Matrix metalloproteinases at key junctions in the pathomechanism of stroke

Matrix metalloproteinases play a crucial role in the remodelling of the extracellular matrix through direct degradation of its structural proteins and control of extracellular signaling. The most common cause of ischemic brain damage is an atherothrombotic lesion in the supplying arteries. The progress of the atherosclerotic plaque development and the related thrombotic complications are mediated in part by matrix metalloproteinases. In addition to their role in the underlying disease, various members of this protease family are upregulated in the acute phase of ischemic brain damage as well as in the post-ischemic brain recovery following stroke. This review summarizes the current understanding of the matrix metalloproteinase-related molecular events at three stages of the ischemic cerebrovascular disease (in the atherosclerotic plaque, in the neurovascular unit of the brain and in the regenerating brain tissue)

Subsurface ablation of atherosclerotic plaque using ultrafast laser pulses

We perform subsurface ablation of atherosclerotic plaque using ultrafast pulses. Excised mouse aortas containing atherosclerotic plaque were ablated with ultrafast near-infrared (NIR) laser pulses. Optical coherence tomography (OCT) was used to observe the ablation result, while the physical damage was inspected in histological sections. We characterize the effects of incident pulse energy on surface damage, ablation hole size, and filament propagation. We find that it is possible to ablate plaque just below the surface without causing surface damage, which motivates further investigation of ultrafast ablation for subsurface atherosclerotic plaque removal

Localization of lipopolysaccharide from Escherichia Coli into human atherosclerotic plaque

Experimental studies showed that gut-derived lipopolysaccharide (LPS) is pro-atherogenic, however, its relationship with human atherosclerosis is still to be defined. We investigate if gut-derived LPS from Escherichia Coli localizes in human carotid plaque and its potential role as pro-inflammatory molecule in the atherosclerotic lesion. LPS from Escherichia Coli and Toll-like receptor 4 (TLR4) were studied in specimens from carotid and thyroid arteries of 10 patients undergoing endarterectomy and 15 controls matched for demographic and clinical characteristics. Blood LPS were significantly higher in patients compared to controls. Immunochemistry analysis revealed positivity for antibodies against LPS and TLR4 coincidentally with positivity for CD68 only in the atherosclerotic plaque of carotid arteries but not in thyroid arteries; the positivity for LPS and TLR4 was greater in the area with activated macrophages. LPS concentration similar to that detected in atherosclerotic plaque resulted in a dose-dependent TLR4-mediated Nox2 up-regulation by human monocytes. These data provide the first evidence that LPS from Escherichia Coli localizes in human plaque and may contribute to atherosclerotic damage via TLR4-mediated oxidative stress

Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice

Background and aims Observational studies show a peak incidence of cardiovascular events after major surgery. For example, the risk of myocardial infarction increases 25-fold early after hip replacement. The acuteness of this increased risk suggests abrupt enhancement in plaque vulnerability, which may be related to intra-plaque inflammation, thinner fibrous cap and/or necrotic core expansion. We hypothesized that acute systemic inflammation following major orthopedic surgery induces such changes. Methods ApoE−/− mice were fed a western diet for 10 weeks. Thereafter, half the mice underwent mid-shaft femur osteotomy followed by realignment with an intramedullary K-wire, to mimic major orthopedic surgery. Mice were sacrificed 5 or 15 days post-surgery (n = 22) or post-saline injection (n = 13). Serum amyloid A (SAA) was measured as a marker of systemic inflammation. Paraffin embedded slides of the aortic root were stained to measure total plaque area and to quantify fibrosis, calcification, necrotic core, and inflammatory cells. Results Surgery mice showed a pronounced elevation of serum amyloid A (SAA) and developed increased plaque and necrotic core area already at 5 days, which reached significance at 15 days (p = 0.019; p = 0.004 for plaque and necrotic core, respectively). Macrophage and lymphocyte density significantly decreased in the surgery group compared to the control group at 15 days (p = 0.037; p = 0.024, respectively). The density of neutrophils and mast cells remained unchanged. Conclusions Major orthopedic surgery in ApoE−/− mice triggers a systemic inflammatory response. Atherosclerotic plaque area is enlarged after surgery mainly due to an increase of the necrotic core. The role of intra-plaque inflammation in this response to surgical injury remains to be fully elucidated. © 2016 Elsevier Ireland Lt

Atherosclerotic carotid plaque composition: a 3T and 7T MRI-histology correlation study

Background and Purpose Carotid artery atherosclerotic plaque composition may influence plaque stability and risk of thromboembolic events, and non-invasive plaque imaging may therefore permit risk stratification for clinical management. Plaque composition was compared using non-invasive in-vivo (3T) and ex-vivo (7T) MRI and histopathological examination. Methods Thirty three endarterectomy cross sections, from 13 patients, were studied. The datasets consisted of in-vivo 3T MRI, ex-vivo 7T MRI and histopathology. Semi-automated segmentation methods were used to measure areas of different plaque components. Bland- Altman plots and mean difference with 95% confidence interval were carried out. Results There was general quantitative agreement between areas derived from semi-automated segmentation of MRI data and histology measurements. The mean differences and 95% confidence bounds in the relative to total plaque area between 3T versus Histology were: fibrous tissue 4.99 % (-4.56 to 14.56), lipid-rich/necrotic core (LR/NC) with haemorrhage - 1.81% (-14.11 to 10.48), LR/NC without haemorrhage -2.43% (-13.04 to 8.17), and calcification -3.18% (-11.55 to 5.18). The mean differences and 95% confidence bounds in the relative to total plaque area between 7T and histology were: fibrous tissue 3.17 % (-3.17 to 9.52), LR/NC with haemorrhage -0.55% (-9.06 to 7.95), LR/NC without haemorrhage - 12.62% (-19.8 to -5.45), and calcification -2.43% (-9.97 to 4.73). Conclusions This study provides evidence that semi-automated segmentation of 3T/7T MRI techniques can help to determine atherosclerotic plaque composition. In particular, the high resolution of ex-vivo 7T data was able to highlight greater detail in the atherosclerotic plaque composition. High field MRI may therefore have advantages for in vivo carotid plaque MR imaging

Assessment of coronary artery outward remodeling in consequence of excision of epicardial adipose tissue in Ossabaw swine

Background Coronary artery disease (CAD) results from the buildup of cholesterol, inflammatory factors, and proliferating smooth muscle cells within a vessel wall. This plaque impedes on the vessel lumen, decreasing the space through which blood can flow, leading to an array of complications in the human body. To offset these effects, the arterial wall undergoes outward remodeling, a compensatory physiologic phenomenon that blood vessels undertake when burdened with a blockage, such as CAD. In a previously conducted study, a coronary epicardial adipose tissue excision (cEATx) surgery was performed above the left anterior descending (LAD) in Ossabaw swine to investigate the effects of local adipose on the progression of CAD. Compared to the sham control group, pigs that underwent the adipectomy procedure revealed focal attenuation of disease progression at the surgical site within the LAD. Unlike, the previous research question, this current study aims to determine if there was an additional global outward remodeling effect by investigating disease progression in the right coronary artery (RCA) of the same animals. By comparing the two sites, we are able to determine whether the outward remodeling observed in the LAD was due to the local surgical procedure or a physiologic compensation for limitations caused by CAD progression. Methods Images of the RCA lumen were collected using intravascular ultrasound (IVUS). Measurements of the external elastic lamina and lumen area were taken of each collected still-frame image. For each pig, the data were averaged across the proximal 15 mm of the RCA at two separate time points (pre- and post-surgery). Pre-surgery measures were obtained the day the surgery took place while post-surgery measures were obtained 3 months later. Percent stenosis, plaque area, outward remodeling, and lumen area were all assessed. Results Progression of CAD in the RCA, represented by percent stenosis, was not significantly slowed in the adipectomy pigs compared to the control group. Outward remodeling in the RCA, represented by an increase in external elastic lamina circumference, was not significantly higher in the adipectomy pigs compared to the control group. Conclusions These data indicate that the cEATx procedure at the LAD did not attenuate CAD progression in the RCA

Machine Learning Framework to Identify Individuals at Risk of Rapid Progression of Coronary Atherosclerosis: From the PARADIGM Registry.

Background Rapid coronary plaque progression (RPP) is associated with incident cardiovascular events. To date, no method exists for the identification of individuals at risk of RPP at a single point in time. This study integrated coronary computed tomography angiography-determined qualitative and quantitative plaque features within a machine learning (ML) framework to determine its performance for predicting RPP. Methods and Results Qualitative and quantitative coronary computed tomography angiography plaque characterization was performed in 1083 patients who underwent serial coronary computed tomography angiography from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry. RPP was defined as an annual progression of percentage atheroma volume ≥1.0%. We employed the following ML models: model 1, clinical variables; model 2, model 1 plus qualitative plaque features; model 3, model 2 plus quantitative plaque features. ML models were compared with the atherosclerotic cardiovascular disease risk score, Duke coronary artery disease score, and a logistic regression statistical model. 224 patients (21%) were identified as RPP. Feature selection in ML identifies that quantitative computed tomography variables were higher-ranking features, followed by qualitative computed tomography variables and clinical/laboratory variables. ML model 3 exhibited the highest discriminatory performance to identify individuals who would experience RPP when compared with atherosclerotic cardiovascular disease risk score, the other ML models, and the statistical model (area under the receiver operating characteristic curve in ML model 3, 0.83 [95% CI 0.78-0.89], versus atherosclerotic cardiovascular disease risk score, 0.60 [0.52-0.67]; Duke coronary artery disease score, 0.74 [0.68-0.79]; ML model 1, 0.62 [0.55-0.69]; ML model 2, 0.73 [0.67-0.80]; all P<0.001; statistical model, 0.81 [0.75-0.87], P=0.128). Conclusions Based on a ML framework, quantitative atherosclerosis characterization has been shown to be the most important feature when compared with clinical, laboratory, and qualitative measures in identifying patients at risk of RPP