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Expert Review of Cardiovascular Therapy 2015An aortic aneurysm is a dilatation in which the aortic diameter is ≥3.0 cm. If left untreated, the aortic wall continues to weaken and becomes unable to withstand the... (Review)
Review
An aortic aneurysm is a dilatation in which the aortic diameter is ≥3.0 cm. If left untreated, the aortic wall continues to weaken and becomes unable to withstand the forces of the luminal blood pressure resulting in progressive dilatation and rupture, a catastrophic event associated with a mortality of 50-80%. Smoking and positive family history are important risk factors for the development of abdominal aortic aneurysms (AAA). Several genetic risk factors have also been identified. On the histological level, visible hallmarks of AAA pathogenesis include inflammation, smooth muscle cell apoptosis, extracellular matrix degradation and oxidative stress. We expect that large genetic, genomic, epigenetic, proteomic and metabolomic studies will be undertaken by international consortia to identify additional risk factors and biomarkers, and to enhance our understanding of the pathobiology of AAA. Collaboration between different research groups will be important in overcoming the challenges to develop pharmacological treatments for AAA.
Topics: Animals; Aorta; Aortic Aneurysm, Abdominal; Disease Models, Animal; Humans
PubMed: 26308600
DOI: 10.1586/14779072.2015.1074861 -
Circulation Research Jan 2020Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not...
Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. To determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis. We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis. Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.
Topics: Aging; Animals; Aorta; Atherosclerosis; Diet, High-Fat; Endothelium, Vascular; Feedback, Physiological; Female; Interleukin-6; Lipoproteins, LDL; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitophagy; Receptors, LDL; Spermidine; Ubiquitin-Protein Ligases
PubMed: 31818196
DOI: 10.1161/CIRCRESAHA.119.315644 -
Circulation Research Jul 2020The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive... (Meta-Analysis)
Meta-Analysis Review
The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2 foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, , which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.
Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Biomarkers; Disease Models, Animal; Flow Cytometry; Leukocytes; Phenotype; Plaque, Atherosclerotic; RNA-Seq; Single-Cell Analysis; Transcriptome
PubMed: 32673538
DOI: 10.1161/CIRCRESAHA.120.316903 -
Journal of Visualized Experiments : JoVE May 2022Apolipoprotein E (Apoe)- or low density lipoprotein receptor (Ldlr)-deficient hyperlipidemic mice are the two most commonly used models for atherosclerosis research....
Apolipoprotein E (Apoe)- or low density lipoprotein receptor (Ldlr)-deficient hyperlipidemic mice are the two most commonly used models for atherosclerosis research. They are used to study the impact of a various genetic factors and different cell types on atherosclerotic lesion formation and as well as test the development of new therapies. Isolation, excision of the whole aorta, and quantification of Oil Red O-stained atherosclerotic lesions are basic morphometric methods used to evaluate atherosclerotic burden. The goal of this protocol is to describe an optimized, step-by-step surgical method to dissect, perfuse-fix, isolate, stain, image and analyze atherosclerotic lesions in mouse aortas with Oil Red O. Because atherosclerotic lesions can form anywhere in the entire aortic tree, this whole aorta Oil Red O staining method has the advantage of evaluating lipid-laden plaques in the entire aorta and all branches in a single mouse. In addition to Oil Red O staining, fresh isolated whole aortas can be used for variety of in vitro and in vivo experiments and cell isolations.
Topics: Aneurysm; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Azo Compounds; Disease Models, Animal; Hyperlipidemias; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Plaque, Atherosclerotic; Staining and Labeling
PubMed: 35575528
DOI: 10.3791/61277 -
Circulation Jul 2019The cells that form the arterial wall contribute to multiple vascular diseases. The extent of cellular heterogeneity within these populations has not been fully...
BACKGROUND
The cells that form the arterial wall contribute to multiple vascular diseases. The extent of cellular heterogeneity within these populations has not been fully characterized. Recent advances in single-cell RNA-sequencing make it possible to identify and characterize cellular subpopulations.
METHODS
We validate a method for generating a droplet-based single-cell atlas of gene expression in a normal blood vessel. Enzymatic dissociation of 4 whole mouse aortas was followed by single-cell sequencing of >10 000 cells.
RESULTS
Clustering analysis of gene expression from aortic cells identified 10 populations of cells representing each of the main arterial cell types: fibroblasts, vascular smooth muscle cells, endothelial cells (ECs), and immune cells, including monocytes, macrophages, and lymphocytes. The most significant cellular heterogeneity was seen in the 3 distinct EC populations. Gene set enrichment analysis of these EC subpopulations identified a lymphatic EC cluster and 2 other populations more specialized in lipoprotein handling, angiogenesis, and extracellular matrix production. These subpopulations persist and exhibit similar changes in gene expression in response to a Western diet. Immunofluorescence for Vcam1 and Cd36 demonstrates regional heterogeneity in EC populations throughout the aorta.
CONCLUSIONS
We present a comprehensive single-cell atlas of all cells in the aorta. By integrating expression from >1900 genes per cell, we are better able to characterize cellular heterogeneity compared with conventional approaches. Gene expression signatures identify cell subpopulations with vascular disease-relevant functions.
Topics: Animals; Aorta; Endothelial Cells; Female; Gene Expression Profiling; Mice; Mice, Inbred C57BL; Single-Cell Analysis
PubMed: 31146585
DOI: 10.1161/CIRCULATIONAHA.118.038362 -
Circulation Research Oct 2018Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the...
RATIONALE
Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis.
OBJECTIVE
We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima.
METHODS AND RESULTS
Single-cell RNA sequencing analysis of CD45 leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining-based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPYSSC foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1β and many other inflammatory transcripts in atherosclerotic aorta.
CONCLUSIONS
RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.
Topics: Animals; Aorta; Cells, Cultured; Humans; Macrophages; Male; Mice; Mice, Inbred C57BL; Plaque, Atherosclerotic; Transcriptome
PubMed: 30359200
DOI: 10.1161/CIRCRESAHA.118.312804 -
World Journal of Emergency Surgery :... Aug 2021Multiple studies regarding the use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in patients with non-compressible torso injuries and... (Meta-Analysis)
Meta-Analysis
Resuscitative endovascular balloon occlusion of the aorta (REBOA) in patients with major trauma and uncontrolled haemorrhagic shock: a systematic review with meta-analysis.
BACKGROUND
Multiple studies regarding the use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in patients with non-compressible torso injuries and uncontrolled haemorrhagic shock were recently published. To date, the clinical evidence of the efficacy of REBOA is still debated. We aimed to conduct a systematic review assessing the clinical efficacy and safety of REBOA in patients with major trauma and uncontrolled haemorrhagic shock.
METHODS
We systematically searched MEDLINE (PubMed), EMBASE and CENTRAL up to June 2020. All randomized controlled trials and observational studies that investigated the use of REBOA compared to resuscitative thoracotomy (RT) with/without REBOA or no-REBOA were eligible. We followed the PRISMA and MOOSE guidelines. Two authors independently extracted data and appraised the risk of bias of included studies. Effect sizes were pooled in a meta-analysis using random-effects models. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Primary outcomes were mortality, volume of infused blood components, health-related quality of life, time to haemorrhage control and any adverse effects. Secondary outcomes were improvement in haemodynamic status and failure/success of REBOA technique.
RESULTS
We included 11 studies (5866 participants) ranging from fair to good quality. REBOA was associated with lower mortality when compared to RT (aOR 0.38; 95% CI 0.20-0.74), whereas no difference was observed when REBOA was compared to no-REBOA (aOR 1.40; 95% CI 0.79-2.46). No significant difference in health-related quality of life between REBOA and RT (p = 0.766). The most commonly reported complications were amputation, haematoma and pseudoaneurysm. Sparse data and heterogeneity of reporting for all other outcomes prevented any estimate.
CONCLUSIONS
Our findings on overall mortality suggest a positive effect of REBOA among non-compressible torso injuries when compared to RT but no differences compared to no-REBOA. Variability in indications and patient characteristics prevents any conclusion deserving further investigation. REBOA should be promoted in specific training programs in an experimental setting in order to test its effectiveness and a randomized trial should be planned.
Topics: Aorta; Balloon Occlusion; Endovascular Procedures; Humans; Injury Severity Score; Shock, Hemorrhagic
PubMed: 34384452
DOI: 10.1186/s13017-021-00386-9 -
Circulation. Cardiovascular Imaging Apr 2018The aorta has 2 main functions, conduit and cushion, and is designed to transmit blood to the periphery and buffer pulsatile stress from ventricular contraction. In the... (Review)
Review
The aorta has 2 main functions, conduit and cushion, and is designed to transmit blood to the periphery and buffer pulsatile stress from ventricular contraction. In the interaction between the structural and functional changes of the aorta, aging and disease processes impact on aortic material properties and hemodynamics. For a comprehensive assessment of changes in aortic structure and function associated with aging and disease, noninvasive cardiovascular imaging techniques, especially magnetic resonance imaging, have recently been developed. Magnetic resonance imaging allows for direct and accurate measurement of different aortic characteristics including structural measures such as aortic area or volume, aortic length, curvature, and aortic wall thickness and functional measures such as aortic strain, distensibility, and pulse wave velocity. Excellent reproducibility of magnetic resonance imaging methods allows us to assess the response of the whole aorta to both pharmacological and nonpharmacological therapies. Aortic flow and functional assessment could be added to clinical routine cardiac magnetic resonance as a comprehensive imaging modality primarily performed for the noninvasive evaluation of left ventricular function, left ventricular load, and vascular/ventricular coupling. New techniques such as 4-dimensional flow could provide and further elucidate the combined age-related effects of altered aortic geometry and function. This following review will describe the pathophysiological aspects of the aorta and the ability, value, and prospects of cardiovascular imaging, especially magnetic resonance imaging, to study age-related changes in aortic structure and function and assess the relationship between these alterations and cardiovascular disease.
Topics: Aging; Aorta; Aortic Diseases; Humans; Magnetic Resonance Imaging; Risk Factors; Vascular Patency; Vascular Stiffness
PubMed: 29653929
DOI: 10.1161/CIRCIMAGING.117.005617 -
Tidsskrift For Den Norske Laegeforening... Dec 2020
Topics: Aorta; Aorta, Abdominal; Humans
PubMed: 33322885
DOI: 10.4045/tidsskr.20.0921 -
Nature Medicine Oct 2020Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed...
Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart-brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.
Topics: Age Factors; Anatomy, Cross-Sectional; Aorta; Biological Specimen Banks; Cardiovascular Diseases; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Heart; Heart Function Tests; Humans; Image Processing, Computer-Assisted; Machine Learning; Magnetic Resonance Imaging; Male; Myocardium; Phenomics; Phenotype; Polymorphism, Single Nucleotide; Sex Factors; Structure-Activity Relationship; United Kingdom
PubMed: 32839619
DOI: 10.1038/s41591-020-1009-y