates observed in developed countries. About 75% of bladder cancer patients are men [2]. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are diagnostic tools in oncology, liver diseases, and rheumatoid arthritis, which may prove to be a valuable prognostic tool in clinical setting [3]. The aim of the present study was to assess the prognostic power of plasma MMPs and TIMP-1 in patients with UBC of different stages.&#x0D; &#x0D; Methods: This study enrolled 29 patients with UBC (27 males, 2 females), aged 52-76 years. Preoperative study for all patients included blood test, blood chemistry, urine analysis, immunogram, computer tomography, tumor biopsy. The spread of cancer was characterized based on TNM clinical classification 7th review (2009). Stage distribution of patients were as following: Stage I – 6 patients; Stage II - 5; Stage III - 7; Stage IV - 8 patients). The control group consisted of 15 healthy individuals (8 females and 22 males; aged 30-35 years). Plasma levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and TIMP-1 were determined by ELISA before the curative procedure and correlated afterwards with clinical parameters of the patient. Data analysis was conducted using Microsoft Excel 2010.&#x0D; &#x0D; Results: Plasma levels of MMP-9 were significantly higher (by 1.5-2.0 times) in all patients with UBC compared to controls. Plasma level of MMP-8 in Stage III UBC patients was 1.2 times higher than in control group. The levels of MMP-1 and MMP-2 were increased compared to controls, and their elevation correlated with increase in cancer stage. Plasma level of MMP-3 in patients with bladder cancer Stage I, II and III were higher compared to controls by 1.3, 1.2 and 1.2 times respectively. High plasma levels of TIMP-1 were determined in patients with Stages III and IV, which raises question as to its role and function in advanced stage disease, as it may have a protective role in the mechanism of invasion by inhibiting extracellular matrix degradation.&#x0D; Conclusion: In patients with urinary bladder cancer the plasma levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and TIMP-1 are elevated. We demonstrated that elevation pattern of MMP-1, MMP-2 and MMP-9 could serve as potential plasma marker for monitoring the cancer progression.

C-1562T polymorphism of matrix metalloproteinase-9 (MMP-9) gene associated with elevated level of plasma MMP-9 concentration in patient with acute myocardial infarction (AMI) in Denpasar-Bali

C-1562T polymorphism of matrix metalloproteinase-9 (MMP-9) gene associated with elevated level of plasma MMP-9 concentration in patient with acute myocardial infarction (AMI) in Denpasar-Bali

Relationship of biomarkers of extracellular matrix with myocardial function in Type 2 diabetes mellitus.

The study evaluated the relationship of extracellular matrix and renin angiotensin system with myocardial dysfunction in Type 2 diabetes mellitus. All patients underwent resting and exercise echocardiography, including conventional parameters, E/E' ratio, global longitudinal strain and diastolic function reserve index. Plasma matrix metalloproteinase-1, TIMP-1, amino-terminal propeptide of type I and type III procollagen and renin angiotensin system activity were measured. As patients with diastolic dysfunction had a higher plasma level of TIMP-1 and propeptide of type III procollagen than those with no diastolic dysfunction. After multivariate adjustment, TIMP-1 associated with E/E' (both at rest and stress) and diastolic function reserve index. TIMP-1 is independently associated with myocardial diastolic dysfunction in patients with Type 2 diabetes mellitus.

A novel workflow combining plaque imaging, plaque and plasma proteomics identifies biomarkers of human coronary atherosclerotic plaque disruption

BackgroundAtherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation.MethodsWe developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption.ResultsWe compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid-rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non-lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC–MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption.ConclusionThis novel approach for biomarker discovery in human coronary artery plaque disruption can identify new biomarkers related to human coronary artery plaque composition and disruption.

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation.

Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury. Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy. Hyperglycemic rats had an increased infarct volume with an increased blood-brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments. We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion-induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood-brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a possible target for reduction of the deleterious impact of hyperglycemia in acute ischemic stroke.

Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke

We sought to investigate the relationship between blood–brain barrier (BBB) permeability and microstructural white matter integrity, and their potential impact on long-term functional outcomes in patients with acute ischemic stroke (AIS). We studied 184 AIS subjects with perfusion-weighted MRI (PWI) performed <9 h from last known well time. White matter hyperintensity (WMH), acute infarct, and PWI-derived mean transit time lesion volumes were calculated. Mean BBB leakage rates (K2 coefficient) and mean diffusivity values were measured in contralesional normal-appearing white matter (NAWM). Plasma matrix metalloproteinase-2 (MMP-2) levels were studied at baseline and 48 h. Admission stroke severity was evaluated using the NIH Stroke Scale (NIHSS). Modified Rankin Scale (mRS) was obtained at 90-days post-stroke. We found that higher mean K2 and diffusivity values correlated with age, elevated baseline MMP-2 levels, greater NIHSS and worse 90-day mRS (all p < 0.05). In multivariable analysis, WMH volume was associated with mean K2 (p = 0.0007) and diffusivity (p = 0.006) values in contralesional NAWM. In summary, WMH severity measured on brain MRI of AIS patients is associated with metrics of increased BBB permeability and abnormal white matter microstructural integrity. In future studies, these MRI markers of diffuse cerebral microvascular dysfunction may improve prediction of cerebral tissue infarction and functional post-stroke outcomes.

Matrix Degradation in Human Immunodeficiency Virus Type 1–Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study

Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation. MMP activity differed between HIV-1-infected and -uninfected TB patients and corresponded with specific TB clinical phenotypes. HIV-1-infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation, but increased plasma PIIINP, compared to HIV-1-uninfected TB patients. Elevated extrapulmonary extracellular matrix turnover was associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil derived and M. tuberculosis-antigen driven. Mycobacterium tuberculosis-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in vitro. MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrix turnover in HIV-1-infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibition is a potential host-directed therapy strategy for prevention and treatment of TB-IRIS.

RECAST (Remote Ischemic Conditioning After Stroke Trial): A Pilot Randomized Placebo Controlled Phase II Trial in Acute Ischemic Stroke.

Repeated episodes of limb ischemia and reperfusion (remote ischemic conditioning [RIC]) may improve outcome after acute stroke. We performed a pilot blinded placebo-controlled trial in patients with acute ischemic stroke, randomized 1:1 to receive 4 cycles of RIC within 24 hours of ictus. The primary outcome was tolerability and feasibility. Secondary outcomes included safety, clinical efficacy (day 90), putative biomarkers (pre- and post-intervention, day 4), and exploratory hemodynamic measures. Twenty-six patients (13 RIC and 13 sham) were recruited 15.8 hours (SD 6.2) post-onset, age 76.2 years (SD 10.5), blood pressure 159/83 mm Hg (SD 25/11), and National Institutes of Health Stroke Scale (NIHSS) score 5 (interquartile range, 3.75-9.25). RIC was well tolerated with 49 out of 52 cycles completed in full. Three patients experienced vascular events in the sham group: 2 ischemic strokes and 2 myocardial infarcts versus none in the RIC group (P=0.076, log-rank test). Compared with sham, there was a significant decrease in day 90 NIHSS score in the RIC group, median NIHSS score 1 (interquartile range, 0.5-5) versus 3 (interquartile range, 2-9.5; P=0.04); RIC augmented plasma HSP27 (heat shock protein 27; P<0.05, repeated 2-way ANOVA) and phosphorylated HSP27 (P<0.001) but not plasma S100-β, matrix metalloproteinase-9, endocannabinoids, or arterial compliance. RIC after acute stroke is well tolerated and appears safe and feasible. RIC may improve neurological outcome, and protective mechanisms may be mediated through HSP27. A larger trial is warranted. URL: http://www.isrctn.com. Unique identifier: ISRCTN86672015.

Plasma matrix metalloproteinases are associated with incident cardiovascular disease and all-cause mortality in patients with type 1 diabetes: a 12-year follow-up study

BackgroundAltered regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular events and all-cause mortality in type 1 diabetic patients.MethodsWe prospectively followed 337 type 1 diabetic patients [mean age 41.4 years (9.6), 39% female], 170 with and 167 without diabetic nephropathy, with median follow-up of 12.3 years. Survival analyses were applied to investigate differences in plasma MMP-1, -2, -3, -9, -10, and TIMP-1-levels in patients with and without a cardiovascular event and in those who died vs survivors. All analyses were adjusted for age, sex, duration of diabetes, HbA1c, nephropathy and for other conventional cardiovascular risk factors.ResultsAfter adjustment for potential confounders, higher MMP-2 plasma levels were significantly associated with higher incidence of cardiovascular events [HR 1.49 (95% CI 1.11; 1.99)], and higher plasma levels of MMP-1 [1.38 (1.07; 1.78)], MMP-2 [1.60 (1.19; 2.15)] and MMP-3 [1.39 (1.05; 1.85)] were associated with all-cause mortality. All associations were independent of low-grade inflammation and endothelial dysfunction as estimated by plasma markers. Associations between MMP-2 and cardiovascular events and between MMP-3 and mortality were attenuated after further adjustment for eGFR and changes in eGFR.ConclusionsHigher levels of MMP-2 are associated with CVD and higher MMP-1, -2 and -3 with all-cause mortality. In addition, associations between MMP-2 and CVD, and MMP-3 and mortality were attenuated after adjustment for eGFR while both MMPs were associated with eGFR decline, indicating a possible mediating role of eGFR.

Impact of matrix metalloproteinase 9 rs3918242 genetic variant on lipid-lowering efficacy of simvastatin therapy in Chinese patients with coronary heart disease

BackgroundGenetic variation of matrix metalloproteinase 9 (MMP-9) gene polymorphism has been suggested to modulate coronary heart diseases (CHD), yet the underlying mechanisms are not well understood.MethodsWe investigated the association of MMP9 rs3918242 single nucleotide polymorphism with inflammation and lipid-lowering efficacy after simvastatin treatment in Chinese patients with CHD. Fasting serum lipid profile and plasma inflammatory mediators were determined at baseline in 264 patients with CHD and 186 healthy control subjects, and after HMG-CoA reductase inhibitor simvastatin treatment (20 mg/day) for 12 weeks in CHD subjects.ResultsWe found that plasma MMP-9, TNF-α and IL-10 levels were significantly elevated in patients with CHD compared to control subjects before treatment. The plasma MMP9 in CHD patients carrying rs3918242 CC, CT and TT genotypes were comparable. Interestingly, CHD patients carrying TT genotype had significantly higher level of triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) than those carrying CC genotype (P <0.05). Simvastatin treatment significantly reduced LDL-C, TG and plasma inflammatory mediator levels in CHD patients. The reduction of LDL-C upon simvastatin therapy was significantly greater in patients carrying TT genotype than those carrying CC genotype (P <0.05).ConclusionsMMP9 rs3918242 TT genotype is associated with elevated serum TG and LDL-C, and enhanced LDL-C-lowering response upon simvastatin treatment in Chinese patients with CHD.Clinical trial registrationThis study was retrospectively registered at Chinese Clinical Trial Registry (Registration number: ChiCTR-ROC-17010971) on March 23rd 2017.

Plasma levels of matrix metalloproteinase 9 in patients undergoing off-pump coronary artery bypass grafting.

Matrix metalloproteinase 9 (MMP9) has recently emerged as a risk predictor in patients with cardiovascular diseases. However, little is known about the significance of increased plasma MMP9 in patients with perioperative myocardial injury. We aimed to investigate the role of MMP9 in the occurrence of myocardial injury during off-pump coronary artery bypass grafting (OPCAB). A total of 34 consecutive patients with coronary artery diseases (CAD) were recruited in this prospective, observational study. All patients were operated for OPCAB surgery. Serial blood samples were collected preoperatively and 12 hours after surgery. MMP9, together with cardiac troponin I (cTnI), creatinine kinase myocardial b fraction (CK-MB), C-reactive protein (CRP), and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in plasma were measured at each time-point. MMP9 levels increased significantly at 12 hours after surgery, attaining nearly 2 times the baseline levels (P=0.0001). There was a significant correlation between preoperative (pre-OP) circulating levels of MMP9 and the left ventricular ejection fraction (LVEF) (r=0.48; P=0.004) as well as European System for Cardiac Operative Risk Evaluation (EuroSCORE) II (r=0.43; P=0.012). Patients were in New York Heart Association (NYHA) functional class III or IV heart failure showed a significantly higher MMP9 levels (1,348.0±337.2 vs. 630.4±93.0 ng/L, P=0.012) as compared to the patients in NYHA functional class I and II. No significant correlation was observed between MMP9 and age (P=0.612), serum creatinine (P=0.185), CRP (P=0.207), NT-proBNP (P=0.058). A significant correlation was observed in these data between the post-OP MMP9 and cTnI (r=0.35; P=0.003). Our study first established a connection between MMP9 and OPCAB procedure, suggesting that MMP9 could be a novel biomarker for identifying perioperative myocardial injury in patients undergoing OPCAB.