Association of bone turnover biomarkers with severe intracranial and extracranial artery stenosis in type 2 diabetes mellitus patients

BACKGROUND Intracranial and extracranial artery stenosis is associated with cerebral infarction.Vascular calcification and atherosclerosis are the main causes of stenosis and major risk factors for cardiovascular and cerebrovascular events in patients with type 2 diabetes mellitus(T2DM).Bone turnover biomarkers(BTMs)are associated with vascular calcification,atherosclerosis,glucose,and lipid metabolism.AIM To investigate the association of circulating BTM levels with severe intracranial and extracranial artery stenosis in patients with T2DM.METHODS For this cross-sectional study including 257 T2DM patients,levels of the BTMs serum osteocalcin(OC),C-terminal cross-linked telopeptide of type I collagen(CTX),and procollagen type I N-peptide were measured by electrical chemiluminescent immunoassay,and artery stenosis was assessed by color Doppler and transcranial Doppler.Patients were grouped according to the existence and location(intracranial vs.extracranial)of artery stenosis.Correlations between BTM levels,previous stroke,stenosis location,and glucose and lipid metabolism were analyzed.RESULTS T2DM patients with severe artery stenosis had a higher frequency of previous stroke and levels of all three tested BTMs(all P<0.05)than patients without.Some differences in OC and CTX levels were observed according to the location of artery stenosis.Significant associations were also observed between BTM levels and some glucose and lipid homeostasis parameters.On multivariate logistic regression analysis,all BTMs were significant predictors of artery stenosis in T2DM patients with and without adjustment for confounding factors(all P<0.001),and receiver operating characteristic curve analysis demonstrated the ability of BTM levels to predict artery stenosis in T2DM patients.CONCLUSION BTM levels were found to be independent risk factors for severe intracranial and extracranial artery stenosis and were differentially associated with glucose and lipid metabolism in patients with T2DM.Therefore,BTMs may be promising biomarkers and potential therapeutic targets for artery stenosis.

A novel cerebrovascular drug-coated balloon catheter for treating symptomatic intracranial atherosclerotic stenosis lesions:Study protocol for a prospective,multicenter,single-arm,target-value clinical trial

Background:Previous single-center studies have demonstrated that drug-coated balloons(DCBs)may reduce restenosis rates,which is an important factor affecting the prognosis for intracranial interventional therapy.However,currently available cardiac DCBs are not always suitable for the treatment of intracranial atherosclerotic stenosis(ICAS).This study aimed to evaluate the safety and efficacy of a novel DCB catheter designed for patients with severely symptomatic ICAS.Methods:This prospective,multicenter,single-arm,target-value clinical trial was conducted in 9 Chinese stroke centers to evaluate the safety and efficacy of a novel DCB catheter for treating symptomatic severe ICAS.Primary metrics and other indicators were collected and analyzed using SAS version 9.4(SAS Institute,Cary,NC,USA).Results:A total of 155 patients were enrolled in this study.The preliminary collection of follow-up data has been completed,while data quality control is ongoing.Conclusion:Results of this study demonstrated the patency rate,safety,and effectiveness of a novel on-label paclitaxel DCB designed for the treatment of ICAS.Ethics and dissemination:This study,involving human participants,was reviewed and approved by the Ethics Committee of Drugs(Devices)Clinical Experiment at Henan Provincial People’s Hospital(reference number:2020-145-03)and other research centers participating in the clinical trial.The results of this study will be presented at international conferences and sent to peer-reviewed journals for publication.Standard protocol items:The Recommendations for Interventional Trials checklist was used when drafting the study protocol.Trial registration number:Registered with the Chinese Clinical Trial Registry on June 11,2021(Chi CTR2100047223).

Clinical utilization of microembolus detection by transcranial Doppler sonography in intracranial stenosis-occlusive disease

Objective To discuss the clinical ultiliazation and significance of microembolus detection by transcranial Doppler （TCD） sonography in intracranial stenosis-occlusive disease. Data sources All related articles in this review were mainly searched from PubMed published in English from 1996 to 2012 using the terms of microembolic signal, transcranial Doppler, intracranial stenosis, stroke. Study selection Original articles and reviews were selected if they were related to the clinical utilization of microembolus detection in intracranial stenosis-occlusive disease. Results Intracranial stenosis is a significant cause of cerebral emboli, and microembolus detection by TCD sonography were widely used in exploring the mechanisms of ischemic stroke with intracranial stenosis （including the middle cerebral artery stenosis and the vertebral-basilar stenosis）, evaluating the prognosis of acute stroke, evaluating the therapeutic effects, and predicting the recurrent events of stroke. Conclusion Microembolus detection by TCD sonography plays an important role in the cerebral ischemic stroke patients with intracranial stenosis.

Value of cerebral perfusion and vascular reserve for the treatment of symptomatic intracranial arterial stenosis

BACKGROUND： It is crucial to understand cerebral perfusion and vascular reserve in stegnotic arterial blood-supply regions to treat ischemic cerebrovascular diseases. However, effects on symptomatic intracranial arterial stenosis （SICAS） need to be further studied in additional applications. OBJECTIVE： To evaluate and summarize the effects of cerebral perfusion and vascular reserve on the treatment of SICAS. RETRIEVAL STRATEGY： A computer-based online search of English language publications from January 2000 to July 2007 was conducted in PubMed to identify publications that addressed cerebral perfusion and vascular reserve of SICAS. Search key words were ＂intracranial stenosis, perfusion, brain reserve＂. Relevant data were also searched with the China Journal Net, using the same key words in Chinese from January 2000 to January 2007. In total, 101 articles were retrieved. Inclusion criteria： （1） Articles describing the current status for the diagnosis and treatment of SICAS; （2） Articles concerning research developments of cerebral perfusion and vascular reserve of SICAS. Exclusion criteria： duplicated articles. LITERATURE EVALUATION： This study included 21 articles of experimental studies and conference reports. DATA SYNTHESIS： When performing interventional surgery in SICAS patients, it is important to understand cerebral perfusion and vascular reserve in addition to knowing the clinical symptoms and degrees of arterial stenosis. In recent years, there are a growing number of reports on measurements of vascular reserve through the use of magnetic resonance perfusion imaging （MR-PWI）. Investigations demonstrate cerebral perfusion and vascular reserve decrease in many SICAS patients. Many studies show that both improve after surgical intervention. CONCLUSION： Cerebral perfusion could provide direct evidence of whether ischemia has occurred in the brain. Because of lateral circulation and cerebral vascular reserve, intracranial vascular stenosis and/or decreased intracranial vascular blood-flow does not suggest decreased perfusion to the blood-supply region. It is important to understand the cerebral perfusion and vascular reserve before performing interventional surgery in SICAS patients.

Matrix metalloproteinase 9 level as an indicator for restenosis following cervical and intracranial angioplasty and stenting

Cervical and intracranial angioplasty and stenting is an effective and safe method of reducing the risk of ischemic stroke, but it may be affected by in-stent restenosis. The present study in-vestigated serum level of matrix metalloproteinase 9 as a predictor of restenosis after 40 patients underwent cervical and/or intracranial angioplasty and stenting. Results showed that resteno-sis occurred in 30% （3/10） of patients when the serum level of matrix metalloproteinase 9 at 3 days after surgery was 2.5 times higher than preoperative level. No restenosis occurred when the serum level of matrix metalloproteinase 9 at 3 days after surgery was not 2.5 times higher than preoperative level. Restenosis occurred in 12% （2/17） of patients when the serum level of matrix metalloproteinase 9 was higher than preoperative level for more than 30 days after surgery, but only occurred in 4% （1/23） of patients when the serum level of matrix metalloproteinase 9 was higher than preoperative level for less than 30 days after surgery. However, the differences observed were not statistically signiifcant （P 〉 0.05）. Experimental ifndings indicate that when the serum level of matrix metalloproteinase 9 is 2.5 times higher than preoperative level at 3 days after cervi-cal and intracranial angioplasty and stenting, it may serve as a predictor of in-stent restenosis.

Effects of cilostazol on the progression and regression of symptomatic intracranial artery stenosis:it reduces the risk of ischemic stroke

OBJeCTIve：To assess the efifcacy and safety of cilostazol on the progression and regression of symptomatic intracranial artery stenosis. DATA ReTRIvAL： We searched the main databases for eligible trials including Medline （from 1966 to June 2014）, Embase （from 1980 to June 2014）, Cochrane Library （Issue 6, 2014）, Chinese National Knowledge Infrastructure （from 1995 to June 2014）, Current Controlled Trials （http：//controlled-trials.com）, Clinical Trials.gov （http：//clinicaltrials.gov）, and Chinese Clinical Trial Registry （http：//www.chictr.org）. All studies regarding prevention and treatment of symptomatic intracranial arterial stenosis by cilostazol were collected. The Mesh or text keywords were the En-glish words： “cilostazol, phosphodiesterase 3 inhibitor, atherosclerosis, and ischemic stroke.” No restrictions were put on publications or publication language. SeLeCTION CRITeRIA：Grade A or B randomized controlled trials were selected according to the quality of evaluation criteria from the Cochrane Collaboration, in which cilostazol and aspi-rin were used to evaluate the effects of cilostazol in the treatment of patients with symptomatic intracranial artery stenosis. The quality of study methodology was evaluated based on criteria de-scribed in Cochrane Reviewer’s Handbook 5.0.1. RevMan 5.2 software was used for data analysis. MAIN OUTCOMe MeASUReS： Clinical efifcacy and safety of cilostazol in stopping progression and promoting regression of symptomatic intracranial artery stenosis were measured by magnet-ic resonance angiography and transcranial Doppler. ReSULTS：Two randomized controlled trials with a total of 203 patients were included in this study. The results showed that while cilostazol was associated with a significantly reduced progression of intracranial artery stenosis （OR = 0.21, 95%CI： 0.09–0.47,P 〈 0.01）, it had no beneifcial effect on symptom regression （OR = 1.42, 95%CI： 0.80–2.51,P = 0.24）. During the follow-up period, although some adverse effects developed, including headache, gastrointestinal disturbance, and dizziness, incidences of bleeding were lower than in aspirin-treated patients. CONCLUSION：Cilostazol may prevent the progression of symptomatic intracranial artery ste-nosis, which could reduce the incidence of ischemic stroke.

Stenting of Intracranial Artery Stenosis:Complications and Management

Background and Purpose Symptomatic intracranial artery stenosis is a high-risk factor of ipsilateral ischemic stroke. Angioplasty with stent has been introduced to treat patients with transient ischemic attack (TIA) and minor stroke attributed to intracranial stenosis since 1996. However, procedure-related neurological complications, either ischemic or hemorrhagic, could result in stroke and death, and benefits of stenting might be offset by higher disable stroke and death. So, the neurovascular angioplasty team should make great efforts to control procedural complications below an acceptable level, such as 10%, because it is impossible to avoid complication absolutely. The team should also be able to recognize, analyze and manage various procedure-related complications, to reduce the risk of disable stroke and death. The purposes of this article were to report our experiences of 20 complications, which occurred during the period of periprocedure.Methods Between September 5, 2001 and August 12, 2004, a total of 155 patients with 170 symptomatic intracranial stenoses of ≥ 50% received intracranial stenting. The management strategies for complication were as follow: ① intra-thrombus urokinase thrombolysis through micro-catheter for acute or subacute occlusion. ② another stenting for dissection. ③ antiplatelet and anticoagulation therapy for penetrator events. ④ continuing nimodipine intravenously for vasospasm. ⑤ to control blood pressure below 110 / 70 mm Hg, to neutralize heparin with protamine sulfate and to discontinue antithrombotic agents, etc, for intracranial hemorrhage. Disable stroke was defined as one that led to a modified Rankin scale (mRS) score of ≥2, 30 days after stroke. Results Procedure -related neurological complications occurred in 20 patients (12.9%, 20/ 155) and 20 lesions (11.7%, 20/ 170), including 6 intracranial hemorrhage (symptomatic, n=4; asymptomatic, n=2), 13 ischemic cerebral events (stroke, n=12; transient ischemic attacks, n=1) and 1 asymptomatic dissection. The probable causes, managements and outcomes of 20 complications are shown in table. Finally, by the means of aggressive endovascular and medical therapies, disable stroke and death within 30 days was 3.2% (5/155) and 1.3% (2/155), respectively. Conclusions Higher risk of procedure-related neurological complications may occur in stenting of intracranial stenosis. To reduce the possibility of disable stroke and death within 30 days, it is mandatory to develop strict procedural and periprocedural management strategies.

Clinical usefulness of ankle brachial index and brachial-ankle pulse wave velocity in patients with ischemic stroke

Ankle brachial index （ABI） and brachial-ankle pulse wave velocity （baPWV） are widely used noninvasive modalities to evaluate atherosclerosis. Recently, evidence has increased supporting the use of ABI and baPWV as markers of cerebrovascular disease. This study sought to examine the relationship between ABI and baPWV with ischemic stroke. This study also aimed to determine which pathogenic mechanism, large artery disease （LAD） or small vessel disease （SVD）, is related to ABI or baPWV. Retrospectively, 121 patients with ischemic stroke and 38 subjects with no obvious ischemic stroke history were recruited. First, ABI and baPWV were compared between the groups. Then, within the stroke group, the relevance of ABI and baPWV with regard to SVD and LAD, which were classified by brain magnetic resonance image （MRI） and magnetic resonance angiography （MRA） or computed tomography angiography （CTA） findings, was assessed. The baPWV was higher in the stroke group than non-stroke group （1,944.18±416.6 cm/s vs. 1,749.76±669.6 crn/s, P 〈 0.01）. Regarding LAD, we found that mean ABI value was lower in the group with extracranial large artery stenosis （P 〈 0.01）, and there was an inverse linear correlation between ABI and the grade of extracranial large artery stenosis （P〈 0.01）. For SVD, there was a significant correlation between SVD and baPWV （2,057.6±456.57 cm/s in the SVD （＋） group vs. 1,491±271.62 cm/s in the SVD （-） group; P 〈 0.01）. However, the grade of abnormalities detected in SVD did not correlate linearly with baPWV. These findings show that baPWV is a reliable surrogate marker ofischemic stroke. Furthermore, baPWVand ABI can be used to indicate the presence of small vessel disease and large arterial disease, respectively.

An elevated platelet-to-lymphocyte ratio is associated with a higher risk of intracranial atherosclerotic stenosis

Background:Previous studies have shown that inflammation plays an important role in intracranial atherosclerotic stenosis(ICAS).The platelet-to-lymphocyte ratio(PLR)has recently emerged as a potential inflammatory biomarker.This study aimed to explore the association of the PLR with ICAS in a Chinese Han population.Methods:A total of 2134 participants(518 with ICAS,1616 without ICAS)were enrolled in this study.ICAS was defined as atherosclerotic stenosis>50%or the occlusion of several main intracranial arteries.Multivariable logistic regression analyses were used to assess the association of the PLR with ICAS.Additional subgroup analyses were performed according to age(<60 vs.≥60 years)and acute ischemic stroke.Results:Multivariate regression analysis showed that a high PLR was associated with a higher risk of ICAS in all participants(P<0.001).Compared with the lowest quartile,the fourth PLR quartile was significantly associated with ICAS(OR 1.705,95%confidence interval 1.278–2.275,P<0.001).In the subgroups stratified by age,an association between the PLR and ICAS was found in the late-life group(P<0.001),but not in the mid-life group(P=0.650).In the subgroups stratified by acute ischemic stroke,the relationship between an elevated PLR and a higher risk of ICAS remained unchanged(stroke group,P<0.001;non-stroke group,P=0.027).Conclusions:An elevated PLR was associated with a higher risk of ICAS in a Chinese Han population.The PLR might serve as a potential biomarker for ICAS in the elderly population.

Endovascular treatment of acute M1 occlusions due to underlying intracranial atherosclerotic severe stenosis

Background:Endovascular treatment(EVT)for acute ischemic stroke with an occlusion of the M1 segment due to intracranial atherosclerotic severe stenosis(ICASS)remains challenging.This study aimed to evaluate the safety and efficacy of EVT for ICASS-related M1 acute occlusion.Methods:We retrospectively reviewed all patients with an ICASS-related M1 acute occlusion who underwent EVT at our institution between January 2015 and December 2020.Clinical presentation,baseline characteristics,angiographic and clinical results,technical feasibility,perioperative complications,and follow-up results were evaluated.Results:Twenty-two patients with ICASS-related M1 acute occlusion were included.Eight patients(36.4%)received bridging therapy,and the other 14 patients(63.6%)directly underwent EVT.Fifteen patients(68.2%)treated with balloon dilations and stenting as rescue treatment.Six patients(27.3%)received single balloon angioplasty,and 5 of these patients were treated with staged stenting.One case(4.5%)failed recanalization at the first EVT,and successful revascularization was achieved a month later.The mean procedure time was 67.2±20.8 min.Successful revascularization(mTICI≥2b)was achieved in 95.5%(21/22)of patients.Perioperative complications developed in two patients(9.1%)including one hemorrhagic event and one thromboembolic event.Angiographic follow-up was available in 20 patients(90.9%)at an average of 8.6±3.0 months.The degree of stenosis was worse(10-30%)in 6 cases(30%)compared with the initial outcomes.The favorable outcomes(mRS≤2)at 3-month follow-up was achieved in 19 patients(86.4%).Conclusions:ICASS-related occlusion in the M1 segment often required a rescue therapy including balloon angioplasty with/without stenting,and this treatment strategy was safe and effective.But single balloon angioplasty at the first EVT generally cannot achieve satisfactory results and often needed staged stenting treatment.

Multiple factor analysis of symptomatic intracranial arterial stenosis

Objective: To discuss the correlation among intracranial arterial stenosis and its risk factors. Methods: A total of 486 patients with transient ischemic attack(TIA) or ischemic cerebral infarction were examined using color doppler flow imaging(CDFI) and transcranial doppler ultrosonography(TCD). According to the degrees of extracranial arterial stenosis, patients with mild-to-moderate extracranial stenosis were classified into group A(435 cases) while those with constant severe stenosis or occlusion were classified into group B(51 cases). The differences between the two groups of risk factors were compared, and the multi-factor logistic regression analysis of risk factors associated with moderately severe intracranial arterial stenosis was performed. Results:(1) The risk factors that were significantly associated with intracranial arterial stenosis included age(P = 0.034) and gender(P = 0.044).(2) Intracranial artery stenosis was observed in both anterior and posterior cerebral arteries in patients with hypertension, diabetes, and coronary heart disease respectively(P < 0.05).(3) Compared with group A, patients in group B were older(P = 0.000), with a higher proportion of men(P = 0.037), and the intracranial arterial stenosis degrees were significantly higher(P = 0.013).(4) Multi-factor logistic regression analysis showed that diabetes is a risk factor for moderately severe intracranial arterial stenosis(P < 0.05), and hyperlipidemia is a protective factor(P = 0.012). Conclusions: Age, gender, hypertension, diabetes, coronary heart disease, and smoking are risk factors for the distribution of intracranial arterial stenosis. The degrees of intracranial arterial stenosis are related with extracranial arterial stenosis. Diabetes is a risk factor for moderately severe intracranial arterial stenosis while hyperlipidemia is a protective factor.

Fabrication of Intracranial Vascular Nitinol Alloy Stents with Improved Mechanical Property and Endothelialization Function

Intracranial vascular stenting has been widely used for ischemic stroke.However,there are complication risks with stent implantation,such as poor wall apposition,stent migration,thromboembolism and stent restenosis,due to the mismatched radial force and conformability of the stents."Therefore,a novel intracranial vascular nitinol stent was fabricated in order to improve mechanical property and endothelialization function.The bending moment of the stents was calculated to be 0.346 N mm,which shows improved conformability.The radial force of the stents evaluated by the flat plate test was0.0112 N/mm,within the range of the commercially available stent force(0.0065-0.0116 N/mm).Furthermore,the TyrIle-Gly-Ser-Arg(YIGSR)peptide derived from laminin was grafted onto the stent surfaces to promote endothelialization on vascular stents evaluated by the proliferation,adhesion and migration of human umbilical vein endothelial cells in vitro.The nitinol stents with improved mechanical property and endothelialization function are expected to reduce the recurrence risk of ischemic stroke after implantation.