CircSKA3 is Associated With the Risk of Extracranial Artery Stenosis and Plaque Instability Among Ischemic Stroke Patients.

Circular RNA circSKA3 (spindle and kinetochore-related complex subunit 3) has been identified as a prognostic factor in ischemic stroke. The objective of this study was to investigate the association of circSKA3 with the risk of extracranial artery stenosis (ECAS) and plaque instability in patients with ischemic stroke. We constructed a competing endogenous RNA (ceRNA) network regulated by circSKA3 based on differentially expressed circRNAs and mRNAs between five patients and five controls. Gene Ontology (GO) analysis was performed on the 65 mRNAs within the network, revealing their primary involvement in inflammatory biological processes. A total of 284 ischemic stroke patients who underwent various imaging examinations were included for further analyses. Each 1 standard deviation increase in the log-transformed blood circSKA3 level was associated with a 56.3% increased risk of ECAS (P = 0.005) and a 142.1% increased risk of plaque instability (P = 0.005). Patients in the top tertile of circSKA3 had a 2.418-fold (P < 0.05) risk of ECAS compared to the reference group (P for trend = 0.02). CircSKA3 demonstrated a significant but limited ability to discriminate the presence of ECAS (AUC = 0.594, P = 0.015) and unstable carotid plaques (AUC = 0.647, P = 0.034). CircSKA3 improved the reclassification power for ECAS (NRI: 9.86%, P = 0.012; IDI: 2.97%, P = 0.007) and plaque instability (NRI: 36.73%, P = 0.008; IDI: 7.05%, P = 0.04) beyond conventional risk factors. CircSKA3 played an important role in the pathogenesis of ischemic stroke by influencing inflammatory biological processes. Increased circSKA3 was positively associated with the risk of ECAS and plaque instability among ischemic stroke patients.

Safety of Apixaban Monotherapy for Non-Valvular Atrial Fibrillation-Related Acute Stroke with Intra-/Extracranial Artery Stenosis.

INTRODUCTION: We investigated whether apixaban is safe for the prevention of further adverse events in non-valvular atrial fibrillation (NVAF) patients with intra-/extracranial artery stenosis (Stenosis group) compared with acute large vessel occlusion without intra-/extracranial artery stenosis (No stenosis group). We also examined whether combination therapy using apixaban and antiplatelet is safe. METHODS: ALVO (Apixaban on clinical outcome of patients with Large Vessel Occlusion [LVO] or stenosis) was a historical and prospective multicenter registry at 38 centers in Japan. Patients with NVAF and acute LVO or stenosis who received apixaban within 14 days after onset were included. We conducted the post hoc analysis using the ALVO dataset. We compared patients with stenosis versus those without stenosis in terms of the primary outcome, which was defined as a composite of all-cause death, major bleeding events, and ischemic events 365 days after onset. RESULTS: Of the 662 patients, 54 (8.2%) patients were classified into the Stenosis group, and 104 patients of the total (16%) reached the primary outcome. The cumulative incidence of primary outcome was not significantly different between the No stenosis and the Stenosis groups (hazard ratio [HR] 1.2, 95% confidence interval [CI]: 0.64-2.4; p = 0.52). Even after adjustment for predictive clinical variates, no significant difference in the primary endpoint between the No stenosis and the Stenosis groups was shown (adjusted HR 1.2, 95% CI: 0.59-2.5; p = 0.60). Fifty patients (7.6%) used an antiplatelet with apixaban. Among the Stenosis group patients, the cumulative incidence of the primary outcome was significantly higher among patients treated with an antiplatelet and apixaban (HR 3.5, 95% CI: 1.0-12; p = 0.048). CONCLUSION: Apixaban monotherapy appears safe for the prevention of further adverse events in the Stenosis group patients similar to the No stenosis group patients. Concomitant use of an antiplatelet might not be favorable in patients with stenosis.

Arterial pre-hypertension and hypertension in intracranial versus extracranial cerebrovascular stenosis.

BACKGROUND AND PURPOSE: Since it has remained unclear whether arterial pre-hypertension is a risk factor for cerebrovascular diseases, potential associations between arterial pre-hypertension and intracranial arterial stenosis (ICAS) and extracranial arterial stenosis (ECAS) were assessed. METHODS: The population-based Asymptomatic Polyvascular Abnormalities in Community Study was a sub-study of employees and retirees of the coal mining industry in China. Our study examined asymptomatic polyvascular abnormalities in a general population and with an age of 40+ years without history of stroke, transient ischaemic attacks and coronary heart disease. ICAS was diagnosed by transcranial Doppler sonography and was defined by peak flow velocity criteria; ECAS was diagnosed by carotid duplex sonography and was defined by the diameter of the common carotid artery or internal carotid artery. RESULTS: Out of 4422 study participants, 711 (16.1%) subjects showed an asymptomatic ICAS and 292 (6.6%) showed an asymptomatic ECAS. After adjusting for relevant risk factors, higher prevalence of ICAS was significantly associated with higher prevalence of pre-hypertension [odds ratio (OR) 1.55; 95% confidence interval (CI) 1.11, 2.16; P = 0.010] and hypertension (OR 1.80; 95% CI 1.53, 2.11; P < 0.001). Stratified by gender, the association was stronger for men than for women. Asymptomatic ECAS was not significantly associated with the prevalence of pre-hypertension (OR 0.78; 95% CI 0.55, 1.10) or of hypertension (OR 1.06; 95% CI 0.91, 1.24). CONCLUSIONS: The results suggest that arterial pre-hypertension in addition to hypertension is associated with a higher prevalence of asymptomatic ICAS, more in men.

Elevated hs-CRP and Symptomatic Intracranial/Extracranial Artery Stenosis Predict Stroke Recurrence after Acute Ischemic Stroke or TIA.

AIM: This study aimed to investigate the relationship between symptomatic or asymptomatic intracranial/extracranial artery stenosis and high-sensitivity C-reactive protein (hs-CRP) levels in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). METHODS: This study included 10404 patients from the Third China National Stroke Registry. Patients were divided into four or six groups according to patterns of intracranial or extracranial artery stenosis and hs-CRP levels. The outcomes were recurrence of ischemic stroke, stroke, and combined vascular events (CVE) at 1 year. The associations between different combinations of hs-CRP levels and patterns of artery stenosis and recurrent events were analyzed by multivariable Cox regression models. RESULTS: Patients in Group III (hs-CRP ＜3＋symptomatic intracranial or extracranial artery stenosis) had higher risk of recurrent ischemic stroke (adjusted hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.20-2.48, p=0.003). Those in Group VI (hs-CRP ≥ 3＋symptomatic intracranial or extracranial artery stenosis) had the highest risk of recurrent ischemic stroke (HR 2.04, 95% CI 1.42-2.92, p=0.0001) within 1 year compared with Group I (hs-CRP ＜3＋no artery stenosis). Asymptomatic intracranial or extracranial artery stenosis did not increase the risk of ischemic events compared with no artery stenosis regardless of hs-CRP levels. CONCLUSION: Symptomatic intracranial or extracranial artery stenosis was associated with increased risk of recurrent ischemic stroke, stroke, and CVE at 1 year in patients with AIS or TIA, especially in patients with elevated hs-CRP levels. Asymptomatic intracranial or extracranial artery stenosis did not increase the risk of ischemic events compared with no artery stenosis regardless of hs-CRP levels.

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.

Movement Disorders Associated With Cerebral Artery Stenosis: A Nationwide Study.

Background: Studies of secondary movement disorder (MD) caused by cerebrovascular diseases have primarily focused on post-stroke MD. However, MD can also result from cerebral artery stenosis (CAS) without clinical manifestations of stroke. In this study, we aimed to investigate the clinical characteristics of MD associated with CAS. Materials and Methods: A nationwide multicenter retrospective analysis was performed based on the data from patients with CAS-associated MDs from 16 MD specialized clinics in South Korea, available between January 1999 and September 2019. CAS was defined as the >50% luminal stenosis of the major cerebral arteries. The association between MD and CAS was determined by MD specialists using pre-defined clinical criteria. The collected clinical information included baseline demographics, features of MD, characteristics of CAS, treatment, and MD outcomes. Statistical analyses were performed to identify factors associated with the MD outcomes. Results: The data from a total of 81 patients with CAS-associated MD were analyzed. The mean age of MD onset was 60.5 ± 19.7 years. Chorea was the most common MD (57%), followed by tremor/limb-shaking, myoclonus, and dystonia. Atherosclerosis was the most common etiology of CAS (78%), with the remaining cases attributed to moyamoya disease (MMD). Relative to patients with atherosclerosis, those with MMD developed MD at a younger age (p < 0.001) and had a more chronic mode of onset (p = 0.001) and less acute ischemic lesion (p = 0.021). Eight patients who underwent surgical treatment for CAS showed positive outcomes. Patients with acute MD onset had a better outcome than those with subacute-to-chronic MD onset (p = 0.008). Conclusions: This study highlights the spectrum of CAS-associated with MD across the country. A progressive, age-dependent functional neuronal modulation in the basal ganglia due to CAS may underlie this condition.

Diagnostic yield of TOF-MRA for detecting incidental vascular lesions in patients with cognitive impairment: An observational cohort study.

Objectives: The role of three-dimensional (3D) TOF-MRA in patients with cognitive impairment is not well established. We evaluated the diagnostic yield of 3D TOF-MRA for detecting incidental extra- or intracranial artery stenosis and intracranial aneurysm in this patient group. Methods: This retrospective study included patients with cognitive impairment undergoing our brain MRI protocol from January 2013 to February 2020. The diagnostic yield of TOF-MRA for detecting incidental vascular lesions was calculated. Patients with positive TOF-MRA results were reviewed to find whether additional treatment was performed. Logistic regression analysis was conducted to identify the clinical risk factors for positive TOF-MRA findings. Results: In total, 1,753 patients (mean age, 70.2 ± 10.6 years; 1,044 women) were included; 199 intracranial aneurysms were detected among 162 patients (9.2%, 162/1,753). A 3D TOF-MRA revealed significant artery stenoses (>50% stenosis) in 162 patients (9.2%, 162/1,753). The overall diagnostic yield of TOF-MRA was 16.8% (294/1,753). Among them, 92 patients (31.3%, 92/294) underwent either medical therapy, endovascular intervention, or surgery. In total, eighty-one patients with stenosis were prescribed with either antiplatelet medications or lipid-lowering agent. In total, fifteen patients (aneurysm: 11 patients, stenosis: 4 patients) were further treated with endovascular intervention or surgery. Thus, the "number needed to scan" was 19 for identifying one patient requiring treatment. Multivariate logistic regression analysis showed that being female (odds ratio [OR] 2.05) and old age (OR 1.04) were the independent risk factors for intracranial aneurysm; being male (OR 1.52), old age (OR 1.06), hypertension (OR 1.78), and ischemic heart disease history (OR 2.65) were the independent risk factors for significant artery stenosis. Conclusions: Our study demonstrated the potential benefit of 3D TOF-MRA, given that it showed high diagnostic yield for detecting vascular lesions in patients with cognitive impairment and the considerable number of these lesions required further treatment. A 3D TOF-MRA may be included in the routine MR protocol for the work-up of this patient population, especially in older patients and patients with vascular risk factors.

The relationship between severe extracranial artery stenosis or occlusion and cerebral small vessel disease in patients with large artery atherosclerotic cerebral infarction.

Background and purpose: Extracranial artery stenosis (ECAS) is associated with the presence of individual markers of cerebral small vessel disease (CSVD). Here, we investigated the relationship between severe extracranial artery stenosis or occlusion and CSVD in patients with large artery atherosclerotic (LAA) cerebral infarction. Methods: A total of 128 patients with LAA cerebral infarction who met our specific inclusion criteria were selected, including 92 males and 36 females. These patients were divided into three groups based on whether they had severe symptomatic extracranial arterial stenosis or occlusion, severe asymptomatic extracranial artery stenosis or occlusion, or severe extracranial artery stenosis or occlusion (both symptomatic and asymptomatic). Intra-group comparisons were then performed to examine whether there were any differences in the total CSVD scores and Fazekas scores. Results: Patients with severe extracranial arterial stenosis or occlusion and those with severe asymptomatic extracranial arterial stenosis or occlusion had a significantly higher total CSVD score (P < 0.05), but there were no significant differences between the groups in terms of Fazekas scores. Furthermore, there were no significant difference in the total CSVD scores and Fazekas scores when compared between patients with or without severe symptomatic extracranial arterial stenosis or occlusion. Conclusion: Severe stenosis or occlusion of the contralateral extracranial artery may increase the incidence of CSVD in patients with LAA cerebral infarction. Active and effective clinical intervention following comprehensive evaluation should be undertaken for unilateral cerebral infarction patients with severe stenosis or occlusion of the contralateral extracranial arterial.

Association of triglyceride-glucose index with intra- and extra-cranial arterial stenosis: a combined cross-sectional and longitudinal analysis.

PURPOSE: This study aimed to assess the cross-sectional and longitudinal associations of the triglyceride glucose (TyG) index, a simple surrogate marker of insulin resistance, with intra-cranial and extra-cranial artery stenosis (ICAS and ECAS) in Chinese adults. METHODS: Participants were recruited from the Asymptomatic Polyvascular Abnormalities Community study, 5381 participants were enrolled in the cross-sectional analysis, then 3447 and 1853 participants in the longitudinal analysis for incident ICAS and ECAS, respectively. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Multivariable logistic analysis was used to calculate odds ratio (OR) and 95% confidence interval (CI). RESULTS: The results of the cross-sectional and longitudinal analysis were basically the same, as the fully adjusted OR comparing participants in the highest tertile versus lowest tertile of the TyG index was 1.34 (95% CI, 1.13-1.59) for the prevalence of ECAS and 1.85 (95% CI, 1.26-2.71) for incident ECAS, respectively. The addition of TyG index to a conventional model had an incremental effect on the predictive value for ECAS. However, we did not observe any significant association between the TyG index and ICAS. CONCLUSIONS: Elevated TyG index was significantly associated with a higher risk of ECAS, but not with ICAS in Chinese adults. This conclusion lends support to the clinical significance of the TyG index for the assessment of artery stenosis, especially for ECAS.

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 cm/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 of ischemic stroke. Furthermore, baPWV and ABI can be used to indicate the presence of small vessel disease and large arterial disease, respectively.