RESUMEN
BACKGROUND AND AIMS: Systemic low-grade inflammation, measured by plasma high-sensitivity C-reactive protein (hsCRP) levels, is an important risk factor for atherosclerotic cardiovascular disease (ASCVD). To date, however, it is unknown whether plasma hsCRP is associated with adverse histological plaque features. METHODS: Plaques were derived during carotid endarterectomy. Patients with hsCRP levels ≥2 mg/L were evaluated for pro-inflammatory and adverse plaque characteristics, as well as future ASCVD events, and compared with patients with low hsCRP levels. Logistic and linear regression analyses in addition to subdistribution hazard ratios were conducted, adjusted for cardiovascular risk factors. RESULTS: A total of 1096 patients were included, of which 494 (46.2 %) had hsCRP levels ≥2 mg/L. Elevated hsCRP levels 2 mg/L were independently associated with levels of plaque interleukin 6, beta coefficient of 109.8 (95 % confidence interval (CI): 33.4, 186.5; p = 0.005) pg/L, interleukin 8 levels, 194.8 (110.4, 378.2; p = 0.03) pg/L and adiponectin plaque levels, -16.8 (-30.1, -3.6; p = 0.01) µg/L, compared with plaques from patients with low hsCRP levels. Histological analysis revealed increased vessel density in high hsCRP patients, odds ratio (OR) of 1.57 (1.20, 2.09; p = 0.001), larger lipid core, 1.35 (1.02, 1.73; p = 0.04), and increased macrophage content, 1.32 (1.02, 1.73; p = 0.04). Over a 3-year follow-up period, hsCRP levels ≥2 mg/L were associated with a hazard ratio of 1.81 (1.03, 3.16; p = 0.04) for coronary artery disease event risk. CONCLUSIONS: The distinct inflammatory and histological features observed in carotid plaques among individuals with hsCRP levels ≥2 mg/L underscore the utility of plasma hsCRP as a potent identifier for patients harboring high-risk plaques.
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Biomarcadores , Proteína C-Reactiva , Endarterectomía Carotidea , Inflamación , Fenotipo , Placa Aterosclerótica , Humanos , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Masculino , Placa Aterosclerótica/sangre , Femenino , Anciano , Persona de Mediana Edad , Biomarcadores/sangre , Inflamación/sangre , Mediadores de Inflamación/sangre , Factores de Riesgo , Adiponectina/sangre , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/patología , Interleucina-6/sangre , Interleucina-8/sangre , Arterias Carótidas/patología , Modelos Logísticos , Pronóstico , Receptores InmunológicosRESUMEN
BACKGROUND: Various factors, including blood, inflammatory, infectious, and immune factors, can cause ischemic stroke. However, the primary cause is often the instability of cervical arteriosclerosis plaque. It is estimated that 18-25% of ischemic strokes are caused by the rupture of carotid plaque.1 Plaque stability is crucial in determining patient prognosis. Developing a highly accurate, non-invasive, or minimally invasive technique to assess carotid plaque stability is crucial for diagnosing and treating stroke.Previous research by our group has demonstrated that the expression levels of CHOP (C/EBP homologous protein) and GRP78 (glucose-regulated protein 78) are correlated with the stability of atherosclerotic plaques.2 OBJECT: This research assesses changes in GRP78 and CHOP expressions in human umbilical vein endothelial cells(HUVEC) following experiments within the hemodynamic influencing factors test system. Additionally, it includes conducting an empirical study on the impact of blood flow shear force on the stability of human carotid atherosclerotic plaques. The objective is to explore the implications of blood flow shear force on the stability of carotid atherosclerotic plaques. METHOD: The hemodynamic influencing factors test bench system was configured with low (Group A, 4 dyns/cm²), medium (Group B, 8 dyns/cm²), and high shear force groups (Group C, 12 dyns/cm²). Relative expression levels of GRP78 and CHOP proteins in human umbilical vein endothelial cells were measured using Western blot analysis, and quantitative analysis of GRP78 and CHOP mRNA was conducted using RT-qPCR. Meanwhile, plaques from 60 carotid artery patients, retrieved via Carotid Endarterectomy (CEA), were classified into stable (S) and unstable (U) groups based on pathological criteria. Shear force at the carotid bifurcation was measured preoperatively using ultrasound. Western blot and RT-qPCR were used to analyze the relative expression levels of GRP78 and CHOP proteins and mRNA, respectively, in the plaque specimens from both groups. RESULT: Expression levels of GRP78, CHOP proteins, and their mRNAs were assessed in groups A, B, and C via Western blot and RT-qPCR. Results showed that in the low-shear group, all markers were elevated in group A compared to groups B and C. Statistical analysis revealed significantly lower shear forces at the carotid bifurcation in group U compared to group S. In group U plaques, GRP78 and CHOP expressions were significantly higher in group U than in group S. CONCLUSION: Blood flow shear forces variably affect the expression of GRP78 and CHOP proteins, as well as their mRNA levels, in vascular endothelial cells. The lower the shear force and fluid flow rate, the higher the expression of GRP78 and CHOP, potentially leading to endoplasmic reticulum stress(ERS), which may destabilize the plaque.
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Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico , Placa Aterosclerótica , Factor de Transcripción CHOP , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/cirugía , Enfermedades de las Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/patología , Estenosis Carotídea/fisiopatología , Estenosis Carotídea/metabolismo , Células Cultivadas , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , ARN Mensajero/metabolismo , Estrés Mecánico , Factor de Transcripción CHOP/metabolismo , Factor de Transcripción CHOP/genéticaRESUMEN
BACKGROUND: Metabolism is increasingly recognized as a key regulator of the function and phenotype of the primary cellular constituents of the atherosclerotic vascular wall, including endothelial cells, smooth muscle cells, and inflammatory cells. However, a comprehensive analysis of metabolic changes associated with the transition of plaque from a stable to a hemorrhaged phenotype is lacking. METHODS: In this study, we integrated two large mRNA expression and protein abundance datasets (BIKE, n = 126; MaasHPS, n = 43) from human atherosclerotic carotid artery plaque to reconstruct a genome-scale metabolic network (GEM). Next, the GEM findings were linked to metabolomics data from MaasHPS, providing a comprehensive overview of metabolic changes in human plaque. RESULTS: Our study identified significant changes in lipid, cholesterol, and inositol metabolism, along with altered lysosomal lytic activity and increased inflammatory activity, in unstable plaques with intraplaque hemorrhage (IPH+) compared to non-hemorrhaged (IPH-) plaques. Moreover, topological analysis of this network model revealed that the conversion of glutamine to glutamate and their flux between the cytoplasm and mitochondria were notably compromised in hemorrhaged plaques, with a significant reduction in overall glutamate levels in IPH+ plaques. Additionally, reduced glutamate availability was associated with an increased presence of macrophages and a pro-inflammatory phenotype in IPH+ plaques, suggesting an inflammation-prone microenvironment. CONCLUSIONS: This study is the first to establish a robust and comprehensive GEM for atherosclerotic plaque, providing a valuable resource for understanding plaque metabolism. The utility of this GEM was illustrated by its ability to reliably predict dysregulation in the cholesterol hydroxylation, inositol metabolism, and the glutamine/glutamate pathway in rupture-prone hemorrhaged plaques, a finding that may pave the way to new diagnostic or therapeutic measures.
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Enfermedades de las Arterias Carótidas , Ácido Glutámico , Glutamina , Macrófagos , Redes y Vías Metabólicas , Fenotipo , Placa Aterosclerótica , Humanos , Glutamina/metabolismo , Ácido Glutámico/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/genética , Rotura Espontánea , Arterias Carótidas/patología , Arterias Carótidas/metabolismo , Metabolómica , Bases de Datos Genéticas , Inflamación/metabolismo , Inflamación/genética , Inflamación/patología , Metabolismo Energético , Conjuntos de Datos como Asunto , MasculinoRESUMEN
The prevalence of cardiovascular diseases (CVDs) is increasing in the last decades, even is the main cause of death in first world countries being atherosclerosis one of the principal triggers. Therefore, there is an urgent need to decipher the underlying mechanisms involved in atherosclerosis progression. In this respect, microRNAs dysregulation is frequently involved in the progression of multiple diseases including CVDs. Our aim was to demonstrate that let-7d-5p unbalance could contribute to the pathophysiology of atherosclerosis and serve as a potential diagnostic biomarker. We evaluated let-7d-5p levels in vascular biopsies and exosome-enriched extracellular vesicles (EVs) from patients with carotid atherosclerosis and healthy donors. Moreover, we overexpressed let-7d-5p in vitro in vascular smooth muscle cells (VSMCs) to decipher the targets and the underlying mechanisms regulated by let-7d-5p in atherosclerosis. Our results demonstrate that let-7d-5p was significantly upregulated in carotid plaques from overweight patients with carotid atherosclerosis. Moreover, in EVs isolated from plasma, we found that let-7d-5p levels were increased in carotid atherosclerosis patients compared to control subjects specially in overweight patients. Receiver Operating Characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker for atherosclerosis. In VSMCs, we demonstrated that increased let-7d-5p levels impairs cell proliferation and could serve as a protective mechanism against inflammation by impairing NF-κB pathway without affecting insulin resistance. In summary, our results highlight the role of let-7d-5p as a potential therapeutic target for atherosclerosis since its overexpression induce a decrease in inflammation and VSMCs proliferation, and also, as a novel non-invasive diagnostic biomarker for atherosclerosis in overweight patients.
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Aterosclerosis , Proliferación Celular , MicroARNs , Músculo Liso Vascular , Miocitos del Músculo Liso , FN-kappa B , Humanos , MicroARNs/genética , MicroARNs/metabolismo , FN-kappa B/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Masculino , Femenino , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Persona de Mediana Edad , Anciano , Inflamación/metabolismo , Inflamación/patología , Biomarcadores/metabolismo , Transducción de Señal , Progresión de la Enfermedad , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologíaRESUMEN
Circulating amyloid-beta 1-40 (Αb40) has pro-atherogenic properties and could serve as a biomarker in atherosclerotic cardiovascular disease (ASCVD). However, the association of Ab40 levels with morphological characteristics reflecting atherosclerotic plaque echolucency and composition is not available. Carotid atherosclerosis was assessed in consecutively recruited individuals without ASCVD (n = 342) by ultrasonography. The primary endpoint was grey scale median (GSM) of intima-media complex (IMC) and plaques, analysed using dedicated software. Vascular markers were assessed at two time-points (median follow-up 35.5 months). In n = 56 patients undergoing carotid endarterectomy, histological plaque features were analysed. Plasma Αb40 levels were measured at baseline. Ab40 was associated with lower IMC GSM and plaque GSM and higher plaque area at baseline after multivariable adjustment. Increased Ab40 levels were also longitudinally associated with decreasing or persistently low IMC and plaque GSM after multivariable adjustment (p < 0.05). In the histological analysis, Ab40 levels were associated with lower incidence of calcified plaques and plaques without high-risk features. Ab40 levels are associated with ultrasonographic and histological markers of carotid wall composition both in the non-stenotic arterial wall and in severely stenotic plaques. These findings support experimental evidence linking Ab40 with plaque vulnerability, possibly mediating its established association with major adverse cardiovascular events.
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Péptidos beta-Amiloides , Biomarcadores , Arterias Carótidas , Placa Aterosclerótica , Humanos , Masculino , Femenino , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/patología , Anciano , Persona de Mediana Edad , Biomarcadores/sangre , Péptidos beta-Amiloides/metabolismo , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Ultrasonografía/métodos , Grosor Intima-Media Carotídeo , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/patología , Endarterectomía CarotideaRESUMEN
Atherosclerosis manifests itself differently in men and women with respect to plaque initiation, progression and plaque composition. The observed delay in plaque progression in women is thought to be related to the hormonal status of women. Also features associated with the vulnerability of plaques to rupture seem to be less frequently present in women compared to men. Current invasive and non-invasive imaging modalities allow for visualization of plaque size, composition and high risk vulnerable plaque features. Moreover, image based modeling gives access to local shear stress and shear stress-related plaque growth. In this review, current knowledge on sex-related differences in plaque size, composition, high risk plaque features and shear stress related plaque growth in carotid and coronary arteries obtained from imaging are summarized.
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Arterias Carótidas , Enfermedad de la Arteria Coronaria , Vasos Coronarios , Placa Aterosclerótica , Estrés Mecánico , Humanos , Femenino , Masculino , Factores Sexuales , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/patología , Angiografía Coronaria , Valor Predictivo de las Pruebas , Factores de Riesgo , Progresión de la EnfermedadRESUMEN
Objective: It has been shown that clonal mutations occur in hematopoietic stem cells with advancing age and increase the risk of death due to atherosclerotic vascular diseases, similarly to myeloproliferative neoplasms. Endothelial cells (ECs) and hematopoietic stem cells develop from common stem cells called hemangioblasts in the early embryonic period. However, the presence of hemangioblasts in the postnatal period is controversial. In this study, JAK2 gene variants were examined in patients with atherosclerotic carotid disease and without any hematological malignancies. Materials and Methods: Ten consecutive patients (8 men and 2 women) with symptomatic atherosclerotic carotid stenosis were included in this study. ECs (CD31+CD45-) were separated from tissue samples taken by carotid endarterectomy. JAK2 variants were examined in ECs, peripheral blood mononuclear cells, and oral epithelial cells of the patients with next-generation sequencing. Results: The median age of the patients was 74 (range: 58-80) years and the median body mass index value was 24.44 (range: 18.42-30.85) kg/m2. Smoking history was present in 50%, hypertension in 80%, diabetes in 70%, and ischemic heart disease in 70% of the cases. The JAK2V617F mutation was detected in the peripheral blood mononuclear cells of 3 of the 10 patients, and 2 patients also had the JAK2V617F mutation in their ECs. The JAK2V617F mutation was not found in the oral epithelial cells of any of the patients. Conclusion: In this study, for the first time in the literature, we showed that the JAK2V617F mutation was found somatically in both peripheral blood cells and ECs in patients with atherosclerosis. This finding may support that ECs and hematopoietic cells originate from a common clone or that somatic mutations can be transmitted to ECs by other mechanisms. Examining the molecular and functional changes caused by the JAK2V617F mutation in ECs may help open a new avenue for treating atherosclerosis.
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Células Endoteliales , Janus Quinasa 2 , Mutación , Humanos , Janus Quinasa 2/genética , Masculino , Femenino , Células Endoteliales/patología , Células Endoteliales/metabolismo , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/patología , Leucocitos Mononucleares/metabolismo , Aterosclerosis/genéticaAsunto(s)
Enfermedades de las Arterias Carótidas , Contaminación Ambiental , Microplásticos , Placa Aterosclerótica , Humanos , Microplásticos/análisis , Nanopartículas/análisis , Placa Aterosclerótica/química , Placa Aterosclerótica/patología , Enfermedades de las Arterias Carótidas/patología , Factores de Riesgo de Enfermedad Cardiaca , QuirófanosAsunto(s)
Enfermedades de las Arterias Carótidas , Microplásticos , Placa Aterosclerótica , Humanos , Microplásticos/efectos adversos , Microplásticos/análisis , Nanopartículas/efectos adversos , Nanopartículas/análisis , Placa Aterosclerótica/química , Placa Aterosclerótica/etiología , Placa Aterosclerótica/ultraestructura , Enfermedades de las Arterias Carótidas/etiología , Enfermedades de las Arterias Carótidas/patología , Cromatografía de Gases y Espectrometría de Masas , Microscopía Electrónica de RastreoRESUMEN
BACKGROUND: Epigenetic age estimators (clocks) are predictive of human mortality risk. However, it is not yet known whether the epigenetic age of atherosclerotic plaques is predictive for the risk of cardiovascular events. METHODS: Whole-genome DNA methylation of human carotid atherosclerotic plaques (n=485) and of blood (n=93) from the Athero-Express endarterectomy cohort was used to calculate epigenetic age acceleration (EAA). EAA was linked to clinical characteristics, plaque histology, and future cardiovascular events (n=136). We studied whole-genome DNA methylation and bulk and single-cell transcriptomics to uncover molecular mechanisms of plaque EAA. We experimentally confirmed our in silico findings using in vitro experiments in primary human coronary endothelial cells. RESULTS: Male and female patients with severe atherosclerosis had a median chronological age of 69 years. The median epigenetic age was 65 years in females (median EAA, -2.2 [interquartile range, -4.3 to 2.2] years) and 68 years in males (median EAA, -0.3 [interquartile range, -2.9 to 3.8] years). Patients with diabetes and a high body mass index had higher plaque EAA. Increased EAA of plaque predicted future events in a 3-year follow-up in a Cox regression model (univariate hazard ratio, 1.7; P=0.0034) and adjusted multivariate model (hazard ratio, 1.56; P=0.02). Plaque EAA predicted outcome independent of blood EAA (hazard ratio, 1.3; P=0.018) and of plaque hemorrhage (hazard ratio, 1.7; P=0.02). Single-cell RNA sequencing in plaque samples from 46 patients in the same cohort revealed smooth muscle and endothelial cells as important cell types in plaque EAA. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally confirmed by TGFß-triggered endothelial-to-mesenchymal transition inducing rapid epigenetic aging in coronary endothelial cells. CONCLUSIONS: Plaque EAA is a strong and independent marker of poor outcome in patients with severe atherosclerosis. Plaque EAA was linked to mesenchymal endothelial and smooth muscle cells. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally validated. Epigenetic aging mechanisms may provide new targets for treatments that reduce atherosclerosis complications.
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Metilación de ADN , Células Endoteliales , Epigénesis Genética , Placa Aterosclerótica , Humanos , Masculino , Femenino , Anciano , Pronóstico , Persona de Mediana Edad , Células Endoteliales/patología , Células Endoteliales/metabolismo , Factores de Edad , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/cirugía , Células Cultivadas , Factores de Riesgo , Medición de RiesgoRESUMEN
BACKGROUND: Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking. METHODS: We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis-gas chromatography-mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs. RESULTS: A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 µg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 µg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001). CONCLUSIONS: In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947.).
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Enfermedades de las Arterias Carótidas , Microplásticos , Placa Aterosclerótica , Humanos , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/etiología , Estenosis Carotídea/patología , Microplásticos/efectos adversos , Infarto del Miocardio/etiología , Infarto del Miocardio/mortalidad , Placa Aterosclerótica/química , Placa Aterosclerótica/etiología , Placa Aterosclerótica/mortalidad , Placa Aterosclerótica/patología , Plásticos/efectos adversos , Estudios Prospectivos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Factores de Riesgo de Enfermedad Cardiaca , Endarterectomía Carotidea , Enfermedades de las Arterias Carótidas/etiología , Enfermedades de las Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/cirugía , Estudios de SeguimientoRESUMEN
INTRODUCTION: Viral infections have been associated with the progression of atherosclerosis and CD8+ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been detected inside human atherosclerotic lesions. These virus-specific CD8+ T-cells have been hypothesized to contribute to the development of atherosclerosis; however, whether they affect disease progression directly remains unclear. In this study, we aimed to characterize the activation status of virus-specific CD8+ T-cells in the atherosclerotic lesion. METHODS: The presence, clonality, tissue enrichment, and phenotype of virus-associated CD8+ T-cells in atherosclerotic lesions were assessed by exploiting bulk T-cell receptor-ß sequencing and single-cell T-cell receptor (α and ß) sequencing datasets on human endarterectomy samples and patient-matched blood samples. To investigate if virus-specific CD8+ T-cells can be activated through T-cell receptor stimulation in the atherosclerotic lesion, the immunopeptidome of human plaques was determined. RESULTS: Virus-associated CD8+ T-cells accumulated more in the atherosclerotic lesion (mean=2.0%), compared with patient-matched blood samples (mean=1.4%; P=0.05), and were more clonally expanded and tissue enriched in the atherosclerotic lesion in comparison with nonassociated CD8+ T-cells from the lesion. Single-cell T-cell receptor sequencing and flow cytometry revealed that these virus-associated CD8+ T-cells were phenotypically highly similar to other CD8+ T-cells in the lesion and that both exhibited a more activated phenotype compared with circulating T-cells. Interestingly, virus-associated CD8+ T-cells are unlikely to be activated through antigen-specific interactions in the atherosclerotic lesion, as no virus-derived peptides were detected on HLA-I in the lesion. CONCLUSIONS: This study suggests that virus-specific CD8+ T-cells are tissue enriched in atherosclerotic lesions; however, their potential contribution to inflammation may involve antigen-independent mechanisms.
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Linfocitos T CD8-positivos , Activación de Linfocitos , Placa Aterosclerótica , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Aterosclerosis/inmunología , Aterosclerosis/virología , Aterosclerosis/patología , Masculino , Fenotipo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Femenino , Persona de Mediana Edad , Anciano , Enfermedades de las Arterias Carótidas/inmunología , Enfermedades de las Arterias Carótidas/virología , Enfermedades de las Arterias Carótidas/patología , Interacciones Huésped-PatógenoRESUMEN
INTRODUCTION: We aimed to compare conventional vessel wall MR imaging techniques and quantitative susceptibility mapping (QSM) to determine the optimal sequence for detecting carotid artery calcification. METHODS: Twenty-two patients who underwent carotid vessel wall MR imaging and neck CT were enrolled. Four slices of 6-mm sections from the bilateral internal carotid bifurcation were subdivided into 4 segments according to clock position (0-3, 3-6, 6-9, and 9-12) and assessed for calcification. Two blinded radiologists independently reviewed a total of 704 segments and scored the likelihood of calcification using a 5-point scale on spin-echo imaging, FLASH, and QSM. The observer performance for detecting calcification was evaluated by a multireader, multiple-case receiver operating characteristic study. Weighted κ statistics were calculated to assess interobserver agreement. RESULTS: QSM had a mean area under the receiver operating characteristic curve of 0.85, which was significantly higher than that of any other sequence (p < 0.01) and showed substantial interreader agreement (κ = 0.68). A segment with a score of 3-5 was defined as positive, and a segment with a score of 1-2 was defined as negative; the sensitivity and specificity of QSM were 0.75 and 0.87, respectively. CONCLUSION: QSM was the most reliable MR sequence for the detection of plaque calcification.
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Enfermedades de las Arterias Carótidas , Variaciones Dependientes del Observador , Placa Aterosclerótica , Valor Predictivo de las Pruebas , Calcificación Vascular , Humanos , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/patología , Femenino , Masculino , Anciano , Persona de Mediana Edad , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/patología , Reproducibilidad de los Resultados , Angiografía por Resonancia Magnética , Estudios Retrospectivos , Anciano de 80 o más Años , Angiografía por Tomografía Computarizada , Arteria Carótida Interna/diagnóstico por imagen , Arteria Carótida Interna/patología , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Atherosclerotic plaques are complex tissues composed of a heterogeneous mixture of cells. However, our understanding of the comprehensive transcriptional and phenotypic landscape of the cells within these lesions is limited. METHODS: To characterize the landscape of human carotid atherosclerosis in greater detail, we combined cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing to classify all cell types within lesions (n=21; 13 symptomatic) to achieve a comprehensive multimodal understanding of the cellular identities of atherosclerosis and their association with clinical pathophysiology. RESULTS: We identified 25 cell populations, each with a unique multiomic signature, including macrophages, T cells, NK (natural killer) cells, mast cells, B cells, plasma cells, neutrophils, dendritic cells, endothelial cells, fibroblasts, and smooth muscle cells (SMCs). Among the macrophages, we identified 2 proinflammatory subsets enriched in IL-1B (interleukin-1B) or C1Q expression, 2 TREM2-positive foam cells (1 expressing inflammatory genes), and subpopulations with a proliferative gene signature and SMC-specific gene signature with fibrotic pathways upregulated. Further characterization revealed various subsets of SMCs and fibroblasts, including SMC-derived foam cells. These foamy SMCs were localized in the deep intima of coronary atherosclerotic lesions. Utilizing cellular indexing of transcriptomes and epitopes by sequencing data, we developed a flow cytometry panel, using cell surface proteins CD29, CD142, and CD90, to isolate SMC-derived cells from lesions. Lastly, we observed reduced proportions of efferocytotic macrophages, classically activated endothelial cells, and contractile and modulated SMC-derived cells, while inflammatory SMCs were enriched in plaques of clinically symptomatic versus asymptomatic patients. CONCLUSIONS: Our multimodal atlas of cell populations within atherosclerosis provides novel insights into the diversity, phenotype, location, isolation, and clinical relevance of the unique cellular composition of human carotid atherosclerosis. These findings facilitate both the mapping of cardiovascular disease susceptibility loci to specific cell types and the identification of novel molecular and cellular therapeutic targets for the treatment of the disease.
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Aterosclerosis , Enfermedades de las Arterias Carótidas , Placa Aterosclerótica , Humanos , Células Endoteliales/metabolismo , Aterosclerosis/patología , Placa Aterosclerótica/patología , Enfermedades de las Arterias Carótidas/patología , Epítopos/metabolismo , Miocitos del Músculo Liso/metabolismoRESUMEN
BACKGROUND: Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Early detection of carotid atherosclerosis can prevent the progression of cardiovascular disease. Many (semi-) automatic methods have been designed for the segmentation of carotid vessel wall and the diagnosis of carotid atherosclerosis (i.e., the lumen segmentation, the outer wall segmentation, and the carotid atherosclerosis diagnosis) on black blood magnetic resonance imaging (BB-MRI). However, most of these methods ignore the intrinsic correlation among different tasks on BB-MRI, leading to limited performance. PURPOSE: Thus, we model the intrinsic correlation among the lumen segmentation, the outer wall segmentation, and the carotid atherosclerosis diagnosis tasks on BB-MRI by using the multi-task learning technique and propose a gated multi-task network (GMT-Net) to perform three related tasks in a neural network (i.e., carotid artery lumen segmentation, outer wall segmentation, and carotid atherosclerosis diagnosis). METHODS: In the proposed method, the GMT-Net is composed of three modules, including the sharing module, the segmentation module, and the diagnosis module, which interact with each other to achieve better learning performance. At the same time, two new adaptive layers, namely, the gated exchange layer and the gated fusion layer, are presented to exchange and merge branch features. RESULTS: The proposed method is applied to the CAREII dataset (i.e., 1057 scans) for the lumen segmentation, the outer wall segmentation, and the carotid atherosclerosis diagnosis. The proposed method can achieve promising segmentation performances (0.9677 Dice for the lumen and 0.9669 Dice for the outer wall) and better diagnosis accuracy of carotid atherosclerosis (0.9516 AUC and 0.9024 Accuracy) in the "CAREII test" dataset (i.e., 106 scans). The results show that the proposed method has statistically significant accuracy and efficiency. CONCLUSIONS: Even without the intervention of reviewers required for the previous works, the proposed method automatically segments the lumen and outer wall together and diagnoses carotid atherosclerosis with high performance. The proposed method can be used in clinical trials to help radiologists get rid of tedious reading tasks, such as screening review to separate normal carotid arteries from atherosclerotic arteries and to outline vessel wall contours.
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Enfermedades Cardiovasculares , Enfermedades de las Arterias Carótidas , Humanos , Enfermedades Cardiovasculares/patología , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/patología , Angiografía por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/métodosRESUMEN
Intraplaque neovascularization (IPN), a key feature of vulnerable carotid plaque, is associated with adverse cardiovascular (CV) events. Statin therapy has been shown to diminish and stabilize atherosclerotic plaque, but its effect on IPN is uncertain. This review investigated the effects of common pharmacologic anti-atherosclerotic therapies on carotid IPN. Electronic databases (MEDLINE, EMBASE and Cochrane Library) were searched from inception until July 13, 2022. Studies evaluating the effect of anti-atherosclerotic therapy on carotid IPN among adults with carotid atherosclerosis were included. Sixteen studies were eligible for inclusion. Contrast-enhanced ultrasound (CEUS) was the most common IPN assessment modality (n=8), followed by dynamic contrast-enhanced MRI (DCE-MRI) (n=4), excised plaque histology (n=3) and superb microvascular imaging (n=2). In fifteen studies, statins were the therapy of interest and one study assessed PCSK9 inhibitors. Among CEUS studies, baseline statin use was associated with a lower frequency of carotid IPN (median OR = 0.45). Prospective studies showed regression of IPN after 6-12 months of lipid-lowering therapy, with more regression observed in treated participants compared to untreated controls. Our findings suggest that lipid-lowering therapy with statins or PCSK9 inhibitors is associated with IPN regression. However, there was no correlation between change in IPN parameters and change in serum lipids and inflammatory markers in statin-treated participants, so it is unclear whether these factors are mediators in the observed IPN changes. Lastly, this review was limited by study heterogeneity and small sample sizes, so larger trials are needed to validate findings.
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Enfermedades de las Arterias Carótidas , Estenosis Carotídea , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Placa Aterosclerótica , Adulto , Humanos , Proproteína Convertasa 9 , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Estudios Prospectivos , Inhibidores de PCSK9 , Medios de Contraste , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Enfermedades de las Arterias Carótidas/patología , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/patología , Ultrasonografía , LípidosRESUMEN
BACKGROUND: Alterations in gut microbiota have been implicated in HIV infection and cardiovascular disease. However, how gut microbial alterations relate to host inflammation and metabolite profiles, and their relationships with atherosclerosis, have not been well-studied, especially in the context of HIV infection. Here, we examined associations of gut microbial species and functional components measured by shotgun metagenomics with carotid artery plaque assessed by B-mode carotid artery ultrasound in 320 women with or at high risk of HIV (65% HIV +) from the Women's Interagency HIV Study. We further integrated plaque-associated microbial features with serum proteomics (74 inflammatory markers measured by the proximity extension assay) and plasma metabolomics (378 metabolites measured by liquid chromatography tandem mass spectrometry) in relation to carotid artery plaque in up to 433 women. RESULTS: Fusobacterium nucleatum, a potentially pathogenic bacteria, was positively associated with carotid artery plaque, while five microbial species (Roseburia hominis, Roseburia inulinivorans, Johnsonella ignava, Odoribacter splanchnicus, Clostridium saccharolyticum) were inversely associated with plaque. Results were consistent between women with and without HIV. Fusobacterium nucleatum was positively associated with several serum proteomic inflammatory markers (e.g., CXCL9), and the other plaque-related species were inversely associated with proteomic inflammatory markers (e.g., CX3CL1). These microbial-associated proteomic inflammatory markers were also positively associated with plaque. Associations between bacterial species (especially Fusobacterium nucleatum) and plaque were attenuated after further adjustment for proteomic inflammatory markers. Plaque-associated species were correlated with several plasma metabolites, including the microbial metabolite imidazole-propionate (ImP), which was positively associated with plaque and several pro-inflammatory markers. Further analysis identified additional bacterial species and bacterial hutH gene (encoding enzyme histidine ammonia-lyase in ImP production) associated with plasma ImP levels. A gut microbiota score based on these ImP-associated species was positively associated with plaque and several pro-inflammatory markers. CONCLUSION: Among women living with or at risk of HIV, we identified several gut bacterial species and a microbial metabolite ImP associated with carotid artery atherosclerosis, which might be related to host immune activation and inflammation. Video Abstract.
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Aterosclerosis , Enfermedades de las Arterias Carótidas , Estenosis Carotídea , Microbioma Gastrointestinal , Infecciones por VIH , Humanos , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Estenosis Carotídea/complicaciones , Estenosis Carotídea/patología , Proteómica , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/patología , Aterosclerosis/complicaciones , Aterosclerosis/patología , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , Biomarcadores/metabolismo , Inflamación/patologíaRESUMEN
AIM: Experimental studies report that intermediate-density lipoprotein (IDL), the precursor of low-density lipoprotein, promotes atherosclerotic plaque formation. However, whether IDL is involved in the development of atherosclerosis in humans is still unclear. The aim of this community-based study is to examine the association between IDL particle (IDL-P) concentrations and the 5-year progression of carotid atherosclerosis. METHODS: Baseline IDL-P concentrations were measured using nuclear magnetic resonance spectroscopy in 927 participants aged 45-74 years with no history of cardiovascular disease (CVD) at baseline. To estimate the association between baseline IDL-P concentrations and 5-year progression of carotid atherosclerosis, indicated by atherosclerotic plaque progression and changes in total plaque area (TPA), multivariable-adjusted regression was employed. RESULTS: During the 5-year follow-up period, 45.8% of participants developed new plaques. Baseline IDL-P concentrations were significantly associated with the progression of carotid atherosclerosis. Participants in the highest quartile of IDL-P concentrations exhibited 1.36-fold (95% confidence interval [CI]: 1.09-1.68) increased progression of carotid plaque and 1.67-fold (95% CI: 1.04-2.69) higher TPA than those in the lowest quartile. These relationships were independent of baseline concentrations of low-density lipoprotein particles and very-low-density lipoprotein particles and their subclasses. CONCLUSIONS: Elevated IDL-P concentrations were independently associated with the progression of carotid atherosclerosis, suggesting that IDL-P is a novel risk factor for the development of atherosclerosis.
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Aterosclerosis , Enfermedades de las Arterias Carótidas , Placa Aterosclerótica , Humanos , Estudios de Cohortes , Lipoproteínas IDL , Enfermedades de las Arterias Carótidas/patología , Lipoproteínas LDL , Factores de RiesgoRESUMEN
BACKGROUND AND PURPOSE: Intraplaque hemorrhage (IPH) in carotid atherosclerosis demonstrates increased signal on magnetic resonance angiography images. Little remains known about how this signal changes on subsequent examinations. MATERIALS AND METHODS: A retrospective observational study was completed of patients that had IPH on a neck MRA between 1/1/2016 and 3/25/2021, defined as ≥ 200 % signal intensity of the sternocleidomastoid muscle on MPRAGE images. Examinations were excluded if the patients had undergone carotid endarterectomy between examinations or had poor quality imaging. IPH volumes were calculated by manually outlining IPH components. Up to 2 subsequent MRAs, if available, were assessed for both the presence and volume of IPH. RESULTS: 102 patients were included, of which 90 (86.5 %) were male. IPH was on the right in 48 patients (average volume = 174.0 mm3), and on the left in 70 patients (average volume 186.9 mm3). 22 had at least one follow-up (average 444.7 days between exams), and 6 had two follow-up MRAs (average 489.5 days between exams). On the first follow-up, 19 (86.4 %) plaques had persistent hyperintense signal in the region of IPH. The second follow-up showed persistent signal in 5/6 plaques (88.3 %). Combined volume of IPH from right and left carotid arteries did not significantly decrease on the first follow-up exam (p = 0.08). CONCLUSIONS: IPH usually retains hyperintense signal on follow-up MRAs, possibly representing recurrent hemorrhage or degraded blood products.
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Enfermedades de las Arterias Carótidas , Estenosis Carotídea , Placa Aterosclerótica , Humanos , Masculino , Femenino , Angiografía por Resonancia Magnética , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/cirugía , Estudios de Seguimiento , Enfermedades de las Arterias Carótidas/patología , Imagen por Resonancia Magnética/métodos , Placa Aterosclerótica/patología , Hemorragia/diagnóstico por imagen , Hemorragia/etiología , Hemorragia/patología , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/cirugía , Estenosis Carotídea/metabolismoRESUMEN
INTRODUCTION: Carotid atherosclerosis may be associated with brain white matter hyperintensities (WMH). Few studies consider women at midlife, a critical time for women's cardiovascular and brain health. We tested the hypothesis that higher carotid intima media thickness (IMT) would be associated with greater WMH volume (WMHV) among midlife women. We explored interactions by apolipoprotein E (APOE) ε4 status. METHODS: Two hundred thirty-nine women aged 45 to 67 underwent carotid artery ultrasound, phlebotomy, and magnetic resonance imaging (MRI). One hundred seventy participants had undergone an ultrasound 5 years earlier. RESULTS: Higher IMT was associated with greater whole brain (B[standard error (SE)] = 0.77 [.31], P = 0.01; multivariable) and periventricular (B[SE] = 0.80 [.30], P = 0.008; multivariable) WMHV. Associations were observed for IMT assessed contemporaneously with the MRI and 5 years prior to the MRI. Associations were strongest for APOE ε4-positive women. DISCUSSION: Among midlife women, higher IMT was associated with greater WMHV. Vascular risk is critical to midlife brain health, particularly for APOE ε4-positive women.