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01 februari 2023, Item does not contain fulltext, BACKGROUND: Aim of this study was to investigate immune cells and subsets in different stages of human coronary artery disease with a novel multiplex immunohistochemistry (mIHC) technique. METHODS: Human left anterior descending coronary artery specimens were analyzed: eccentric intimal thickening (N = 11), pathological intimal thickening (N = 10), fibroatheroma (N = 9), and fibrous plaque (N = 9). Eccentric intimal thickening was considered normal, and pathological intimal thickening, fibroatheroma, and fibrous plaque were considered diseased coronary arteries. Two mIHC panels, consisting of six and five primary antibodies, autofluoresence, and DAPI, were used to detect adaptive and innate immune cells. Via semi-automated analysis, (sub)types of immune cells in whole plaques and specific plaque regions were quantified. RESULTS: Increased numbers of CD3(+) T cells (P < 0.001), CD20(+) B cells (P = 0.013), CD68(+) macrophages (P = 0.003), CD15(+) neutrophils (P = 0.017), and CD31(+) endothelial cells (P = 0.024) were identified in intimas of diseased coronary arteries compared to normal. Subset analyses of T cells and macrophages showed that diseased coronary arteries contained an abundance of CD3(+)CD8(-) non-cytotoxic T cells and CD68(+)CD206(-) non-M2-like macrophages. Proportions of CD3(+)CD45RO(+) memory T cells were similar to normal coronary arteries. Among pathological intimal thickening, fibroatheroma, and fibrous plaque, all immune cell numbers and subsets were similar. CONCLUSIONS: The type of immune response does not differ substantially between different stages of plaque development and may provide context for mechanistic research into immune cell function in atherosclerosis. We provide the first comprehensive map of immune cell subtypes across plaque types in coronary arteries demonstrating the potential of mIHC for vascular research.

01 januari 2023, Item does not contain fulltext, OBJECTIVE: Midaortic syndrome (MAS) is narrowing of the distal thoracic and or abdominal aorta with congenital, inflammatory, or idiopathic aetiology. If left untreated, the prognosis is poor due to hypertensive complications. Follow up data after treatment are sparse, contrary to aortic coarctation. This study aimed to investigate hypertension during follow up after medical, endovascular, and surgical therapy in juveniles and adults. DATA SOURCES: A meta-analysis of case series and reports was performed, focusing on the incidence of hypertension during the follow up of juvenile (i.e., age 0-17 years) and adult MAS patients after medical, endovascular, or surgical therapy. REVIEW METHODS: Search queries were performed in PubMed, Embase, and Web of Science, and eligible articles underwent quality control. Descriptive statistics were reported based on available data, and individual patient data meta-analyses were performed using a one stage approach, accounting for clustering by case series or decades of reporting for case reports. For the meta-analysis, missing outcome and aetiology data were multiply imputed. RESULTS: The number of juveniles and adults who underwent endovascular therapy (33.7% vs. 27.3%; p = .42) and surgery (52.2% vs. 58.0%; p = .46) was similar. At baseline, 92.4% of juveniles and 87.5% of adults were hypertensive, decreasing to 23.2% and 24.1% during a follow up of 23 months (juveniles) and 18 months (adults), respectively. More hypertension was found compared with surgery in juveniles after endovascular therapy (38.1% vs. 10.8%; p = .020). Meta-analysis also demonstrated a trend for hypertension after endovascular therapy in juveniles, whereas hypertension was more prevalent following surgery in adults compared with endovascular therapy or medication. CONCLUSION: This review and meta-analysis investigated therapeutic options for MAS in juveniles and adults. It found that complications and hypertension during follow up were more common in juvenil

Item does not contain fulltext, BACKGROUND: Bicuspid aortic valve (BAV) is associated with ascending aorta aneurysms and dissections. Presently, genetic factors and pathological flow patterns are considered responsible for aneurysm formation in BAV while the exact role of inflammatory processes remains unknown. METHODS: In order to objectify inflammation, we employ a highly sensitive, quantitative immunohistochemistry approach. Whole slides of dissected, dilated and non-dilated ascending aortas from BAV patients were quantitatively analyzed. RESULTS: Dilated aortas show a 4-fold increase of lymphocytes and a 25-fold increase in B lymphocytes in the adventitia compared to non-dilated aortas. Tertiary lymphoid structures with B cell follicles and helper T cell expansion were identified in dilated and dissected aortas. Dilated aortas were associated with an increase in M1-like macrophages in the aorta media, in contrast the number of M2-like macrophages did not change significantly. CONCLUSION: This study finds unexpected large numbers of immune cells in dilating aortas of BAV patients. These findings raise the question whether immune cells in BAV aortopathy are innocent bystanders or contribute to the deterioration of the aortic wall.

Contains fulltext : 247661.pdf (Publisher’s version ) (Open Access)

Radboud University, 03 oktober 2022, Promotores : Vries, I.J.M. de, Srinivas, M. Co-promotores : Kimmenade, R.R.J. van, Staal, A.H.J., Contains fulltext : 281488.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 244629.pdf (Publisher’s version ) (Open Access), The exponential growth of research on cell-based therapy is in major need of reliable and sensitive tracking of a small number of therapeutic cells to improve our understanding of the in vivo cell-targeting properties. (111)In-labeled poly(lactic-co-glycolic acid) with a primary amine endcap nanoparticles ([(111)In]In-PLGA-NH(2) NPs) were previously used for cell labeling and in vivo tracking, using SPECT/CT imaging. However, to detect a low number of cells, a higher sensitivity of PET is preferred. Therefore, we developed (89)Zr-labeled NPs for ex vivo cell labeling and in vivo cell tracking, using PET/MRI. We intrinsically and efficiently labeled PLGA-NH(2) NPs with [(89)Zr]ZrCl(4). In vitro, [(89)Zr]Zr-PLGA-NH(2) NPs retained the radionuclide over a period of 2 weeks in PBS and human serum. THP-1 (human monocyte cell line) cells could be labeled with the NPs and retained the radionuclide over a period of 2 days, with no negative effect on cell viability (specific activity 279 ± 10 kBq/10(6) cells). PET/MRI imaging could detect low numbers of [(89)Zr]Zr-THP-1 cells (10,000 and 100,000 cells) injected subcutaneously in Matrigel. Last, in vivo tracking of the [(89)Zr]Zr-THP-1 cells upon intravenous injection showed specific accumulation in local intramuscular Staphylococcus aureus infection and infiltration into MDA-MB-231 tumors. In conclusion, we showed that [(89)Zr]Zr-PLGA-NH(2) NPs can be used for immune-cell labeling and subsequent in vivo tracking of a small number of cells in different disease models.

Contains fulltext : 239797.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 236797.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 229164.pdf (Publisher’s version ) (Open Access), Perfluorocarbons hold great promise both as imaging agents, particularly for (19)F MRI, and in therapy, such as oxygen delivery. (19)F MRI is unique in its ability to unambiguously track and quantify a tracer while maintaining anatomic context, and without the use of ionizing radiation. This is particularly well-suited for inflammation imaging and quantitative cell tracking. However, perfluorocarbons, which are best suited for imaging - like perfluoro-15-crown-5 ether (PFCE) - tend to have extremely long biological retention. Here, we showed that the use of a multi-core PLGA nanoparticle entrapping PFCE allows for a 15-fold reduction of half-life in vivo compared to what is reported in literature. This unexpected rapid decrease in (19)F signal was observed in liver, spleen and within the infarcted region after myocardial infarction and was confirmed by whole body NMR spectroscopy. We demonstrate that the fast clearance is due to disassembly of the ~200 nm nanoparticle into ~30 nm domains that remain soluble and are cleared quickly. We show here that the nanoparticle ultrastructure has a direct impact on in vivo clearance of its cargo i.e. allowing fast release of PFCE, and therefore also bringing the possibility of multifunctional nanoparticle-based imaging to translational imaging, therapy and diagnostics.