Heart disease constitutes one of the leading causes of morbidity and mortality worldwide. Current therapeutic techniques, such as interventional revascularization, although lifesaving, come along ...with myocardial injury related to the reperfusion itself, called ischemia-reperfusion injury, which is an added factor for increased morbidity. For that reason, there is an imperative need for novel therapies to be developed that would either prevent or treat myocardial injury. Extracellular vesicles (EVs), specifically small EVs (sEVs), have proven to be important mediators of intercellular communication. The fact that they carry information reflecting that of the parental cell makes them an ideal candidate for diagnostic purposes. sEVs derived from immunoregulatory cells, such as mesenchymal stem cells or cardiac progenitor cells, could also be used therapeutically to exert the primary immunomodulatory function but without carrying the side effects related to cell therapy. Furthermore, as a natural product, they have the added advantage of low immunogenicity, offering the potential for safe drug delivery. In the field of cardiology, there has been great interest in the therapeutic and diagnostic potential of sEVs with significant translational potential. Here, we review the potential use of sEVs in the context of myocardial ischemia and ischemia-reperfusion injury.
Abstract
Objectives
To explore the presence of neutrophil extracellular traps (NETs) in inflamed temporal artery biopsies (TABs) of patients with GCA.
Methods
Ten patients with GCA five with limited ...and five with associated generalized vascular involvement, as defined by 18F-fluorodeoxyglucose PET with CT (PET/CT) and eight with PMR were studied. The presence, location, quantitation and decoration of NETs with IL-6, IL-1β and IL-17A were assessed in TABs at the time of disease diagnosis by tissue immunofluorescence and confocal microscopy. Paired serum levels of IL-6 and IL-17A were also evaluated in all patients.
Results
All temporal artery biopsies from GCA, but not PMR, patients had NETs located mainly in the adventitia, adjacent to the vasa vasorum. NETs decorated with IL-6 were present in 8/10 TABs of GCA patients, of whom 5 were PET/CT(+) and 3 PET/CT(–) patients. IL-17A(+) NETs were observed in all GCA patients. IL-1β(+) NETs were not detected in any GCA patient. No relation was found between serum IL-6 and IL-17A levels and NETs containing IL-6 and/or IL-17A.
Conclusions
NETs bearing pro-inflammatory cytokines are present in inflamed GCA-TABs. Future studies with a larger number of patients from different centres will show whether the findings regarding neutrophils/NETs in the TAB are consistent and disclose their clinical impact.
Pancreatic ductal adenocarcinoma (PDA) is frequently driven by oncogenic KRAS(KRAS*) mutations. We developed a mouse model of KRAS*-induced PDA and, based on genetic results demonstrating that KRAS* ...tumorigenicity depends on Myc activity, we evaluated the therapeutic potential of an orally administered anti-Myc drug.
We tested the efficacy of Mycro3, a small-molecule inhibitor of Myc-Max dimerization, in the treatment of mouse PDA (n = 9) and also of xenografts of human pancreatic cancer cell lines (NOD/SCID mice, n = 3-12). Tumor responses to the drug were evaluated by PET/CT imaging, and histological, immunohistochemical, molecular and microarray analyses. The Student's t test was used for differences between groups. All statistical tests were two-sided.
Transgenic overexpression of KRAS* in the pancreas resulted in pancreatic intraepithelial neoplasia in two-week old mice, which developed invasive PDA a week later and became moribund at one month. However, this aggressive form of pancreatic tumorigenesis was effectively prevented by genetic ablation of Myc specifically in the pancreas. We then treated moribund, PDA-bearing mice daily with the Mycro3 Myc-inhibitor. The mice survived until killed at two months. PET/CT image analysis (n = 5) demonstrated marked shrinkage of PDA, while immunohistochemical analyses showed an increase in cancer cell apoptosis and reduction in cell proliferation (treated/untreated proliferation index ratio: 0.29, P < .001, n = 3, each group). Tumor growth was also drastically attenuated in Mycro3-treated NOD/SCID mice (n = 12) carrying orthotopic or heterotopic xenografts of human pancreatic cancer cells (eg, mean tumor weight ± SD of treated heterotopic xenografts vs vehicle-treated controls: 15.2±5.8 mg vs 230.2±43.9 mg, P < .001).
These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA.
Texture analysis has been increasingly used in the field of positron emission tomography (PET)/computed tomography (CT) imaging with Fluorine-18 fluorodeoxyglucose (18F-FDG), aiming at assessing ...tumor heterogeneity. The purpose of the present study is to examine the feasibility of performing texture analysis in carotid arteries, investigate the value of textural features as predictors of potential plaque vulnerability using as reference standards histological and immunohistochemical data and compare their performance with conventional uptake measurements.
67 different 18F-FDG PET-based textural features were extracted from carotid images of 21 patients with high-grade carotid stenosis undergoing endarterectomy. To identify the more reliable predictors, univariate logistic regression analysis was performed. The accuracy was satisfactory in case of an Area Under the Receiver Operating Characteristic (ROC) curve (AUC) ≥ 0.80.
First measure of information correlation (AUC = 0.87, P < 0.001), large zone low gray level emphasis (AUC = 0.87, P < 0.001), and normalized run length non-uniformity (AUC = 0.84, P < 0.001) were the most optimal textural features for identifying characteristics of plaque vulnerability based on histological analysis. Addition of textural features to target-to-background ratio (TBR) (AUC = 0.74, P = 0.031) resulted in an AUC = 0.92 (P < 0.001), however, this did not reach statistical significance (Pdiff = 0.09). Intensity histogram standard deviation (AUC = 0.87, P < 0.001) and joint variance (AUC = 0.81, P = 0.001) were the most efficient features for signal differential in relation to immunohistochemical findings and provided incremental value compared to TBR (Pdiff = 0.02).
Texture analysis can be applied in 18F-FDG PET carotid imaging providing valuable information for plaque characterization.
Fluid Dynamics-Derived Parameters in Coronary Vessels Siogkas, Panagiotis K; Kalykakis, Georgios-Eleftherios; Anagnostopoulos, Constantinos D ...
Advances in experimental medicine and biology,
01/2021, Letnik:
1337
Journal Article
Recenzirano
Continued development in the field of cardiovascular modeling over the past few years has contributed to the production of precise three-dimensional models of main coronary arteries. Computational ...fluid dynamic-derived parameters such as smartFFR, a CT-FFR surrogate, and endothelial shear stress (ESS) can be assessed from non-invasive imaging techniques like computed tomography coronary angiography using novel 3D reconstruction methods and can be used to investigate the functional significance of an artery. The investigation of the different flow conditions for the calculation (steady state vs. transient) of the ESS presents that while there is a difference in the final values, it is not statistically significant. ESS in the whole vessel is higher compared to the lesion-specific segments and smartFFR calculated in lesion segment does not reflect accurately the flow capability of the vessel. Higher ESS is present in vessels with <0.85 smartFFR and both parameters are present higher values in vessels with abnormal PET myocardial perfusion imaging.
Abstract An important evolution has taken place recently in the field of cardiovascular Positron Emission Tomography (PET) imaging. Being originally a highly versatile research tool that has ...contributed significantly to advance our understanding of cardiovascular physiology and pathophysiology, PET has gradually been incorporated into the clinical cardiac imaging portfolio contributing to diagnosis and management of patients investigated for coronary artery disease (CAD). PET myocardial perfusion imaging (MPI) has an average sensitivity and specificity around 90% for the detection of angiographically significant CAD and it is also a very accurate technique for prognostication of patients with suspected or known CAD. In clinical practice, Rubidium-82 (82 Rb) is the most widely used radiopharmaceutical for MPI that affords also accurate and reproducible quantification in absolute terms (ml/min/g) comparable to that obtained by cyclotron produced tracers such as Nitrogen-13 ammonia (13 N-ammonia) and Oxygen-15 labeled water (15 O-water). Quantification increases sensitivity for detection of multivessel CAD and it may also be helpful for detection of early stages of atherosclerosis or microvascular dysfunction. PET imaging combining perfusion with myocardial metabolism using18 F-Fluorodeoxyglucose (18 F FDG), a glucose analog, is an accurate standard for assessment of myocardial hibernation and risk stratification of patients with left ventricular dysfunction of ischemic etiology. It is helpful for guiding management decisions regarding revascularization or medical treatment and predicting improvement of symptoms, exercise capacity and quality of life post-revascularization. The strengths of PET can be increased further with the introduction of hybrid scanners, which combine PET with computed tomography (PET/CT) or with magnetic resonance imaging (PET/MRI) offering integrated morphological, biological and physiological information and hence, comprehensive evaluation of the consequences of atherosclerosis in the coronary arteries and the myocardium.
Objectives
Application of computational fluid dynamics (CFD) to three-dimensional CTCA datasets has been shown to provide accurate assessment of the hemodynamic significance of a coronary lesion. We ...aim to test the feasibility of calculating a novel CTCA-based virtual functional assessment index (vFAI) of coronary stenoses > 30% and ≤ 90% by using an automated in-house-developed software and to evaluate its efficacy as compared to the invasively measured fractional flow reserve (FFR).
Methods and results
In 63 patients with chest pain symptoms and intermediate (20–90%) pre-test likelihood of coronary artery disease undergoing CTCA and invasive coronary angiography with FFR measurement, vFAI calculations were performed after 3D reconstruction of the coronary vessels and flow simulations using the finite element method. A total of 74 vessels were analyzed. Mean CTCA processing time was 25(± 10) min. There was a strong correlation between vFAI and FFR, (
R
= 0.93,
p
< 0.001) and a very good agreement between the two parameters by the Bland–Altman method of analysis. The mean difference of measurements from the two methods was 0.03 (SD = 0.033), indicating a small systematic overestimation of the FFR by vFAI. Using a receiver-operating characteristic curve analysis, the optimal vFAI cutoff value for identifying an FFR threshold of ≤ 0.8 was ≤ 0.82 (95% CI 0.81 to 0.88).
Conclusions
vFAI can be effectively derived from the application of computational fluid dynamics to three-dimensional CTCA datasets. In patients with coronary stenosis severity > 30% and ≤ 90%, vFAI performs well against FFR and may efficiently distinguish between hemodynamically significant from non-significant lesions.
Key Points
Virtual functional assessment index (vFAI) can be effectively derived from 3D CTCA datasets.
In patients with coronary stenoses severity > 30% and ≤ 90%, vFAI performs well against FFR.
vFAI may efficiently distinguish between functionally significant from non-significant lesions.
•SRT is based on a novel numerical implementation of the inverse Radon transform.•SRT is a promising algorithm for evaluating myocardial viability.•SRT appears to be useful for the quantification of ...small hot ROIs.•SRT founds to perform well in low-count preclinical imaging applications.
The Spline Reconstruction Technique (SRT) is a fast algorithm based on a novel numerical implementation of an analytic representation of the inverse Radon transform. The purpose of this study is to provide a comparison between SRT, Filtered Back-Projection (FBP), Ordered Subset Expectation Maximization 2D (2D-OSEM), and the Tera-Tomo 3D algorithm, using phantom data at various acquisition durations as well as small-animal data obtained from the Mediso nanoScan® PET/CT scanner.
For this purpose, the “NEMA NU 4–2008 standards” protocol was employed at five different realizations and acquisition durations. In addition to the image quality metrics described by the NEMA protocol, Cold Region Contrast was also considered as a figure-of-merit. Furthermore, Cold Region Contrast was measured in the myocardial infarction region of six male Wistar rats. The volumetric defect quantification was assessed with dedicated computer software. Lastly, plots of Recovery Coefficient and Spill-Over Ratio as a function of the Percentage Standard Deviation were generated, after smoothing the phantom reconstructions with four different Gaussian filters. Statistical significance was determined by employing the Kruskal-Wallis test or One-way Analysis of Variance depending on the normality of the variable's distribution.
The present study revealed that, at the expense of slightly increased noise in the reconstructed images, SRT resulted in higher Recovery Coefficient values for small hot regions of interest, when compared with FBP and 2D-OSEM at all acquisition durations. Furthermore, SRT reconstructed images exhibit higher Recovery Coefficient values, for all hot regions of interest, when compared to the other 2D algorithms at short acquisition durations. In both phantom and animal studies, SRT achieved a significant improvement over 2D-OSEM for the Spill-Over Ratio and the Cold Region Contrast. These advantages were maintained even after comparing the algorithms at equal noise levels. The Tera-Tomo 3D algorithm (4 subsets, iterations≥ 13) performed significantly better compared to the other algorithms for all figures-of-merit. No statistically significant differences regarding the myocardial defect size were observed between the algorithms investigated.
Overall, SRT appears that could be useful for the quantification of small hot regions of interest, cold regions of interest, as well as in low-count imaging applications.
Graphical abstract
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