RESUMEN
Accurate and early detection of atherosclerosis (AS) is imperative for their effective treatment. However, fluorescence probes for efficient diagnosis of AS often encounter insufficient deep tissue penetration, which hinders the reliable assessment of plaque vulnerability. In this work, a reactive oxygen species (ROS) activated near-infrared (NIR) fluorescence and photoacoustic (FL/PA) dual model probe TPA-QO-B is developed by conjugating two chromophores (TPA-QI and O-OH) and ROS-specific group phenylboronic acid ester. The incorporation of ROS-specific group not only induces blue shift in absorbance, but also inhibits the ICT process of TPA-QO-OH, resulting an ignorable initial FL/PA signal. ROS triggers the convertion of TPA-QO-B to TPA-QO-OH, resulting in the concurrent amplification of FL/PA signal. The exceptional selectivity of TPA-QO-B towards ROS makes it effectively distinguish AS mice from the healthy. The NIR emission can achieve a tissue penetration imaging depth of 0.3 cm. Moreover, its PA775 signal possesses the capability to penetrate tissues up to a thickness of 0.8 cm, ensuring deep in vivo imaging of AS model mice in early stage. The ROS-triggered FL/PA dual signal amplification strategy improves the accuracy and addresses the deep tissue penetration problem simultaneously, providing a promising tool for in vivo tracking biomarkers in life science and preclinical applications.
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Colorantes Fluorescentes , Técnicas Fotoacústicas , Placa Aterosclerótica , Especies Reactivas de Oxígeno , Animales , Especies Reactivas de Oxígeno/metabolismo , Técnicas Fotoacústicas/métodos , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/metabolismo , Colorantes Fluorescentes/química , Ratones , Imagen Óptica/métodos , Ratones Endogámicos C57BL , Humanos , MasculinoAsunto(s)
Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Vasos Coronarios , Placa Aterosclerótica , Valor Predictivo de las Pruebas , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Interpretación de Imagen Radiográfica Asistida por Computador , Reproducibilidad de los Resultados , Automatización , Índice de Severidad de la EnfermedadRESUMEN
Atherosclerosis is a common cardiovascular disease in which the arteries are thickened due to buildup of plaque. This study aims to identify programmed cell death (PCD)-related biomarkers and explore the crucial regulatory mechanisms of atherosclerosis. Gene expression profiles of atherosclerosis and control groups from GSE20129 and GSE23746 were obtained. Necroptosis was elevated in atherosclerosis. Weighted gene coexpression network analysis (WGCNA) was conducted in GSE23746 and GSE56045 to identify PCD-related modules and to perform enrichment analysis. Two necroptosis-related genes (IRF9 and STAT1) were identified and considered as biomarkers. Enrichment analysis showed that these gene modules were mainly related to immune response regulation. In addition, single-cell RNA sequencing data from GSE159677 were obtained and the characteristic cell types of atherosclerosis were identified. A total of 11 immune cell types were identified through UMAP dimension reduction. Most immune cells were mainly enriched in plaque samples, and STAT1 and IRF9 were primarily expressed in T-cells and macrophages. Moreover, the roles of IRF9 and STAT1 were assessed and found to be significantly upregulated in atherosclerosis, which was associated with increased risk of atherosclerosis. This study provides a molecular feature of atherosclerosis, offering an important basis for further research on its pathological mechanisms and the search for new therapeutic targets.
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Aterosclerosis , Biomarcadores , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón , Factor de Transcripción STAT1 , Linfocitos T , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Humanos , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/patología , Biomarcadores/metabolismo , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/genética , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Redes Reguladoras de Genes , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Macrófagos/inmunología , Macrófagos/metabolismo , Transcriptoma/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Placa Aterosclerótica/inmunologíaRESUMEN
To address the conflict between the "fitness" and "feasibility" of body-fitted stents, this paper investigates the impact of various smoothing design strategies on the mechanical behaviour and apposition performance of stent. Based on the three-dimensional projection method, the projection region was fitted with the least squares method (fitting orders 1-6 corresponded to models 1-6, respectively) to achieve the effect of smoothing the body-fitted stent. The simulation included the crimping and expansion process of six groups of stents in stenotic vessels with different degrees of plaque calcification. Various metrics were analyzed, including bending stiffness, stent ruggedness, area residual stenosis rate, contact area fraction, and contact volume fraction. The study findings showed that the bending stiffness, stent ruggedness, area residual stenosis rate, contact area fraction and contact volume fraction increased with the fitting order's increase. Model 1 had the smallest contact area fraction and contact volume fraction, 77.63% and 83.49% respectively, in the incompletely calcified plaque environment. In the completely calcified plaque environment, these values were 72.86% and 82.21%, respectively. Additionally, it had the worst "fitness". Models 5 and 6 had similar values for stent ruggedness, with 32.15% and 32.38%, respectively, which indicated the worst "feasibility" for fabrication and implantation. Models 2, 3, and 4 had similar area residual stenosis rates in both plaque environments. In conclusion, it is more reasonable to obtain the body-fitted stent by using 2nd to 4th order fitting with the least squares method to the projected region. Among them, the body-fitted stent obtained by the 2nd order fitting performs better in the completely calcified environment.
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Stents , Humanos , Diseño de Prótesis , Simulación por Computador , Placa AteroscleróticaRESUMEN
BACKGROUND: Atherosclerosis, serving as the primary pathological mechanism at the core of cardiovascular disease, is now widely acknowledged to be associated with DNA damage and repair, contributing to atherosclerotic plaque formation. Therefore, molecules involved in the DNA repair process may play an important role in the progression of atherosclerosis. Our research endeavors to explore the contributions of specific and interrelated molecules involved in DNA repair (APE1, BRCA1, ERCC2, miR-221-3p, miR-145-5p, and miR-155-5p) to the development of atherosclerotic plaque and their interactions with each other. METHODS & RESULTS: Gene expression study was conducted using the real-time polymerase chain reaction (qRT-PCR) method on samples from carotid artery atherosclerotic plaques and nonatherosclerotic internal mammary arteries obtained from 50 patients diagnosed with coronary artery disease and carotid artery disease. Additionally, 50 healthy controls were included for the determination of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Although no difference was observed in mRNA gene expressions, we noted a decrease in miR-155-5p gene expression (p = 0.003) and an increase in miR-221-3p gene expression (p = 0.015) in plaque samples, while miR-145-5p gene expression remained unchanged (p = 0.57). Regarding serum 8-OHdG levels, patients exhibited significantly higher levels (1111.82 ± 28.64) compared to controls (636.23 ± 24.23) (p < 0.0001). CONCLUSIONS: In our study demonstrating the role of miR-155-5p and miR-221-3p in atherosclerosis, we propose that these molecules are potential biomarkers and therapeutic targets for coronary artery diseases and carotid artery disease.
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Reparación del ADN , MicroARNs , Placa Aterosclerótica , Humanos , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Reparación del ADN/genética , MicroARNs/genética , MicroARNs/metabolismo , Anciano , Estudios Transversales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/metabolismo , Daño del ADN/genética , Regulación de la Expresión Génica/genética , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/metabolismo , Arterias Carótidas/metabolismo , Arterias Carótidas/patología , 8-Hidroxi-2'-Desoxicoguanosina/metabolismoRESUMEN
Objective: To explore the feasibility of using cRGD-GNR-PFP-NPs to assess plaque vulnerability in an atherosclerotic plaque mouse model by dual-modal photoacoustic/ultrasonic imaging. Methods: A nanomolecular probe containing gold nanorods (GNRs) and perfluoropentane (PFP) coated with the cyclic Arg-Gly-Asp (cRGD) peptide were prepared by double emulsion solvent evaporation and carbodiimide methods. The morphology, particle size, potential, cRGD conjugation and absorption features of the nanomolecular probe were characterized, along with its in vitro phase transformation and photoacoustic/ultrasonic dual-modal imaging properties. In vivo fluorescence imaging was used to determine the distribution of cRGD-GNR-PFP-NPs in vivo in apolipoprotein E-deficient (ApoE-/-) atherosclerotic plaque model mice, the optimal imaging time was determined, and photoacoustic/ultrasonic dual-modal molecular imaging of integrin αvß3 expressed in atherosclerotic plaques was performed. Pathological assessments verified the imaging results in terms of integrin αvß3 expression and plaque vulnerability. Results: cRGD-GNR-PFP-NPs were spherical with an appropriate particle size (average of approximately 258.03±6.75 nm), a uniform dispersion, and a potential of approximately -9.36±0.53 mV. The probe had a characteristic absorption peak at 780~790 nm, and the surface conjugation of the cRGD peptide reached 92.79%. cRGD-GNR-PFP-NPs were very stable in the non-excited state but very easily underwent phase transformation under low-intensity focused ultrasound (LIFU) and had excellent photoacoustic/ultrasonic dual-modal imaging capability. Mice fed a high-fat diet for 20 weeks had obvious hyperlipidemia with larger, more vulnerable plaques. These plaques could be specifically targeted by cRGD-GNR-PFP-NPs as determined by in vivo fluorescence imaging, and the enrichment of nanomolecular probe increased with the increasing of plaque vulnerability; the photoacoustic/ultrasound signals of the plaques in the high-fat group were stronger. The pathological assessments were in good agreement with the cRGD-GNR-PFP-NPs plaque accumulation, integrin αvß3 expression and plaque vulnerability results. Conclusion: A phase variant photoacoustic/ultrasonic dual-modal cRGD nanomolecular probe was successfully prepared and can be used to identify plaque vulnerability safely and effectively.
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Fluorocarburos , Oro , Nanotubos , Péptidos Cíclicos , Técnicas Fotoacústicas , Placa Aterosclerótica , Animales , Placa Aterosclerótica/diagnóstico por imagen , Técnicas Fotoacústicas/métodos , Oro/química , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacocinética , Ratones , Nanotubos/química , Fluorocarburos/química , Integrina alfaVbeta3/metabolismo , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Ultrasonografía/métodos , Tamaño de la Partícula , Masculino , Ratones Noqueados para ApoE , Modelos Animales de Enfermedad , PentanosRESUMEN
BACKGROUND: Recent observations in silico and in vivo reported that, during proximal optimisation technique, drug-eluting stents (DES) elongate, challenging conventional wisdom. The interaction between plaque morphology and radial expansion is well established, but little is known about the impact of plaque morphology on elongation. AIMS: We aimed to assess the longitudinal mechanical behaviour of contemporary DES in vivo and evaluate the relationship between post-percutaneous coronary intervention (PCI) stent elongation and lesion morphology, as assessed with optical coherence tomography (OCT). METHODS: Patients treated with OCT-guided PCI to left main or left anterior descending artery bifurcations, between July 2017 and March 2022, from the King's Optical coherence Database Analysis Compendium were included. Patients were excluded if there were overlapping stents, if they had undergone prior PCI, or if there was inadequate image quality. Lesions were characterised as fibrocalcific, fibrous or lipid-rich by pre-PCI OCT. Following stent post-dilatation, stent expansion and final stent length were assessed. The primary outcome was the percentage change in stent length from baseline. RESULTS: Of 501 eligible consecutive patients from this period, 116 were included. The median age was 66 years (interquartile range [IQR] 57-76), 31% were female, and 53.4% were treated for an acute coronary syndrome. A total of 50.0% of lesions were classified as fibrocalcific, 6.9% were fibrous, and 43.1% were lipid-rich. The change in relative stent length was 4.4% (IQR 1.0-8.9), with an increase of 3.1% (IQR 0.5-6.3) in fibrocalcific lesions, 3.3% (IQR 0.5-5.9) in fibrous lesions, and 6.4% (IQR 3.1-11.1) in lipid-rich plaque (p=0.006). In multivariate regression modelling, lipid-rich plaque was an independent predictor of stent elongation (odds ratio 3.689, 95% confidence interval: 1.604-8.484). CONCLUSIONS: Contemporary DES elongate following implantation and post-dilatation, and this is significantly mediated by plaque morphology. This is an important consideration when planning a strategy for DES implantation.
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Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Placa Aterosclerótica , Tomografía de Coherencia Óptica , Humanos , Femenino , Tomografía de Coherencia Óptica/métodos , Masculino , Anciano , Persona de Mediana Edad , Intervención Coronaria Percutánea/instrumentación , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/cirugía , Resultado del Tratamiento , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patologíaRESUMEN
OBJECTIVE: Aim: To study the state of extracranial carotid vessels in patients with atherothrombotic stroke in the early recovery period (ASERP) according to duplex scanning data. PATIENTS AND METHODS: Materials and Methods: 130 patients in ASERP, were studied. 69 men and 61 women. aged (60.42}7.4) years. Duplex scanning of the vessels of the neck was performed on a Siemens Acuson X 300 device with a linear multi-frequency sensor of 4-10 MHz. The classification of stenozoocclusive lesions of vessels was carried out according to the classification of B.V. Gaidar. Atherosclerotic plaques (AP) are divided into 5 types according to the Nicolaides and Gerulaka classification. RESULTS: Results: Atherosclerotic stenoses were found in all patients of ASERP: ( 90%),- in 3.4%. AP type 1 was found in 15% of cases; 2 types - in 33.8%; 3 types - in 26%; type 4 accounted for 12.3% and type 5 accounted for 12.3% of cases. APwhich causing moderate stenosis had a high degree of embologenicity due to the hypoechogenicity and heterogeneity of atherosclerotic plaques of types I, II and III. When the level of stenosis increased, tendency to increase the density and hyperechogenicity of the AP was noted. CONCLUSION: Conclusions: 89% patients with ASERP had non-critical, hemodynamically insignificant stenoses of the carotid arteries. Types II and III AP, mostly of an eccentric structure, dominated. Moderate stenoses were more often caused by echo-negative atherosclerotic layers, which is a source of increased embologenicity, and stenoses of a greater degree, for the most part, were echo-positive.
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Estenosis Carotídea , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estenosis Carotídea/diagnóstico por imagen , Arterias Carótidas/diagnóstico por imagen , Accidente Cerebrovascular Trombótico/diagnóstico por imagen , Placa Aterosclerótica/diagnóstico por imagen , Ultrasonografía Doppler DúplexRESUMEN
Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key 'don't-eat-me' molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors.
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Anemia , Aterosclerosis , Antígeno CD47 , Modelos Animales de Enfermedad , Inflamación , Macrófagos , Nanopartículas , Fagocitosis , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Nanopartículas/química , Antígeno CD47/metabolismo , Antígeno CD47/antagonistas & inhibidores , Porcinos , Inflamación/patología , Fagocitosis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Humanos , Placa Aterosclerótica/patología , Ratones , MasculinoRESUMEN
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD.
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Aterosclerosis , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel , Aterosclerosis/metabolismo , Aterosclerosis/genética , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Animales , Humanos , Modelos Animales de Enfermedad , Transducción de Señal , Cadherinas/metabolismo , Cadherinas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Endoteliales/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Masculino , Receptores Notch/metabolismo , Receptores Notch/genética , Proteínas Relacionadas con las Cadherinas , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologíaRESUMEN
BACKGROUND: Tissue plasminogen activator (tPA) is an effective treatment for acute ischemic stroke. Although initial improvement is observed when administered for branch atheromatous disease (BAD), some cases subsequently worsen. Clinical data on the characteristics of these patients is lacking, and the benefits of tPA are unclear. OBJECTIVE: To analyze rebound cases and elucidate the clinical characteristics and outcomes associated with tPA administration in BAD. METHODS: This multicenter retrospective study was conducted in Japan. Worsening after initial improvement of a condition is termed as rebound, and such cases were compared with other types of ischemic stroke in patients with and without rebound. The characteristics of patients with BAD who rebounded were examined. RESULTS: The study included 93 patients. Among the patients who were administered tPA, the NIHSS scores at 24 h and 7 days post-tPA were significantly higher in patients with BAD than in patients with other types of infarcts. The group with BAD exhibited a significantly higher rate of rebound than other groups (37.5 % vs. 0 %, P < 0.001). However, no differences were observed in outcomes between patients who experienced rebound after tPA administration and those who did not. CONCLUSIONS: Reevaluation and changing the strategy of tPA use in patients with BAD may be necessary. However, this study does not totally discourage its use, as specific patients can benefit.
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Fibrinolíticos , Activador de Tejido Plasminógeno , Humanos , Activador de Tejido Plasminógeno/uso terapéutico , Activador de Tejido Plasminógeno/administración & dosificación , Masculino , Femenino , Anciano , Estudios Retrospectivos , Fibrinolíticos/uso terapéutico , Fibrinolíticos/administración & dosificación , Persona de Mediana Edad , Anciano de 80 o más Años , Resultado del Tratamiento , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Japón , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/diagnóstico por imagenRESUMEN
Atherosclerosis is a chronic inflammatory condition of the arteries and represents the primary cause of various cardiovascular diseases. Despite ongoing progress, finding effective anti-inflammatory therapeutic strategies for atherosclerosis remains a challenge. Here, we assessed the potential of molecular magnetic resonance imaging (MRI) to visualize the effects of 01BSUR, an anti-interleukin-1ß monoclonal antibody, for treating atherosclerosis in a murine model. Male apolipoprotein E-deficient mice were divided into a therapy group (01BSUR, 2 × 0.3 mg/kg subcutaneously, n = 10) and control group (no treatment, n = 10) and received a high-fat diet for eight weeks. The plaque burden was assessed using an elastin-targeted gadolinium-based contrast probe (0.2 mmol/kg intravenously) on a 3 T MRI scanner. T1-weighted imaging showed a significantly lower contrast-to-noise (CNR) ratio in the 01BSUR group (pre: 3.93042664; post: 8.4007067) compared to the control group (pre: 3.70679168; post: 13.2982156) following administration of the elastin-specific MRI probe (p < 0.05). Histological examinations demonstrated a significant reduction in plaque size (p < 0.05) and a significant decrease in plaque elastin content (p < 0.05) in the treatment group compared to control animals. This study demonstrated that 01BSUR hinders the progression of atherosclerosis in a mouse model. Using an elastin-targeted MRI probe, we could quantify these therapeutic effects in MRI.
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Aterosclerosis , Elastina , Interleucina-1beta , Animales , Masculino , Ratones , Anticuerpos Monoclonales , Apolipoproteínas E/deficiencia , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Medios de Contraste/química , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Elastina/metabolismo , Gadolinio/química , Gadolinio/farmacología , Interleucina-1beta/metabolismo , Imagen por Resonancia Magnética/métodos , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológicoRESUMEN
Intravascular ultrasound and optical coherence tomography are used with increasing frequency for the care of coronary patients and in research studies. These imaging tools can identify culprit lesions in acute coronary syndromes, assess coronary stenosis severity, guide percutaneous coronary intervention (PCI), and detect vulnerable plaques and patients. However, they have significant limitations that have stimulated the development of multimodality intracoronary imaging catheters, which provide improvements in assessing vessel wall pathology and guiding PCI. Prototypes combining 2 or even 3 imaging probes with complementary attributes have been developed, and several multimodality systems have already been used in patients, with near-infrared spectroscopy intravascular ultrasound-based studies showing promising results for the identification of high-risk plaques. Moreover, postmortem histology studies have documented that hybrid imaging catheters can enable more accurate characterization of plaque morphology than standalone imaging. This review describes the evolution in the field of hybrid intracoronary imaging; presents the available multimodality catheters; and discusses their potential role in PCI guidance, vulnerable plaque detection, and the assessment of endovascular devices and emerging pharmacotherapies targeting atherosclerosis.
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Enfermedad de la Arteria Coronaria , Vasos Coronarios , Imagen Multimodal , Intervención Coronaria Percutánea , Placa Aterosclerótica , Valor Predictivo de las Pruebas , Tomografía de Coherencia Óptica , Ultrasonografía Intervencional , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Intervención Coronaria Percutánea/instrumentación , Diseño de Equipo , Catéteres Cardíacos , Difusión de Innovaciones , Cateterismo Cardíaco/instrumentación , Espectroscopía Infrarroja Corta , AnimalesRESUMEN
BACKGROUND: Visceral adipose tissue in individuals with obesity is an independent cardiovascular risk indicator. However, it remains unclear whether adipose tissue influences common cardiovascular diseases, such as atherosclerosis, through its secreted exosomes. METHODS: The exosomes secreted by adipose tissue from diet-induced obesity mice were isolated to examine their impact on the progression of atherosclerosis and the associated mechanism. Endothelial apoptosis and the proliferation and migration of vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque were evaluated. Statistical significance was analyzed using GraphPad Prism 9.0 with appropriate statistical tests. RESULTS: We demonstrate that adipose tissue-derived exosomes (AT-EX) exacerbate atherosclerosis progression by promoting endothelial apoptosis, proliferation, and migration of VSMCs within the plaque in vivo. MicroRNA-132/212 (miR-132/212) was detected within AT-EX cargo. Mechanistically, miR-132/212-enriched AT-EX exacerbates palmitate acid-induced endothelial apoptosis via targeting G protein subunit alpha 12 and enhances platelet-derived growth factor type BB-induced VSMC proliferation and migration by targeting phosphatase and tensin homolog in vitro. Importantly, melatonin decreases exosomal miR-132/212 levels, thereby mitigating the pro-atherosclerotic impact of AT-EX. CONCLUSION: These data uncover the pathological mechanism by which adipose tissue-derived exosomes regulate the progression of atherosclerosis and identify miR-132/212 as potential diagnostic and therapeutic targets for atherosclerosis.
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Apoptosis , Aterosclerosis , Movimiento Celular , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Exosomas , Ratones Endogámicos C57BL , MicroARNs , Músculo Liso Vascular , Miocitos del Músculo Liso , Placa Aterosclerótica , Animales , MicroARNs/metabolismo , MicroARNs/genética , Exosomas/metabolismo , Exosomas/patología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Masculino , Transducción de Señal , Células Cultivadas , Obesidad/metabolismo , Obesidad/patología , Ratones Noqueados para ApoE , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Endoteliales/efectos de los fármacos , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/genética , Becaplermina/farmacología , Becaplermina/metabolismo , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Ratones , HumanosRESUMEN
AIM: To study metabolic molecules (adiponectin, adipsin, resistin, glucagon-like peptide-1 (GLP-1), glucagon, secretin) of adipose tissue in atherosclerotic plaques (AP) and their associations with AP instability in men with coronary atherosclerosis. MATERIAL AND METHODS: Metabolic molecules (adipocytokines and metabolic hormones) of adipose tissue can act as enzymes, hormones or growth factors in modulating insulin resistance and lipid and glucose metabolism and indirectly influence the course of the atherosclerotic process. This study included 48 men from whom 139 coronary artery (CA) samples were collected during coronary artery bypass grafting, after obtaining the informed consent. According to the histological conclusion, 84 (60.4%) CA plaques were stable, 44 (31.7%) were unstable, and 11 histological samples had a conditionally unchanged CA intima (7.9%). The concentrations of adiponectin, adipsin, resistin, GLP-1, glucagon, and secretin were measured in AP homogenates by multiplex analysis using the Human Metabolic Hormone V3 panel (MILLIPLEX, Germany). During the study, demographic and anthropometric characteristics, medical history, and presence of chronic diseases were recorded. RESULTS: The glucagon concentration in the conditionally unchanged intima was 16.7% lower and in the fragments of unstable atherosclerotic plaques 41.2% lower than in fragments of stable APs. However, the glucagon concentration in stable APs was 28% higher than in unstable APs. The secretin concentration in the conditionally unchanged intima was also lower than in stable APs by 41.2%, while in stable APs, the secretin concentration was 20% higher than in unstable APs. The adiponectin concentrations were directly correlated with serum high-density lipoprotein cholesterol (HDL-C) concentrations (r=0.286; p=0.002), while the secretin concentrations were inversely correlated with serum HDL-C concentrations (r= -0.199; p=0.038). The probability of having an unstable AP (in relation to conditionally unchanged intima) increases by 35.8% with an increase in the AP glucagon concentration by 1 pg/mg protein. The probability of having a stable AP (in relation to unchanged intima) increases by 29.4% with an increase in the AP glucagon concentration by 1 pg/mg protein and by 10.1% with an increase in the AP secretin concentration by 1 pg/mg protein. CONCLUSION: The AP adiponectin concentration directly correlates and the AP secretin concentration inversely correlates with the serum concentration of HDL-C. The presence of both stable and unstable APs is directly associated with the AP glucagon concentration in men with coronary atherosclerosis. The AP secretin concentration is directly associated with plaque stability in men with coronary atherosclerosis. Further thorough study of the identified markers in atherosclerotic lesions will allow using them as potential targets for therapy.
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Tejido Adiposo , Enfermedad de la Arteria Coronaria , Placa Aterosclerótica , Humanos , Masculino , Enfermedad de la Arteria Coronaria/metabolismo , Persona de Mediana Edad , Placa Aterosclerótica/metabolismo , Tejido Adiposo/metabolismo , Anciano , Adipoquinas/metabolismoRESUMEN
OBJECTIVES: To explore the value of middle cerebral artery (MCA) plaque characteristics in predicting the outcomes of subacute ischemic stroke and the incremental value of the previous diet on predictive performance. METHODS: One hundred and thirty-seven subacute ischemic stroke patients attributed to MCA plaques were included and analyzed in this prospective study. The National Institute of Health Stroke Scale (NIHSS) score, Mediterranean Diet Adherence Screener (MEDAS) score, and other clinical data were assessed. The plaque area, degree of stenosis, plaque burden, enhancement ratio, remodeling type, and intraplaque hemorrhage were measured using high-resolution MR vessel wall imaging (HR-VWI). Multivariable logistic regression analysis and receiver operating characteristic curve analysis were performed to assess the predictive performance of clinical and plaque characteristics for subacute ischemic stroke outcomes at 3 months. RESULTS: Patients with poor outcomes exhibited high NIHSS scores, and low MEDAS scores (P<0.001). Plaque burden, enhancement ratio, and degree of stenosis were significantly higher in patients with poor outcomes (P<0.001). Multivariate analyses further indicated that NIHSS score (P=0.001), MEDAS score (P=0.013), and enhancement ratio (P=0.011) were independent predictors of subacute ischemic stroke outcomes. The three models' area under the curve (AUC) values were 0.811, 0.844, and 0.794. Combining these three factors resulted in an AUC of 0.908 (P<0.001). CONCLUSIONS: The combination of NIHSS score, MEDAS score, and enhancement ratio showed significant superiority in the prognostic evaluation of subacute ischemic stroke. Clinical data combined with plaque characteristics improves the accuracy of 3-month outcome prediction on subacute ischemic stroke.
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Accidente Cerebrovascular Isquémico , Humanos , Masculino , Femenino , Pronóstico , Estudios Prospectivos , Persona de Mediana Edad , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Anciano , Placa Aterosclerótica/diagnóstico por imagen , Angiografía por Resonancia Magnética/métodos , Arteria Cerebral Media/diagnóstico por imagen , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Atherosclerosis (AS) is the leading cause of cardiovascular disease. Foam cells, with elevated lipid droplets (LDs) and HClO levels, are the main components of the atherosclerotic plaques that are characteristic of AS. Super-resolution imaging can be used to visualize the distribution of LDs in foam cells at the nanometer level, facilitating the identification of LDs and HClO. In the present study, we report the development of a ratiometric fluorescent probe, SFL-HClO, for super-resolution imaging of LDs and HClO. Super-resolution imaging with this probe revealed the precise structure of LDs at the suborganelle level. Moreover, the fluorescence behavior of SFL-HClO on the surface of LDs verified its excellent performance in detecting HClO in the foam cells. SFL-HClO can sequentially and specifically respond to LDs and HClO via "turn-on" and ratiometric signal output, respectively, thus contributing to precise imaging of foam cells. Importantly, we demonstrate that SFL-HClO can be used to report on upregulated HClO in atherosclerotic plaques in the aorta of AS mice, providing a suitable fluorescent tool for early atherosclerotic disease assessment.
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Aterosclerosis , Colorantes Fluorescentes , Células Espumosas , Ácido Hipocloroso , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Células Espumosas/patología , Animales , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/patología , Ratones , Ácido Hipocloroso/análisis , Células RAW 264.7 , Imagen Óptica , Humanos , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/química , Placa Aterosclerótica/patología , Ratones Endogámicos C57BL , Gotas Lipídicas/químicaRESUMEN
BACKGROUND: Menopausal vasomotor symptoms (VMS) are increasingly emphasized as a potentially important cardiovascular risk factor, but their role is still unclear. We assessed the association between VMS and subclinical atherosclerotic cardiovascular disease in peri- and postmenopausal women. METHODS AND RESULTS: Using a cross-sectional study design, questionnaire data were collected from a population-based sample of women aged 50 to 64. The questionnaire asked whether menopause was/is associated with bothersome VMS. A 4-point severity scale was used: (1) never, (2) mild, (3) moderate, and (4) severe. The VMS duration and time of onset were also assessed. Associations with subclinical atherosclerotic cardiovascular disease, detected via coronary computed tomography angiography, coronary artery calcium score, and carotid ultrasound were assessed using the outcome variables "any coronary atherosclerosis," "segmental involvement score >3," "coronary artery calcium score >100," and "any carotid plaque," using logistic regression. Covariate adjustments included socioeconomic, lifestyle, and clinical factors. Of 2995 women, 14.2% reported ever severe, 18.1% ever moderate, and 67.7% ever mild/never VMS. Using the latter as reference, ever severe VMS were significantly associated with coronary computed tomography angiography-detected coronary atherosclerosis (multivariable adjusted odds ratio, 1.33 [95% CI, 1.02-1.72]). Corresponding results for ever severe VMS persisting >5 years or beginning before the final menstrual period were 1.50 (95% CI, 1.07-2.11) and 1.66 (95% CI, 1.10-2.50), respectively. No significant association was observed with segmental involvement score >3, coronary artery calcium score >100, or with any carotid plaque. CONCLUSIONS: Ever occurring severe, but not moderate, VMS were significantly associated with subclinical coronary computed tomography angiography-detected atherosclerosis, independent of a broad range of cardiovascular risk factors and especially in case of long durations or early onset.
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Enfermedades de las Arterias Carótidas , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Sofocos , Humanos , Femenino , Persona de Mediana Edad , Estudios Transversales , Sofocos/epidemiología , Sofocos/fisiopatología , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/fisiopatología , Menopausia , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Factores de Riesgo , Enfermedades Asintomáticas , Sistema Vasomotor/fisiopatología , Placa Aterosclerótica/epidemiología , Calcificación Vascular/epidemiología , Calcificación Vascular/diagnóstico por imagen , Modelos LogísticosRESUMEN
(1) Background: Atherosclerosis is a leading cause of vascular death worldwide. High urinary phosphate has recently been identified as a cardiovascular risk factor, but its role has not been fully established. The aim of this study was to investigate the association between urinary phosphate and subclinical atherosclerosis in the carotid, femoral as well as coronary territories; (2) Methods: We performed a cross-sectional analysis of a sample of 1169 middle-aged men, aged 50.9 years (SD 3.7), without previous cardiovascular disease, belonging to the Aragon Workers Health Study (AWHS). Urinary phosphate was analyzed in urine samples using the Fiske-Subbarow method. The presence of carotid plaque and femoral plaque was assessed by ultrasound and coronary artery calcium score (CACS) by computed tomography. Demographic, anthropometric and clinical data were collected at annual medical examinations. Logistic regression models were used to estimate the prevalence of adjusted atherosclerosis in the different vascular arteries; (3) Results: A significant inverse association was observed between urinary phosphate and subclinical atherosclerosis in the carotid [OR 95% CI 0.69 (0.49-0.99)] and coronary (CACS > 200) [OR 95% CI 0.46 (0.23-0.88)] arteries; however, no statistically significant association was found between urinary phosphate and the presence of atheroma plaques in the femoral territory [OR 1.02 (0.72-1.45)]; (4) Conclusions: In middle-aged men, a higher urinary phosphate concentration is associated with a lower prevalence of subclinical carotid and coronary atherosclerosis compared with those with a lower urinary phosphate concentration.
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Aterosclerosis , Fosfatos , Humanos , Masculino , Persona de Mediana Edad , Estudios Transversales , Fosfatos/orina , Aterosclerosis/orina , Aterosclerosis/epidemiología , Factores de Riesgo , Arteria Femoral , Placa Aterosclerótica/orina , Placa Aterosclerótica/epidemiología , Prevalencia , Adulto , Enfermedad de la Arteria Coronaria/orina , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/etiología , España/epidemiologíaRESUMEN
Stroke is the second leading cause of death and a major cause of disability around the world, and the development of atherosclerotic plaques in the carotid arteries is generally considered the leading cause of severe cerebrovascular events. In recent years, new reports have reinforced the role of an accurate histopathological analysis of carotid plaques to perform the stratification of affected patients and proceed to the correct prevention of complications. This work proposes applying an unsupervised learning approach to analyze complex whole-slide images (WSIs) of atherosclerotic carotid plaques to allow a simple and fast examination of their most relevant features. All the code developed for the present analysis is freely available. The proposed method offers qualitative and quantitative tools to assist pathologists in examining the complexity of whole-slide images of carotid atherosclerotic plaques more effectively. Nevertheless, future studies using supervised methods should provide evidence of the correspondence between the clusters estimated using the proposed textural-based approach and the regions manually annotated by expert pathologists.