Atherosclerosis Research Research Articles

Omics research in atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid deposition within the arterial intima, as well as fibrous tissue proliferation and calcification. AS has long been recognized as one of the primary pathological foundations of cardiovascular diseases in humans. Its pathogenesis is intricate and not yet fully elucidated. Studies have shown that AS is associated with oxidative stress, inflammatory response, lipid deposition, and changes in cell phenotype. Unfortunately, there is currently no effective prevention or targeted treatment for AS. The rapid advancement of omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, has opened up novel avenues to elucidate the fundamental pathophysiology and associated mechanisms of AS. Here, we review articles published over the past decade and focus on the current status, challenges, limitations, and prospects of omics in AS research and clinical practice. Emphasizing potential targets based on omics technologies will improve our understanding of this pathological condition and assist in the development of potential therapeutic approaches for AS-related diseases.

The ASAP study: association of atherosclerosis with pathobiology in a caucasian cohort—a study of 3400 autopsy reports

Cardiovascular plaques result from atherosclerosis. Autopsy investigations of unnatural deaths provide atherosclerosis research. A Central European cohort was studied in a cross-sectional study to determine the origin of atherosclerosis and the link between arterial status and pathobiological variables. This study incorporated 3400 autopsy reports (n = 2318 men; aged 0─96 years; 1928─2010) of persons who died by unnatural causes (suicide, homicide, accident). Age, sex, BMI, abdominal fat thickness, and arterial status of six vascular areas were gathered. The arterial state was divided into five subgroups according to its status. BMI declined from 22.82 kg/m2 in 1931 to 18.43 kg/m2 in 1947, then increased to 27.88 kg/m2 in 2005. Atherosclerotic degeneration begins in the abdominal aorta, then the thoracic, coronary, carotid, ascending, and cerebral arteries. All blood arteries deteriorated faster in men than women until 55. Abdominal aorta damage was the fastest in both sexes. Age is the biggest predictor of atherosclerosis, followed by sex, overweight, and abdominal thickness, according to logistic regression. This is the largest Central European autopsy investigation of six vascular areas. Both sexes develop atherosclerosis in the abdominal aorta in the first decade of life. Being overweight increases the risk. The findings of this study aid healthcare providers in personalized therapy.

Deep Learning-Based Detection of Carotid Plaques Informs Cardiovascular Risk Prediction and Reveals Genetic Drivers of Atherosclerosis.

Atherosclerotic cardiovascular disease, the leading cause of global mortality, is driven by lipid accumulation and plaque formation within arterial walls. Carotid plaques, detectable via ultrasound, are a well-established marker of subclinical atherosclerosis. In this study, we trained a deep learning model to detect plaques in 177,757 carotid ultrasound images from 19,499 UK Biobank (UKB) participants (aged 47-83 years) to assess the prevalence, risk factors, prognostic significance, and genetic architecture of carotid atherosclerosis in a large population-based cohort. The model demonstrated high performance metrics with accuracy, sensitivity, specificity, and positive predictive value of 89.3%, 89.5%, 89.2%, and 82.9%, respectively, identifying carotid plaques in 45% of the population. Plaque presence and count were significantly associated with future cardiovascular events over a median follow-up period of up to 7 years, leading to improved risk reclassification beyond established clinical prediction models. A genome-wide association study (GWAS) meta-analysis of carotid plaques (29,790 cases, 36,847 controls) uncovered two novel genomic loci (p < 5×10 -8 ) with downstream analyses implicating lipoprotein(a) and interleukin-6 signaling, both targets of investigational drugs in advanced clinical development. Observational and Mendelian randomization analyses showed associations between smoking, low-density-lipoprotein (LDL) cholesterol, and high blood pressure and the odds of carotid plaque presence. Our study underscores the potential of carotid plaque assessment for improving cardiovascular risk prediction, provides novel insights into the genetic basis of subclinical atherosclerosis, and offers a valuable resource for advancing atherosclerosis research at the population scale.

Factor XI/XIa Inhibitors: What We Now Know

The emerging class of agents targeting factor XI/XIa offers the paradigm-shifting possibility of ‘haemostasis-sparing anticoagulation’: protection from stroke and other thromboembolic events with a benign bleeding profile. With three investigational agents now into late-phase development, two presentations delivered at the European Society of Cardiology (ESC) Congress 2024, held in London, UK, have added to our knowledge of this innovative and diverse class. The first of these presentations shared the full data from the OCEANIC-AF Phase III trial, in which the small molecule factor XIa inhibitor asundexian was compared with the factor Xa inhibitor apixaban for stroke prevention in atrial fibrillation, and reviewed the probable reasons for the failure of this trial to meet its efficacy endpoint. The second presentation was a secondary analysis from the AZALEA-TIMI 71 Phase II trial, in which the safety of the monoclonal antibody factor XI inhibitor abelacimab was compared with that of the factor Xa inhibitor rivaroxaban in patients with atrial fibrillation undergoing invasive procedures. This article is based on a post-ESC interview with Jeffrey I. Weitz, Professor of Medicine and Biochemistry and Biomedical Sciences at McMaster University, Canada; Canada Research Chair (Tier 1) in Thrombosis and the Heart and Stroke Foundation; J.F. Mustard Chair in Cardiovascular Research; Executive Director of the Thrombosis and Atherosclerosis Research Institute (TaARI), in Hamilton, Canada; and Secretary General of the International Society on Thrombosis and Haemostasis (ISTH). It assesses the current status and future prospects of the factor XI/XIa inhibitor class in light of these recent developments.

Atherosclerosis on a Chip: A 3-Dimensional Microfluidic Model of Early Arterial Events in Human Plaques.

Realistic reconstruction of the in vivo human atherosclerotic environment requires the coculture of different cell types arranged in atherosclerotic vessel-like structures with exposure to flow and circulating cells, presenting challenges for disease modeling. This study aimed to develop a 3-dimensional tubular microfluidic model with quadruple coculture of human aortic smooth muscle cells, human umbilical cord vein endothelial cells, and foam cells to recreate a complex human atherosclerotic vessel in vitro to study the effects of flow and circulating immune cells. We developed a coculture protocol utilizing BFP (blue fluorescent protein)-labeled human aortic smooth muscle cells, GFP (green fluorescent protein)-labeled human umbilical cord vein endothelial cells, and THP-1 macrophage-derived, Dil-labeled oxidized LDL (low-density lipoprotein) foam cells within a fibrinogen/collagen I-based 3-dimensional ECM (extracellular matrix). Perfusion experiments were conducted for 24 hours on both atherosclerotic vessels and healthy vessels (BFP-labeled human aortic smooth muscle cells and GFP-labeled human umbilical cord vein endothelial cells without foam cells). Additionally, perfusion with circulating THP-1 monocytes was performed to observe cell extravasation and recruitment. The resulting vessels displayed early lesion morphology, with a layered composition including an endothelium and media, and foam cells accumulating in the subendothelial space. The layered wall composition of both atherosclerotic and healthy vessels remained stable under perfusion. Circulating THP-1 monocytes demonstrated cell extravasation into the atherosclerotic vessel wall and recruitment to the foam cell core. The qPCR analysis indicated increased expression of atherosclerosis markers in the atherosclerotic vessels and adaptation of vascular smooth muscle cell migration in response to flow and the plaque microenvironment, compared with control vessels. The human 3-dimensional atherosclerosis model demonstrated stability under perfusion and allowed for the observation of immune cell behavior, providing a valuable tool for the atherosclerosis research field.

Cryptococcosis, tuberculosis, and a kidney cancer fail to fit the atherosclerosis paradigm for foam cell lipid content.

Foam cells are dysfunctional, lipid-laden macrophages associated with chronic inflammation of diverse origin. The long-standing paradigm that foam cells are cholesterol-laden derives from atherosclerosis research. We previously showed that, in tuberculosis, foam cells surprisingly accumulate triglycerides. Here, we utilized bacterial ( Mycobacterium tuberculosis ), fungal ( Cryptococcus neoformans ), and human papillary renal cell carcinoma (pRCC) models to address the need for a new explanation of foam cell biogenesis. We applied mass spectrometry-based imaging to assess the spatial distribution of storage lipids relative to foam-cell-rich areas in lesional tissues, and we characterized lipid-laden macrophages generated under corresponding in vitro conditions. The in vivo data and the in vitro findings showed that cryptococcus-infected macrophages accumulate triglycerides, while macrophages exposed to pRCC- conditioned-medium accumulated both triglycerides and cholesterol. Moreover, cryptococcus- and mycobacterium-infected macrophages accumulated triglycerides in different ways. Collectively, the data show that the molecular events underlying foam cell formation are specific to disease and microenvironment. Since foam cells are potential therapeutic targets, recognizing that their formation is disease-specific opens new biomedical research directions.

Unlocking the Potential of Pig Models in Atherosclerosis Research: Insights, Applications, and Future Directions

Background: Choosing an adequate model for studying human diseases, such as atherosclerosis, poses significant challenges. While small animals like mice and rats have been widely employed, the suitability of these models for specific research goals and objectives may vary. Furthermore, differences in lipid physiology and platelet quantities between rodents and humans can impact the translational relevance of findings. Large animal models, particularly swine, offer physiological similarities to humans and present a more accurate representation of clinical complications such as acute myocardial infarction and stroke. Objectives: This review aims to comprehensively evaluate the utility of the swine model in atherosclerosis research by examining the physiological and cardiovascular similarities between swine and humans. It also seeks to explore the significance of hyperlipidemia and atherosclerosis in pigs, considering both natural and genetically engineered mutant pig models. Additionally, the review aims to provide an overview of the potential applications of swine models in atherosclerosis regression research, thereby highlighting the advantages and limitations of employing swine in atherosclerosis studies. Conclusion: This review offers insights into the potential of the swine model as a valuable and versatile tool for expanding the horizons of atherosclerosis research, emphasizing the need for further exploration and utilization of large animal models in cardiovascular research.

Targeting macrophages with multifunctional nanoparticles to detect and prevent atherosclerotic cardiovascular disease.

Despite the emergence of novel diagnostic, pharmacological, interventional, and prevention strategies, atherosclerotic cardiovascular disease remains a significant cause of morbidity and mortality. Nanoparticle (NP)-based platforms encompass diverse imaging, delivery, and pharmacological properties that provide novel opportunities for refining diagnostic and therapeutic interventions for atherosclerosis at the cellular and molecular levels. Macrophages play a critical role in atherosclerosis and therefore represent an important disease-related diagnostic and therapeutic target, especially given their inherent ability for passive and active NP uptake. In this review, we discuss an array of inorganic, carbon-based, and lipid-based NPs that provide magnetic, radiographic, and fluorescent imaging capabilities for a range of highly promising research and clinical applications in atherosclerosis. We discuss the design of NPs that target a range of macrophage-related functions such as lipoprotein oxidation, cholesterol efflux, vascular inflammation, and defective efferocytosis. We also provide examples of NP systems that were developed for other pathologies such as cancer and highlight their potential for repurposing in cardiovascular disease. Finally, we discuss the current state of play and the future of theranostic NPs. Whilst this is not without its challenges, the array of multifunctional capabilities that are possible in NP design ensures they will be part of the next frontier of exciting new therapies that simultaneously improve the accuracy of plaque diagnosis and more effectively reduce atherosclerosis with limited side effects.

Awareness of Atherosclerosis and Cardiovascular Events Among Undergraduate Healthcare Professionals

The word atherosclerosis consists of two parts: atherosis (accumulation of fats accompanied by several macrophages) and sclerosis (fibrosis layer comprising smooth muscle cells. The presence of hyperlipaemia is the major risk issue factor for coronary artery disease. In 2016 advances in atherosclerosis research were focused on the discovery and validation of newly targeted genetics and mechanistic connection to atherothrombotic heart diseases. The Survey on awareness about the risk factors and complications of liver cirrhosis among college students was conducted using a Google form link. We have distributed our survey among 100 college students. Pie charts and Bar diagrams were used to represent output variables. Results showed that the knowledge of cardiovascular 54.00 % said No and 46.00 % said yes. Stroke caused due to lack of blood supply to 44.00 % said heart, 50.00 % said brain, and 6.00 % said I don’t know. These findings conclude that the majority of the population is unaware of the risk factors such as obesity, LDL, and family history, which lead to the development of atherosclerosis, but only a few populations are aware of stress, smoking, coronary heart attack, cholesterol, sleep apnea, HDL, work pressure, physical activity, heart disease, and coronary disease that leads to atherosclerosis.

Effect of lipid-lowering therapy on carotid plaque burden in older adults

BackgroundLittle is known about the benefits of lipid-lowering medications in those age ≥ 75 years. We assessed the effect of lipid-lowering medications on progression to severe atherosclerosis in patients age > 75. MethodsData was retrospectively obtained from the Stroke Prevention & Atherosclerosis Research Centre, Canada. Atherosclerosis burden was measured as carotid total plaque area (TPA), a powerful predictor of cardiovascular risk. Survival time free of severe atherosclerosis (SFSA) was defined as the period when TPA remained <1.19 cm2. Kaplan–Meier, multiple Cox proportional hazard and hierarchical mixed-effect models were used to determine the effects of lipid-lowering medications on progression to severe atherosclerosis. ResultsIn total 1404 cases (mean age 81 ± 4 years; women 52%) were included. Those taking lipid-lowering medications were more likely to have a history of diabetes and a higher burden of atherosclerosis at baseline. In Kaplan–Meier analysis, the SFSA was significantly longer in those receiving lipid-lowering therapy. In multivariable-adjusted analyses, those not receiving lipid lowering therapy (irrespective of their vascular disease at baseline) were more likely to have TPA > 1.19 cm2 (hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.09,0.71). Similar findings were observed in mixed effects models when plaque progression was defined as any change >0.05 cm2 per year (odds ratio (OR):2.17, 95% CI:1.38,3.57). ConclusionLipid-lowering therapy is effective in controlling the burden of atherosclerosis among older adults with and without vascular disease. The measurement of plaque burden can guide selection and follow-up of those who may benefit from treatment.

A targeted proteomics method for quantifying plasma apolipoprotein kinetics in individual mice using stable isotope labeling

Altered apolipoprotein kinetics play a critical role in promoting dyslipidemia and atherogenesis. Human apolipoprotein kinetics have been extensively evaluated, but similar studies in mice are hampered by the lack of robust methods suitable for the small amounts of blood that can be collected at sequential time points from individual mice. We describe a targeted liquid chromatography tandem mass spectrometry method for simultaneously quantifying the stable isotope enrichment of several apolipoproteins represented by multiple peptides in serial blood samples (15 μl each) obtained after retro-orbital injection of 13C6,15N2-lysine (Lys8) in mice. We determined apolipoprotein fractional clearance rates (FCRs) and production rates (PRs) in WT mice and in two genetic models widely used for atherosclerosis research, LDL receptor–deficient (Ldlr−/−) and apolipoprotein E–deficient (Apoe−/−) mice. Injection of Lys8 produced a unique and readily detectable mass shift of labeled compared with unlabeled peptides with sensitivity allowing robust kinetics analyses. Ldlr−/− mice showed slower FCRs of APOA1, APOA4, total APOB, APOB100, APOCs, APOE and APOM, while FCRs of APOA1, APOB100, APOC2, APOC3, and APOM were not lower in Apoe−/− mice versus WT mice. APOE PR was increased in Ldlr−/− mice, and APOB100 and APOA4 PRs were reduced in Apoe−/− mice. Thus, our method reproducibly quantifies plasma apolipoprotein kinetics in different mouse models. The method can easily be expanded to include a wide range of proteins in the same biospecimen and should be useful for determining the kinetics of apolipoproteins in animal models of human disease.

A critical appreciation of pathway analysis in atherosclerotic disease. Cellular phenotypic plasticity as an illustrative example

The rapid advancements in genome-scale (omics) techniques has created significant opportunities to investigate complex disease mechanisms in tissues and cells. Nevertheless, interpreting -omics data can be challenging, and pathway enrichment analysis is a frequently used method to identify candidate molecular pathways that drive gene expression changes. With a growing number of -omics studies dedicated to atherosclerosis, there has been a significant increase in studies and hypotheses relying on enrichment analysis.This brief review discusses the benefits and limitations of pathway enrichment analysis within atherosclerosis research. We highlight the challenges of identifying complex biological processes, such as cell phenotypic switching, within -omics data. Additionally, we emphasize the need for more comprehensive and curated gene sets that reflect the biological complexity of atherosclerosis.Pathway enrichment analysis is a valuable tool for gaining insights into the molecular mechanisms of atherosclerosis. Nevertheless, it is crucial to remain aware of the intrinsic limitations of this approach. By addressing these weaknesses, enrichment analysis in atherosclerosis can lead to breakthroughs in identifying the mechanisms of disease progresses, the identification of key driver genes, and consequently, advance personalized patient care.

Association of Common Foods with Inflammation and Mortality: Analysis from a Large Prospective Cohort Study.

Some dietary patterns are associated with inflammation, while others lower inflammation and improve health. However, many people cannot follow a complete, healthy diet. Therefore, this study's aim was to identify specific foods associated chronic inflammation and mortality. The study used Multi-Ethnic Study of Atherosclerosis (MESA) research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. Three plant-based and three animal-based MESA food categories were chosen based on perceived availability in the western diet. The assessed food categories were avocado, ham, sausage, eggs, greens, and broccoli. Inflammatory markers assessed were interleukin-6 (IL-6), fibrinogen antigen, C-reactive protein, D-Dimer, interleukin-2, matrix metalloproteinase 3, necrosis factor-a soluble receptors, oxidized LDL (oxLDL), and total homocysteine. The primary outcome was the multivariable association of foods and inflammatory markers with all-cause mortality. All inflammatory makers, except oxLDL, were associated with mortality in univariate analysis. The effect was largest with IL-6 and D-dimer. The category of broccoli had the most consistent association in univariate analyses with lower inflammation and lower mortality odds. Low and high broccoli consumption versus no consumption were associated with lower mortality odds in the multivariable models with IL-6 and D-dimer. Consumption of the MESA-defined food category "broccoli" (i.e., broccoli, cabbage, cauliflower, brussels sprouts, sauerkraut, and kimchee) was associated with lower inflammation and lower mortality odds. These findings should be validated in randomized controlled trials testing a "food is medicine" approach to identify which, if any, of these foods may have potential as an herbal therapeutic for chronic inflammation.

Sensitivity analysis of the mechanical properties on atherosclerotic arteries rupture risk with an artificial neural network method

Considering the differences between individuals, in this paper, an uncertainty analysis model for predicting rupture risk of atherosclerotic arteries is established based on a back-propagation artificial neural network. The influence of isotropy and anisotropy on the rupture risk of atherosclerotic arteries is analyzed, and the results demonstrate the effectiveness of the artificial neural network in predicting the rupture risk. Moreover, the rupture risk of atherosclerotic arteries at different inflation sizes are simulated. This study contributes to a better understanding of the underlying mechanisms of atherosclerotic arteries rupture and promotes the advancement of artificial neural networks in atherosclerosis research.

Extracellular Vesicles as Mediators in Atherosclerotic Cardiovascular Disease.

Atherosclerosis is a chronic inflammatory disease of the arterial intima, characterized by accumulation of lipoproteins and accompanying inflammation, leading to the formation of plaques that eventually trigger occlusive thrombotic events, such as myocardial infarction and ischemic stroke. Although many aspects of plaque development have been elucidated, the role of extracellular vesicles (EVs), which are lipid bilayer-delimited vesicles released by cells as mediators of intercellular communication, has only recently come into focus of atherosclerosis research. EVs comprise several subtypes that may be differentiated by their size, mode of biogenesis, or surface marker expression and cargo. The functional effects of EVs in atherosclerosis depend on their cellular origin and the specific pathophysiological context. EVs have been suggested to play a role in all stages of plaque formation. In this review, we highlight the known mechanisms by which EVs modulate atherogenesis and outline current limitations and challenges in the field.

Lipoprotein (a) in atherosclerosis: A bibliometric and visualization analysis

Abstract: Lipoprotein (a) [Lp (a)] is a complex polymorphic lipoprotein consisting of one low-density lipoprotein particle with one molecule of apolipoprotein B100 and another apolipoprotein (a) linked by a disulfide bond. In recent years, due to its causal role in premature atherosclerotic cardiovascular diseases and calcified aortic stenosis, Lp (a) has attracted more and more attention. Our study aimed to illustrate the trend of Lp (a) research in atherosclerosis (AS) through bibliometric analysis. The Science Citation Index-Expanded was used to locate Lp (a) and AS studies published between December 1, 2012 and December 1, 2022. VOSviewer and CiteSpace bibliometric software packages were used to analyze literature information. LP (a) has seen an overall increase in annual publications. The United States had the highest number of publications worldwide, with 192 publications. The University of California, San Diego, has contributed significantly to Lp (a) with 29 publications and led research collaboration. In the past few decades, there has been close collaboration between countries or regions, institutions, and authors. In addition, the European Heart Journal was the most cited, followed by the Journal of Lipid Research and AS with 2033, 1096, and 806 citations, respectively. Recent studies were on genes and lipid-lowering therapies. Our study comprehensively evaluated the research status and trends of Lp (a) in AS worldwide for the first time and provided a valuable reference for clinical researchers.

Confounding Effects of Tamoxifen: Cautionary and Practical Considerations for the Use of Tamoxifen-Inducible Mouse Models in Atherosclerosis Research-Brief Report.

In recent years, fate-mapping lineage studies in mouse models have led to major advances in vascular biology by allowing investigators to track specific cell populations in vivo. One of the most frequently used lineage tracing approaches involves tamoxifen-inducible CreERT-LoxP systems. However, tamoxifen treatment can also promote effects independent of Cre recombinase activation, many of which have not been fully explored. To elucidate off-target effects of tamoxifen, male and female mice were either unmanipulated or injected with tamoxifen or corn oil. All mice received PCSK9 (proprotein convertase subtilisin/kexin type 9)-AAV (adeno-associated virus) injections and a modified Western diet to induce hypercholesterolemia. After 2 weeks, serum cholesterol and liver morphology were assessed. To determine the duration of any tamoxifen effects in long-term atherosclerosis experiments, mice received either 12 days of tamoxifen at baseline or 12 days plus 2 sets of 5-day tamoxifen boosters; all mice received PCSK9-AAV injections and a modified Western diet to induce hypercholesterolemia. After 24 weeks, serum cholesterol and aortic sinus plaque burden were measured. After 2 weeks of atherogenic treatment, mice injected with tamoxifen demonstrated significantly reduced serum cholesterol levels compared with uninjected- or corn oil-treated mice. However, there were no differences in PCSK9-mediated knockdown of LDL (low-density lipoprotein) receptors between the groups. Additionally, tamoxifen-treated mice exhibited significantly increased hepatic lipid accumulation compared with the other groups. Finally, the effects of tamoxifen remained for at least 8 weeks after completion of injections, with mice demonstrating persistent decreased serum cholesterol and impaired atherosclerotic plaque formation. In this study, we establish that tamoxifen administration results in decreased serum cholesterol, decreased plaque formation, and increased hepatic lipid accumulation. These alterations represent significant confounding variables in atherosclerosis research, and we urge future investigators to take these findings into consideration when planning and executing their own atherosclerosis experiments.

The common marmoset monkey as a promising animal model for atherosclerosis research

The common marmoset monkey as a promising animal model for atherosclerosis research

An adaptively weighted ensemble of multiple CNNs for carotid ultrasound image segmentation

Carotid atherosclerotic plaques cause stroke when plaques rupture and clog the blood vessels that deliver blood to brain. Ultrasound measurements (i.e. total-plaque-area and intima-media-thickness) are mainly used to monitor the progression and regression of plaques. Recently, deep learning has provided powerful tools for ultrasound carotid image segmentation. However, the performances of deep learning models vary on different network architectures. In this paper, we report on the development of an adaptively weighted ensemble of multiple convolutional neural networks (CNNs) for carotid ultrasound image segmentation, aiming at combining the advantages of different CNN models to achieve higher accuracy and better generalization performance. During the joint training of the ensemble networks, the model weights and sample weights were combined to improve the segmentation performance. This adaptively weighted ensemble algorithm was applied to three UNet++ models with different backbones (ResNet152, DenseNet169 and VGG19), and evaluated on 510 carotid ultrasound images from 144 subjects who were followed in the Stroke Prevention and Atherosclerosis Research Centre (SPARC, London, Canada). The experimental results show that our method increases the segmentation accuracy, and reduces the distance errors as compared to using a single classifier, three ensemble algorithms (average weighting, majority voting and SegNet-UNet+) and a published carotid segmentation algorithm. With high accuracy and low variance, the proposed adaptively weighted ensemble model could be used to measure carotid plaques in clinical practice and clinical trials.

Validating human and mouse tissues commonly used in atherosclerosis research with coronary and aortic reference tissue: similarities but profound differences in disease initiation and plaque stability

ObjectiveCharacterization of the atherosclerotic process fully relies on histological evaluation and staging through a consensus grading system. So far, a head-to-head comparison of atherosclerotic process in experimental models and tissue resources commonly applied in atherosclerosis research with the actual human atherosclerotic process is missing. Material and MethodsAspects of the atherosclerotic process present in established murine atherosclerosis models and human carotid endarterectomy specimen were systematically graded using the modified American Heart Association histological classification (Virmani classification). Aspects were aligned with the atherosclerotic process observed in human coronary artery and aortic atherosclerosis reference tissues that were available through biobanks based on human tissue/organ donor material. ResultsApart from absent intraplaque hemorrhages in aortic lesions, the histological characteristics of the different stages of human coronary and aortic atherosclerosis are similar. Carotid endarterectomy samples all represent end-stage “fibrous calcified plaque” lesions, although secondary, progressive, and vulnerable lesions with gross morphologies similar to coronary/aortic lesions occasionally present along the primary lesions. For the murine lesions, clear histological parallels were observed for the intermediate lesion types (“pathological intimal thickening,” and “early fibroatheroma”). However, none of the murine lesions studied progressed to an equivalent of late fibroatheroma or beyond. Notable contrasts were observed for disease initiation: whereas disease initiation in humans is characterized by a mesenchymal cell influx in the intima, the earliest murine lesions are exclusively intimal, with subendothelial accumulation foam cells. A mesenchymal (and medial) response are absent. In fact, it is concluded that the stage of “adaptive intimal thickening” is absent in all mouse models included in this study. ConclusionsThe Virmani classification for coronary atherosclerosis can be applied for systematically grading experimental and clinical atherosclerosis. Application of this histological grading tool shows clear parallels for intermediate human and murine atherosclerotic lesions. However, clear contrasts are observed for disease initiation, and late stage atherosclerotic lesions. Carotid endarterectomy all represent end-stage fibrous calcified plaque lesions, although secondary earlier lesions may present in a subset of samples.