Outcomes of Excimer Laser Ablation Combined with Drug-coated Balloon in Atherosclerotic Lesions of the Popliteal Artery.

BACKGROUND: The treatment of atherosclerotic lesions in the popliteal artery is challenging. This study aims to investigate the efficacy and safety of excimer laser ablation (ELA) combined with drug-coated balloon (DCB) for these lesions. METHODS: From June 2019 to December 2021, data of patients who underwent ELA combined with DCB in the popliteal artery were retrospectively reviewed. Demographics, lesion characteristics, periprocedural complications, and follow-up information were analyzed. The primary endpoint was primary patency. Secondary endpoints included major amputation-free survival rate, technical success, bailout stenting, clinically-driven target lesion reintervention, improvement of ankle-brachial index (ABI), and Rutherford class. RESULTS: A total of 61 patients were enrolled. The mean age was 73.4 ± 11.7 years. 20 (32.8%) patients had stenotic lesions, while 41 (67.2%) patients had chronic total occlusions. The mean length of these lesions was 7.3 ± 2.8 cm. Procedure technical success rate was 95.1%. Bailout stent was performed in 3 (4.9%) patients. Intraprocedural distal embolization occurred in 3 (4.9%) patients, while flow limiting dissections occurred in 3 (4.9%) patients. The mean ABI was significantly improved from 0.45 ± 0.13 at baseline to 0.90 ± 0.12 after ELA, 0.88 ± 0.11 at 6 months and 0.85 ± 0.12 at 12 months during the follow-up period. The median follow-up time was 28.2 ± 6.1 months. Reintervention was performed in 5 (8.2%) patients. The 2-year primary patency was 83.5%. CONCLUSIONS: ELA combined with DCB is a safe and effective strategy in the treatment of popliteal artery atherosclerotic lesions with low rates of bail-out stenting and high primary patency.

Safety and Effectiveness of Excimer Laser Ablation Combined With Drug-Coated Balloon for Atherosclerotic Obliterans in the Lower Extremity.

PURPOSE: To evaluate the safety and effectiveness of excimer laser ablation (ELA) combined with drug-coated balloon (DCB) for atherosclerotic obliterans (ASO) of the lower extremities. MATERIALS AND METHODS: From June 2019 to December 2020, all eligible patients were enrolled. Demographics, characteristics of lesions, complications, and follow-up information were collected and analyzed. The primary endpoint was major amputation-free survival (MAFS). Secondary endpoints included technical success, primary patency, bailout stent, distal embolization, target lesion reintervention (TLR), and ulcer healing rate. Major amputation-free survival and primary patency were calculated by Kaplan-Meier analysis. RESULTS: A total of 71 patients were enrolled. Forty-eight (81.7%) patients presented critical limb ischemia (CLI) and 48.6% of them was calcification class 4 according to Peripheral Arterial Calcium Scoring System (PACSS). Chronic totally occluded (CTO) disease was the most common lesion in 66.0% of them and superficial femoral artery (SFA) was the most common segment in 59.6%. Technical success rate was 93.0%. One-year follow-up was finished in 25 (35.2%) patients. The primary patency and MAFS were 92.0%±27.6% and 96.0%±20.0% at 12 months, respectively. During the mean follow-up of 9.4±4.3 months, clinically-driven TLR occurred in 2 (2.8%) patients, and major and minor amputation occurred in 2 (2.8%) and 1 (1.4%) patient, respectively. CONCLUSION: The early results demonstrated that ELA was an effective treatment in de novo, in-stent restenosis (ISR) and CTO lesions. Meanwhile, ELA could prepare the lumen for the use of DCB and reduce the implantation of stents, especially in segments unsuitable for stenting. Mid-term and long-term results need to be awaited.

Clock Gene Bmal1 Disruption in Vascular Smooth Muscle Cells Worsens Carotid Atherosclerotic Lesions.

BACKGROUND: Clock system disruptions are associated with cardiovascular diseases. We previously demonstrated Bmal1 (brain muscle aryl nuclear translocase like-1) expression is significantly attenuated in plaque-derived vascular smooth muscle cells (VSMCs). However, the influence of Bmal1 disruption in VSMCs and its molecular targets are still unclear. Here, we aim to define how Bmal1 disruption in VSMCs influences the atherosclerosis lesions. METHODS: The relationship among Bmal1, neurological symptoms, and plaque stability was investigated. VSMC Bmal1-/- and VSMC Bmal1+/+mice were generated and injected with adeno associated virus encoding mutant proprotein convertase subtilisin/kexin type 9 to induce atherosclerosis. Carotid artery ligation and cuff placement were performed in these mice to confirm the role of Bmal1 in atherosclerosis progression. The relevant molecular mechanisms were then explored. RESULTS: Bmal1 expression in the carotid plague was significantly lower in symptomatic patients as well as in unstable plaques. Moreover, Bmal1 reduction is an independent risk factor for neurological symptoms and plaque instability. Besides, VSMC Bmal1-/- mice exhibit aggravated atherosclerotic lesions. Further study demonstrated that Bmal1 downregulation in VSMCs increased VSMC migration, monocyte transmigration, reactive oxygen species levels, and VSMCs apoptosis. As for the mechanism, we revealed that Bmal1 suppresses VSMCs migration by inhibiting RAC1 activity in 2 ways: by activating the transcription of RhoGDIα and by interacting with RAC1. Besides, Bmal1 was shown to preserve antioxidant function in VSMCs by activating Nrf2 (nuclear factor erythroid 2-related factor 2) and Bcl-2 transcription. CONCLUSIONS: Bmal1 disruption in VSMCs worsens atherosclerosis by promoting VSMC migration and monocyte transmigration and impairing antioxidant function. Therefore, Bmal1 may be a potential therapeutic target and biomarker of atherosclerosis in the future.

Results of Excimer Laser Ablation Combined with Drug-Coated Balloon for Atherosclerotic Obliterans of Lower Extremity and Risk Factors for Loss of Primary Patency.

BACKGROUND: The results of excimer laser ablation (ELA) combining with drug-coated balloon (DCB) in the treatment for atherosclerotic obliterans (ASO) remains unclear. METHODS: Retrospectively enrolled patients who underwent ELA combined with DCB in 2 centers. The primary endpoint was primary patency, and secondary endpoints included technical success, procedure-related complications, major amputation, clinically driven target lesions reintervention (CD-TLR), measurements of ankle-brachial index (ABI), and quality of life (QoL). RESULTS: 102 patients were enrolled. The primary patency was 86.7% (95% confidence interval [CI]: 72.9%-89.0%) at 12 months and 82.6% (95% CI: 78.2%-92.1%) at 24 months. The freedom from reintervention was 87.8% (95% CI: 79.5%-92.9%) at 12 months and 86.6% (95% CI: 78.1%-92.0%) at 24 months. The ABI measurement and QoL were significantly improved at each follow-up point. Sixteen (15.7%) patients lost the primary patency. Patients losing the primary patency demonstrated higher Rutherford class (P = 0.004), worse runoff (P < 0.001), higher Peripheral Arterial Calcium Scoring System (PACSS) (P < 0.001), and smaller ratio of tube diameter to reference vessel diameter (TD/RVD) (P < 0.001) compared with patients without losing it. The run-off ≥7 (adjusted odds ratio [aOR]: 34.3; 95% CI: 2.9-398.3; P = 0.005) and TD/RVD <4.9 (aOR: 24.7; 95% CI: 1.7-359.5; P = 0.019) were independent risk factors for loss of primary patency. CONCLUSIONS: ELA combined with DCB seemed an effective and safe treatment for ASO of lower extremity, and it could not only reduce the implantation of stent but significantly improve QoL. The run-off ≥7 and TD/RVD <4.9 were independent risk factors for loss of primary patency.

Long-term outcomes of endovascular treatment for aortic pseudoaneurysm in patients with Behçet's disease.

OBJECTIVES: Behçet's disease (BD) is a multisystem inflammatory disorder with unknown etiology, and its aneurysmal lesions are associated with high mortality due to the high risk of rupture. This study intended to further explore the long-term safety and efficacy of endovascular therapy for BD-related aortic pseudoaneurysm (BAP). METHODS: From January 2009 to May 2021, 17 BAP patients who underwent endovascular repair were retrospectively identified and enrolled. Adequate immunosuppressive treatment was instituted before and after endovascular treatment unless emergency surgery was required. The patients were followed up at 3, 6, and 12 months and yearly after the primary endovascular intervention by computed tomography angiography (CTA) examination. RESULTS: Nineteen BAPs were identified among 17 patients. BAPs located at the aortic arch were found in three patients (17.6%), descending thoracic aorta in 5 (29.4%), and abdominal aorta in 10 (58.8%; suprarenal abdominal aorta in 2 [11.8%], and infrarenal abdominal aorta in 8 [47.1%]). The mean ESR during admission was 56.5 ± 24.9 mm/h (range = 30.0-120.0 mm/h), which fell to 22.7 ± 18.4 mm/h (range = 2.0-74.0 mm/h) before the endovascular intervention (p < 0.001). The rate of favorable immunosuppressive control before intervention is 76.5% (13/17). Technical success was achieved in all patients. Median follow-up time was 57.0 months (interquartile range [IQR] = 21.3-67.3 months). Pseudoaneurysm recurrence was observed in four patients, type I endoleak in one, pseudoaneurysms sac dilation in one, and external iliac artery occlusion in 1. Two patients died of pseudoaneurysm rupture. Five-year accumulated overall rate, recurrence-free rate, and reintervention-free survival rate of BAP patients were 92.8%, 75.4%, and 71.8%, respectively. CONCLUSION: Endovascular treatment in BAP patients seemed to be associated with long-term safety and efficacy with a 5-year overall survival rate of 92.8%. Adequate immunosuppressive treatment was essential for BAP patients to prevent aortic pseudoaneurysm recurrence and improve the prognosis.

Excimer laser ablation combined with drug-coated balloon versus drug-coated balloon in the treatment of de novo atherosclerotic lesions in lower extremities (ELABORATE): study protocol for a real-world clinical trial.

BACKGROUND: The efficacy and validity of excimer laser ablation (ELA) in the in-stent restenosis (ISR) has been confirmed. However, its application in de novo atherosclerotic lesions of lower extremity artery disease (LEAD) has not been clearly defined and its procedure has not been standardized. METHODS: ELABORATE is a prospective, multicenter, real-world study designed to evaluate the efficacy and safety between ELA combined with drug-coated balloon (DCB) and DCB alone in de novo atherosclerotic lesions of LEAD. DISCUSSION: ELABORATE is a prospective, multicenter, real-world study designed to assess the efficacy and safety between ELA combined with drug-coated balloon (DCB) and DCB alone in patients with de novo atherosclerotic lesions of LEAD. According to the real-world situation, eligible patients will be allocated to ELA + DCB group (group E) and DCB group (group C). Baseline and follow-up information (at 3, 6, and 12 months) will be collected. The primary efficacy point is primary patency at 12-months, and the secondary efficacy points include clinically driven target lesion reintervention (CD-TLR), change of Rutherford class, ankle-brachial index and ulcer healing rate. These indexes will be assessed and recorded at 3, 6, and 12-month follow-up. Also, safety evaluation, including major adverse event, all-cause mortality through 30-day follow-up, unplanned major amputation, bailout stent and distal embolization, will also be evaluated by an independent core laboratory. All the data will be collected and recorded by the electric data capture system. This study will be finished in 3 years and the 12-month results will be available in 2023. All the patients will be followed for 5 years. Trial registration number Chinese Clinical Trial Registry (ChiCTR2100051263). Registered 17 September 2019. http://www.chictr.org.cn/listbycreater.aspx .

Clinical features and outcomes after endovascular therapy for penetrating aortic ulcer and intramural hematoma.

OBJECTIVES: To identify the differences between clinical features and outcomes after endovascular therapy for penetrating aortic ulcer (PAU) and intramural hematoma (IMH). METHODS: From January 2009 to March 2020, patients who underwent endovascular therapy for PAU and IMH were enrolled. Information on patient demographics, presentation, PAU and IMH morphology, laboratory examination, and clinical follow-up information was collected and analyzed. Univariate analysis was performed to identify the differences between IMH and PAU, and Kaplan-Meier was used to calculate the cumulative survival rate and freedom from reintervention. RESULTS: A total of 114 patients were enrolled; 80 (70.2%) of them were diagnosed with PAU. Compared with PAU, patients with IMH were younger (p = 0.006), more likely to be admitted emergently (p = 0.001), had longer hospital stay (p = 0.028), and had higher levels of C-reactive protein (p = 0.030). Meanwhile, patients with IMH were more likely to be associated with hypertension (p = 0.020) and pleural effusion (p < 0.001) and less likely to have a history of acute coronary syndrome (p = 0.019) and prior cardiovascular intervention (p = 0.017). The five-year freedom from reintervention and cumulative survival rate were 94.2% (95% confidential interval, 88.9%-99.9%) and 87.8% (95% confidential interval, 79.5%-96.9%) in PAU patients and 89.6% (95% confidential interval, 75.8%-99.9%) and 85.1% (95% confidential interval, 68.0%-99.9%) in IMH patients, respectively. There was no significant difference in freedom from reintervention (p = 0.795) or cumulative survival rate (p = 0.817). CONCLUSIONS: IMH appeared to occur in younger patients with hypertension and usually had an acute onset, while PAU was more likely to be found incidentally in older patients with atherosclerosis. Endovascular therapy was effective in both IMH and PAU patients with encouraging outcomes.

Outcomes of endovascular stent graft repair for penetrating aortic ulcers with or without intramural hematoma.

OBJECTIVE: We investigated the outcomes of endovascular repair for penetrating aortic ulcers (PAUs) with and without intramural hematoma (IMH). METHODS: Patients with PAUs who had undergone thoracic endovascular aortic repair (TEVAR) or endovascular abdominal aortic repair (EVAR) at our center were enrolled. Patient demographics, presenting symptoms, and anatomic characteristics were collected and analyzed to investigate the TEVAR/EVAR indications, perioperative complications, and mortality. RESULTS: We identified 138 patients with PAU. Of the 138 patients, 58 (42.0%) had also had IMH. Compared with the patients without IMH, the patients with IMH had had significantly greater emergency admission rates (P < .01), a larger aortic diameter (P = .03), and a greater incidence of stent-induced new entry development (P = .02). No significant differences were found in mortality or freedom from reintervention between patients with PAUs with and without IMH during follow-up. However, the cumulative survival rates calculated using Kaplan-Meier analysis for patients who had undergone TEVAR/EVAR during their first hospitalization were significantly greater than those who had undergone delayed TEVAR/EVAR during follow-up. CONCLUSIONS: TEVAR/EVAR was safe and effective, with encouraging outcomes for patients with PAUs with or without IMH, and can be used more aggressively for symptomatic patients. The presence of PAUs with IMH did not seem to adversely affect long-term mortality. However, but stent-induced new entry was more likely to develop.

Perioperative and Follow-up Results of Carotid Artery Stenting and Carotid Endarterectomy in Patients with Carotid Near-Occlusion.

BACKGROUND: The aim was to compare perioperative and follow-up results of carotid artery stenting (CAS) and carotid endarterectomy (CEA) in patients with carotid near-occlusion (NO). METHODS: A retrospective analysis was conducted from January 2012 to June 2017 on consecutive patients with NO in our center. Perioperative complications, recurrence rate of ischemic stroke, restenosis rate, and mortality in follow-up were compared between the CAS group and CEA group. RESULTS: 92 patients (CAS group, 54 and CEA group, 38) were identified. Perioperative (30-day) results were as follows: the rate of new lesions on diffusion-weighted imaging (DWI) was higher in the CAS group (n = 31, 57.4%) than in the CEA group (n = 13, 34.2%) (P = 0.03); no differences were found in ischemic stroke, transient ischemic attack (TIA), cardiac infarction, and death rate between the two groups. Results from follow-up with a mean period of 28.3 (range from 3 to 60) months were as follows: the restenosis rate was lower in the CAS group (n = 1, 1.8%) than the CEA group (n = 4, 10.5%) (P = 0.04); no differences were found in ischemic stroke, TIA, and the death rate between the two groups. Kaplan-Meier survival curves showed that the five-year survival rate was 85.8% of the CAS group and 82.7% of the CEA group (P = 0.61); the five-year rate of freedom from target-lesion restenosis was 93.3% of the CAS group and 80.4% of the CEA group (P = 0.02). CONCLUSIONS: Both CAS and CEA can be used for carotid NO with the same rate of TIA/stroke and long-term survival. The rate of new lesions on DWI after CAS was higher than that in CEA in the perioperative period. CAS had a lower restenosis rate than CEA in follow-up, which might be more beneficial for remodeling of the distal internal carotid artery.

Prognostic Nomogram for Patients with Hostile Neck Anatomy after Endovascular Abdominal Aortic Aneurysm Repair.

OBJECTIVE: Since the introduction of endovascular aortic aneurysm repair (EVAR), the morphology of aneurysm neck has a great impact on prognosis of patients who underwent elective abdominal aortic aneurysm (AAA) repair. In this study, we aimed to analyze the morphologic features and prognosis after EVAR for patients with hostile neck anatomy and tried to create a novel prognostic nomogram in predicting EVAR-related adverse events. METHODS: We retrospectively reviewed 812 patients with infra-renal AAA who underwent elective EVAR procedures between January 2010 and December 2015 at our single center and identified patients with hostile neck. Univariable and multivariable analyses were performed to determine the significant prognostic factors for EVAR-related adverse events, which were then integrated to build a nomogram. The model was subjected to bootstrap resamples for internal validation. The discriminative ability was presented with calibration plots and measured by concordance index (C-index) and area under the curve (AUC) from receiver-operating characteristic curve. RESULTS: The overall EVAR-related adverse events rate for 323 patients with hostile neck was 12.1%. By multivariable analysis, significant risk factors of adverse events included female (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.18-5.62; P = 0.017), conical neck (OR, 4.66; 95% CI, 1.5-14.51; P = 0.008), short neck (OR, 2.71; 95% CI, 1.49-4.94; P = 0.001), and angulated neck (OR, 3.26; 95% CI, 1.43-7.43; P = 0.005). A nomogram was developed based on the results of multivariable analysis. Calibration plots presented an excellent agreement between model predicted and actually observed risk of adverse events after internal validation. The discrimination ability of this risk predictive model was reasonable (C-index = 0.79; AUC = 0.81, 95% CI, 0.73-0.89). CONCLUSIONS: EVAR is a feasible and safe treatment for most of patients with hostile neck. We developed and validated a novel model for predicting the risk of adverse events after EVAR and clarified high-risk patients.

Serum tumor necrosis factor α levels are associated with new ischemic brain lesions after carotid artery stenting.

OBJECTIVE: New diffusion-weighted imaging (DWI) lesions on magnetic resonance imaging (MRI) after carotid artery stenting (CAS) are associated with an increased risk of future cerebrovascular events. Therefore, we evaluated the association between the expression levels of serum inflammatory markers and new DWI lesions after CAS and the presence of intraplaque hemorrhage (IPH). We also explored the mechanisms underlying this association. METHODS: A total of 225 inpatients with severe carotid artery stenosis were consecutively enrolled in this cohort study. Serum inflammatory marker levels were detected in all patients by enzyme-linked immunosorbent assay. In the final analysis, 128 patients who underwent CAS and received pretreatment and post-treatment MRI scans were enrolled. DWI was performed to detect new ischemia brain lesions. T1-weighted, T2-weighted, and time-of-flight sequences were also conducted to identify IPH. RESULTS: Serum tumor necrosis factor α (TNF-α) levels were significantly higher in symptomatic patients as well as in IPH+ patients identified by carotid MRI. New DWI lesions were identified in 50% of patients after CAS. Univariate analysis showed that DWI+ patients after CAS exhibited older mean age, higher mean TNF-α levels, and more IPH on preoperative MRI and were less likely to have right carotid stenosis than DWI- patients. Multivariate logistic regression analyses revealed that serum TNF-α concentrations were associated with new DWI lesions after CAS (odds ratio, 1.245; 95% confidence interval, 1.068-1.451; P = .005). Finally, the specificity and sensitivity of serum TNF-α levels in predicting DWI+ patients after CAS were 0.828 and 0.453, respectively. CONCLUSIONS: Higher serum TNF-α levels are associated with a higher likelihood of new DWI lesions after CAS and the presence of IPH. Therefore, TNF-α is a potentially valuable predictor of acute ischemic cerebral lesions after CAS and the presence of IPH.

Morphology and Outcomes of Total Endovascular Treatment of Type B Aortic Dissection with Aberrant Right Subclavian Artery.

OBJECTIVES: To characterize the morphology of type B aortic dissection with aberrant right subclavian artery (ARSA) and present early and midterm outcomes of total endovascular treatment for affected patients. METHODS: From January 2010 to December 2015, patients with ARSA and type B aortic dissection treated with total endovascular techniques were enrolled. The angle of the aortic arch was measured on pre-operative CTA. Sixty age and gender matched normal aortic arch patients with type B aortic dissection served as controls. Primary outcomes were technical success, 30 day mortality, and late survival. Secondary outcomes included in hospital morbidity, re-intervention rate, and patency of the subclavian artery. RESULTS: A total of 13 patients (8 men, 5 women; mean age 58 years) were included. The mean angle of the aortic arch in patients with ARSA was significantly smaller than in normal aortic arch patients (117.2° ± 10.8° vs. 124.2° ± 9.4°, respectively; p = .024). Simple thoracic endovascular aortic repair (TEVAR) and TEVAR plus a parallel graft technique were performed in six and seven patients, respectively. Primary technique success was achieved in 11 of the 13 (84.6%) patients. A bird beak configuration occurred significantly more frequently in patients with ARSA than in normal aortic arch patients (91.7% vs. 48.3%, respectively; p = .035). The median follow-up time was 36 months. One patient received a secondary procedure because of a new onset entry tear at the distal end of the stent graft. No posterior circulation stroke, permanent spinal cord ischaemia, or ischaemia of the upper arm was observed. CONCLUSIONS: Type B aortic dissection with ARSA was associated with a steep aortic arch. Total endovascular treatment for these patients was feasible and safe. Stent grafts with better flexibility and appropriate extension of the proximal landing zone with a parallel graft technique are suggested based on the observed outcomes.

Intracellular high cholesterol content disorders the clock genes, apoptosis-related genes and fibrinolytic-related genes rhythmic expressions in human plaque-derived vascular smooth muscle cells.

BACKGROUND: The clock genes are involved in regulating cardiovascular functions, and their expression disorders would lead to circadian rhythm disruptions of clock-controlled genes (CCGs), resulting in atherosclerotic plaque formation and rupture. Our previous study revealed the rhythmic expression of clock genes were attenuated in human plaque-derived vascular smooth muscle cells (PVSMCs), but failed to detect the downstream CCGs expressions and the underlying molecular mechanism. In this study, we examined the difference of CCGs rhythmic expression between human normal carotid VSMCs (NVSMCs) and PVSMCs. Furthermore, we compared the cholesterol and triglycerides levels between two groups and the link to clock genes and CCGs expressions. METHODS: Seven health donors' normal carotids and 19 carotid plaques yielded viable cultured NVSMCs and PVSMCs. The expression levels of target genes were measured by quantitative real-time PCR and Western-blot. The intracellular cholesterol and triglycerides levels were measured by kits. RESULT: The circadian expressions of apoptosis-related genes and fibrinolytic-related genes were disordered. Besides, the cholesterol levels were significant higher in PVSMCs. After treated with cholesterol or oxidized low density lipoprotein (ox-LDL), the expressions of clock genes were inhibited; and the rhythmic expressions of clock genes, apoptosis-related genes and fibrinolytic-related genes were disturbed in NVSMCs, which were similar to PVSMCs. CONCLUSION: The results suggested that intracellular high cholesterol content of PVSMCs would lead to the disorders of clock genes and CCGs rhythmic expressions. And further studies should be conducted to demonstrate the specific molecular mechanisms involved.

The rhythmic expression of clock genes attenuated in human plaque-derived vascular smooth muscle cells.

BACKGROUND: Acute myocardial infarction and stroke are more likely to occur in the early morning. Circadian pacemakers are considered to be involved in the process. Many peripheral tissues and cells also contain clock systems. In this study, we examined whether the primary cultured human plaque-derived vascular smooth muscle cells (VSMCs) process circadian rhythmicity; furthermore, we investigated the expression difference of clock genes between normal human carotid VSMCs and human plaque-derived VSMCs. METHODS: Fifty-six human carotid plaques provided the atherosclerotic tissue, and 21 samples yielded viable cultured primary VSMCs. The normal carotid VSMCs were cultured from donors' normal carotids. The mRNA levels of the target genes were measured by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). RESULTS: After serum shock, both types of cells showed clear circadian expressions of Bmal1, Cry1, Cry2, Per1, Per2, Per3 and Rev-erbα mRNA; meanwhile the Clock mRNA show a rhythmic expression in plaque-derived SMCs but not in normal carotid VSMCs. The expression levels of these main clock genes were significantly attenuated in human plaque-derived VSMCs compared with normal human carotid VSMCs. The rhythm of Bmal1 mRNA in plaque-derived VSMCs was changed. CONCLUSION: The present results demonstrate that the human plaque-derived VSMCs possess different circadian rhythmicity from that of normal carotid VSMCs. The rhythm changes of clock genes in plaque-derived VSMCs may be involved in the process of atherosclerosis and finally promote the rupture of plaque.

Costunolide mitigates inflammation and promotes extracellualr matrix integrity of thoracic aortic dissection by inhibiting NF-κB signaling.

BACKGROUND: Thoracic aortic dissection (TAD) is one of the most fatal cardiovascular diseases. One of its important pathological characteristics is the local inflammatory response. Many studies have found that Macrophage polarization plays an extremely critical role in the inflammatory progression and tissue remodeling of TAD. Costunolide (CTD) has an improving effect on oxidative stress and inflammation in the body. However, whether it can promote the integrity of extracellular matrix in Aortic dissection and its mechanism are still unclear. METHODS: The male C57BL/6J mice were used to construct an animal model of TAD with ß-aminopropionitrile (BAPN) (100 mg/kg/day, lasting for 28 days), and then CTD (10 mg/kg or 100 mg/kg) was injected intraperitoneally for 28 days to check the survival rate, TAD incidence, aortic morphology and other indicators of the mice. Using hematoxylin-eosin (HE), Masson, Elastin van Gieson (EVG) staining, immunofluorescence (IF), and immunohistochemical staining, the study aimed to determine the therapeutic effects of CTD on an animal model with BAPN-induced TAD. To enhance the examination of the regulatory mechanism of CTD, we conducted transcriptome sequencing on arterial tissues of mice in both the BAPN group and the BAPN + CTD100 group. Next, ANG II were used to construct TAD model in vascular smooth muscle cells (VMSCs). The effects of CTD on the proliferation, migration, invasion, and apoptosis of ANG II-induced cells are to be detected. The expression of MMP2, MMP9, P65, and p-P65 in each group will be examined using Western blot. Finally, the overexpression of IκB kinaseß (IKKß) will be established in VMSCs cells to further explore the protective function of CTD. RESULTS: The result showed that CTD significantly inhibited BAPN induced mortality and TAD incidence in the animal model, improved aortic vascular morphology, promoted the integrity of extracellular matrix in TAD, reduced tissue inflammation, reduced the accumulation of M1 macrophage, promoted M2 macrophage polarization, and reduced the expression of NF-κB pathway related proteins. Mechanistically, CTD significantly weakened the proliferation, migration, invasion, and apoptosis. p-P65 protein expression of TAD cells were induced by ANG II and IKK-ß. CONCLUSION: CTD has the potential to alleviate inflammation, VSMC apoptosis, MMP2/9 levels, and enhance extracellular matrix integrity in TAD by inhibiting the NF-κB signaling pathway.

One month follow-up of carotid endarterectomy with in-hospital preoperative aspirin monotherapy and postoperative dual antiplatelet therapy in asymptomatic and symptomatic patients: A multi-center study.

Background: There is currently no consensus regarding the optimal perioperative antiplatelet strategy for carotid artery surgery. This multicentre study aimed to analyse the association between preoperative aspirin monotherapy following postoperative dual antiplatelet therapy (DAPT) and the risk for stroke and death after carotid endarterectomy (CEA). Methods: This cohort study included 821 patients with carotid artery stenosis who underwent CEA. Primary outcomes included any stroke or death up to the one-month postoperative follow-up. Multilevel multivariate regression analyses and descriptive statistics were performed. Results: Patients were predominantly male (53 %), with a mean age of 66.2 years. The primary outcome occurred in 1.6 % of patients. Univariate and multivariate analyses revealed that patients with chronic obstructive pulmonary disease (COPD) exhibited a high risk for stroke or death (P = 0.011). The occurrence of any local complications in the neck was accompanied by an increase in diastolic blood pressure (DBP) (P = 0.007). Patients with a high systolic blood pressure (SBP) (P = 0.002) experienced a longer operative duration. The length of hospital stay was longer in the patients with COPD (P = 0.020), minor stroke (P = 0.011), and major stroke (P = 0.001). A positive linear correlation was found between SBP and operative duration in the overall population (ß 0.4 [95 % confidence interval (CI) 0.1-0.7]; P = 0.002). The resultant curve for DBP and any local complications in the neck exhibited a two-stage change and one breakpoint in the entire population (k = 68 mmHg, <68; odds ratio [OR] 0.9 [95 % CI 0.7-1.1], P = 0.461; ≥68: OR 1.1 [95 % CI 1.0-1.1], P = 0.003). Conclusions: Preoperative aspirin monotherapy and postoperative DAPT were safe and effective antiplatelet treatments for patients who underwent CEA.

Extracellular traps and the role in thrombosis.

Thrombotic complications pose serious health risks worldwide. A significant change in our understanding of the pathophysiology of thrombosis has occurred since the discovery of extracellular traps (ETs) and their prothrombotic properties. As a result of immune cells decondensing chromatin into extracellular fibers, ETs promote thrombus formation by acting as a scaffold that activates platelets and coagulates them. The involvement of ETs in thrombosis has been reported in various thrombotic conditions including deep vein thrombosis (DVT), pulmonary emboli, acute myocardial infarction, aucte ischemic stroke, and abdominal aortic aneurysms. This review summarizes the existing evidence of ETs in human and animal model thrombi. The authors described studies showing the existence of ETs in venous or arterial thrombi. In addition, we studied potential novel therapeutic opportunities related to the resolution or prevention of thrombosis by targeting ETs.

CLOCK regulates Drp1 mRNA stability and mitochondrial homeostasis by interacting with PUF60.

Circadian genes such as Clock, Bmal1, Cryptochrome1/2, and Period1/2/3 constitute the precise circadian system. ClockΔ19 is a commonly used mouse model harboring a circadian clock gene mutation, which lacks the EXON-19-encoded 51 amino acids. Previous reports have shown that ClockΔ19 mice have severe metabolic abnormalities. Here, we report that the mitochondria of ClockΔ19 mice exhibit excessive fission and dysfunction. We also demonstrate that CLOCK binds to the RNA-binding protein PUF60 through its EXON 19. Further, we find that PUF60 directly maintains mitochondrial homeostasis through regulating Drp1 mRNA stability, while the association with CLOCK can competitively inhibit this function. In ClockΔ19 mice, CLOCKΔ19 releases PUF60, leading to enhanced Drp1 mRNA stability and persistent mitochondrial fission. Our results reveal a direct post-transcriptional role of CLOCK in regulating mitochondrial homeostasis via Drp1 mRNA stability and that the loss of EXON 19 of CLOCK in ClockΔ19 mice leads to severe mitochondrial homeostasis disorders.

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.

Bmal1 Downregulation Worsens Critical Limb Ischemia by Promoting Inflammation and Impairing Angiogenesis.

Critical limb ischemia (CLI) is the most advanced clinical stage of peripheral vascular disease with high mobility and mortality. CLI patients suffer from lower extremity rest pain, ulceration, and gangrene caused by insufficient blood and oxygen supply. Seeking for effective biomarkers and therapeutic targets is of great significance for improving the life quality of CLI patients. The circadian clock has been reported to be involved in the progression of kinds of cardiovascular diseases. Whether and how circadian genes play a role in CLI remains unknown. In this study, by collecting femoral artery and muscle specimens of CLI patients who underwent amputation, we confirmed that the circadian gene Bmal1 is downregulated in the CLI femoral artery and ischemic distal lower limb muscle. Furthermore, we verified that Bmal1 affects CLI by regulating lipid metabolism, inflammation, and angiogenesis. A hindlimb ischemia model performed in wild-type and Bmal1-/- mice confirmed that Bmal1 disruption would lead to impaired angiogenesis. In vitro experiments indicated that the decreased expression of Bmal1 would increase ox-LDL uptake and impair endothelial cell functions, including proliferation, migration, and tube formation. As for mechanisms, Bmal1 represses inflammation by inhibiting lipid uptake and by activating IL-10 transcription and promotes angiogenesis by transcriptionally regulating VEGF expression. In conclusion, we provide evidence that the circadian gene Bmal1 plays an important role in CLI by inhibiting inflammation and promoting angiogenesis. Thus, Bmal1 may be an effective biomarker and a potential therapeutic target in CLI.