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Background PI3K-Akt signaling was proved to be closely related to atherosclerosis, in which hypertension is an important risk factor for atherosclerosis. Studies have shown that genetic susceptibility is vital in the etiology of symptomatic intracranial atherosclerotic stenosis (sICAS), but few candidate genes were identified. This research explores latent connections between single nucleotide polymorphisms (SNPs) of PI3K-Akt related genes and sICAS with hypertension in Han Chinese subjects. Methods Eight genes related to the PI3K-Akt pathway in 400 sICAS patients and 1007 healthy controls of Han nationality were sequenced, and further subgroup analysis based on hypertension was carried out. Chi-squared testing and multiple logistic regression in dominant, recessive, and additive models were used to evaluate the association between SNPs and risk of sICAS with hypertension. When linkage disequilibrium exists in different loci of the same gene, tagSNP represents the SNP in haplotype block. Results There were 4 common variants of 1 candidate gene differently distributed between sICAS with or without hypertension. Among these four common variations, INSR rs3745551 was significantly related to the risk of sICAS with hypertension after multiple regression analysis, with the T allele being more prevalent in the sICAS with hypertension. Conclusion The variant of the INSR rs3745551 loci may be crucial in the pathogenesis of sICAS with hypertension in Chinese Han populations. Furthermore, the C allele at this locus may be a potentially harmful variant in sICAS with hypertension.

Yunfang Luo,1,* Fang Yu,1,* Xianjing Feng,1 Di Liao,1 Yuanlin Ying,1 Xi Li,1 Qin Huang,1 Zeyu Liu,1 Minping Wei,1 Tingting Zhao,1 Lin Zhang,1 Ruxin Tu,1 Jian Xia1– 3 1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, Hunan, People’s Republic of China; 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian XiaDepartment of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of ChinaTel +86 731 84327216Fax +86 731 84327401. Email xjian1216@csu.edu.cnPurpose: Previous studies have shown a rising incidence of early-onset symptomatic intracranial atherosclerosis (sICAS), which has brought a severe economic burden to social development. This study aimed to evaluate the molecular biomarkers associated with early-onset sICAS and to seek possible intervention strategies for early prevention.Patients and Methods: We consecutively recruited patients with sICAS and divided them into two groups based on age: early-onset sICAS group as age ≤ 60 years old and late-onset sICAS group as age > 60 years old. We collected and compared the demographic data and laboratory results of each group. A bivariate logistic regression model was applied to evaluate the independent molecular biomarkers of early-onset sICAS.Results: A total of 1007 subjects with sICAS were enrolled in this study, comprising 519 patients in the early-onset sICAS group and 488 patients in the late-onset sICAS group. Bivariate logistic regression analysis demonstrated an increased level of white blood cell, platelet, albumin globulin ratio, free triiodothyronine, and a decreased level of total bile acid, urea nitrogen, high-density lipoprotein, homocysteine, and fibrinogen in the early-onset sICAS group when compared to the late-onset group.Conclusion: Our study showed the relevance between early sICAS and circulating levels of different molecular biomarkers. Detection of these related molecular biomarkers may provide a simple way for early sICAS preventions in the future.Keywords: ischemic stroke, symptomatic intracranial atherosclerosis, molecular biomarkers

Purpose: The aim of this study was screening for single nucleotide polymorphisms (SNPs) associated with white matter hyperintensities (WMHs) in symptomatic intracranial atherosclerotic stenosis (sICAS) patients and exploring a possible connection in the genetic background between macrovascular disease and small vessel disease. Methods: There were 400 sICAS patients enrolled in the study. Fazekas scores were applied to WMH classification. Healthy controls were referred to 1,000 Genome Project and GeneSky company who provided 1,007 Chinese healthy controls. Fast target sequencing technology was used to select the SNPs of 102 genes related to the pathogenesis of sICAS in the sICAS patients. Results: The allele frequencies of 88 SNPs were significantly different between the sICAS group and the healthy controls (p < 0.05). The allele frequencies of 53 SNPs were significantly different between the sICAS patients with and without WMHs (p < 0.05). Further analysis found that matrix metalloproteinase 9 (MMP9) rs17576 was simultaneously related to sICAS and WMHs. The frequency of the rs17576 A allele was significantly lower in sICAS patients when compared to the normal controls (p = 0.03, OR [95% CI] = 0.75 [0.625–0.91]). Also, the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.009), dominant (p = 0.014), and recessive (p= 0.023) models. The frequency of the rs17576 A allele was significantly higher in sICAS with WMH patients, compared to those without WMHs (p = 0.022, OR [95% CI] = 1.54 [1.06–2.22]); the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.019) and recessive (p = 0.032) models. Logistic regression analysis showed that age, hypertension, and MMP9 rs17576 AA genotype were independent risk factors for sICAS with WMHs. Conclusion: MMP9 rs17576 may be simultaneously associated with the risk of sICAS and WMHs.

Background: The contribution of metabolic profile to the cerebral collateral circulation in acute ischemic stroke (AIS) has not been fully outlined. In this study, we conducted a metabolomic study to assess the relationship between the metabolic biomarkers and the collateral status of AIS.Methods: A two-stage study was conducted from September 2019 to June 2021 in our hospital. There were 96 subjects including 66 patients with AIS and 30 healthy controls in the discovery stage and 80 subjects including 53 patients with AIS and 27 healthy controls in the validation stage. Collateral circulation was assessed by the Tan score based on computed tomographic angiography (CTA). Liquid chromatography-tandem mass spectrometry was used to identify differential metabolic markers. Then, an ELISA was employed to detect the plasma levels of sphingosine-1-phosphate (S1P).Results:There were 114 differential metabolites between patients with AIS and control groups and 37 differential metabolites between good collateral circulation (GCC) and poor collateral circulation (PCC) groups. The pathway enrichment analysis revealed that arginine biosynthesis was the only statistically significant pathway between AIS and control groups and sphingolipid metabolism was the only statistically significant pathway between GCC and PCC groups. The differential metabolites sphinganine-1-phosphate (SA1P) and S1P belong to the sphingolipid metabolism. In the discovery stage, when the GCC group was compared with the PCC group, the receiver operating characteristic (ROC) analysis showed that plasma SA1P relative levels demonstrated an area under the curve (AUC) of 0.719 (95% CI: 0.582–0.834), and S1P levels demonstrated an AUC of 0.701 (95% CI: 0.567–0.819). In addition, both plasma SA1P and S1P relative levels showed significant negative correlations with the 90-day modified Rankin Scale (mRS) score. In the validation sample, higher plasma S1P levels were independent predictors of GCC (p = 0.014), and plasma S1P levels demonstrated an AUC of 0.738 (95% CI: 0.599–0.849) to differentiate patients with GCC from patients with PCC. In addition, plasma S1P levels also showed significant negative correlations with the 90-day mRS score.Conclusion: We first illustrated the association between plasma metabolic profiles and cerebral collateral circulation in patients with AIS. Plasma S1P levels might be a potential diagnostic biomarker for predicting collateral circulation status in patients with AIS.

Background: Bilirubin plays a paradoxical role in the pathological mechanism of stroke. To date, few clinical studies have investigated the effect of serum bilirubin on symptomatic intracranial atherosclerotic stenosis (sICAS). This study aims to evaluate the connection between serum bilirubin and sICAS.Methods: From September 2015 to May 2020, 1,156 sICAS patients without hepatobiliary diseases admitted to our hospital were included. Patients were distributed into none-mild (0–49%), moderate (50–69%) and severe-occlusion sICAS groups (70–100%) by the degree of artery stenosis. Moderate and severe-occlusion sICAS patients were classified into three groups by the number of stenotic arteries (single-, two- and multiple-vessel stenosis). The relationship between serum bilirubin levels and sICAS was analyzed by logistic regression analysis.Results: In univariable analyses, sICAS patients with severe and multiple atherosclerotic stenoses had lower levels of total bilirubin (Tbil), direct bilirubin (Dbil), and indirect bilirubin (Ibil). In multinomial logistic regression analyses, when compared with the highest tertile of bilirubin, lower levels of Tbil, Dbil, and Ibil showed higher risks of severe-occlusion sICAS (95% CI: 2.018–6.075 in tertile 1 for Tbil; 2.380–7.410 in tertile 1 for Dbil; 1.758–5.641 in tertile 1 for Ibil). Moreover, the logistic regression analyses showed that lower levels of Tbil, Dbil, and Ibil were related to multiple (≥3) atherosclerotic stenoses (95% CI: 2.365–5.298 in tertile 1 and 2.312–5.208 in tertile 2 for Tbil; 1.743–3.835 in tertile 1 and 1.416–3.144 in tertile 2 for Dbil; 2.361–5.345 in tertile 1 and 1.604–3.545 in tertile 2 for Ibil) when compared with tertile 3.Conclusions: Our findings suggest that lower bilirubin levels may indicate severe and multiple intracranial atherosclerotic stenoses.

Background: Neutrophil-to-lymphocyte ratio (NLR) is an indicator of poor prognosis in acute ischemic stroke (AIS), but associations between NLR with stroke severity and prognosis of intracranial atherosclerotic stenosis (ICAS)-related ischemic events have not been well-elucidated; therefore, we aimed to evaluate whether admission NLR levels correlate with the early stroke severity and short-term functional prognosis in patients with symptomatic intracranial atherosclerotic stenosis (sICAS).Methods: This retrospective study enrolled 899 consecutive patients with AIS attributed to ICAS at Xiangya Hospital stroke center between May 2016 and September 2020. The initial stroke severity was rated by the admission National Institutes of Health Stroke Scale (NIHSS) scores, and the short-term prognosis was evaluated using the 14-day modified Rankin Scale (mRS) scores after stroke onset. A severe stroke was defined as NIHSS >8; an unfavorable functional outcome was defined as mRS scores of 3–6. Admission NLR was determined based on circulating neutrophil and lymphocyte counts.Results: The median admission NLR of all patients was 2.80 [interquartile range (IQR), 2.00–4.00]. In univariate analysis, admission NLR was significantly elevated in patients with severe stroke and poor short-term prognosis. After multivariate adjustment, admission NLR levels were significantly correlated with severe stroke [odds ratio (OR), 1.132; 95% confidence interval (95% CI), 1.038–1.234; P = 0.005] and unfavorable short-term prognosis (OR, 1.102; 95% CI, 1.017–1.195; P = 0.018) in Model 1. In Model 2, the highest NLR tertile (≥3.533) remained an independent predictor of severe stroke (OR, 2.736; 95% CI, 1.590–4.708; P < 0.001) and unfavorable functional outcome (OR, 2.165; 95% CI, 1.416–3.311; P < 0.001) compared with the lowest NLR tertile (P < 0.001] and short-term prognosis (AUC, 0.613; 95% CI, 0.575–0.650; P < 0.001). The nomograms were constructed to create the predictive models of the severity and short-term outcome of sICAS.Conclusions: Elevated admission NLR levels were independently associated with the initial stroke severity and could be an early predictor of severity and poor short-term prognosis in AIS patients with ICAS, which might help us identify a target group timely for preventive therapies.

Background and Objective: Recently, AMP-activated protein kinase (AMPK) signaling was confirmed to be intimately associated with atherosclerosis. Evidence indicates that genetic susceptibility play...

Background: Adipokines have been proven to be associated with atherosclerotic diseases such as ischemic stroke and coronary heart disease. The role of novel adipokines in the development of symptomatic intracranial atherosclerotic stenosis (sICAS) and extracranial atherosclerotic stenosis (sECAS) has not yet been investigated. This study aimed to evaluate the plasma levels of novel adipokines in patients with sICAS and sECAS and their associations with the prognosis of sICAS groups.Methods: A total of 134 patients with acute ischemic stroke attribute to large-artery atherosclerosis (LAA) and 66 age- and sex-matched controls without atherosclerotic stenosis (NCAS) were included in this study. The LAA group was further sub-classified as sICAS (n = 102) and sECAS (n = 32) according to the location of atherosclerosis. Demographics, clinical parameters, angiographical features and plasma levels of novel adipokines (apelin, visfatin, omentin, RBP-4) were assayed and compared among groups.Results: LAA patients had significantly lower levels of omentin [39.92 (30.74–52.61) ng/ml vs. 54.42 (34.73–79.91) ng/ml, P < 0.001] and visfatin [11.32 (7.62–16.44) ng/ml vs. 13.01 (9.46–27.54) ng/ml, P < 0.001] than those in the NCAS group. Multiple logistic regression analysis identified that the lowest tertile of omentin was independently associated with LAA (OR, 3.423; 95% CI, 1.267–9.244, when referenced to the third tertile). Levels of omentin, visfatin and RBP-4 showed no significant difference between sICAS and sECAS groups. However, median concentrations of apelin were lower in sECAS [84.94 (46.88–130.41) ng/mL) than in sICAS [118.64 (93.22–145.08) ng/mL, P = 0.002] and NCAS [114.38 (80.56–162.93) ng/mL, P = 0.004]. Logistic regression analysis showed that the lowermost tertile of apelin was independently associated with sECAS (OR, 5.121; 95% CI, 1.597–16.426) when adjusted for risk factors. As for sICAS patients, spearman coefficient analysis showed no significant correlation between these four adipokines and the severity of sICAS or the number of vessels with intracranial stenoses. Patients with severe stroke had lower levels of apelin (P = 0.005), while the other three adipokines showed no such difference. During follow up, no difference was found between these four novel adipokines and short- and long-term outcome of sICAS.Conclusions: Lower levels of omentin are independent biomarkers of LAA while low apelin plasma levels seem to be risk factors of sECAS.

Background: Genetic factors underlying predisposition to Symptomatic Intracranial Atherosclerotic Stenosis (sICAS) remain unknown, the purpose of the present study was to identify genetic variants that confer susceptibility to sICAS in a Chinese Han population. Methods: The study population comprised of 379 Chinese individuals, including 193 patients with sICAS and 186 unrelated healthy controls. A total of 96 polymorphisms selected by genome-wide association or candidate-gene association studies of atherosclerosis and atherosclerotic diseases were examined in the present study with the use of Illumina VeraCode technology. Statistical analyses were performed with PLINK and SPSS software, and each genotype was assessed according to dominant, recessive, and additive genetic models. Results: Comparisons between subjects with sICAS and controls revealed that rs3798220 of the lipoprotein(a) gene (LPA) and rs9818870 of the muscle RAS oncogene homolog gene (MRAS) were significantly (P0.0005). Conclusion: LPA rs3798220 might be susceptibility loci for sICAS in Chinese Han individuals. Keywords: Symptomatic Intracranial Atherosclerotic Stenosis; risk factors; candidate gene; SNP.

It is uncertain that the effect of free triiodothyronine (FT3) within normal ranges on initial severity and early functional outcomes in acute ischemic stroke (AIS) patients with Intracranial Atherosclerotic Stenosis (ICAS). The predictive values of white blood cell (WBC) and FT3 are also unclear in symptomatic ICAS (sICAS) patients.We consecutively reviewed 848 ischemic stroke patients admitted into Xiangya Hospital within 72 h after symptom onset. sICAS was defined as AIS patient with degree of ICAS ≥50% proved by magnetic resonance angiography, computed tomography angiography or digital subtraction angiography. WBC and FT3 were assessed within 24 h after admission. Neurological severity was evaluated on admission using the National Institutes of Health Stroke Scale (NIHSS). Stroke outcomes were defined by the modified Rankin Scale (mRS) on the 14th day after admission.Logistic regression analysis showed that hypertension, lower FT3 and higher WBC concentrations independently associated with severe stroke [FT3 (odds ratio(OR) = 0.543, 95% confidence interval(95% CI): 0.383-0.769); hypertension (OR = 0.436, 95% CI: 0.238-0.800); WBC (OR = 1.17; 95% CI:1.041-1.316]. Besides, lower FT3, higher FT4, higher WBC and higher plasma glucose concentrations independently associated with unfavorable outcomes [FT3 (OR = 0.460; 95% CI: 0.306-0.690); FT4 (OR = 1.151; 95% CI: 1.055-1.255); WBC (OR = 1.178; 95% CI: 1.039-1.334); Plasma glucose (OR = 1.160; 95% CI: 1.002-1.342)].Lower FT3 levels within normal ranges and higher WBC count are independently associated with the severity and early poor prognosis of sICAS simultaneously, FT3 and WBC count might be important biomarkers for sICAS patients.

The current study was conducted to identify independent predictors of severity and short-term outcome of first-ever ischemic stroke in young adults.We retrospectively enrolled 325 consecutive patients aged 18-49 years with first-ever ischemic stroke admitted to our center between April 2013 and June 2015. Variables were systematically registered and compared between patients with different neurological severity (mild stroke: National Institutes of Health Stroke Scale [NIHSS] ≤ 8 and severe stroke:8) and different stroke outcome (favorable: modified Rankin scale score 0-2 and unfavorable: 3-5 or death) at 14 days after stroke onset.A total of 325 patients fulfilled the inclusion criteria. There were 242 patients with mild stroke. They exhibited lower white blood cell (WBC), globulin, plasma glucose, fibrinogen (Fib) levels and higher albumin, albumin/globulin (A/G), free triiodothyronine (FT3) levels. Logistic regression analysis showed that FT3 (≧3.18) and WBC (≧7.1) were independent predictors. There were 122 patients demonstrating an unfavorable outcome. Higher WBC, globulin, plasma glucose and Fib levels, lower albumin, FT3, A/G levels, higher NIHSS score and longer hospital stay were significantly associated with unfavorable outcome. In the logistic regression model, we found that A/G (≧1.56), FT3 (≧4.09) and WBC (≧7.1) were independent predictors for short-term outcome.Our data suggested that higher A/G, FT3 levels served as independent predictors of favorable outcome, and a higher FT3 value may also predict mild stroke, while higher WBC may predict a poor functional outcome and severe stroke in patients with acute ischemia.