MiR-127-3p enhances macrophagic proliferation via disturbing fatty acid profiles and oxidative phosphorylation in atherosclerosis.

BACKGROUND: Atherosclerosis is a chronic pathology, leading to acute coronary heart disease or stroke. MiR-127 has been found significantly upregulated in advanced atherosclerosis. But its function in atherosclerosis remains unexplored. We explored the role of miR-127-3p in regulating atherosclerosis development and its downstream mechanisms. METHODS: The expression profile of miR-127 in carotid atherosclerotic plaques of 23 patients with severe carotid stenosis was detected by RT-qPCR and in situ hybridization. Primary bone marrow-derived macrophages (BMDM) stimulated with oxidized low-density lipoprotein were used as an in vitro model. CCK-8, EdU, RT-qPCR, and flow cytometry were used to detect the proliferative capacity and polarization of BMDM, which were infected by lentivirus-carrying plasmid to upregulate or downregulate miR-127-3p expression, respectively. RNA sequencing combined with bioinformatic analysis and targeted fatty acid metabolomics approach were used to detect the transcriptome and lipid metabolites. The association between miR-127-3p and its target was verified by dual-luciferase activity reporting and Western blotting. Oxygen consumption rate of BMDM were detected using seahorse analysis. High-cholesterol-diet-fed low density lipoprotein deficient (LDLR-/-) mice, with-or-without carotid tandem-stenosis surgery, were treated with miR-127-3p agomir or antagomir to examine its effect on plaque development and stability. RESULTS: miR-127-3p, not -5p, is elevated in human advanced carotid atheroma and its expression is positively associated with macrophage accummulation in plaques. In vitro, miR-127-3p-overexpressed macrophage exhibites increased proliferation capacity and facilitates M1 polariztion whereas the contrary trend is present in miR-127-3p-inhibited macrophage. Stearoyl-CoA desaturase-1 (SCD1) is one potential target of miR-127-3p. miR-127-3p mimics decreases the activity of 3' untranslated regions of SCD-1. Furthermore, miR-127-3p downregulates SCD1 expression, and reversing the expression of SCD1 attenuates the increased proliferation induced by miR-127-3p overexpression in macrophage. miR-127-3p overexpression could also lead to decreased content of unsaturated fatty acids (UFAs), increased content of acetyl CoA and increased level of oxidative phosphorylation. In vivo, miR-127-3p agomir significantly increases atherosclerosis progression, macrophage proliferation and decreases SCD1 expression and the content of UFAs in aortic plaques of LDLR-/- mice. Conversely, miR-127-3p antagomir attenuated atherosclerosis, macrophage proliferation in LDLR-/- mice, and enhanced carotid plaque stability in mice with vulnerable plaque induced. CONCLUSION: MiR-127-3p enhances proliferation in macrophages through downregulating SCD-1 expression and decreasing the content of unsaturated fatty acid, thereby promoting atherosclerosis development and decreasing plaque stability. miR-127-3p/SCD1/UFAs might provide potential therapeutic target for anti-inflammation and atherosclerosis.

Biological significance of METTL5 in atherosclerosis: comprehensive analysis of single-cell and bulk RNA sequencing data.

BACKGROUND: N6-methyladenosine (m6A) methylation is involved in the pathogenesis of atherosclerosis (AS). Limited studies have examined the role of the m6A methyltransferase METTL5 in AS pathogenesis. METHODS: This study subjected the AS dataset to differential analysis and weighted gene co-expression network analysis to identify m6A methylation-associated differentially expressed genes (DEGs). Next, the m6A methylation-related DEGs were subjected to consensus clustering to categorize AS samples into distinct m6A subtypes. Single-cell RNA sequencing (scRNA-seq) analysis was performed to investigate the proportions of each cell type in AS and adjacent healthy tissues and the expression levels of key m6A regulators. The mRNA expression levels of METTL5 in AS and healthy tissues were determined using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RESULTS: AS samples were classified into two subtypes based on a five-m6A regulator-based model. scRNA-seq analysis revealed that the proportions of T cells, monocytes, and macrophages in AS tissues were significantly higher than those in healthy tissues. Additionally, the levels of m6A methylation were significantly different between AS and healthy tissues. METTL5 expression was upregulated in macrophages, smooth muscle cells (SMCs), and endothelial cells (ECs). qRT-PCR analysis demonstrated that the METTL5 mRNA level in AS tissues was downregulated when compared with that in healthy tissues. CONCLUSIONS: METTL5 is a potential diagnostic marker for AS subtypes. Macrophages, SMCs, and ECs, which exhibit METTL5 upregulation, may modulate AS progression by regulating m6A methylation levels.

Comparative effectiveness and safety of laser, needle, and "quick fenestrater" in in situ fenestration during thoracic endovascular aortic repair.

Background: Special instruments are needed for the revascularization of aortic branches in in situ fenestration during thoracic endovascular aortic repair (TEVAR). This prospective study compared the effectiveness and safety of three currently used fenestraters: laser, needle, and Quick Fenestrater (QF). Methods: In all, 101 patients who underwent TEVAR for aortic disease (dissection, n = 62; aneurysm, n = 16, or ulcer, n = 23) were enrolled. All patients were randomly assigned to three groups: 34 were assigned to laser fenestration, 36 to needle fenestration, and 31 to QF fenestration. The epidemiological data, treatment, imaging findings, and follow-up outcomes were analyzed using data from the medical records. Results: The technical success rates of the laser, needle, and QF fenestration groups were 94.1%, 94.4%, and 100% (p > 0.05). After correction of mixed factors such as age and gender, it was showed the average operative time (Laser group: 130.01 ± 9.36 min/ Needle group: 149.80 ± 10.18 min vs. QF group: 101.10 ± 6.75 min, p < 0.001), fluoroscopy time (Laser group: 30.16 ± 9.81 min/ Needle group: 40.20 ± 9.91 min vs. QF group: 19.91 ± 5.42 min, p < 0.001), fenestration time (Laser group 5.50 ± 3.10 min / Needle group 3.50 ± 1.50 min vs. QF group 0.67 ± 0.06 min, p < 0.001), and guide wire passage time after fenestration (Laser group 5.10 ± 1.70 min / Needle group 4.28 ± 1.60 min vs. QF group 0.07 ± 0.01 min, p < 0.001) were all shorter with QF fenestration than with the other two tools. The overall perioperative complication rates of the laser, needle, and QF fenestration groups were 5.9%, 5.6%, and 0% (p > 0.05): One case of sheath thermal injury and one case of vertebral artery ischemia occurred in the laser fenestration group; one case each of access site hematoma and brachial artery thrombosis were reported in the needle fenestration group. 89 (88.1%, 89/101) patients were followed for a median of 12.6 ± 1.6 months. The overall postoperative complication rates of the laser, needle, and QF fenestration groups were 3.3%, 6.5%, and 0% (p > 0.05): In the laser fenestration group, there was one death due to postoperative ST-segment elevation myocardial infarction; in the needle fenestration group, one patient developed occlusion of the bridge stent; no complications occurred in the QF group. Conclusion: All three fenestration methods were effective in reconstructing supra-arch artery during TEVAR. QF fenestration required less contrast agent, with a shorter surgery duration and fewer complications than laser and needle fenestration.

Protein arginine methyltransferase 5-mediated arginine methylation stabilizes Kruppel-like factor 4 to accelerate neointimal formation.

AIMS: Accumulating evidence supports the indispensable role of protein arginine methyltransferase 5 (PRMT5) in the pathological progression of several human cancers. As an important enzyme-regulating protein methylation, how PRMT5 participates in vascular remodelling remains unknown. The aim of this study was to investigate the role and underlying mechanism of PRMT5 in neointimal formation and to evaluate its potential as an effective therapeutic target for the condition. METHODS AND RESULTS: Aberrant PRMT5 overexpression was positively correlated with clinical carotid arterial stenosis. Vascular smooth muscle cell (SMC)-specific PRMT5 knockout inhibited intimal hyperplasia with an enhanced expression of contractile markers in mice. Conversely, PRMT5 overexpression inhibited SMC contractile markers and promoted intimal hyperplasia. Furthermore, we showed that PRMT5 promoted SMC phenotypic switching by stabilizing Kruppel-like factor 4 (KLF4). Mechanistically, PRMT5-mediated KLF4 methylation inhibited ubiquitin-dependent proteolysis of KLF4, leading to a disruption of myocardin (MYOCD)-serum response factor (SRF) interaction and MYOCD-SRF-mediated the transcription of SMC contractile markers. CONCLUSION: Our data demonstrated that PRMT5 critically mediated vascular remodelling by promoting KLF4-mediated SMC phenotypic conversion and consequently the progression of intimal hyperplasia. Therefore, PRMT5 may represent a potential therapeutic target for intimal hyperplasia-associated vascular diseases.

Treatment of inadvertent cervical arterial catheterization: Single-center experience.

OBJECTIVES: Inadvertent arterial catheterization can occur during transjugular central venous catheter insertion and should be promptly treated to prevent serious consequences. Although many treatment modalities are available, no exist guidelines regarding the selection of treatment. We aimed to describe our experience with the treatment of 11 patients who underwent inadvertent cervical arterial catheterization and propose an algorithm for the selection of treatment methods. METHODS: We retrospectively identified all patients who were treated for inadvertent arterial catheterization at our center between January 2016 and March 2021. We reviewed patient profiles, images, treatment methods, and follow-up data. RESULTS: Eleven patients were included (eight men and three women, age: 36-73 years). Ten catheter misplacements were in the right common carotid artery. The remaining catheter was inserted into the right subclavian artery after penetrating the right common carotid artery. Two catheters were 5-Fr and nine catheters were 11.5-Fr. Two patients underwent manual compressions, three underwent open surgery, three underwent stent-graft repairs, and four underwent Perclose Proglide closure. Clinical success was achieved in all 11 patients. Primary technical success was achieved in 10 patients. In one patient, unsuccessful manual compression was followed by successful stent-graft repair; the manual compression failed to prevent bleeding, possibly because of the long-term oral administration of aspirin for coronary heart disease. The mean follow-up was 5.4 months (range, 1-12 months). The overall mortality rate was zero, and no vascular or neurological events occurred. CONCLUSIONS: The existing data show that the current protocol for the treatment of inadvertent cervical arterial catheterization at our center is safe and effective. However, the data are insufficient and require further clinical validation.

Histone methyltransferase Smyd2 drives vascular aging by its enhancer-dependent activity.

BACKGROUND: Vascular aging is one of the important factors contributing to the pathogenesis of cardiovascular diseases. However, the systematic epigenetic regulatory mechanisms during vascular aging are still unclear. Histone methyltransferase SET and MYND domain-containing protein 2 (Smyd2) is associated with multiple diseases including cancer and inflammatory diseases, but whether it is involved in endothelial cell senescence and aging-related cardiovascular diseases has not been directly proved. Thus, we aim to address the effects of Smyd2 on regulating angiotensin II (Ang II)-induced vascular endothelial cells (VECs) senescence and its epigenetic mechanism. METHODS AND RESULTS: The regulatory role of Smyd2 in Ang II-induced VECs senescence was confirmed by performing loss and gain function assays. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis was used to systematically screen the potential enhancer during VECs senescence. Here, we found that Smyd2 was significantly upregulated in Ang II-triggered VECs, and deficiency of Smyd2 attenuated senescence-associated phenotypes both in vitro and in vivo. Mechanically, Ang II-induced upregulation of Smyd2 could increase the mono-methylation level of histone 3 lysine 4 (H3K4me1), resulting in a hyper-methylated chromatin state, then further activating enhancers adjacent to key aging-related genes, such as Cdkn1a and Cdkn2a, finally driving the development of vascular aging. CONCLUSIONS: Collectively, our study uncovered that Smyd2 drives a hyper-methylated chromatin state via H3K4me1 and actives the enhancer elements adjacent to key senescence genes such as Cdkn1a and Cdkn2a, and further induces the senescence-related phenotypes. Targeting Smyd2 possibly unveiled a novel therapeutic candidate for vascular aging-related diseases.

Deletion of BACH1 Attenuates Atherosclerosis by Reducing Endothelial Inflammation.

BACKGROUND: The transcription factor BACH1 (BTB and CNC homology 1) suppressed endothelial cells (ECs) proliferation and migration and impaired angiogenesis in the ischemic hindlimbs of adult mice. However, the role and underlying mechanisms of BACH1 in atherosclerosis remain unclear. METHODS: Mouse models of atherosclerosis in endothelial cell (EC)-specific-Bach1 knockout mice were used to study the role of BACH1 in the regulation of atherogenesis and the underlying mechanisms. RESULTS: Genetic analyses revealed that coronary artery disease-associated risk variant rs2832227 was associated with BACH1 gene expression in carotid plaques from patients. BACH1 was upregulated in ECs of human and mouse atherosclerotic plaques. Endothelial Bach1 deficiency decreased turbulent blood flow- or western diet-induced atherosclerotic lesions, macrophage content in plaques, expression of endothelial adhesion molecules (ICAM1 [intercellular cell adhesion molecule-1] and VCAM1 [vascular cell adhesion molecule-1]), and reduced plasma TNF-α (tumor necrosis factor-α) and IL-1ß levels in atherosclerotic mice. BACH1 deletion or knockdown inhibited monocyte-endothelial adhesion and reduced oscillatory shear stress or TNF-α-mediated induction of endothelial adhesion molecules and/or proinflammatory cytokines in mouse ECs, human umbilical vein ECs, and human aortic ECs. Mechanistic studies showed that upon oscillatory shear stress or TNF-α stimulation, BACH1 and YAP (yes-associated protein) were induced and translocated into the nucleus in ECs. BACH1 upregulated YAP expression by binding to the YAP promoter. BACH1 formed a complex with YAP inducing the transcription of adhesion molecules. YAP overexpression in ECs counteracted the antiatherosclerotic effect mediated by Bach1-deletion in mice. Rosuvastatin inhibited BACH1 expression by upregulating microRNA let-7a in ECs, and decreased Bach1 expression in the vascular endothelium of hyperlipidemic mice. BACH1 was colocalized with YAP, and the expression of BACH1 was positively correlated with YAP and proinflammatory genes, as well as adhesion molecules in human atherosclerotic plaques. CONCLUSIONS: These data identify BACH1 as a mechanosensor of hemodynamic stress and reveal that the BACH1-YAP transcriptional network is essential to vascular inflammation and atherogenesis. BACH1 shows potential as a novel therapeutic target in atherosclerosis.

Long-segment common carotid occlusion presenting with limb-shaking transient ischemic attack: Case report.

Background: Limb-shaking transient ischemic attack (LS-TIA) is a rare manifestation of carotid artery occlusion. Common carotid artery occlusion (CCAO) is a relatively rare condition, and both its natural history and recommendations for treatment are still unclear. Case description: A 67-year-old female suffered from transient episodes of unilateral limb shaking. Computer tomographic angiography (CTA) showed long-segment occlusion of the right common carotid artery. Computer tomographic perfusion (CTP) demonstrated hypoperfusion of the corpus striatum, which suggests that hemodynamic failure is a potential mechanism underlying the LS-TIA secondary to common carotid artery occlusion. The occlusion was successfully recanalized by retrograde common carotid endarterectomy, and the episodes of left limb shaking disappeared after surgery. Conclusions: The occlusion was successfully recanalized by retrograde common carotid endarterectomy, and the episodes of left limb shaking disappeared after surgery. Hypoperfusion of the corpus striatum might be a potential mechanism underlying the LS-TIA secondary to common carotid occlusion.

A Novel Fenestrating Device: Quick Fenestrater for Reconstructing Supra-aortic Arteries In Situ During Thoracic Endovascular Aortic Repair.

BACKGROUND: In situ fenestration (ISF) is an effective approach for reconstructing supra-aortic branches during thoracic endovascular aortic repair (TEVAR). A dedicated device is needed for ISF. METHODS: The Quick Fenestrater (QF) underwent in vitro, animal-based, and initial clinical testing. In vitro, the polytetrafluoroethylene and Dacron aortic endografts were fenestrated using the QF, and the structure of the graft, fenestration hole, and shed particulate material were evaluated. Eight white swine had QF-aided ISF combined with TEVAR and bridge-stent implantation. The outcomes were assessed using intraoperative angiography and biopsy. Finally, 13 patients were treated with QF-assisted ISF combined with TEVAR, and the success rate, technical details, and intra- and postoperative complications were recorded. RESULTS: The endograft structure was not damaged during in vitro testing. The fenestration hole was clean, and no particulate material was detected. In animal studies, all animals survived, the supra-aortic arteries were patent, and the endografts and bridge stents had normal morphology. In clinical studies, the technical success rate was 100%, and no fenestration-related neurologic complications or death occurred. One patient had a local access-related hematoma perioperatively and recovered after conservative treatment. Three patients had type III endoleaks, which resolved with no additional treatment. During a mean follow-up of 22.1 ± 6 months, no thoracic complications were identified, and the bridge stents were patent with no endoleaks. No adverse cerebrovascular events, cardiovascular events, or death occurred. CONCLUSIONS: QF-assisted ISF is a safe and effective method for the reconstruction of supra-aortic branches during TEVAR. Intermediate-term follow-up results validate the application of the novel fenestration device.

A Novel Vascular-Friendly Thoracic Stent Graft for Endovascular Repair of Acute Complicated Type B Aortic Dissection.

PURPOSE: To evaluate the safety and efficacy of a novel vascular-friendly thoracic stent graft for patients with acute complicated type B aortic dissection (ac-TBAD). METHODS: A multicenter retrospective study was undertaken in which we prospectively collected data in consecutive ac-TBAD patients treated by thoracic endovascular aortic repair (TEVAR) with the Ankura Thoracic Stent. Complications, true lumen rate (TLR), and mortality were recorded. Follow-up computed tomography angiography (CTA) was performed at 1, 6, and 12 months postoperatively and yearly thereafter. RESULTS: Altogether, 63 patients with ac-TBAD in four medical centers were included. No deaths or serious complications occurred during the perioperative period. The mean follow-up time was 30.1 ± 18.9 months. All-cause mortality rate was 3.1% (n = 2). TEVAR-related mortality rate was 1.6% (n = 1) because of retrograde type A dissection (RTAD) at 6 months. The other death was caused by acute myocardial infarction (AMI) during the third postoperative month. A distal endoleak detected at 3 months in one patient (1.6%) was treated by reintervention. The use of this novel vascular-friendly thoracic stent graft in ac-TBAD postoperative patients significantly improved their TLR. CONCLUSION: The novel vascular-friendly thoracic stent graft showed satisfactory results, with favorable stability of the aortic diameter during follow-up.

A systematic review and meta-analysis of incidence, prognosis, and laboratory indicators of venous thromboembolism in hospitalized patients with coronavirus disease 2019.

OBJECTIVE: We have summarized the incidence, anticoagulation panels, laboratory characteristics, and mortality of venous thromboembolism (VTE) in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: After systematically searching PubMed, Embase, the Cochrane Library, MedRxiv, and BioRxiv, a systematic review and meta-analysis of 18 retrospective, 6 prospective observational, and 2 cross-sectional studies was performed according to the guidelines of the PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement. RESULTS: Overall, 4382 hospitalized patients with COVID-19 were included. Men accounted for significantly more patients than did women (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.25-2.02; P < .001). The total incidence of VTE among the patients with COVID-19 was 28.3% (95% CI, 21.6%-35.4%), with an incidence of 38.0% (95% CI, 29.1%-47.4%) and 17.2% (95% CI, 11.4%-23.8%) among those with severe and general COVID-19, respectively. The total incidence of deep vein thrombosis (DVT) of the lower extremities was 18.3% (95% CI, 10.8%-27.2%). The incidence of DVT was 22.1% (95% CI, 11.0%-35.5%) and 12.8% (95% CI, 5.0%-23.3%) in those with severe and general COVID-19, respectively. The total incidence of pulmonary embolism was 17.6% (95% CI, 12.3%-23.5%), with a rate of 21.7% (95% CI, 14.8%-29.3%) in severe cases and 12.5% (95% CI, 6.1%-23.5%) in general cases. When COVID-19 severity was unclassified, the mortality for the patients with VTE was not significantly greater (25.2%; 95% CI, 12.2%-40.5%) than that for those without VTE (10.2%; 95% CI, 3.4%-19.5%; OR, 1.88; 95% CI, 0.46-7.64; P = .377). However, among the patients with severe COVID-19, those who had developed VTE had significantly greater mortality compared with those without VTE (OR, 2.02; 95% CI, 1.15-3.53; P = .014). The patients with COVID-19 and VTE had significantly higher D-dimer levels than did similar patients without VTE in multiple studies. CONCLUSIONS: The occurrence of VTE, DVT, and pulmonary embolism has been substantial among hospitalized patients with COVID-19, especially among those with severe COVID-19. Patients with severe COVID-19 and VTE had significantly greater mortality compared with similar patients without VTE. An increased D-dimer level might be an indicator of the occurrence of VTE in patients with COVID-19.

Endovascular and Hybrid Interventions for Extracranial Juxta-Skullbase Carotid Artery Aneurysms: Experience and Long-Term Results.

BACKGROUND: Hybrid and endovascular procedures maybe effective and less invasive alternatives to open surgery for treatment of extracranial carotid artery aneurysm (ECAA), but the optimal management of juxta-skullbase ECAA is controversial. OBJECTIVE: This study evaluated the long-term effects of hybrid and endovascular procedures in treating juxta-skullbase ECAA. METHODS: The records of 9 consecutive patients who underwent hybrid or endovascular interventions for juxta-skullbase ECAA in a single center from April 2014 to May 2020 were retrospectively reviewed. RESULTS: Four patients presented with a pulsating mass, 1 with dysphagia, 1 with pain in the left temporal region, 1 with dizziness and headache, 1 with cerebral infarction, and 1 with dizziness and cerebral infarction. Seven true aneurysms, 1 false aneurysm, and 1 dissecting aneurysm were diagnosed with CTA in the 9 patients (mean age, 50.8±20.3 years; 1 male). The aneurysms were divided into two subgroups: 4 type I, and 5 type IIb according to a recent classification. Per schedule, 7 patients (4 type I and 3 type IIb) were treated with endovascular intervention, and 2 (type IIb) were treated with hybrid procedures. The technique success rate was 88.9%. One patient (type IIb) who was scheduled to be treated with an endovascular procedure was transferred to a hybrid procedure because of failure of the endovascular procedure. Eleven covered stents were implanted to exclude the aneurysms. During follow-up (mean duration 31.2±23.2 months), all aneurysms were proven excluded, no significant complication occurred, and preoperative symptoms resolved. One patient (type I) in the endovascular group had occlusion of the internal carotid artery but no symptoms; the internal carotid artery was patent in the other 8 patients. CONCLUSIONS: Hybrid and endovascular procedures were found effective and durable alternatives to open operation for treatment of extracranial juxta-skullbase carotid aneurysm.

Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway.

RATIONALE: SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. OBJECTIVE: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. METHODS AND RESULTS: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE-/- (apolipoprotein E) background and atherogenesis (high-cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE-/- mice. Myeloid cell-specific SNX10 deficiency (Δ knockout [KO]) attenuated atherosclerosis progression in APOE-/- mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of ΔKO mice. In vitro experiments showed that SNX10 deficiency-inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT (protein kinase B). The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB (transcription factor EB), thereby enhanced lysosomal biogenesis and LAL (lysosomal acid lipase) activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. CONCLUSIONS: Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment.

Carotid Occlusion Accentuates Aortic Stenosis and Cardiac Remodeling With Preserved Systolic Function in LDL Receptor-Deficient Mice.

Background: Carotid atherosclerotic disease is associated with aortic stenosis and reduced cardiac function. The causality between carotid and cardiac pathologies is unknown. We aim to explore the effects of carotid stenosis or occlusion on cardiac pathology and function. Methods and Results: We produced carotid obstruction or stenosis in 36 atherogenic mice with 150- or 300-µm tandem surgery or sham surgery. The structure and function of the heart were assessed by histology and animal ultrasound. The 150-µm group had larger plaque burden and thicker valve leaflets in the aortic root than did the control group. Also, the two surgery groups had a thicker left ventricular posterior wall and smaller internal diameter compared with controls. Increased myocardial fibrosis was also found in the 150-µm group compared with controls, although the surgery groups had preserved systolic function compared with that of controls. Conclusions: In a mouse model, carotid occlusion accentuated the formation of aortic stenosis and promoted ventricular remodeling without impairing systolic function. Carotid atherosclerotic plaque may be a pathogenic factor for aortic stenosis and ventricular remodeling.

Two-Stage Hybrid Approach for Treatment of Abdominal Aortic Pseudoaneurysm Combined with Superior Mesenteric Artery Occlusion Secondary to Vasculo-Behçet's Disease.

Behçet's disease (BD) is a chronic multisystem autoinflammatory disorder. Multiple arterial involvement in vasculo-BD was extremely rare. A 40-year-old man suffered from abdominal pain and increased lower back pain. He was diagnosed with BD 4 years ago. Computed tomography angiography indicated a 40 mm × 90 mm abdominal aortic saccular pseudoaneurysm and a proximal superior mesenteric artery (SMA) occlusion. We report here a case of successful treatment for abdominal aortic pseudoaneurysm (AAP) and SMA occlusion in a complicated vasculo-BD using 2-stage procedure, including endovascular intervention for AAP and hybrid approach with laparotomy and retrograde canalization and revascularization for SMA occlusion. Retrograde open mesenteric stenting was effective in the treatment of SMA occlusion in patients with vasculo-BD.

A Single-Center, Randomized, Controlled Comparison of the Transradial vs Transfemoral Approach for Cerebral Angiography: A Learning Curve Analysis.

Purpose: To compare the characteristics and learning curve of the transfemoral approach (TFA) vs the transradial approach (TRA) for cerebral angiography. Materials and Methods: Between February 2016 and April 2017, 101 patients undergoing cerebral angiography were enrolled. Fifty-one patients (mean age 67 years; 40 men) were randomized to TFA and 50 (mean age 68 years; 41 men) to TRA using a computer-generated random table. The patients' demographic and angiographic data were recorded and analyzed. The learning curve of a novice interventionist was analyzed for procedure time, puncture time, fluoroscopy time, and contrast volume as markers of technical proficiency with TFA compared with TRA. Median values are given with the interquartile range (IQR). Results: Procedure time [35 (IQR 30, 47.5) vs 31.0 (IQR 25.0, 48.9) minutes, p=0.16), fluoroscopy time [10.3 (IQR 7.6, 13.9) vs 9.4 (IQR 6.1, 17.6) minutes, p=0.70], contrast volume [105 (IQR 92, 120) vs 95.5 (IQR 90, 111.3) mL, p=0.13), radiation exposure [390.2 (IQR 268.2, 617.9) vs 455.8 (IQR 286.8, 602.3) mGy, p=0.74], and the number of catheter exchanges [1 (IQR 1, 3) vs 1 (IQR 1, 1), p=0.06] were not significantly different between the TFA and TRA groups, respectively, but puncture time was shorter with TFA than with TRA [0.6 (IQR 0.5, 1.1) vs 1 (IQR 0.6, 1.9) minutes, p=0.01]. The learning curve was steeper with TRA than with TFA in the beginning stages of training, but with increasing experience, the procedure and fluoroscopy times were better for TRA than for TFA. Training progress was made earlier in TRA. Conclusion: TRA is a reasonable alternative to TFA for cerebral angiography. TRA has a shorter learning curve for novice interventionists.

High glucose upregulates osteopontin expression by FoxO1 activation in macrophages.

Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE-/- mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt -1918 ~ -713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.

Fra-1 plays a critical role in angiotensin II-induced vascular senescence.

Vascular aging has a strong relationship with cardiovascular disease. Fos-related antigen 1 (Fra-1), also referred to as Fos-like antigen 1, is a transcription factor and has been reported to be involved in many pathologic processes. Here, we demonstrate that Fra-1 plays a critical role in angiotensin II (Ang II)-induced vascular senescence. Fra-1 expression is increased significantly in Ang II-induced rat aortic endothelial cell (RAEC) senescence and the arteries from Ang II-infused mice. Interestingly, silencing Fra-1 blocks Ang II-induced senescence phenotypes in RAECs, including decreased senescence-associated ß-galactosidase staining, and mitigated proliferation suppression and senescence-associated secretory phenotype. Further, knocking down Fra-1 inhibits vascular aging phenotypes in an Ang II-infused mice model. The up-regulated Fra-1 also exists in human atherosclerotic plaques and Ang II-induced vascular smooth muscle cells as well as in replicated senescence RAECs. Mechanistic studies reveal that Fra-1 preferentially associates with c-Jun and binds to the cyclin-dependent kinase inhibitor 1a (p21) and cyclin-dependent kinase inhibitor 2a (p16) promoter region, leading to elevated gene expression, which causes senescence-related phenotypes. In conclusion, our results identify that Fra-1 plays a novel and key role in promoting vascular aging by directly binding and transcriptionally activating p21 and p16 signaling, suggesting intervention of Fra-1 is a potential strategy for preventing aging-associated cardiovascular disorders.-Yang, D., Xiao, C., Long, F., Wu, W., Huang, M., Qu, L., Liu, X., Zhu, Y. Fra-1 plays a critical role in angiotensin II-induced vascular senescence.

Endovascular Therapy of a Giant Renal Artery Aneurysm Combined With High-Flow Renal Arteriovenous Fistula Using a Patent Ductus Arteriosus Occluder.

Renal artery aneurysm (RAA) concomitant with a renal arteriovenous fistula (RAVF) is extremely rare. A 32-year-old man suffered from a giant RAA combined with high-flow RAVF. The computer tomographic angiography (CTA) demonstrated a RAA, which is 6.3 cm in length and 2.1 cm in diameter, combined with an arteriovenous fistula between the right renal artery and right renal vein (fistula area:1.05 cm × 1.0 cm). After a comprehensive preoperative assessment, a patent ductus arteriosus occluder (PDAO) was implanted. At a 1-year follow-up, the CTA study showed that the PDAO was in situ and there was no recanalization of the lesion. At a third-year follow-up, ultrasound examination showed an image of right renal atrophy. The results of long-term follow-up demonstrate that PDAO is safe and effective for the management of RAAs combined with high-flow RAVF.

Hybrid Surgery for Nontaper or Nonstump Lesions in Symptomatic Subacute or Chronic Internal Carotid Occlusion: A Better Solution.

BACKGROUND: Internal carotid artery occlusion (ICAO) causes transient ischemic attack and cerebral infarction. ICAO management remains clinically challenging. We discuss a hybrid treatment combining carotid endarterectomy and endovascular intervention (E-I) for patients with nontaper or nonstump lesions of symptomatic ICAO. METHODS: We treated 32 patients with consecutive nontaper or nonstump ICAO with neurological symptoms with hybrid treatment or E-I. We analyzed the epidemiology, symptoms, angiographic morphology, technical success rate, and perioperative complications. RESULTS: Of the 32 patients, 17 were treated with hybrid surgery and 15, E-I. The demographic data and lesion characteristics were similar between the 2 groups. The overall recanalization success rate was 71.9%. The rate for hybrid surgery was better than that for E-I (88.2% vs. 53.3%). The postoperative cerebral hyperperfusion rate showed no difference between the 2 groups (11.8% vs. 6.7%). Ipsilateral cerebral perfusion improved after treatment. The mean transition time and time to peak were greater than normal (normal values, <6 seconds and <8 seconds, respectively). Both increased significantly after treatment (mean transition time, 11.30 seconds vs. 7.25 seconds; time to peak, 19.30 seconds vs. 15.50 seconds). The incidence of perioperative complications from hybrid surgery was less than that with E-I (5.9% vs. 40.0%). Recurrent cerebrovascular events (5.9% vs. 13.3%) and the 3-month modified Rankin scale score (2.76 ± 0.66 vs. 2.93 ± 0.70) did not differ between the 2 groups. CONCLUSIONS: Recanalization of nontaper or nonstump ICAO with hybrid treatment was more successful than that with E-I, with fewer perioperative complications. The carotid endarterectomy procedure enables easier wire crossing across the occlusion and reduces potential technology-related complications by requiring a shorter lesion and fewer dissections and minimizing the effect of calcification.