RESUMEN
Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.
Asunto(s)
Autofagia , Proteína 58 DEAD Box , Glaucoma , Presión Intraocular , Malla Trabecular , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedades de la Aorta , Autofagia/efectos de los fármacos , Proteína 58 DEAD Box/metabolismo , Proteína 58 DEAD Box/genética , Hipoplasia del Esmalte Dental , Glaucoma/patología , Glaucoma/metabolismo , Glaucoma/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Pérdida Auditiva Sensorineural/metabolismo , Interferón beta/metabolismo , Presión Intraocular/genética , Metacarpo/anomalías , Ratones Endogámicos C57BL , Enfermedades Musculares , Mutación , Odontodisplasia , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Atrofia Óptica/patología , Osteoporosis , Linaje , Receptores Inmunológicos , Malla Trabecular/metabolismo , Malla Trabecular/efectos de los fármacos , Calcificación VascularRESUMEN
BACKGROUND: The metabolic alterations occurring within the arterial architecture during atherosclerosis development remain poorly understood, let alone those particular to each arterial tunica. We aimed first to identify, in a spatially resolved manner, the specific metabolic changes in plaque, media, adventitia, and cardiac tissue between control and atherosclerotic murine aortas. Second, we assessed their translatability to human tissue and plasma for cardiovascular risk estimation. METHODS: In this observational study, mass spectrometry imaging (MSI) was applied to identify region-specific metabolic differences between atherosclerotic (n=11) and control (n=11) aortas from low-density lipoprotein receptor-deficient mice, via histology-guided virtual microdissection. Early and advanced plaques were compared within the same atherosclerotic animals. Progression metabolites were further analyzed by MSI in 9 human atherosclerotic carotids and by targeted mass spectrometry in human plasma from subjects with elective coronary artery bypass grafting (cardiovascular risk group, n=27) and a control group (n=27). RESULTS: MSI identified 362 local metabolic alterations in atherosclerotic mice (log2 fold-change ≥1.5; P≤0.05). The lipid composition of cardiac tissue is altered during atherosclerosis development and presents a generalized accumulation of glycerophospholipids, except for lysolipids. Lysolipids (among other glycerophospholipids) were found at elevated levels in all 3 arterial layers of atherosclerotic aortas. LPC(18:0) (lysophosphatidylcholine; P=0.024) and LPA(18:1) (lysophosphatidic acid; P=0.025) were found to be significantly elevated in advanced plaques as compared with mouse-matched early plaques. Higher levels of both lipid species were also observed in fibrosis-rich areas of advanced- versus early-stage human samples. They were found to be significantly reduced in human plasma from subjects with elective coronary artery bypass grafting (P<0.001 and P=0.031, respectively), with LPC(18:0) showing significant association with cardiovascular risk (odds ratio, 0.479 [95% CI, 0.225-0.883]; P=0.032) and diagnostic potential (area under the curve, 0.778 [95% CI, 0.638-0.917]). CONCLUSIONS: An altered phospholipid metabolism occurs in atherosclerosis, affecting both the aorta and the adjacent heart tissue. Plaque-progression lipids LPC(18:0) and LPA(18:1), as identified by MSI on tissue, reflect cardiovascular risk in human plasma.
Asunto(s)
Enfermedades de la Aorta , Aterosclerosis , Enfermedades Cardiovasculares , Placa Aterosclerótica , Humanos , Animales , Ratones , Placa Aterosclerótica/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/metabolismo , Factores de Riesgo , Aterosclerosis/diagnóstico , Aterosclerosis/metabolismo , Aorta/diagnóstico por imagen , Aorta/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Glicerofosfolípidos/metabolismo , Factores de Riesgo de Enfermedad CardiacaRESUMEN
BACKGROUND: Women with a history of preeclampsia have evidence of premature atherosclerosis and increased risk of myocardial infarction and stroke compared with women who had a normotensive pregnancy. Whether this is due to common risk factors or a direct impact of prior preeclampsia exposure has never been tested in a mouse atherosclerosis model. METHODS: Pregnant LDLR-KO (low-density lipoprotein receptor knockout; n=35) female mice were randomized in midgestation to sFlt1 (soluble fms-like tyrosine kinase 1)-expressing adenovirus or identical control adenovirus. Postpartum, mice were fed high-fat diet for 8 weeks to induce atherogenesis. Comparison between the control and preeclampsia models was made for metabolic parameters, atherosclerosis burden and composition by histology, plaque inflammation by flow cytometry, and aortic cytokines and inflammatory markers using a cytokine array. RESULTS: In pregnant LDLR-KO mice, sFlt1 adenovirus significantly induced serum sFlt1, blood pressure, renal endotheliosis, and decreased pup viability. After 8 weeks of postpartum high fat feeding, body weight, fasting glucose, plasma cholesterol, HDL (high-density lipoprotein), and LDL (low-density lipoprotein) were not significantly different between groups with no change in aortic root plaque size, lipid content, or necrotic core area. Flow cytometry demonstrated significantly increased CD45+ aortic arch leukocytes and CD3+T cells and aortic lysate contained more CCL (CC motif chemokine ligand) 22 and fetuin A and decreased expression of IGFBP6 (insulin-like growth factor-binding protein 6) and CCL21 in preeclampsia-exposed mice compared with controls. CONCLUSIONS: In atherogenic LDLR-KO mice, exposure to sFlt1-induced preeclampsia during pregnancy increases future atherosclerotic plaque inflammation, supporting the concept that preeclampsia directly exacerbates atherosclerotic inflammation independent of preexisting risk factors. This mechanism may contribute to ischemic vascular disease in women after preeclampsia pregnancy.
Asunto(s)
Enfermedades de la Aorta , Aterosclerosis , Placa Aterosclerótica , Preeclampsia , Humanos , Femenino , Animales , Ratones , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Enfermedades de la Aorta/genética , Ratones Noqueados , Aterosclerosis/genética , Inflamación/metabolismo , Lipoproteínas LDL/metabolismo , Receptores de LDL/genética , Citocinas , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Arterial stiffening may contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease. We aimed to assess relations of vascular hemodynamic measures with measures of hepatic steatosis and fibrosis in the community. METHODS: Our sample was drawn from the Framingham Offspring, New Offspring Spouse, Third Generation, Omni-1, and Omni-2 cohorts (N=3875; mean age, 56 years; 54% women). We used vibration-controlled transient elastography to assess controlled attenuation parameter and liver stiffness measurements as measures of liver steatosis and liver fibrosis, respectively. We assessed noninvasive vascular hemodynamics using arterial tonometry. We assessed cross-sectional relations of vascular hemodynamic measures with continuous and dichotomous measures of hepatic steatosis and fibrosis using multivariable linear and logistic regression. RESULTS: In multivariable models adjusting for cardiometabolic risk factors, higher carotid-femoral pulse wave velocity (estimated ß per SD, 0.05 [95% CI, 0.01-0.09]; P=0.003), but not forward pressure wave amplitude and central pulse pressure, was associated with more liver steatosis (higher controlled attenuation parameter). Additionally, higher carotid-femoral pulse wave velocity (ß=0.11 [95% CI, 0.07-0.15]; P<0.001), forward pressure wave amplitude (ß=0.05 [95% CI, 0.01-0.09]; P=0.01), and central pulse pressure (ß=0.05 [95% CI, 0.01-0.09]; P=0.01) were associated with more hepatic fibrosis (higher liver stiffness measurement). Associations were more prominent among men and among participants with obesity, diabetes, and metabolic syndrome (interaction P values, <0.001-0.04). Higher carotid-femoral pulse wave velocity, but not forward pressure wave amplitude and central pulse pressure, was associated with higher odds of hepatic steatosis (odds ratio, 1.16 [95% CI, 1.02-1.31]; P=0.02) and fibrosis (odds ratio, 1.40 [95% CI, 1.19-1.64]; P<0.001). CONCLUSIONS: Elevated aortic stiffness and pressure pulsatility may contribute to hepatic steatosis and fibrosis.
Asunto(s)
Enfermedades de la Aorta , Presión Arterial , Hígado Graso , Cirrosis Hepática , Rigidez Vascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Hígado Graso/complicaciones , Cirrosis Hepática/complicaciones , Estudios Longitudinales , Enfermedades de la Aorta/complicaciones , Estudios TransversalesRESUMEN
BACKGROUND: Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis. METHODS: On an Apoe-/- background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed. RESULTS: Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin ß2-mediated adhesion of monocytes but did not impair integrin α4ß1-dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn2+- or chemokine-induced activation of integrin α4ß1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4ß1 but was not affected by talin1 deletion or antibodies to integrin ß2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin ß3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin ß3. CONCLUSIONS: Integrin α4ß1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4ß1 activation to the high-affinity state and integrin α4ß1-mediated monocyte recruitment. Yet, talin1 is required for integrin ß3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.
Asunto(s)
Aterosclerosis , Adhesión Celular , Modelos Animales de Enfermedad , Macrófagos , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Células Mieloides , Talina , Animales , Talina/metabolismo , Talina/genética , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/metabolismo , Células Mieloides/metabolismo , Células Mieloides/patología , Macrófagos/metabolismo , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/prevención & control , Masculino , Antígenos CD18/metabolismo , Antígenos CD18/genética , Integrina alfa4beta1/metabolismo , Integrina alfa4beta1/genética , Monocitos/metabolismo , Monocitos/inmunología , Placa Aterosclerótica , Ratones , Células Cultivadas , Aorta/patología , Aorta/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. METHODS: Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1ß or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis. RESULTS: Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1ß antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1ß antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap. CONCLUSIONS: Taken together, IL-1ß appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.
Asunto(s)
Aterosclerosis , Modelos Animales de Enfermedad , Interleucina-1beta , Ratones Noqueados para ApoE , Miocitos del Músculo Liso , Placa Aterosclerótica , Animales , Interleucina-1beta/metabolismo , Aterosclerosis/patología , Aterosclerosis/prevención & control , Aterosclerosis/metabolismo , Aterosclerosis/genética , Ratones , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Masculino , Dieta Occidental , Ratones Endogámicos C57BL , Aorta/patología , Aorta/metabolismo , Aorta/efectos de los fármacos , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/prevención & control , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Dieta Alta en Grasa , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Tronco Braquiocefálico/patología , Tronco Braquiocefálico/metabolismo , Tronco Braquiocefálico/efectos de los fármacosRESUMEN
BACKGROUND: Trem2 (triggering receptor on myeloid cells 2), a surface lipid receptor, is expressed on foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, and anti-inflammatory responses. Studies examining the role of Trem2 in atherosclerosis have shown that deletion of Trem2 leads to impaired foamy macrophage lipid uptake, proliferation, survival, and cholesterol efflux. Thus, we tested the hypothesis that administration of a Trem2 agonist antibody (AL002a) to atherogenic mice would enhance macrophage survival and decrease necrotic core formation to improve plaque stability. METHODS: To model a therapeutic intervention approach, atherosclerosis-prone mice (Ldlr [low-density lipoprotein receptor]-/-) were fed a high-fat diet for 8 weeks, then transitioned to treatment with AL002a or isotype control for an additional 8 weeks while continuing on a high-fat diet. RESULTS: AL002a-treated mice had increased lesion size in both the aortic root and whole mount aorta, which correlated with an expansion of plaque macrophage area. This expansion was due to increased macrophage survival and proliferation in plaques. Importantly, plaques from AL002a-treated mice showed improved features of plaque stability, including smaller necrotic cores, increased fibrous caps, and greater collagen deposition. Single-cell RNA sequencing of whole aorta suspensions from isotype- and AL002a-treated atherosclerotic mice revealed that Trem2 agonism dramatically altered foamy macrophage transcriptome. This included upregulation of oxidative phosphorylation and increased expression of collagen genes. In vitro studies validated that Trem2 agonism with AL002a promoted foamy macrophage oxidized low-density lipoprotein uptake, survival, and cholesterol efflux. CONCLUSIONS: Trem2 agonism expands atherosclerotic plaque macrophages by promoting cell survival and proliferation but improves features of plaque stability by rewiring foamy macrophage function to enhance cholesterol efflux and collagen deposition.
Asunto(s)
Aterosclerosis , Modelos Animales de Enfermedad , Células Espumosas , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica , Receptores Inmunológicos , Animales , Receptores Inmunológicos/agonistas , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Aterosclerosis/patología , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Células Espumosas/metabolismo , Células Espumosas/patología , Células Espumosas/efectos de los fármacos , Masculino , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores de LDL/deficiencia , Proliferación Celular/efectos de los fármacos , Dieta Alta en Grasa , Supervivencia Celular/efectos de los fármacos , Necrosis , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/prevención & controlRESUMEN
BACKGROUND: Tissue resident memory T (TRM) cells are a T-cell subset that resides at the site of prior antigen recognition to protect the body against reoccurring encounters. Besides their protective function, TRM cells have also been implicated in inflammatory disorders. TRM cells are characterized by the expression of CD69 and transcription factors Hobit (homolog of Blimp-1 [B lymphocyte-induced maturation protein 1] in T cells) and Blimp-1. As the majority of T cells in the arterial intima expresses CD69, TRM cells may contribute to the pathogenesis of atherosclerosis as well. Here, we aimed to assess the presence and potential role of TRM cells in atherosclerosis. METHODS: To identify TRM cells in human atherosclerotic lesions, a single-cell RNA-sequencing data set was interrogated, and T-cell phenotypes were compared with that of integrated predefined TRM cells. The presence and phenotype of TRM in atherosclerotic lesions was corroborated using a mouse model that enabled tracking of Hobit-expressing TRM cells. To explore the function of TRM cells during atherogenesis, RAG1-/- (recombination activating gene 1 deficient) LDLr-/- (low-density lipoprotein receptor knockout) mice received a bone marrow transplant from HobitKO/CREBlimp-1flox/flox mice, which exhibit abrogated TRM cell formation, whereafter the mice were fed a Western-type diet for 10 weeks. RESULTS: Human atherosclerotic lesions contained T cells that exhibited a TRM cell-associated gene signature. Moreover, a fraction of these T cells clustered together with predefined TRM cells upon integration. The presence of Hobit-expressing TRM cells in the atherosclerotic lesion was confirmed in mice. These lesion-derived TRM cells were characterized by the expression of CD69 and CD49α. Moreover, we demonstrated that this small T-cell subset significantly affects lesion composition, by reducing the amount of intralesional macrophages and increasing collagen content. CONCLUSIONS: TRM cells, characterized by the expression of CD69 and CD49α, constitute a minor population in atherosclerotic lesions and are associated with increased lesion stability in a Hobit and Blimp-1 knockout mouse model.
Asunto(s)
Aterosclerosis , Modelos Animales de Enfermedad , Memoria Inmunológica , Macrófagos , Células T de Memoria , Ratones Endogámicos C57BL , Placa Aterosclerótica , Receptores de LDL , Animales , Aterosclerosis/patología , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/genética , Humanos , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/patología , Receptores de LDL/genética , Receptores de LDL/deficiencia , Ratones , Masculino , Ratones Noqueados , Antígenos de Diferenciación de Linfocitos T/metabolismo , Antígenos de Diferenciación de Linfocitos T/genética , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Fenotipo , Femenino , Antígenos CD/metabolismo , Antígenos CD/genética , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismoRESUMEN
BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE-/- and Gsdmd-/- ApoE-/- mice, bone marrow transplantation, and AAV (adeno-associated virus serotype 9)-F4/80-shGSDMD (shRNA-GSDMD) were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd-/- attenuates the atherosclerotic lesion area in high-fat diet-fed ApoE-/- mice. We performed single-cell RNA sequencing of ApoE-/- and Gsdmd-/- ApoE-/- mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 (GSDMD inhibitor Y1) can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.
Asunto(s)
Aterosclerosis , Modelos Animales de Enfermedad , Factor 3 Regulador del Interferón , Péptidos y Proteínas de Señalización Intracelular , Macrófagos , Proteínas de la Membrana , Ratones Endogámicos C57BL , Mitocondrias , FN-kappa B , Proteínas de Unión a Fosfato , Piroptosis , Transducción de Señal , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Ratones , FN-kappa B/metabolismo , Mitocondrias/metabolismo , Mitocondrias/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones Noqueados para ApoE , Placa Aterosclerótica , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/prevención & control , GasderminasRESUMEN
BACKGROUND: Cellular communication among different types of vascular cells is indispensable for maintaining vascular homeostasis and preventing atherosclerosis. However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat atherosclerosis remain unknown. We hypothesized that endothelial autophagy mediates the cellular communication in vascular tissue through exosome-mediated delivery of atherosclerosis-related genes. METHODS: Rapamycin and adeno-associated virus carrying Atg7 short hairpin RNA under the Tie (TEK receptor tyrosine kinase) promoter were used to activate and inhibit vascular endothelial autophagy in high-fat diet-fed ApoE-/- mice, respectively. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue were used to explore the effects of endothelial autophagy on endothelial function and atherosclerosis and its molecular mechanisms. Quantitative polymerase chain reaction and miRNA sequencing were performed to determine changes in miRNA expression in exosomes. Immunofluorescence and exosome coculture experiments were conducted to examine the role of endothelial autophagy in regulating the communication between endothelial cells and smooth muscle cells (SMCs) via exosomal miRNA. RESULTS: Endothelial autophagy was inhibited in thoracic aortas of high-fat diet-fed ApoE-/- mice. Furthermore, rapamycin alleviated high-fat diet-induced atherosclerotic burden and endothelial dysfunction, while endothelial-specific Atg7 depletion aggravated the atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue analysis revealed that miR-204-5p was significantly increased in endothelial cells after high-fat diet exposure, which directly targeted Bcl2 to regulate endothelial cell apoptosis. Importantly, endothelial autophagy activation decreased excess miR-204-5p by loading miR-204-5p into multivesicular bodies and secreting it through exosomes. Moreover, exosomal miR-204-5p can effectively transport to SMCs, alleviating SMC calcification by regulating target proteins such as RUNX2 (runt-related transcription factor 2). CONCLUSIONS: Our study revealed the exosomal pathway by which endothelial autophagy protects atherosclerosis: endothelial autophagy activation transfers miR-204-5p from endothelial cells to SMCs via exosomes, both preventing endothelial apoptosis and alleviating SMC calcification. REGISTRATION: URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2200064155.
Asunto(s)
Aterosclerosis , Autofagia , Comunicación Celular , Modelos Animales de Enfermedad , Exosomas , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , MicroARNs , Miocitos del Músculo Liso , MicroARNs/metabolismo , MicroARNs/genética , Exosomas/metabolismo , Exosomas/genética , Animales , Aterosclerosis/patología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Humanos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Masculino , Ratones , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Proteína 7 Relacionada con la Autofagia/metabolismo , Proteína 7 Relacionada con la Autofagia/genética , Células Cultivadas , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Placa Aterosclerótica , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/prevención & control , Enfermedades de la Aorta/metabolismo , Técnicas de Cocultivo , Transducción de Señal , Aorta Torácica/metabolismo , Aorta Torácica/patología , Dieta Alta en GrasaRESUMEN
BACKGROUND: Atherosclerosis is driven by the infiltration of the arterial intima by diverse immune cells and smooth muscle cells (SMCs). CD8+ T cells promote lesion growth during atherosclerotic lesion development, but their role in advanced atherosclerosis is less clear. Here, we studied the role of CD8+ T cells and their effects on SMCs in established atherosclerosis. METHODS: CD8+ T cells were depleted in (SMC reporter) low-density lipoprotein receptor-deficient (Ldlr-/-) mice with established atherosclerotic lesions. Atherosclerotic lesion formation was examined, and single-cell RNA sequencing of aortic SMCs and their progeny was performed. Additionally, coculture experiments with primary aortic SMCs and CD8+ T cells were conducted. RESULTS: Although we could not detect differences in atherosclerotic lesion size, an increased plaque SMC content was noted in mice after CD8+ T-cell depletion. Single-cell RNA sequencing of aortic lineage-traced SMCs revealed contractile SMCs and a modulated SMC cluster, expressing macrophage- and osteoblast-related genes. CD8+ T-cell depletion was associated with an increased contractile but decreased macrophage and osteoblast-like gene signature in this modulated aortic SMC cluster. Conversely, exposure of isolated aortic SMCs to activated CD8+ T cells decreased the expression of genes indicative of a contractile SMC phenotype and induced a macrophage and osteoblast-like cell state. Notably, CD8+ T cells triggered calcium deposits in SMCs under osteogenic conditions. Mechanistically, we identified transcription factors highly expressed in modulated SMCs, including Runx1, to be induced by CD8+ T cells in cultured SMCs in an IFNγ (interferon-γ)-dependent manner. CONCLUSIONS: We here uncovered CD8+ T cells to control the SMC phenotype in atherosclerosis. CD8+ T cells promote SMC dedifferentiation and drive SMCs to adopt features of macrophage-like and osteoblast-like, procalcifying cell phenotypes. Given the critical role of SMCs in atherosclerotic plaque stability, CD8+ T cells could thus be explored as therapeutic target cells during lesion progression.
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Aterosclerosis , Linfocitos T CD8-positivos , Desdiferenciación Celular , Modelos Animales de Enfermedad , Músculo Liso Vascular , Miocitos del Músculo Liso , Placa Aterosclerótica , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/inmunología , Ratones , Aterosclerosis/patología , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/inmunología , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Células Cultivadas , Masculino , Receptores de LDL/genética , Receptores de LDL/deficiencia , Fenotipo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Aorta/patología , Aorta/inmunología , Aorta/metabolismo , Técnicas de Cocultivo , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismoRESUMEN
BACKGROUND: Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects. METHODS: We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit ß5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit ß1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr-/- and APOE*3-Leiden.CETP mice. RESULTS: ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. CONCLUSIONS: We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.
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Tejido Adiposo Blanco , Aterosclerosis , Modelos Animales de Enfermedad , Síndrome Metabólico , Ratones Endogámicos C57BL , Complejo de la Endopetidasa Proteasomal , Receptores de LDL , Animales , Aterosclerosis/patología , Aterosclerosis/prevención & control , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/inmunología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/patología , Receptores de LDL/genética , Receptores de LDL/deficiencia , Complejo de la Endopetidasa Proteasomal/metabolismo , Masculino , Inhibidores de Proteasoma/farmacología , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Enfermedades de la Aorta/prevención & control , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/enzimología , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Placa Aterosclerótica , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ratones Noqueados para ApoE , Ratones , Metabolismo Energético/efectos de los fármacos , OligopéptidosRESUMEN
Vascular calcification is a pathological process commonly associated with atherosclerosis, chronic kidney disease, and diabetes. Paraspeckle protein NONO is a multifunctional RNA/DNA binding protein involved in many nuclear biological processes but its role in vascular calcification remains unclear. Here, we observed that NONO expression was decreased in calcified arteries of mice and patients with CKD. We generated smooth muscle-specific NONO-knockout mice and established three different mouse models of vascular calcification by means of 5/6 nephrectomy, adenine diet to induce chronic kidney failure, or vitamin D injection. The knockout mice were more susceptible to the development of vascular calcification relative to control mice, as verified by an increased calcification severity and calcium deposition. Likewise, aortic rings from knockout mice showed more significant vascular calcification than those from control mice ex vivo. In vitro, NONO deficiency aggravated high phosphate-induced vascular smooth muscle cell osteogenic differentiation and apoptosis, whereas NONO overexpression had a protective effect. Mechanistically, we demonstrated that the regulation of vascular calcification by NONO was mediated by bone morphogenetic protein 2 (BMP2). NONO directly bound to the BMP2 promoter using its C-terminal region, exerting an inhibitory effect on the transcription of BMP2. Thus, our study reveals that NONO is a novel negative regulator of vascular calcification, which inhibits osteogenic differentiation of vascular smooth muscle cell and vascular calcification via negatively regulating BMP2 transcription. Hence, NONO may provide a promising target for the prevention and treatment of vascular calcification.
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Proteína Morfogenética Ósea 2 , Modelos Animales de Enfermedad , Ratones Noqueados , Músculo Liso Vascular , Miocitos del Músculo Liso , Osteogénesis , Insuficiencia Renal Crónica , Transcripción Genética , Calcificación Vascular , Animales , Humanos , Masculino , Ratones , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/prevención & control , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/metabolismo , Apoptosis/efectos de los fármacos , Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 2/genética , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones Endogámicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Regiones Promotoras Genéticas , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/prevención & control , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Calcificación Vascular/patología , Calcificación Vascular/prevención & control , Calcificación Vascular/metabolismo , Calcificación Vascular/genética , Calcificación Vascular/etiologíaRESUMEN
OBJECTIVE: The risk of aortic dissection (AoD) is increased in Turner syndrome (TS) but predicting those at risk is difficult. Based on scarce evidence, preventive aortic surgery is recommended when aortic diameter increases >5 mm/year. To investigate the aortic growth rate in TS and TS-related conditions associated with aortic growth. We also reported our experience of women who suffered aortic dissection (AoD), and who had preventive aortic replacement. METHODS: 151 adult TS were retrospectively identified. Women who had more than one transthoracic echocardiogram (TTE) after age 16 years were included in the aortic growth study. Aortic diameters at sinuses of Valsalva (SoV) and ascending aorta (AA) were analysed by two experts. RESULTS: 70/151 women had more than one TTE (interscan interval 4.7 years). Mean aortic growth was 0.13 ± 0.59 mm/year at SoV and 0.23 ± 0.82 mm/year at AA. Known risk factors for aortic dilatation and TS-related conditions were not associated with aortic growth. 4/151 women experienced AoD (age 25±8 years): two had paired scans for aortic growth, which was 0.67 mm/year at both SoV and AA in the first woman, and 11 mm/year (SoV) and 4 mm/year (AA) in the second. Only 1/4 of women with AoD survived; she used a TS cardiac-alert card to inform emergency personnel about her risk of AoD. 5/151 had a preventive aortic replacement, but one died post-operatively. CONCLUSIONS: Mean aortic growth in our TS population was increased compared to non-TS women and was not associated with currently known risk factors for AoD, suggesting that aortic growth rate itself could be a useful variable to stratify who is at risk for AoD.
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Enfermedades de la Aorta , Disección Aórtica , Síndrome de Turner , Adulto , Femenino , Humanos , Adolescente , Adulto Joven , Síndrome de Turner/complicaciones , Síndrome de Turner/epidemiología , Estudios Retrospectivos , Enfermedades de la Aorta/complicaciones , Enfermedades de la Aorta/epidemiología , Medición de RiesgoRESUMEN
BACKGROUND: We investigated the early and midterm efficacy and safety of covered endovascular reconstruction of the aortic bifurcation (CERAB) in the treatment of aortoiliac disease (AID). METHODS: A systematic search on PubMed, Scopus, and Web of Science for articles published by August 2023 was performed. The primary end points were primary patency and secondary patency. RESULTS: Eleven retrospective case series, involving 579 patients, were incorporated in the review with 88.9% of the included lesions being categorized as Trans-Atlantic Inter-Society Consensus (TASC) C or D. The pooled primary patency estimates at 12, 24 and 36 months were 94.4% (95% confidence interval [CI], 89.4-99.7), 84.4% (95% CI, 72.3-98.5) and 83.8% (95% CI, 71.4-98.3) respectively. The mean primary patency time, representing the period during which individuals remained event-free, was 51.9 months (95% CI, 43.6-55.4). The pooled 36 months primary patency for studies with a predominantly claudicant patient population (>75% of patients) was 89.4% (95% CI, 78.5-100.0), compared with 71.5% (95% CI, 45.6-100.0) for studies with a mixed population (50% of patients). The pooled 36 months primary patency for studies with a predominantly TASC D patient population (>82% of patients) was 70.4% (95% CI, 46.4-100.0) compared with 91.0% (95% CI, 79.1-100.0) for studies with a more homogenous cohort. The pooled secondary patency estimates at 12, 24, and 36 months were 98.6% (95% CI, 96.2-100.0), 97% (95% CI, 93.1-100.0), and 97% (95% CI, 93.1-100.0), respectively. The pooled technical success, 30-day mortality and 30-day systemic complications estimates were 95.9% (95% CI, 93.7- 97.4), 1.9% (95% CI, 1.0-3.5), and 6.4% (95% CI, 4.4-9.1), respectively. The pooled intraoperative and postoperative 30-day CERAB-related complications estimates were 7.3% (95% CI, 2.0-23.0) and 4.2% (95% CI, 0.7-21.0), respectively. The pooled major amputation and target lesion reinterventions by the end of follow-up were 1.9% (95% CI, 1.0-3.4) and 13.9% (95% CI, 9.9-19.2), respectively. The pooled access site complication estimate was 11.7% (95% CI, 5.9-21.7). CONCLUSIONS: Although this review has showcased the safety and feasibility of the CERAB technique in treating AID, it has also highlighted the necessity for a close and prolonged follow-up period extending beyond 1 year. Moreover, the favorable secondary patency estimates predominantly attained via endovascular reinterventions emphasize a potentially advantageous characteristic of the CERAB technique, particularly valuable when addressing late-stage AID disease or anatomically complex lesions.
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Enfermedades de la Aorta , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Arteria Ilíaca , Grado de Desobstrucción Vascular , Humanos , Procedimientos Endovasculares/efectos adversos , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/instrumentación , Implantación de Prótesis Vascular/mortalidad , Enfermedades de la Aorta/cirugía , Enfermedades de la Aorta/diagnóstico por imagen , Enfermedades de la Aorta/fisiopatología , Enfermedades de la Aorta/mortalidad , Arteria Ilíaca/cirugía , Arteria Ilíaca/diagnóstico por imagen , Arteria Ilíaca/fisiopatología , Factores de Tiempo , Stents , Factores de Riesgo , Resultado del Tratamiento , Anciano , Femenino , Masculino , Prótesis Vascular , Persona de Mediana Edad , Enfermedad Arterial Periférica/fisiopatología , Enfermedad Arterial Periférica/cirugía , Enfermedad Arterial Periférica/diagnóstico por imagen , Diseño de PrótesisRESUMEN
OBJECTIVE: Aortic endarterectomy (AE), once a treatment of choice for aortoiliac occlusive disease, is now rarely performed in favor of endovascular procedures or open aortobifemoral bypass. However, in select patients with paravisceral or aortoiliac occlusive disease, AE remains a viable alternative for revascularization, either as a primary procedure or after prior interventions have failed. Here, we evaluated outcomes for an extended series of patients undergoing paravisceral or aortoiliac endarterectomy, demonstrating that these procedures can be an excellent alternative with acceptable morbidity and mortality in properly selected patients. METHODS: A single institution retrospective review of 20 patients who underwent AE from 2017 to 2023 was performed. RESULTS: Five patients (25%) underwent paravisceral endarterectomy and 15 (75%) underwent aortoiliac endarterectomy. There were no perioperative mortalities. One paravisceral patient died 3 months postoperatively from complications of pneumonia. Three patients in the paravisceral group required reinterventions; one acutely due to thrombosis of the superior mesenteric artery (SMA) requiring extension of the endarterectomy and patch angioplasty on postoperative day 0, one due to stenosis at the distal edge of the endarterectomy 1 month postoperatively, successfully treated with SMA stenting, and one at 10-month follow-up due to SMA stenosis at the distal aspect of the endarterectomy, also successfully treated with SMA stenting. With these reinterventions, the 1-year primary patency in the paravisceral group was 40%, primary-assisted patency was 80%, and secondary patency was 100%. In the aortoiliac group, 1-year primary, primary-assisted, and secondary patency were 91%, 91%, and 100%, respectively. One patient developed iliac thrombosis 10 days postoperatively owing to an intimal flap distal to the endarterectomy site. She and one other patient, a young man with an undefined hypercoagulable disorder, ultimately required neoaortoiliac reconstructions at 18 and 32 months postoperatively, respectively (the latter in the setting of stopping anticoagulation). The remaining 13 patients experienced no complications. All patients had rapid resolution of clinical symptoms, and median postoperative ankle-brachial indexes of 1.06 on the right and 1.00 on the left, representing a median improvement from preoperative ankle-brachial indexes of +0.59 on the right and +0.56 on the left (P < .01 and P < .01). CONCLUSIONS: In this series of 20 patients undergoing paravisceral and infrarenal aortoiliac endarterectomy, AE was associated with no perioperative mortality, relatively low and manageable morbidity, and excellent clinical outcomes in patients with both paravisceral and aortoiliac occlusive disease. SMA-related early reintervention was not uncommon in the paravisceral group, and attention should be given particularly to the distal endarterectomy site. AE remains a viable treatment for severe multivessel paravisceral or aortoiliac occlusive disease isolated to the aorta and common iliac arteries in select patients.
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Enfermedades de la Aorta , Arteriopatías Oclusivas , Procedimientos Endovasculares , Trombosis , Masculino , Femenino , Humanos , Resultado del Tratamiento , Constricción Patológica/etiología , Grado de Desobstrucción Vascular , Enfermedades de la Aorta/diagnóstico por imagen , Enfermedades de la Aorta/cirugía , Enfermedades de la Aorta/etiología , Endarterectomía/efectos adversos , Endarterectomía/métodos , Procedimientos Endovasculares/efectos adversos , Aorta Abdominal/cirugía , Trombosis/etiología , Estudios Retrospectivos , Arteriopatías Oclusivas/diagnóstico por imagen , Arteriopatías Oclusivas/cirugía , Arteriopatías Oclusivas/etiología , Arteria Ilíaca/diagnóstico por imagen , Arteria Ilíaca/cirugíaRESUMEN
OBJECTIVE: The aim of this study was to evaluate the role of intravascular ultrasound (IVUS) for the technical assessment of kissing stents (KSs) and covered endovascular reconstruction of the aortic bifurcation (CERAB) in the treatment of aortoiliac obstructive disease involving the aortic bifurcation. METHODS: We conducted a single-center retrospective review of patients undergoing endovascular treatment of severe aorto-iliac obstructive disease (2019-2023). IVUS was performed in patients treated by KSs or CERAB according to preoperative indications, in cases of moderate/severe calcifications, mural thrombus, total occlusions, and lesion extension towards the proximity of renal or hypogastric arteries. Indications for IVUS-guided intraoperative revisions were residual stenosis or compression >30%, incomplete stent-to-wall apposition, or flow-limiting dissection at the landing site. Follow-up assessment was performed at 6 and 12 months, and then yearly. Thirty-day outcomes and 2-year patency rates were evaluated. Logistic regression was used to identify factors associated with significant technical defects detected by IVUS needing intraoperative revision. RESULTS: IVUS was used for the technical assessment of 102 patients treated by KSs (n = 57; 56%) or CERAB (n = 45; 44%) presenting with severe intermittent claudication (39%), rest pain (39%), or ischemic tissue loss (25%). Twenty-nine significant technical defects were identified by IVUS in 25 patients (25%) who then had successful intraoperative correction by additional ballooning (n = 23; 80%) or stenting (n = 6; 20%). Patients with a severely calcified chronic total occlusion (odds ratio, 1.85; 95% confidence interval, 1.01-5.27; P = .044) or severely calcified narrow aortic bifurcation with <12 mm diameter (odds ratio, 2.34; 95% confidence interval, 1.10-8.64; P = .032) were at increased risk for IVUS-guided intraoperative revision. There were no postoperative deaths and no major adverse events. Two-year primary patency was 100%. CONCLUSIONS: IVUS was used for the technical assessment of KSs/CERAB in a selected cohort of patients with severe aorto-iliac obstructive disease. This allowed the identification and intraoperative correction of a significant technical defect not detected by completion angiogram in one-quarter of patients, achieving optimal 2-year results. IVUS assessment of KSs/CERAB may be considered especially in patients with a calcified total occlusion or narrow aortic bifurcation.
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Enfermedades de la Aorta , Procedimientos Endovasculares , Arteria Ilíaca , Stents , Ultrasonografía Intervencional , Grado de Desobstrucción Vascular , Humanos , Estudios Retrospectivos , Masculino , Femenino , Anciano , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/instrumentación , Resultado del Tratamiento , Persona de Mediana Edad , Enfermedades de la Aorta/diagnóstico por imagen , Enfermedades de la Aorta/cirugía , Enfermedades de la Aorta/fisiopatología , Arteria Ilíaca/diagnóstico por imagen , Arteria Ilíaca/fisiopatología , Arteria Ilíaca/cirugía , Factores de Tiempo , Anciano de 80 o más Años , Valor Predictivo de las Pruebas , Factores de Riesgo , Arteriopatías Oclusivas/diagnóstico por imagen , Arteriopatías Oclusivas/fisiopatología , Arteriopatías Oclusivas/cirugíaRESUMEN
OBJECTIVE: The aim of this multicenter national study was to compare the outcomes of primary open surgery by aorto-bifemoral bypass (ABFB) with those performed after a failed endovascular treatment (EVT) by kissing stent technique for complex aortoiliac occlusive disease (AIOD) lesions (TransAtlantic Inter-Society Consensus [TASC] II C and D). METHODS: All consecutive ABFB cases carried out at 12 vascular surgery centers between 2016 and 2021 were retrospectively collected and analyzed. Data included patients' baseline demographics and clinical characteristics, procedural details, perioperative outcomes, and follow-up results (survival, patency, amputation). The study cohort was divided into two groups based on indications for ABFB: primary treatment vs secondary treatment after EVT failure. RESULTS: Overall, 329 patients underwent ABFB during the study period (71% males; mean age, 64 years), of which 285 were primary treatment and 44 were after prior EVT. At baseline, no significant differences were found between study groups in demographics and clinical characteristics. TASC C and D lesions were similarly represented in the study groups (TASC C: 22% vs 78%; TASC D: 16% vs 84%). No major differences were found between study groups in terms of procedural details, early mortality, and perioperative complications. At 5 years, primary patency rates were significantly higher for primary ABFB (88%; 95% confidence interval [CI], 93.2%-84%) as compared with ABFB after prior EVT (69%; 95% CI 84.9%-55%; log rank P value < .001); however, the 5-year rates of secondary patency (100% vs 95%; 95% CI, 100%-86%) and limb salvage (97%; 95% CI, 99%-96 vs 97%; 95% CI, 100%-94%) were similar between study groups. CONCLUSIONS: Surgical treatment of TASC C/D AIOD with ABFB seems to be equally safe and effective when performed after prior EVT, although primary ABFB seemed to have higher primary patency rates. Despite the need for more frequent reinterventions, secondary patency and limb salvage rates were similar. However, future large prospective trials are required to confirm these findings.
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Enfermedades de la Aorta , Procedimientos Endovasculares , Arteria Ilíaca , Stents , Grado de Desobstrucción Vascular , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/instrumentación , Procedimientos Endovasculares/métodos , Anciano , Arteria Ilíaca/fisiopatología , Arteria Ilíaca/cirugía , Arteria Ilíaca/diagnóstico por imagen , Enfermedades de la Aorta/cirugía , Enfermedades de la Aorta/diagnóstico por imagen , Enfermedades de la Aorta/fisiopatología , Enfermedades de la Aorta/mortalidad , Factores de Tiempo , Arteria Femoral/fisiopatología , Arteria Femoral/cirugía , Arteria Femoral/diagnóstico por imagen , Factores de Riesgo , Enfermedad Arterial Periférica/fisiopatología , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/cirugía , Enfermedad Arterial Periférica/terapia , Recuperación del Miembro , Resultado del Tratamiento , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/instrumentación , Amputación QuirúrgicaRESUMEN
BACKGROUND: Covered endovascular reconstruction of aortic bifurcation (CERAB) is increasingly used as a first line-treatment in patients with aortoiliac occlusive disease (AIOD). We sought to compare the outcomes of patients who underwent CERAB compared with the gold standard of aortobifemoral bypass (ABF). METHODS: The Vascular Quality Initiative was queried for patients who underwent ABF or CERAB from 2009 to 2021. Propensity scores were generated using demographics, comorbidities, Rutherford class, and urgency. The two groups were matched using 5-to-1 nearest-neighbor match. Our primary outcomes were 1-year estimates of primary patency, major adverse limb events (MALEs), MALE-free survival, reintervention-free survival, and amputation-free survival. Standard statistical methods were used. RESULTS: A total of 3944 ABF and 281 CERAB cases were identified. Of all patients with AIOD, the proportion of CERAB increased from 0% to 17.9% between 2009 and 2021. Compared with ABF, patients who underwent CERAB were more likely to be older (64.7 vs 60.2; P < .001) and more often had diabetes (40.9% vs 24.1%; P < .001) and end-stage renal disease (1.1% vs 0.3%; P = .03). In the matched analysis (229 CERAB vs 929 ABF), ABF patients had improved MALE-free survival (93.2% [±0.9%] vs 83.2% [±3%]; P < .001) and lower rates of MALE (5.2% [±0.9%] vs 14.1% [±3%]; P < .001), with comparable primary patency rates (98.3% [±0.3%] vs 96.6% [±1%]; P = .6) and amputation-free survival (99.3% [±0.3%] vs 99.4% [±0.6%]; P = .9). Patients in the CERAB group had significantly lower reintervention-free survival (62.5% [±6%] vs 92.9% [±0.9%]; P < .001). Matched analysis also revealed shorter length of stay (1 vs 7 days; P < .001), as well as lower pulmonary (1.2% vs 6.6%; P = .01), renal (1.8% vs 10%; P < .001), and cardiac (1.8% vs 12.8%; P < .001) complications among CERAB patients. CONCLUSIONS: CERAB had lower perioperative morbidity compared with ABF with a similar primary patency 1-year estimates. However, patients who underwent CERAB experienced more major adverse limb events and reinterventions. Although CERAB is an effective treatment for patients with AIOD, further studies are needed to determine the long-term outcomes of CERAB compared with the established durability of ABF and further define the role of CEARB in the treatment of AIOD.
Asunto(s)
Enfermedades de la Aorta , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Arteria Femoral , Recuperación del Miembro , Grado de Desobstrucción Vascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/mortalidad , Enfermedades de la Aorta/cirugía , Enfermedades de la Aorta/diagnóstico por imagen , Enfermedades de la Aorta/mortalidad , Enfermedades de la Aorta/fisiopatología , Arteria Femoral/cirugía , Arteria Femoral/fisiopatología , Arteria Femoral/diagnóstico por imagen , Factores de Tiempo , Factores de Riesgo , Amputación Quirúrgica , Arteria Ilíaca/cirugía , Arteria Ilíaca/fisiopatología , Arteria Ilíaca/diagnóstico por imagen , Medición de Riesgo , Arteriopatías Oclusivas/cirugía , Arteriopatías Oclusivas/fisiopatología , Arteriopatías Oclusivas/diagnóstico por imagen , Arteriopatías Oclusivas/mortalidad , Prótesis Vascular , Resultado del Tratamiento , Bases de Datos Factuales , Complicaciones Posoperatorias/etiologíaRESUMEN
OBJECTIVE: Global Registry for Endovascular Aortic Treatment (GREAT) is an international prospective multicenter registry collecting real-world data on performance of W. L. Gore thoracic and abdominal aortic endografts. This analysis evaluated the long-term differences in patient survival and device performance in patients undergoing thoracic endovascular aortic repair (TEVAR) for any thoracic aortic pathology. METHODS: From August 2010 to October 2016, 5014 patients were enrolled in GREAT. The population of interest was comprised of only patients treated for thoracic aortic pathologies. Through 5 years, primary outcomes were all-cause and aortic-related mortality, stroke, aortic rupture, endoleaks, migration, fracture, compression, paraplegia, and any reintervention through 5 years, grouped by pathology. Secondary outcomes were reintervention rate and freedom from serious device- and aortic-related events. RESULTS: The 578 patients with thoracic aortic pathologies enrolled in GREAT and identified for this analysis were categorized by common pathologies: thoracic aneurysm (n = 239), thoracic dissection (n = 203), arch (n = 26), and other (n = 110). The mean age of this population was 66.1 ± 12.8 years, and 64.7% were male. Procedure survival was 99.7%. In the overall group, at index procedure to 30 days and 31 days to 5 years, Kaplan-Meier estimates of freedom from all-cause mortality were 99.6% and 66.4%, respectively, and for aortic-related mortality were 97.7% and 94.6%, respectively. Aortic rupture rate was 0.5% (n = 3) at 30 days and 1.4% (n = 8) through 5 years. Stroke and spinal cord ischemic events were 1.9% (n = 11) and 1.6% (n = 9) at 30 days and at 5 years were 3.6% (n = 20), 0.5% (n = 3), respectively. Reinterventions were required in 7.3% (n = 42) at 30 days and 12.4% (n = 69) through 5 years. The number of patients with endoleaks at 30 days was 2.1% (n = 12): n = 3 (1.1%) for each of types IA, 1B, and II; n = 2 (0.3%) for type III; and n = 4 (0.7%) for unspecified. Through 5 years, the percentage of patients was 8.3% (n = 40): n = 15 (3.1%) for type IA; n = 10 (2.1%) for type IB; n = 11 (2.3%) for type II; and n = 9 (1.9%) for unspecified. One patient (0.2%) had stent migration at 30 days (aneurysm group); none were reported through 5 years. There were no incidents of stent compression or fracture from index procedure through 5 years. CONCLUSIONS: Data herein demonstrates durability and support for treatment of thoracic aortic disease with the GORE TAG conformable thoracic stent graft, including no incidents of stent compression/fracture and high freedom from aortic-related mortality. The planned analysis of follow-up to 10 years in GREAT will be beneficial.