Zhenyu Shi

Updated Systematic Review and Meta-Analysis of Randomized Clinical Trials Comparing Carotid Artery Stenting and Carotid Endarterectomy in the Treatment of Carotid Stenosis

BACKGROUND To compare carotid artery stenting (CAS) versus carotid endarterectomy (CEA) in the treatment of carotid stenosis, including two recently published, large, prospective, randomized trials of these therapies. METHODS We searched electronic databases for prospective, randomized, controlled trials involving carotid stenosis patients who underwent CAS or CEA, focusing on studies published in 1995 to 2010. Primary outcomes were death, stroke, and myocardial infarction. RESULTS Thirteen trials containing 7,501 patients were analyzed, and odds ratios (ORs) were calculated for CAS versus CEA. The risk of stroke or death within 30 days was higher after CAS than CEA (OR = 1.57; 95% confidence interval [CI] = 1.11-2.22), especially in previously symptomatic patients (OR = 1.89; 95% CI = 1.48-2.41). However, the risk of stroke or death within 1 year was comparable (OR = 1.12; 95% CI = 0.55-2.30). In a subgroup analysis, the risk of death and disabling stroke at 30 days did not differ significantly between CEA and CAS (death: OR = 1.43; 95% CI = 0.85-2.40; disabling stroke: OR = 1.28; 95% CI = 0.89-1.83), whereas the rate of nondisabling stroke within 30 days was much higher in the CAS group (OR = 1.87; 95% CI = 1.40-2.50). The risks of myocardial infarction within 30 days and 1 year were significantly less for CAS. CONCLUSION CAS is inferior to CEA with regard to the incidence of stroke or death for periprocedural outcomes, especially in symptomatic patients. However, CAS was associated with a lower incidence of myocardial infarction. These procedures may be considered complementary rather than competing modes of therapy, each of which can be optimized with careful patient selection.

Patients carrying CYP2C19 loss of function alleles have a reduced response to clopidogrel therapy and a greater risk of in-stent restenosis after endovascular treatment of lower extremity peripheral arterial disease

OBJECTIVE This study evaluated the relationship between the cytochrome P450 (CYP) 2C19 genotype and the antiplatelet effect of clopidogrel therapy and investigated whether genotyping can predict the risk of ischemic events after endovascular treatment (ET) of lower extremity peripheral arterial disease. METHODS From January 2011 to July 2012, 120 consecutive patients with arteriosclerosis obliterans (TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease [TASC II] A-C) in the superficial femoral artery were included in a prospectively maintained database. Patients received 75 mg clopidogrel and 100 mg aspirin daily for at least 5 days before TaqMan (Life Technologies, Grand Island, NY) of CYP2C19 single-nucleotide polymorphisms and thromboelastography of the clopidogrel response. ET was subsequently performed, and follow-up evaluations, including duplex ultrasound imaging and ankle-brachial index assessment, were performed at 1, 3, 6, and 12 months after ET. During the follow-up, stent patency was assessed by ultrasound imaging, computed tomography angiography, or digital subtraction angiography. RESULTS A total of 74 ET procedures were performed. Fifty of the enrolled patients (41.7%) completed the follow-up examinations and were included in the analysis. The mean duration of follow-up was 9.8 ± 2.1 months (range, 1-30 months). Carriers of at least one CYP2C19 loss-of-function (LOF) allele had a diminished pharmacodynamic response to clopidogrel (51.6 ± 20.1 vs. 39.8 ± 15.2 for patients without and with LOF alleles, respectively; P = .022). Carriers of one LOF allele had an increased incidence of ischemic events compared with patients without any LOF alleles (59.0% vs. 20.8%, respectively; P = .008). This trend was even more evident in patients with two LOF alleles compared with patients with no LOF alleles (100% vs. 20.8% ischemic events; P = .002). The cumulative primary patency rate at 12 months was 56.0%, with significant differences between groups (73.1% vs. 34.6% in patients without and with LOF alleles, respectively; P = .0.006). CYP2C19 LOF carrier status was associated with an increased rate of primary end points (P = .007). On the basis of their adenosine diphosphate-induced platelet aggregation, patients with high platelet reactivity had a significantly higher risk of ischemic events (P = .012). CYP2C19 genotypic classification (adjusted hazard ratio, 2.688; 95% confidence interval, 1.366-5.288; P = .004) and history of smoking (adjusted hazard ratio, 2.430; 95% confidence interval, 1.024-5.765; P = .044) were independent risk factors for ischemic events. CONCLUSIONS CYP2C19 LOF alleles were associated with a diminished platelet response to clopidogrel treatment. Patients carrying CYP2C19 LOF alleles who are treated with clopidogrel may trend toward a poor prognosis after ET.

hCLOCK Causes Rho-Kinase-Mediated Endothelial Dysfunction and NF-κB-Mediated Inflammatory Responses

Background. The human Circadian Locomotor Output Cycle protein Kaput (CLOCK) gene was originally discovered as a regulator of essential human daily rhythms. This seemingly innocuous gene was then found to be associated with a multitude of human malignancies, via several biochemical pathways. We aimed to further investigate the role of hCLOCK in the hypoxia-oxidative stress response system at the biochemical level. Methods. Expression levels of Rho GTPases were measured in normoxic and hypoxic states. The effect of hCLOCK on the hypoxic response was evaluated with the use of a retroviral shRNA vector system, a Rho inhibitor, and a ROS scavenger by analyzing expression levels of hCLOCK, Rho GTPases, and NF-κB pathway effectors. Finally, in vitro ROS production and tube formation in HUVECs were assessed. Results. Hypoxia induces ROS production via hCLOCK. hCLOCK activates the RhoA and NF-κB signaling pathways. Conversely, inhibition of hCLOCK deactivates these pathways. Furthermore, inhibition of RhoA or decreased levels of ROS attenuate these pathways, but inhibition of RhoA does not lead to decreased levels of ROS. Overall findings show that hypoxia increases the expression of hCLOCK, which leads to ROS production, which then activates the RhoA and NF-κB pathways. Conclusion. Our findings suggest that hypoxic states induce vascular oxidative damage and inflammation via hCLOCK-mediated production of ROS, with subsequent activation of the RhoA and NF-κB pathways.

CLOCK Promotes Endothelial Damage by Inducing Autophagy through Reactive Oxygen Species

A number of recent studies have implicated that autophagy was activated by reactive oxygen species (ROS). Our previous report indicated that CLOCK increased the accumulation of ROS under hypoxic conditions. In this study, we investigated the mechanisms by which CLOCK mediated endothelial damage, focusing on the involvement of oxidative damage and autophagy. Overexpression of CLOCK in human umbilical vein endothelial cells (HUVECs) showed inhibition of cell proliferation and higher autophagosome with an increased expression of Beclin1 and LC3-I/II under hypoxic conditions. In contrast, CLOCK silencing reversed these effects. Interestingly, pretreatment with 3-methyladenine (3-MA) resulted in the attenuation of CLOCK-induced cell autophagy and but did not influence the production of intracellular reactive oxygen species (ROS). Furthermore, Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid-disodium salt), a ROS scavenger, significantly attenuated CLOCK-induced cell autophagy. In addition, we found that overexpression of CLOCK had no significant effects on the production of ROS and expression of Beclin1 and LC3-I/II under normoxic conditions in HUVEC. In this present investigation, our results suggested a novel mechanism of action of CLOCK in HUVECs, opening up the possibility of targeting CLOCK for the treatment of vascular diseases.

Endovascular therapy for stanford type B aortic dissection in 102 cases.

OBJECTIVE To share our experience of 102 cases of endovascular therapy for Stanford type B aortic dissection. METHODS Multiple imaging diagnostic modalities were used preoperatively to obtain the anatomical parameters of the aortic dissection. Stent grafts were implanted using digital subtraction angiography and intravascular ultrasound guidance. Follow-up computed tomography angiography 1 week and 1 year postoperatively was used to evaluate treatment efficacy and reveal complications such as endoleak, migration and fracture of the stent graft. RESULTS Clinical success was achieved in 101 cases (99.0%); one patient (1.0%) died within the perioperative period. Neither postoperative paraplegia nor conversion occurred. Endoleak occurred in 18 cases (17.6%). CONCLUSION Endovascular therapy for Stanford type B aortic dissection is less invasive and leads to less severe complications and shorter hospital stay compared with traditional surgery. The short- and mid-term efficacy are persuasive, but further follow-up is required to determine long-term efficacy.

The Association Between Obstructive Sleep Apnea and Carotid Intima–Media Thickness: A Systematic Review and Meta-Analysis

Obstructive sleep apnea (OSA) has been suggested as a risk factor for carotid atherosclerosis. The present meta-analysis aimed to evaluate the association between OSA and carotid intima–media thickness (CIMT). Eighteen studies comparing CIMT of patients with OSA versus non-OSA patients were included. Quantitative data synthesis was used to pool weighted standardized difference in means (SMD) of CIMT in a random-effects model. Compared to healthy controls, patients with OSA had a significantly higher CIMT (SMD: 0.881; 95% confidence interval [CI]: 0.647-1.115; P < .001). Due to the great heterogeneity, a subgroup analysis was conducted based on the study design. The pooled SMD of CIMT between patients with OSA and healthy controls were 0.810 (95% CI: 0.676-0.943; P < .001) and 1.008 (95% CI: 0.506-1.510; P < .001) in matched and unmatched group, respectively. Moreover, the correlation of apnea–hypopnea index and CIMT was moderate (r = .389; 95% CI: 0.315-0.459; P < .001). After adjustment for several major confounders, OSA is an independent risk factor for CIMT. These findings remind clinicians to screen for cardiovascular diseases in patients with OSA.

Upregulation of the gene expression of CLOCK is correlated with hypoxia‑inducible factor 1α in advanced varicose lesions

According to previous literature, venous hypoxia and the hypoxia‑inducible factor (HIF) pathway may contribute to the pathogenesis of varicose veins (VVs). It is widely accepted that the circadian locomotor output cycles kaput (CLOCK) gene affects nucleotide excision repair, DNA damage checkpoints and apoptosis in mammalian organisms; however, the expression levels of CLOCK in varicose veins remain to be elucidated. The aim of the present study was to detect the expression of the circadian clock gene in initial and advanced varicose lesions and analyze the correlation between the CLOCK gene, HIF‑1α, and its target gene, vascular endothelial growth factor (VEGF), in VVs. Sections of the great saphenous veins (GSVs) were obtained from patients undergoing ligation and stripping for VVs (n=70) and a control group undergoing coronary artery bypass grafting with GSV harvest (n=11). All VV patients had incompetent GSVs, according to color flow duplex scanning. C‑class VVs were determined according to the clinical‑etiology‑anatomy‑pathophysiology classification for venous diseases following physical examination of the patients with VV. Reverse transcription‑quantitative polymerase chain reaction was used to determine the expression levels of the CLOCK gene, HIF‑1α and VEGF. Immunohistochemical analysis was also performed. The patients with VVs were divided into those with initial varicose lesions (C3 and C4) and advanced varicose lesions (C5 and C6). In total, 21 of the patients had C3 lesions, 23 had C4 lesions, 14 had C5 lesions and 12 had C6 chronic venous disease. The expression of the CLOCK gene was significantly higher in the VV lesions of the GSV, compared with the normal GSVs (P<0.0001). The same trend was found in the expression levels of HIF‑1α and its target gene, VEGF, in the VV lesions (P=0.003 and P<0.0001, respectively). Subgroup analysis revealed that the expression levels of the CLOCK gene, HIF‑1α and VEGF were significantly higher in the advanced stage varicose lesions, compared with the initial varicose lesions (P<0.0001, P=0.0014 and P<0.0001, respectively). However, no statistically significant difference was identified in the expression levels of the aforementioned genes in the C3 and C4 lesions. The results demonstrated that the expression gene levels of CLOCK, HIF‑1α and its target gene, VEGF, increased significantly in advanced stage varicose lesions. Therefore, upregulation of the CLOCK gene in the vessel walls of veins may be involved in the pathogenesis of VVs and the progression of venous disease.

A New Adjustable Puncture Device for In Situ Fenestration During Thoracic Endovascular Aortic Repair

Purpose: To describe a new adjustable puncture system for in situ fenestration in thoracic endovascular aortic repair (TEVAR). Technique: An adjustable puncture needle for use in conjunction with a steerable 8-F, 55-cm Fustar sheath is demonstrated in a 65-year-old man with acute complicated type B dissection involving the left subclavian artery (LSA). The puncture device features an inflatable balloon at the tip, a central lumen for 0.018-inch guidewires, and a 3-level puncture depth. After thoracic stent-graft deployment at zone 2, the needle/sheath combination was delivered from a left brachial artery access. The needle was adjusted perpendicular to the fabric of the stent-graft with the assistance of the steerable sheath. The balloon at the tip was inflated to center the needle, and the puncture depth was selected on the puncture needle system. Holding the sheath and puncture needle together, a hole was created in the graft fabric. The aperture was sequentially dilated to accommodate the mating stent selected to maintain perfusion to the LSA. This new device has been successfully applied in 6 patients treated with TEVAR for different arch pathologies. Conclusion: This new puncture device could assist in situ fenestration and improve the technical success rate.

Outcomes and aortic remodelling after proximal thoracic endovascular aortic repair of post type B aortic dissection thoracic aneurysm.

BACKGROUND The objective was to explore the outcomes and aortic remodelling after proximal thoracic endovascular aortic repair (TEVAR) in post type B aortic dissection thoracic aneurysm with a maximal diameter ≥ 5.5cm. PATIENTS AND METHODS 34 cases of type B aortic dissection thoracic aneurysm undergoing proximal TEVAR (coverage of the primary entry and the aneurysm extent) from 2008 to 2013 were retrospectively reviewed with follow-up for at least 2 years. The primary endpoints were 30-day mortality and survival at 2 years. The secondary endpoints were major complication and re-intervention. The aortic remodelling was investigated by comparison of the maximum diameter of the aneurysm and the diameter of true and false lumen at the same level between baseline and 2 years after TEVAR. Besides, we also analysed the possible relevant factors of aortic remodelling including the course of dissection, the involvement of dissection, and the length and shape of the stent graft. RESULTS The 30 day mortality was 2.9 % (1/34). The paraplegia rate post-TEVAR was 2.9 % (1/34). Overall, 32 out of the 34 cases were followed-up for 24 - 79 months. At 2 years, the overall and aortic specific survival were 87.5 % and 90.3 % respectively. The two year freedom from re-intervention rate was 87.5 %. Compared to the preoperative data, maximum diameter of descending aorta at 2 years demonstrated a slight increase (65.4±14.1mm Vs 63.9±9.1mm), but without significance (P>0.05). Meanwhile, we noticed a significant increase of true lumen (P < 0.01) and decrease of false lumen (P < 0.01) at the same level. Relevant analysis showed that positive aortic remodelling of the maximum diameter was associated with chronic phase (≥ 90 days of dissection onset) (P < 0.05) and the application of 150 - 170mm stent grafts (P < 0.05). CONCLUSIONS Proximal TEVAR of post type B dissection thoracic aneurysm had generally favourable short- and mid-term outcomes with low paraplegia rate. Besides, it can achieve a certain extent of aortic remodelling.

Severe compression of a bailout self-expanding chimney stent for rescuing the miscoverage of left common carotid artery during TEVAR of a type B aortic dissection.

A 54-year-old man who suffered from paraplegia due to type B aortic dissection was treated with a Valiant stent-graft. However, attempts to gain secure proximal sealing resulted in an inadvertent coverage of the left common carotid artery by the endograft. The blood flow in the left common carotid artery was restored by a transcarotid Smart Control stent in a chimney fashion. At 6- and 18-month follow-up, computed tomography scan showed that the chimney stent was severely compressed by the stent graft, although the patient remained neurologically asymptomatic.