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Heart (British Cardiac Society) Nov 2015
Review
Topics: Acute Coronary Syndrome; Diagnostic Imaging; Disease Management; Humans; Plaque, Atherosclerotic; Risk Assessment; Secondary Prevention; Stroke
PubMed: 26363045
DOI: 10.1136/heartjnl-2014-307099 -
Current Opinion in Lipidology Oct 2014Atherosclerotic plaque rupture and subsequent acute events, such as myocardial infarction and stroke, contribute to the majority of cardiovascular-related deaths.... (Review)
Review
PURPOSE OF REVIEW
Atherosclerotic plaque rupture and subsequent acute events, such as myocardial infarction and stroke, contribute to the majority of cardiovascular-related deaths. Calcification has emerged as a significant predictor of cardiovascular morbidity and mortality, challenging previously held notions that calcifications stabilize atherosclerotic plaques. In this review, we address this discrepancy through recent findings that not all calcifications are equivalent in determining plaque stability.
RECENT FINDINGS
The risk associated with calcification is inversely associated with calcification density. As opposed to large calcifications that potentially stabilize the plaque, biomechanical modeling indicates that small microcalcifications within the plaque fibrous cap can lead to sufficient stress accumulation to cause plaque rupture. Microcalcifications appear to derive from matrix vesicles enriched in calcium-binding proteins that are released by cells within the plaque. Clinical detection of microcalcifications has been hampered by the lack of imaging resolution required for in-vivo visualization; however, recent studies have demonstrated promising new techniques to predict the presence of microcalcifications.
SUMMARY
Microcalcifications play a major role in destabilizing atherosclerotic plaques. The identification of critical characteristics that lead to instability along with new imaging modalities to detect their presence in vivo may allow early identification and prevention of acute cardiovascular events.
Topics: Calcinosis; Humans; Myocardial Infarction; Plaque, Atherosclerotic; Stroke
PubMed: 25188916
DOI: 10.1097/MOL.0000000000000105 -
Immunological Reviews Nov 2014Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the... (Review)
Review
Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype.
Topics: Animals; Atherosclerosis; Cell Movement; Humans; Macrophage Activation; Macrophages; Phenotype; Plaque, Atherosclerotic; Transcription Factors
PubMed: 25319333
DOI: 10.1111/imr.12218 -
Minerva Urology and Nephrology Apr 2023
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Abdomen; Aorta; Nephrectomy
PubMed: 36286401
DOI: 10.23736/S2724-6051.22.05062-5 -
Biomaterials Nov 2023Atherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation....
Atherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation. Characterization of the morphology and vulnerability of the lesion is essential for effective clinical management. Here, near-infrared auto-photoacoustic (NIRAPA) imaging is shown to detect plaque components and, when combined with ultrasound imaging, to differentiate stable and vulnerable plaque. In an ex vivo study of photoacoustic imaging of excised plaque from 25 patients, 88.2% sensitivity and 71.4% specificity were achieved using a clinically-relevant protocol. In order to determine the origin of the NIRAPA signal, immunohistochemistry, spatial transcriptomics and spatial proteomics were co-registered with imaging and applied to adjacent plaque sections. The highest NIRAPA signal was spatially correlated with bilirubin and associated blood-based residue and with the cytoplasmic contents of inflammatory macrophages bearing CD74, HLA-DR, CD14 and CD163 markers. In summary, we establish the potential to apply the NIRAPA-ultrasound imaging combination to detect vulnerable carotid plaque and a methodology for fusing molecular imaging with spatial transcriptomic and proteomic methods.
Topics: Humans; Plaque, Atherosclerotic; Photoacoustic Techniques; Proteomics; Atherosclerosis; Ultrasonography
PubMed: 37776766
DOI: 10.1016/j.biomaterials.2023.122314 -
Current Medical Research and Opinion Jun 2016Objective Evidence from coronary imaging studies suggests an association between increased atherosclerotic plaque burden and cardiovascular disease (CVD) outcomes. A... (Review)
Review
Relationship between changes in coronary atherosclerotic plaque burden measured by intravascular ultrasound and cardiovascular disease outcomes: a systematic literature review.
Objective Evidence from coronary imaging studies suggests an association between increased atherosclerotic plaque burden and cardiovascular disease (CVD) outcomes. A systematic review was performed to evaluate the relationship between coronary atherosclerotic plaque burden changes measured by intravascular ultrasound (IVUS) and CVD outcomes. Research design and methods Rigorous systematic review methodology was used to identify prospective studies of any design assessing the relationship between atherosclerotic plaque volume (percentage or total atheroma volume [PAV or TAV]) changes and CVD outcomes, using multivariable analyses. Main outcome measures CVD outcomes including major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs). Results Literature searches from inception to February 2015 retrieved 6958 records after de-duplication. From these four studies (14 papers) were included. One study reported a significantly lower rate of CVD outcomes associated with a greater reduction in PAV (hazard ratio [HR] 0.26, 95% confidence interval [CI] 0.07-0.83). One study reported that large plaque volume was significantly associated with a greater risk of major adverse cardiac events (MACEs) (HR 1.73, 95% CI: 1.02-2.96). Similarly, a third study reported a significant increase in MACE with an increase in baseline PAV (HR 1.51, 95% CI: 1.06-2.51). Only one potentially inadequately powered Japanese study did not find a statistically significant relationship between PAV changes and MACE. Conclusions The current evidence suggests an independent and statistically significant association between increases in coronary atherosclerotic plaque burden measured by IVUS and greater long-term risk of future CVD outcomes. However, this evidence comes from a limited number of studies which mainly focus on Japanese populations and populations after PCI. Further large prospective studies are required to confirm these findings.
Topics: Cardiovascular Diseases; Humans; Plaque, Atherosclerotic; Proportional Hazards Models; Prospective Studies; Ultrasonography, Interventional
PubMed: 26949994
DOI: 10.1185/03007995.2016.1162775 -
Journal of Controlled Release :... Sep 2016Atherosclerosis treatments are generally aimed at altering systemic lipid metabolism such that atherogenesis, the formation of plaque, is curtailed. The plaques...
Atherosclerosis treatments are generally aimed at altering systemic lipid metabolism such that atherogenesis, the formation of plaque, is curtailed. The plaques themselves offer some potential therapeutic targets. For example, selective depletion of macrophages, which play a key role in atherogenesis, inhibits plaque formation. However, it has not been possible to take advantage of these targets because the drugs that have been tested have not been sufficiently selective. We have developed a peptide, LyP-1, which specifically targets atherosclerotic plaques, penetrates into plaque interior, and accumulates in plaque macrophages. In tumors, LyP-1 can cause apoptosis in cells that take up the peptide. Here we show, using three different atherosclerosis models in ApoE null mice that prolonged systemic treatment with LyP-1 triggers apoptosis of plaque macrophages and reduces plaque in advanced hypoxic plaques, and that it does so without increasing necrotic core of plaques or causing detectable side effects. We also show that LyP-1 recognizes human plaque. These findings suggest that LyP-1 could serve as a lead compound for the development of a new class of anti-atherosclerosis drugs.
Topics: Animals; Apolipoproteins E; Apoptosis; Female; Humans; Hypoxia; Macrophages; Male; Mice; Mice, Knockout; Peptides, Cyclic; Plaque, Atherosclerotic
PubMed: 27423327
DOI: 10.1016/j.jconrel.2016.07.020 -
European Journal of Vascular and... Nov 2021Mast cells (MCs) are important contributors to atherosclerotic plaque progression. For prospective studies on mast cell contributions to plaque instability, the... (Observational Study)
Observational Study
OBJECTIVE
Mast cells (MCs) are important contributors to atherosclerotic plaque progression. For prospective studies on mast cell contributions to plaque instability, the distribution of intraplaque MCs needs to be elucidated. Plaque stability is generally histologically assessed by dividing the plaque specimen into segments to be scored on an ordinal scale. However, owing to competitive use, studies may have to deviate to adjacent segments, yet intersegment differences of plaque characteristics, especially MCs, are largely unknown. Therefore, the hypothesis that there is no segment to segment difference in MC distribution between atherosclerotic plaque segments was tested, and intersegment associations between MCs and other plaque characteristics was investigated.
METHODS
Twenty-six carotid atherosclerotic plaques from patients undergoing carotid endarterectomy included in the Athero-Express Biobank were analysed. The plaque was divided in 5 mm segments, differentiating between the culprit lesion (segment 0), adjacent segments (-1/+1) and more distant segments (-2/+2) for the presence of MCs. The associations between the intersegment distribution of MCs and smooth muscle cells, macrophage content, and microvessel density in the culprit lesion were studied.
RESULTS
A statistically significant difference in MCs/mm between the different plaque segments (p < .001) was found, with a median of 2.79 (interquartile range [IQR] 1.63 - 7.10) for the culprit lesion, 1.34 (IQR 0.26 - 4.45) for the adjacent segment, and 0.62 (0.14 - 2.07) for the more distant segment. Post hoc analyses showed that intersegment differences were due to differences in MCs/mm between the culprit and adjacent segment (p = .037) and between the culprit lesion and the more distant segment (p < .001). MCs/mm in multiple different segments were positively correlated with microvessel density and macrophage content in the culprit lesion.
CONCLUSION
MC numbers reveal significant intersegment differences in human carotid plaques. Future histological studies on MCs should use a standardised segment for plaque characterisation as plaque segments cannot be used interchangeably for histological MC analyses.
Topics: Aged; Carotid Stenosis; Cell Proliferation; Cohort Studies; Endarterectomy, Carotid; Female; Humans; Male; Mast Cells; Middle Aged; Netherlands; Plaque, Atherosclerotic
PubMed: 34531119
DOI: 10.1016/j.ejvs.2021.07.008 -
Scientific Reports Dec 2020Complications of atherosclerosis are the leading cause of morbidity and mortality worldwide. Various genetically modified mouse models are used to investigate disease...
Complications of atherosclerosis are the leading cause of morbidity and mortality worldwide. Various genetically modified mouse models are used to investigate disease trajectory with classical histology, currently the preferred methodology to elucidate plaque composition. Here, we show the strength of light-sheet fluorescence microscopy combined with deep learning image analysis for characterising and quantifying plaque burden and composition in whole aorta specimens. 3D imaging is a non-destructive method that requires minimal ex vivo handling and can be up-scaled to large sample sizes. Combined with deep learning, atherosclerotic plaque in mice can be identified without any ex vivo staining due to the autofluorescent nature of the tissue. The aorta and its branches can subsequently be segmented to determine how anatomical position affects plaque composition and progression. Here, we find the highest plaque accumulation in the aortic arch and brachiocephalic artery. Simultaneously, aortas can be stained for markers of interest (for example the pan immune cell marker CD45) and quantified. In ApoE-/- mice we observe that levels of CD45 reach a plateau after which increases in plaque volume no longer correlate to immune cell infiltration. All underlying code is made publicly available to ease adaption of the method.
Topics: Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Deep Learning; Disease Models, Animal; Female; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Plaque, Atherosclerotic; Receptors, LDL
PubMed: 33299076
DOI: 10.1038/s41598-020-78632-4 -
Journal of Clinical Lipidology 2020Reducing the residual risk of cardiovascular (CV) events in patients with atherosclerosis continues to be a challenge. Thus, understanding how cholesterol spontaneously... (Review)
Review
Reducing the residual risk of cardiovascular (CV) events in patients with atherosclerosis continues to be a challenge. Thus, understanding how cholesterol spontaneously self assembles into metastable structures that evolve into flat plate cholesterol crystals (CCs) in atherosclerotic plaque, and why they fundamentally change the nature of the disease provides a paradigm for the development of additional therapies. Specifically, flat plate CCs that form within lysosomes of macrophages may become large enough to disrupt lysosomal membranes leading to the release of cathepsin B and CCs fragments directly into the cytosol. In the cytosol, the surface of flat plate CCs can be recognized by complosome that together with cathepsin B may trigger pyrin domain-containing inflammasome. In addition, flat plate CCs in the cytosol may trigger caspase 8 initiating apoptosis. In the interstitial space, the surface of flat plate CCs can be recognized by complement and receptors on proinflammatory cells, and larger fragments can induce "frustrated phagocytosis" that together perpetuate inflammatory injury. In addition, rapid transition of metastable CCs into large flat plate CCs within lipid rich plaques can lead to traumatic injury by expansion of the plaque's necrotic core causing plaque disruption or rupture that may precipitate further inflammation. Other crystalloids in plaque including monosodium urate and calcium phosphate crystals can augment these processes. Thus, therapies that further limit the deposition of cholesterol in the vascular bed, slow the formation of flat plate CCs and inhibit crystal-induced inflammation may lead to further reduce CV risk in patients with established CV disease.
Topics: Animals; Atherosclerosis; Cholesterol; Humans; Plaque, Atherosclerotic
PubMed: 32792218
DOI: 10.1016/j.jacl.2020.07.003