BMAL1 modulates smooth muscle cells phenotypic switch towards fibroblast-like cells and stabilizes atherosclerotic plaques by upregulating YAP1.

BACKGROUND: Ischemic heart diseases and ischemic stroke are closely related to circadian clock and unstable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) can stabilize or destabilize an atherosclerotic lesion through phenotypic switch. BMAL1 is not only an indispensable core component in circadian clock but also an important regulator in atherosclerosis and VSMCs proliferation. However, little is known about the modulation mechanisms of BMAL1 in VSMCs phenotypic switch and atherosclerotic plaque stability. METHODS: We integrated histological analysis of human plaques, in vivo experiments of VSMC-specific Bmal1-/- mice, in vitro experiments, and gene set enrichment analysis (GSEA) of public datasets of human plaques to explore the function of BMAL1 in VSMCs phonotypic switch and plaque stability. FINDINGS: Comparing to human unstable plaques, BMAL1 was higher in stable plaques, accompanied by elevated YAP1 and fibroblast maker FSP1 which were positively correlated with BMAL1. In response to Methyl-ß-cyclodextrin-cholesterol, oxidized-low-density-lipoprotein and platelet-derived-growth-factor-BB, VSMCs embarked on phenotypic switch and upregulated BMAL, YAP1 and FSP1. Besides, BMAL1 overexpression promoted VSMCs phonotypic switch towards fibroblast-like cells by transcriptionally upregulating the expression of YAP1. BMAL1 or YAP1 knock-down inhibited VSMCs phonotypic switch and downregulated FSP1. Furthermore, VSMC-specific Bmal1-/- mice exhibited VSMCs with lower YAP1 and FSP1 levels, and more vulnerable plaques with less collagen content. In addition, BMAL1 suppressed the migration of VSMCs. The GSEA results of public datasets were consistent with our laboratory findings. INTERPRETATION: Our results highlight the importance of BMAL1 as a major regulator in VSMCs phenotypic switch towards fibroblast-like cells which stabilize an atherosclerotic plaque.

Preoperative high lymphocyte-to-monocyte ratio is associated with intraoperative type I endoleak in patients with TAA with TEVAR.

OBJECTIVES: Various inflammatory factors are closely associated with the incidence of thoracic aortic aneurysms (TAAs). Furthermore, the severity of inflammation is closely related to the absolute value and proportion of each leukocyte subgroup. Only few reports have analyzed the importance of lymphocyte-monocyte ratio (LMR) as a potential inflammatory marker in vascular diseases. Therefore, we aimed to investigate the effect of peripheral blood LMR on thoracic endovascular aortic repair (TEVAR) in patients with TAA. METHODS: A retrospective study of the clinical data collected in our hospital between January 2016 and January 2021 was performed on 162 patients with TAA treated with TEVAR, based on the inclusion and exclusion criteria for patient selection. Based on whether the patient had the clinical symptoms at admission and the occurrence of type I endoleaks during operation, patients were divided into two groups, respectively: an intraoperative type I endoleak group (n = 34) and a group without intraoperative type I endoleak (n = 128), and a group with clinical symptoms (n = 31) and a group without clinical symptoms (n = 131). The clinical data of these two groups were compared, the free from second intervention rates related to endoleak and the preoperatively LMR of the two groups was calculated. LMR was calculated preoperatively. Receiver-operating characteristic curve analysis was used to determine the cut-off for preoperative LMR values. Based on the cut-off point, patients were divided into a high LMR group (n = 34) and a low LMR group (n = 128). The clinical data of the two groups were compared, and further stratified analysis was performed. RESULTS: A total of 162 patients were included in the analysis. All patients were successfully implanted with a thoracic aorta stent graft. The preoperative LMR level and postoperative endoleak-related secondary intervention rate were higher in the type I endoleak group than those in the group without intraoperative type I endoleaks. The preoperative C-reactive protein (CRP) level of patients with TAA with clinical symptoms was higher than that of asymptomatic patients. There was a negative correlation between preoperative CRP and LMR levels. In addition, in symptomatic or asymptomatic patients, the LMR level was associated with the occurrence of intraoperative type I endoleaks. After excluding the influence of type of endografts, our results showed that the clinical symptoms did not affect the occurrence of the intraoperative type I endoleak, and patients with intraoperative type I endoleak had a higher rate of postoperative secondary intervention. CONCLUSION: Patients with TAA with type I endoleaks during TEVAR had an increased rate of secondary intervention related to endoleaks. Patients with TAA with high LMR levels before TEVAR were more likely to have endoleaks during operation.

Intraoperative Stent-Graft-Induced Aortic Intimal Intussusception During TEVAR for Type B Aortic Dissection.

BACKGROUND: Aortic intimal intussusception is well described in the natural progression of type A aortic dissection. Only 3 cases of aortic intimal intussusception were reported to be related to thoracic endovascular aortic repair (TEVAR) for Stanford type B aortic dissection. In our study, we are reporting a rare but potentially fatal complication, the intraoperative stent-graft (SG)-induced aortic intimal intussusception (ISAII); this study reports a series of endovascular repair for ISAII cases. By presenting the ISAII definition, the diagnostic steps to rule out or to identify the condition, and the techniques to resolve it, we intended to raise the awareness of this severe complication, so that physicians can adapt to overcome the complications while performing TEVAR. MATERIALS AND METHODS: ISAII was defined as the partial or circumferential disruption of the distal intimal flap as an intraoperative complication of endovascular treatment. From January 2014 to June 2020, 1,096 patients underwent TEVAR for Stanford type B aortic dissection at our hospital. Among them, 14 ISAII complications were witnessed. All these patients underwent endovascular repair for ISAII lesions, and their data were extracted for analysis. RESULTS: The ISAII lesions were classified into 3 types according to their location in different aortic segments: type I, ISAII was limited within the intended SG coverage segment; type II, ISAII occurred after SG introduction or deployment, and the detached intimal flap extended beyond the intended SG coverage segment but did not affect the abdominal aortic visceral branches; type III, ISAII occurred during SG introduction or deployment, and the detached intimal flap descended to the abdominal aortic segment with visceral branches. Our results showed ISAII as a rare complication with an incidence of 1.28% (14/1096), and endovascular repair for all types of ISAII is an effective treatment. With a mean follow-up of 27.36 months (range 5-71 months), all the ISAII lesions were stable, and all the major aortic branches, SGs, and bare stents were patent. CONCLUSIONS: The management of this potentially devastating intraoperative complication relies on accurate diagnosis and prompt management. Our results suggested that endovascular repair for ISAII is effective and durable for correcting this complication. GRAPHICAL ABSTRACT: [Formula: see text].

Identification of potential therapeutic targets for atherosclerosis by analysing the gene signature related to different immune cells and immune regulators in atheromatous plaques.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease that affects multiple arteries. Numerous studies have shown the inherent immune diversity in atheromatous plaques and suggest that the dysfunction of different immune cells plays an important role in atherosclerosis. However, few comprehensive bioinformatics analyses have investigated the potential coordinators that might orchestrate different immune cells to exacerbate atherosclerosis. METHODS: Immune infiltration of 69 atheromatous plaques from different arterial beds in GSE100927 were explored by single-sample-gene-set enrichment analysis (presented as ssGSEA scores), ESTIMATE algorithm (presented as immune scores) and CIBERSORT algorithm (presented as relative fractions of 22 types of immune cells) to divide these plaques into ImmuneScoreL cluster (of low immune infiltration) and ImmuneScoreH cluster (of high immune infiltration). Subsequently, comprehensive bioinformatics analyses including differentially-expressed-genes (DEGs) analysis, protein-protein interaction networks analysis, hub genes analysis, Gene-Ontology-terms and KEGG pathway enrichment analysis, gene set enrichment analysis, analysis of expression profiles of immune-related genes, correlation analysis between DEGs and hub genes and immune cells were conducted. GSE28829 was analysed to cross-validate the results in GSE100927. RESULTS: Immune-related pathways, including interferon-related pathways and PD-1 signalling, were highly enriched in the ImmuneScoreH cluster. HLA-related (except for HLA-DRB6) and immune checkpoint genes (IDO1, PDCD-1, CD274(PD-L1), CD47), RORC, IFNGR1, STAT1 and JAK2 were upregulated in the ImmuneScoreH cluster, whereas FTO, CRY1, RORB, and PER1 were downregulated. Atheromatous plaques in the ImmuneScoreH cluster had higher proportions of M0 macrophages and gamma delta T cells but lower proportions of plasma cells and monocytes (p < 0.05). CAPG, CECR1, IL18, IGSF6, FBP1, HLA-DPA1 and MMP7 were commonly related to these immune cells. In addition, the advanced-stage carotid plaques in GSE28829 exhibited higher immune infiltration than early-stage carotid plaques. CONCLUSIONS: Atheromatous plaques with higher immune scores were likely at a more clinically advanced stage. The progression of atherosclerosis might be related to CAPG, IGSF6, IL18, CECR1, FBP1, MMP7, FTO, CRY1, RORB, RORC, PER1, HLA-DPA1 and immune-related pathways (IFN-γ pathway and PD-1 signalling pathway). These genes and pathways might play important roles in regulating immune cells such as M0 macrophages, gamma delta T cells, plasma cells and monocytes and might serve as potential therapeutic targets for atherosclerosis.

Long-term results of extensive aortoiliac occlusive disease (EAIOD) treated by endovascular therapy and risk factors for loss of primary patency.

BACKGROUND: Although endovascular therapy has been widely used for focal aortoiliac occlusive disease (AIOD), its performance for extensive AIOD (EAIOD) is not fully evaluated. We aimed to demonstrate the long-term results of EAIOD treated by endovascular therapy and to identify the potential risk factors for the loss of primary patency. METHODS: Between January 2008 and June 2018, patients with a clinical diagnosis of the 2007 TransAtlantic Inter-Society Consensus II (TASC II) C and D AIOD lesions who underwent endovascular treatment in our institution were enrolled. Demographic, diagnosis, procedure characteristics, and follow-up information were reviewed. Univariate analysis was used to identify the correlation between the variables and the primary patency. A multivariate logistic regression model was used to identify the independent risk factors associated with primary patency. Five- and 10-year primary and secondary patency, as well as survival rates, were calculated by Kaplan-Meier analysis. RESULTS: A total of 148 patients underwent endovascular treatment in our center. Of these, 39.2% were classified as having TASC II C lesions and 60.8% as having TASC II D lesions. The technical success rate was 88.5%. The mean follow-up time was 79.2 ±â€Š29.2 months. Primary and secondary patency was 82.1% and 89.4% at 5 years, and 74.8% and 83.1% at 10 years, respectively. The 5-year survival rate was 84.2%. Compared with patients without loss of primary patency, patients with this condition showed significant differences in age, TASC II classification, infrainguinal lesions, critical limb ischemia (CLI), and smoking. Multivariate logistic regression analysis showed age <61 years (adjusted odds ratio [aOR]: 6.47; 95% CI: 1.47-28.36; P = 0.01), CLI (aOR: 7.81; 95% CI: 1.92-31.89; P = 0.04), and smoking (aOR: 10.15; 95% CI: 2.79-36.90; P < 0.01) were independent risk factors for the loss of primary patency. CONCLUSION: Endovascular therapy was an effective treatment for EAIOD with encouraging patency and survival rate. Age <61 years, CLI, and smoking were independent risk factors for the loss of primary patency.

Incidence and risk factors for retrograde type A dissection and stent graft-induced new entry after thoracic endovascular aortic repair.

OBJECTIVE: Stent graft (SG)-induced new entry (SINE) and retrograde type A dissection (RTAD) are serious device-related complications occurring after thoracic endovascular aortic repair (TEVAR) for Stanford type B aortic dissection (TBAD) and may lead to endograft-related complications including retrograde dissection and death. The purpose of this study was to investigate the incidence and risk factors for the development of RTAD and SINE after TEVAR for TBAD and to identify the complications associated with this. METHODS: From April 2005 to October 2013, there were 997 patients who underwent TEVAR for TBAD; 852 were followed up (0-6 years; mean, 2.6 years), and 59 SINEs developed in 53 patients. The oversizing ratio and incidence of RTAD and SINE were compared between proximal bare stent (PBS) and non-PBS groups and RTAD and SINE and non-RTAD and non-SINE groups. The baseline characteristics and SG configurational factors potentially affecting both RTAD and distal SINE were analyzed. RESULTS: There was no significant difference between PBS and non-PBS groups in the incidence of RTAD. A greater oversizing ratio was related to a higher distal SINE rate. SINE was seen more frequently in smokers and in patients with hypertension, Marfan syndrome, and TEVAR in the chronic phase and less frequently in complicated dissection cases. Device-related factors for SINE were SG with a connecting bar and SG length <165 mm. The SG length <165 mm increased the overall proximal and distal SINE incidence in multivariate analysis. CONCLUSIONS: The presence of a PBS is not associated with a higher RTAD rate, whereas the use of an SG with a connecting bar and length <165 mm increases the risk of RTAD and SINE after TEVAR.

Effect of Intravascular Ultrasound-assisted Thoracic Endovascular Aortic Repair for "Complicated" Type B Aortic Dissection.

BACKGROUND: Intravascular ultrasound (IVUS) examination can provide useful information during endovascular stent graft repair. However, its actual clinical utility in thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (type B-AD) remains unclear, especially in complicated aortic dissection. We evaluated the effect of IVUS as a complementary tool during TEVAR. METHODS: From September 2011 to April 2012, we conducted a prospective cohort study of 47 consecutive patients with "complicated" type B-AD diagnosed. We divided the patients into two groups: IVUS-assisted TEVAR group and TEVAR using angiography alone group. The general procedure of TEVAR was performed. We evaluated the perioperative and follow-up events. Patient demographics, comorbidities, preoperative images, dissection morphology, details of operative strategy, intraoperative events, and postoperative course were recorded. RESULTS: A total of 47 patients receiving TEVAR were enrolled. Among them (females, 8.51%; mean age, 57.38 ± 13.02 years), 13 cases (27.66%) were selected in the IVUS-assisted TEVAR group, and 34 were selected in the TEVAR group. All patients were symptomatic. The average diameter values of IVUS measurements in the landing zone were greater than those estimated by computed tomography angiography (31.82 ± 4.21 mm vs. 30.64 ± 4.13 mm, P < 0.001). The technique success rate was 100%. Among the postoperative outcomes, statistical differences were only observed between the IVUS-assisted TEVAR group and TEVAR group for total operative time and the amount of contrast used (P = 0.013 and P < 0.001, respectively). The follow-up ranged from 15 to 36 months for the IVUS-assisted TEVAR group and from 10 to 35 months for the TEVAR group (P = 0.646). The primary endpoints were no statistical difference in the two groups. CONCLUSIONS: Intraoperative IVUS-assisted TEVAR is clinically feasible and safe. For the endovascular repair of "complicated" type B-AD, IVUS may be helpful for understanding dissection morphology and decrease the operative time and the amount of contrast used.

[Endovascular repair for isolated iliac artery aneurysm].

OBJECTIVE: To evaluate the short and middle-term efficacies of endovascular repair for isolated iliac artery aneurysms (IIAAs). METHODS: Retrospective analyses were performed for the clinical and follow-up data of 27 patients undergoing endovascular repair at Department of Vascular Surgery, Affiliated Zhongshan Hospital, Fudan University from January 2008 to December 2012. For asymptomatic aneurysms, repair criterion was a diameter over 3 cm while under 3 cm for symptomatic aneurysms. RESULTS: There were 19 asymptomatic and 8 symptomatic cases. And 25 selective and 2 emergent operations were performed. The interventions included endovascular stent grafts (n = 17), coil embolization (n = 1), both stent grafts and coils (n = 7) and hybrid operations (n = 2). Technical success was achieved in all cases. No delayed healing or infection of inguinal access sites occurred. In-stent thrombosis could be observed in 2 cases. Buttock claudication was observed in one case. Sexual dysfunction occurred in three cases. Endoleaks were confirmed by intraoperative digital subtraction angiography in three cases. There was no occurrence of colorectal ischemia or postoperative aneurysmal rupture. Patients were followed up for a mean period of 33 ± 18 months. One patient died of recurrent renal cell carcinoma. CONCLUSION: Endovascular repair of isolated iliac artery aneurysms provides good short and middle-term patency. It may become a first-choice for treating isolated iliac artery aneurysms in the future.

An experimental model of Stanford type B aortic dissection with intravenous epinephrine injection.

The aim of this study was to create an experimental model of aortic dissection (AD) with a long-term patent false lumen to develop new treatments for Stanford type B aortic dissection. Sixteen adult beagle dogs (weight 14-18 kg) were used. After exposure and partially clamping, the descending aorta was cut through the adventitia to one-third of the depth of the tunica media. The aortic wall was divided into two layers by raspatory. Then half the circumference of the inner layer was cut transversely. All of the proximal layers and the distal outer layers were anastomosed together. Epinephrine was immediately used to expand the false lumen, and the effect was terminated using nitroglycerin when necessary. All dogs underwent both digital subtraction angiography (DSA) and computed tomography angiography (CTA) immediately after and 1 week and 1 month after surgery. The dogs were followed up at 1 day, 3 months, 1 year, and 2 years. The surgery was successful in 12 dogs. Dissection formation was observed immediately after epinephrine administration and confirmed by DSA and CTA. Our results showed typical characteristics of AD, such as a tear, septum, and true and false lumens. This is an easy and feasible way of developing a Stanford type B AD model by intravenous injection of epinephrine. In this canine model of AD, the false lumen has excellent long-term patency and the dissection plane is histologically similar to that in human AD. This model may contribute to the development of new treatments for Stanford type B AD.

Evaluation of acute kidney injury as defined by the risk, injury, failure, loss, and end-stage criteria in critically ill patients undergoing abdominal aortic aneurysm repair.

BACKGROUND: Acute kidney injury (AKI) is considered as a common and significant complication following abdominal aortic aneurysm (AAA) repair. This study aimed to assess the associated risk factors of AKI in the critically ill patients undergoing AAA repair and to evaluate the appropriate AKI management in the specific population. METHODS: We retrospectively examined data from all critically ill patients undergoing AAA repairs at our institution from April 2007 to March 2012. Multivariable analysis was used to identify factors associated with postoperative AKI, which was defined by risk, injury, failure, loss and end-stage (RIFLE) kidney disease criteria. The goal-directed hemodynamic optimization (maintenance of optimal hemodynamics and neutral or negative fluid balance) and renal outcomes were also reviewed. RESULTS: Of the 71 patients enrolled, 32 (45.1%) developed AKI, with 30 (93.8%) cases diagnosed on admission to surgical intensive care unit (SICU). Risk factors for AKI were ruptured AAA (odds ratio (OR) = 5.846, 95% confidence interval (CI): 1.346 - 25.390), intraoperative hypotension (OR = 6.008, 95%CI: 1.176 to 30.683), and perioperative blood transfusion (OR = 4.611, 95%CI: 1.307 - 16.276). Goal-directed hemodynamic optimization resulted in 75.0% complete and 18.8% partial renal recovery. Overall in-hospital mortality was 2.8%. AKI was associated with significantly increased length of stay ((136.9 ± 24.5) hours vs. (70.4 ± 11.3) hours) in Surgical Intensive Care Unit. CONCLUSIONS: Critically ill patients undergoing AAA repair have a high incidence of AKI, which can be early recognized by RIFLE criteria. Rupture, hypotension, and blood transfusion are the significant associated risk factors. Application of goal-directed hemodynamic optimization in this cohort appeared to be effective in improving renal outcome.

Management of multiple type II endoleaks detected by duplex ultrasound after endovascular abdominal aneurysm repair.

We reported a case of multiple type II endoleaks detected by duplex ultrasound after endovascular abdominal aneurysm repair. The patient was undergoing warfarin therapy. Duplex ultrasound was applied as the sole surveillance method during follow-up and provided the concerned information for reintervention. The endoleaks were successfully repaired by coil embolization of the collaterals from the internal iliac artery feeding the fourth lumbar artery.