Prognostic value of tissue inhibitor of metalloproteinase-matrix metalloproteinase biomarkers at 30 days in patients with acute myocardial infarction without reperfusion therapy.
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ABSTRACT:
SUBMITTER: Pang HF
PROVIDER: S-EPMC7909484 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Prognostic value of tissue inhibitor of metalloproteinase-matrix metalloproteinase biomarkers at 30 days in patients with acute myocardial infarction without reperfusion therapy.
Pang Hui-Fang HF Gao Yan Y Liu Jia-Min JM Lu Jia-Peng JP Wang Yan-Ping YP Wang Si-Ming SM Hou Li-Bo LB Tian Ao-Xi AX Gao Yan Y
Chinese medical journal 20201020 4
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Project description:The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.
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Project description:BackgroundDespite a high cardiovascular disease burden, data on patient-reported health status outcomes among individuals with cardiovascular disease in India are limited.Methods and resultsBetween November 2014 and November 2016, we collected health-related quality of life data among 1261 participants in the ACS QUIK trial (Acute Coronary Syndrome Quality Improvement in Kerala). We used a translated, validated version of the Seattle Angina Questionnaire administered 30 days after discharge for acute myocardial infarction, wherein higher scores represent better health status. We compared results across sex, myocardial infarction type, and randomization status using regression models that account for clustering and temporal trends. Mean (SD) age was 60.8 (13.7) years, 62% were men, and 63% presented with ST-segment-elevation myocardial infarction. More than 2 out of 5 respondents (44%) experienced angina 30 days after hospitalization, but most (68% of respondents with angina; 27% of the total sample) experienced it less than once per week (Seattle Angina Questionnaire angina frequency score 60). Respondents rated high median (interquartile range [IQR]) scores for angina frequency (100.0 [80.0-100.0]) overall with similar unadjusted scores by sex, but between-hospitality variability was high. Median (IQR) physical limitation scale response was 58.3 (41.7-77.8), which is consistent with limitations in moderate- and high-intensity activities at 30-day follow-up. Older respondents had more angina frequency and physical limitations and lower treatment satisfaction and quality of life. Women had greater physical limitations (median [IQR], 52.8 [38.9-72.2] for women versus median [IQR], 61.1 [44.4-80.6] for men; P<0.01). Overall treatment satisfaction was high with median (IQR) score, 81.3 (75.0-93.8), but overall quality of life was lower with median (IQR) score, 66.7 (50.0-83.3). Allocation to the quality improvement intervention group had the strongest direct association with higher quality of life (difference, 4.2; P=0.03), but overall effects were modest.ConclusionsThis study represents the largest report of quality of life among myocardial infarction survivors in India with variability across age, sex, and quality improvement intervention status. Wide variability demonstrated across hospitals warrants further study.Clinical trial registrationURL: https://www.clinicaltrials.gov . Unique identifier: NCT02256657.
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Project description:Titin is the largest mammalian (?3000 to 4000 kDa) and myofilament protein that acts as a molecular spring in the cardiac sarcomere and determines systolic and diastolic function. Loss of titin in ischemic hearts has been reported, but the mechanism of titin degradation is not well understood. Matrix metalloproteinase-2 (MMP-2) is localized to the cardiac sarcomere and, on activation in ischemia/reperfusion injury, proteolyzes specific myofilament proteins. Here we determine whether titin is an intracellular substrate for MMP-2 and if its degradation during ischemia/reperfusion contributes to cardiac contractile dysfunction.Immunohistochemistry and confocal microscopy in rat and human hearts showed discrete colocalization between MMP-2 and titin in the Z-disk region of titin and that MMP-2 is localized mainly to titin near the Z disk of the cardiac sarcomere. Both purified titin and titin in skinned cardiomyocytes were proteolyzed when incubated with MMP-2 in a concentration-dependent manner, and this was prevented by MMP inhibitors. Isolated rat hearts subjected to ischemia/reperfusion injury showed cleavage of titin in ventricular extracts by gel electrophoresis, which was confirmed by reduced titin immunostaining in tissue sections. Inhibition of MMP activity with ONO-4817 prevented ischemia/reperfusion-induced titin degradation and improved the recovery of myocardial contractile function. Titin degradation was also reduced in hearts from MMP-2 knockout mice subjected to ischemia/reperfusion in vivo compared with wild-type controls.MMP-2 localizes to titin at the Z-disk region of the cardiac sarcomere and contributes to titin degradation in myocardial ischemia/reperfusion injury.
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Project description:Traditional circulating biomarkers play a fundamental role in the diagnosis and prognosis of acute myocardial infarction (AMI). However, they have several limitations. microRNAs (miRs), a class of RNA molecules that do not encode proteins, function directly at the RNA level by inhibiting the translation of messenger RNAs. Due to their significant roles in disease development, they can be used as biomarkers. Accumulating evidence has revealed an attractive role of miRs as biomarkers of AMI and its associated symptoms, including vulnerable atherosclerotic plaques, and their role in disease diagnosis, platelet activation monitoring, and prognostic outcome prediction. This manuscript will highlight the recent updates regarding the involvement of miRs as biomarkers in AMI and emphasize their value in vulnerable atherosclerotic plaque prediction and monitoring of platelet activation.
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Project description:ObjectiveCurrent findings on the association between MMP-9 rs3918242 and susceptibility to myocardial infarction (MI) are inconsistent, and their definite relationship is discussed in this meta-analysis.MethodsEligible literatures reporting MMP-9 rs3918242 and susceptibility to MI were searched in PubMed, Cochrane Library, CNRI, and VIP using keywords such as "MMP-9", "matrix metallopeptidase-9" and "myocardial infarction", "acute myocardial infarction", "AMI", and "polymorphism". Data from eligible literatures were extracted for calculating OR and corresponding 95% CI using RevMan 5.3 and STATA12.0.ResultsTen independent literatures reporting MMP-9 rs3918242 and susceptibility to MI were enrolled. Compared with subjects carrying CT&TT genotype of MMP-9 rs3918242, susceptibility to MI was lower in those carrying CC genotype (OR = 1.49, 95%CI = 1.19-1.86, P = 0.0004). Such a significance was observed in the overdominant (OR = 1.27, 95%CI = 1.14-1.41, P < 0.0001) and allele genetic models (OR = 1.43, 95%CI = 1.17-1.74, P = 0.0005) as well. This finding was also valid in the Asian population.ConclusionsMutation on MMP-9 rs3918242 has a potential relevance with susceptibility to MI.
| S-EPMC8783703 | biostudies-literature
Project description:New mechanistic insight into how the kidney responds to cardiac injury during acute myocardial infarction (AMI) is required. We hypothesized that AMI promotes inflammation and matrix metalloproteinase-9 (MMP9) activity in the kidney and studied the effect of initiating an Impella CP or veno-arterial extracorporeal membrane oxygenation (VA-ECMO) before coronary reperfusion during AMI. Adult male swine were subjected to coronary occlusion and either reperfusion (ischemia-reperfusion; IR) or support with either Impella or VA-ECMO before reperfusion. IR and ECMO increased while Impella reduced levels of MMP-9 in the myocardial infarct zone, circulation, and renal cortex. Compared to IR, Impella reduced myocardial infarct size and urinary KIM-1 levels, but VA-ECMO did not. IR and VA-ECMO increased pro-fibrogenic signaling via transforming growth factor-beta and endoglin in the renal cortex, but Impella did not. These findings identify that AMI increases inflammatory activity in the kidney, which may be attenuated by Impella support.
| S-EPMC8983528 | biostudies-literature
Project description:BackgroundCardiovascular diseases (CVDs) are the leading cause of premature death for Canadian women, which may be due partly to a lack of awareness of the presentation of acute coronary events in emergency departments (EDs). To address an identified gap in women's cardiovascular care, we sought to describe the clinical and comorbid factors of women who, following discharge from an ED, suffered a myocardial infarction (MI).MethodsDescriptive analyses were completed on a cohort of women who presented to an ED in Alberta, Canada, between January 1, 2010 and December 31, 2020, were discharged, and within 30 days of their index ED visit, were admitted to the hospital with an MI. The cohort was explored for clinical and comorbid data, ED visits pre-MI, type of MI, and presenting complaint/ primary diagnosis for the index ED visit.Results1380 women were included in this analysis with a mean age of 67 (standard deviation ±13) years. The frequencies of hypertension, diabetes, and dyslipidemia among the youngest women, aged 18-45 years, were 47.5%, 31.3%, and 48.8%, respectively. Women across all ages demonstrated a high prevalence of traditional CVD risk factors, and 22% of women presented to an ED 2 or more times within the 30 days pre-MI.ConclusionsRegardless of their age, the women in this cohort had notable CVD risk factors. Future research is required to better understand the phenomenon of women presenting multiple times to an ED pre-MI. Research is needed on life-stage-specific factors of women presenting to EDs pre-MI, to help reduce MI incidence.
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Project description: Not available
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Project description:Matrix metalloproteinase-9 (MMP-9) is robustly elevated in the first week post-myocardial infarction (MI). Targeted deletion of the MMP-9 gene attenuates cardiac remodeling post-MI by reducing macrophage infiltration and collagen accumulation through increased apoptosis and reduced inflammation. In this study, we used a translational experimental design to determine whether selective MMP-9 inhibition early post-MI would be an effective therapeutic strategy in mice. We enrolled male C57BL/6J mice (3-6months old, n=116) for this study. Mice were subjected to coronary artery ligation. Saline or MMP-9 inhibitor (MMP-9i; 0.03μg/day) treatment was initiated at 3h post-MI and the mice were sacrificed at day (D) 1 or 7 post-MI. MMP-9i reduced MMP-9 activity by 31±1% at D1 post-MI (p<0.05 vs saline) and did not affect survival or infarct area. Surprisingly, MMP-9i treatment increased infarct wall thinning and worsened cardiac function at D7 post-MI. While MMP-9i enhanced neutrophil infiltration at D1 and macrophage infiltration at D7 post-MI, CD36 levels were lower in MMP-9i compared to saline, signifying reduced phagocytic potential per macrophage. Escalation and prolongation of the inflammatory response at D7 post-MI in the MMP-9i group was evident by increased expression of 18 pro-inflammatory cytokines (all p<0.05). MMP-9i reduced cleaved caspase 3 levels at D7 post-MI, consistent with reduced apoptosis and defective inflammation resolution. Because MMP-9i effects on inflammatory cells were significantly different from previously observed MMP-9 null mechanisms, we evaluated pre-MI (baseline) systemic differences between C57BL/6J and MMP-9 null plasma. By mass spectrometry, 34 plasma proteins were significantly different between groups, revealing a previously unappreciated altered baseline environment pre-MI when MMP-9 was deleted. In conclusion, early MMP-9 inhibition delayed inflammation resolution and exacerbated cardiac dysfunction, highlighting the importance of using translational approaches in mice.
| S-EPMC5319826 | biostudies-literature
Project description:BackgroundSingle nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes may be associated with myocardial infarction (MI) and coronary artery disease (CAD), but studies of multiple MMP genes and their tissue inhibitors (TIMPs) are scarce. Furthermore, differentiation of predictive ability by end point (MI vs CAD) has not been addressed. This study evaluated the association with MI of SNPs in genes encoding MMPs 1, 2, 3, and 9 and TIMPs 1, 2, and 3.MethodsGenotypes of patients (N = 5148) with MI (n = 1693) and angiographically defined CAD (> or = 1 lesion of > or = 70% stenosis, n = 1967) were compared with MI-free (n = 3455) and non-CAD patients (n = 1122), respectively. Because of linkage disequilibrium, MMP-1 and MMP-3 SNPs (chromosome 11) were combined, as were the 2 MMP-9 SNPs.ResultsFor MI, only MMP-9 group CT/RQ (odds ratio [OR] 1.25, P = .007 vs wild-type CC/RR) had greater MI risk, with TT/QQ having a weak trend (OR 1.43, P = .10). These findings remained (CT/RQ) or were strengthened (TT/QQ) after full adjustment. For CAD, association was found for MMP-1/MMP-3 groups 2G1G/6A6A (OR 1.45, P = .022), 2G1G/6A5A (OR = 1.49, P = .001), 2G1G/5A5A (OR 1.64, P = .003), and 1G1G/5A5A (OR 1.35, P = .035) compared to wild type.ConclusionsComposite MMP-9 genotypes but not other SNPs were associated with MI, whereas MMP-1/MMP-3 genotypes were CAD-associated. The largest MMP/TIMP gene study to date, this study suggests care in selection and definition of clinical phenotypes. Furthermore, this suggests that the evaluated SNPs only approximately account for intragenic variation in these genes and that comprehensive evaluation of all variations in these genes should better elucidate associations with MI and CAD phenotypes.
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