The role of triglyceride-glucose index in the differential diagnosis of atherosclerotic stroke and cardiogenic stroke.

OBJECTIVE: This study aims to investigate the role of the triglyceride glucose (TyG) index in differentiating cardiogenic stroke (CE) from large atherosclerotic stroke (LAA). METHOD: In this retrospective study, patients with acute ischemic stroke were recruited from the First Affiliated Hospital of Soochow University, Lianyungang Second People's Hospital and Lianyungang First People's Hospital. Their general data, medical history and laboratory indicators were collected and TyG index was calculated. Groups were classified by the TyG index quartile to compare the differences between groups. Logistic regression was utilized to assess the relationship between the TyG index and LAA. The receiver operating characteristic curve (ROC) curve was used to evaluate the diagnostic efficiency of the TyG index in differentiating LAA from CE. RESULT: The study recruited 1149 patients. After adjusting for several identified risk factors, groups TyG-Q2, TyG-Q3, and TyG-Q4 had a higher risk of developing LAA compared to group TyG-Q1(odds ratio (OR) = 1.63,95% confidence interval (CI) = 1.11-2.39, OR = 1.72,95%CI = 1.16-2.55, OR = 2.06,95%CI = 1.36-3.09). TyG has certain diagnostic value in distinguishing LAA from CE(AUC = 0.595, 95%CI0.566-0.623;P<0.001). CONCLUSION: Summarily, the TyG index has slight significance in the identification of LAA and CE; it is particularly a marker for their preliminary identification.

Causal relationship between C-reactive protein and ischemic stroke caused by atherosclerosis: A Mendelian randomization study.

OBJECTIVES: This study investigates the association between C-reactive protein (CRP) and ischemic stroke caused by large artery atherosclerosis (LAA). METHODS: Five Mendelian Randomization (MR) methodologies were used for two-sample analyses: Inverse Variance Weighting (IVW), MR-Egger regression, Weighted Median (WM), Simple Mode, and Weighted Mode. CRP exposure data were obtained from aggregated summary statistics from a meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry (n = 343,524; UK Biobank). Stroke data were used as the outcome, with specific dataset details for relevant subtypes (cases = 40,585, controls = 406,111). RESULTS: In the CRP GWAS dataset, selected single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) showed genome-wide significance and a causal relationship with CRP, particularly in relation to LAA stroke. IVW indicated a robust causal connection between CRP and LAA stroke (Beta = 0.151, SE = 0.055, P = 0.006). The WM approach supported this relationship (Beta = 0.176, SE = 0.082, P = 0.033). However, MR-Egger regression suggested a potential absence of a causal link (Beta = 0.098, SE = 0.077, P = 0.206), with minimal influence from horizontal pleiotropy (Intercept = 0.0029; P = 0.317). The Simple mode found no significant association (Beta = 0.046, SE = 0.217, P = 0.834), while the Weighted mode revealed a significant causal association (Beta = 0.138, SE = 0.059, P = 0.020) between CRP and LAA stroke. CONCLUSIONS: MR analysis provides evidence for a potential causal relationship between CRP and an increased risk of LAA stroke.

Short-term glycemic variability and intracranial atherosclerotic plaque stability assessed by high-resolution MR vessel wall imaging in type 2 diabetes mellitus.

OBJECTIVE: To investigate the relationship between short-term glycemic variability in patients with T2DM and the vulnerability of intracranial atherosclerotic plaques using HR-MR-VWI. MATERIALS AND METHODS: In total, 203 patients with acute ischemic stroke (AIS)/transient ischemia (TIA) combined with T2DM were enrolled. All of them underwent HR-MR-VWI during the period between July 2020 and July 2023. 203 patients were divided into groups with higher (1,5-AG≤ 30.7 µmol/L) and lower (1,5-AG> 30.7 µmol/L) short-term glycemic variability. Patients were also divided into the T1WI and non-T1WI hyperintensity groups. Associated factors(FBG, HbA1c, and 1,5-AG)for the T1WI hyperintensity were analyzed by binary logistic regression. We used the area under the curve (AUC), while the sensitivity and specificity were calculated at the optimal threshold. The Delong test was employed to compare the quality of the AUC of the predictors. RESULTS: The group with higher short-term glycemic variability had a higher incidence of the hyperintensity on T1WI, higher degree of enhancement, higher degree of stenosis and smaller lumen area (P < 0.05). The T1WI hyperintensity group had higher HbA1c levels, higher hemoglobin levels and lower 1,5-AG levels(P < 0.05). 1,5-AG (OR = 0.971, 95 % CI: 0.954∼0.988, P = 0.001), HbA1c (OR=1.305, 95 % CI: 1.065∼1.598, P = 0.01) and male sex (OR = 2.048, 95 % CI: 1.016∼4.128, P = 0.045)/(OR=2.102, 95 % CI: 1.058∼4.177, P = 0.034) were independent risk factors for the hyperintensity on T1WI. 1,5-AG demonstrated enhanced performance and yielded the highest AUC of the receiver operator characteristic curve (AUC = 0.726), with sensitivity and specificity values of 0.727 and 0.635 respectively. CONCLUSION: 1,5-AG, HbA1c and male sex are independent predictors of intracranial plaques with T1WI hyperintensity, the greater short-term glycemic variability, the higher incidence of vulnerable plaques.

Association of albumin levels with the risk of intracranial atherosclerosis.

OBJECTIVE: Intracranial artery stenosis from atherosclerosis is one of the etiologies of ischemic stroke. There is a correlation between serum albumin level and atherosclerosis. We aimed to investigate whether serum albumin level is related to intracranial atherosclerosis and its significance. METHODS: A retrospective analysis of 150 individuals who underwent cervical cerebral angiography after admission, including clinical data, imaging data, and laboratory data. Since atherosclerosis cannot be used as a good quantitative indicator, we choose the degree of arterial stenosis to reflect atherosclerosis. SPSS 24 software was used for data analysis, and P < .05 was considered statistically significant. RESULTS: Univariate analysis showed that age, diabetes, and serum albumin level were risk factors for intracranial atherosclerosis (P < .05). Multivariate analysis showed that diabetes and serum albumin levels were independent risk factors for intracranial atherosclerosis (P< 0.05). The average serum albumin level in the non-severe group was 39.80 g/L, and the average serum albumin level in the severe group was 37.60 g/L. The area under the ROC curve of serum albumin was 0.667 (95%CI 0.576-0.758, P = .001), the cutoff value was 0.332176, the sensitivity was 75.9%, and the specificity was 57.3%. CONCLUSION: Serum albumin level is an independent risk factor for intracranial atherosclerosis, and provides a new direction for clinical prevention and treatment.

Lipid Levels and Short-Term Risk of Recurrent Brain Infarcts in Symptomatic Intracranial Stenosis.

OBJECTIVES: Hyperlipidemia is a strong risk factor for intracranial atherosclerotic disease (ICAD) and clinical stroke recurrence. We explored the effect of serum lipid levels on subclinical infarct recurrence in the Mechanisms of earlY Recurrence in Intracranial Atherosclerotic Disease (MYRIAD) study. MATERIALS AND METHODS: We included enrolled MYRIAD patients with lipid measurements and brain MRI at baseline and brain MRI at 6-8 weeks. Infarct recurrence was defined as new infarcts in the territory of the symptomatic artery on brain MRI at 6-8 weeks compared to baseline brain MRI. We assessed the association between baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and recurrent infarct at 6-8 weeks using multivariable logistic regression. RESULTS: Among 74 patients (mean age 64.2±12.9 years, 59.5% were white, 60.8% men), 20 (27.0%) had new or recurrent infarcts. Mean HDL-C (37.2 vs. 43.9 mg/dL, P=0.037) was lower and TG (113.5 vs. 91.3 mg/dL, P=0.008) was higher while TC (199.8 vs. 174.3 mg/dL, P=0.061) and LDL-C (124.3 vs. 101.2 mg/dL, P=0.053) were nominally higher among those with recurrent infarcts than those without. LDL-C (adj. OR 1.022, 95% CI 1.004-1.040, P=0.015) and TG (adj. OR 1.009, 95% CI 1.001-1.016, P=0.021) were predictors of recurrent infarct at 6-8 weeks adjusting for other clinical and imaging factors. CONCLUSIONS: Baseline cholesterol markers can predict early infarct recurrence in patients with symptomatic ICAD. More intensive and rapid lipid lowering drugs may be required to reduce risk of early recurrence.

Association of triglyceride-glucose index and high-sensitivity C-reactive protein with asymptomatic intracranial arterial stenosis: A cross-sectional study.

BACKGROUND AND AIMS: Triglyceride-glucose index (TyG) and high-sensitivity C-reactive protein (hsCRP) have been shown to play important roles in the pathophysiological mechanisms of atherogenesis. However, the cumulative value of TyG and hsCRP in identifying asymptomatic intracranial arterial stenosis (aICAS), as well as its severity and numerical burden, is uncertain. This study seeks to fill this knowledge gap. METHODS AND RESULTS: This study included 1938 participants aged ≥40 years who were free of stroke or transient ischemic attack. All participants were classified into four groups based on the participants' TyG and hsCRP levels, including low-TyG and low-hsCRP, low-TyG and high-hsCRP, high-TyG and low-hsCRP, and high-TyG and high-hsCRP groups. The presence of aICAS was screened via transcranial Doppler ultrasound and confirmed by magnetic resonance angiography. The TyG was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. We used multinomial logistic regression analysis to investigate the cumulative value of TyG and hsCRP on identifying the severity of aICAS or its numerical burden. After adjustment for conventional confounders, isolated high-hsCRP, isolated high-TyG, and high-TyG combined with high-hsCRP were independently associated with moderate-to-severe aICAS. Compared with the low-TyG and low-hsCRP group, participants with high-TyG and high-hsCRP had a 2.6 times higher odds ratio (OR) of having a single moderate-to-severe aICAS and a 3.3 times higher OR of having multiple moderate-to-severe aICASs. CONCLUSION: The cumulative value of TyG and hsCRP may better identify moderate-to-severe aICAS as well as its numerical burden.

Plasma Lipid Profiling Contributes to Untangle the Complexity of Moyamoya Arteriopathy.

Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved in MA. Our aim is to evaluate angiogenic/vasculogenic/inflammatory proteins and lipid profile in plasma of MA patients and control subjects (healthy donors HD or subjects with atherosclerotic cerebrovascular disease ACVD). Angiogenic and inflammatory protein levels were measured by ELISA and a complete lipidomic analysis was performed on plasma by mass spectrometry. ELISA showed a significant decrease for MMP-9 released in plasma of MA. The untargeted lipidomic analysis showed a cumulative depletion of lipid asset in plasma of MA as compared to HD. Specifically, a decrease in membrane complex glycosphingolipids peripherally circulating in MA plasma with respect to HD was observed, likely suggestive of cerebral cellular recruitment. The quantitative targeted approach demonstrated an increase in free sphingoid bases, likely associated with a deregulated angiogenesis. Our findings indicate that lipid signature could play a central role in MA and that a detailed biomarker profile may contribute to untangle the complex, and still obscure, pathogenesis of MA.

Association between serum bilirubin and asymptomatic intracranial atherosclerosis: results from a population-based study.

INTRODUCTION: The effects of bilirubin on asymptomatic intracranial atherosclerosis (aICAS) remain uncertain. OBJECTIVES: To investigate the association between bilirubin and aICAS in rural-dwelling Chinese people. METHODS: This population-based study included 2013 participants from the Kongcun Town Study, which aimed to investigate the prevalence of aICAS in people aged ≥ 40 years who were free of stroke and hepatic and gall disease history. Baseline data were collected via interviews, clinical examinations, and laboratory tests. Total bilirubin (Tbil), direct bilirubin (Dbil), and indirect bilirubin (Ibil) levels were divided into high-concentration group and low-concentration group, respectively. We diagnosed aICAS and moderate-to-severe aICAS (m-saICAS) (≥ 50% stenosis) by integrating transcranial Doppler ultrasound with magnetic resonance angiography. The association between bilirubin and aICAS, as well as m-saICAS, was analyzed using logistic regression. RESULTS: Of the 2013 participants, those in the high-concentration group of Tbil (odds ratio (OR), 0.50; 95% confidence interval (CI), 0.42-0.87), Dbil (OR 0.60, 95%CI 0.41-0.87), and Ibil (OR 0.67; 95%CI 0.47-0.97) had a lower risk of aICAS than those in the low-concentration group after adjusting all confounders. The high concentrations of Tbil, Dbil, and Ibil were also negatively associated with m-saICAS. After stratification according to age, Tbil, Dbil, and Ibil were significantly negatively associated with aICAS among participants aged ≥ 60 years. CONCLUSION: Tbil, Dbil, and Ibil might be independent protective factors for aICAS and moderate-to-severe aICAS in rural-dwelling Chinese people, especially among older participants aged ≥ 60 years.

Importance of lipid ratios for predicting intracranial atherosclerotic stenosis.

BACKGROUND: This study aims to investigate the association of lipid ratios with intracranial atherosclerotic stenosis (ICAS) in a Chinese population. METHODS: This cross-sectional study included 658 consecutive patients with ischemic stroke. Intracranial and extracranial arteries were evaluated for atherosclerotic stenosis using digital subtraction angiography or computed tomography angiography. Lipid ratios [total cholesterol (TC)/high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG)/HDL-C, low-density lipoprotein-cholesterol (LDL-C)/HDL-C, non-high-density lipoprotein-cholesterol (non-HDL-C)/HDL-C, remnant cholesterol (RC)/HDL-C, apolipoprotein B (apo B)/apolipoprotein A-I (apo A-I), and apo B/HDL-C] were calculated. RESULTS: The TC/HDL-C, LDL-C/HDL-C, RC/HDL-C, non-HDL-C/HDL-C, apo B/HDL-C and apo B/apo A-I ratios (all P < 0.05) were significantly associated with ICAS but not with extracranial atherosclerotic stenosis after adjustment for confounding factors. Receiver operating characteristic (ROC) curves analysis revealed that the apo B/apo A-I ratio had the largest area under the ROC curve (AUC) among lipid levels alone and for lipid ratios (AUC = 0.588). Lipid ratios had higher AUC values than those for lipid levels alone for the identification of ICAS. CONCLUSION: The TC/HDL-C, LDL-C/HDL-C, RC/HDL-C, non-HDL-C/HDL-C apo B/HDL-C, and apo B/apo A-I ratios were significantly related to ICAS risk. Compared with the other variables tested, the apo B/apo A-I ratio appeared to be a better discriminator for identifying ICAS risk in stroke patients.

Platelet-Rich Emboli in Cerebral Large Vessel Occlusion Are Associated With a Large Artery Atherosclerosis Source.

Background and Purpose- Nearly 30% of large vessel occlusion acute ischemic stroke clots are from an unknown source. We assessed histological clot composition in a series of patients with large vessel occlusion and investigated correlations between clot composition and stroke pathogenesis. Methods- As part of the multi-institutional STRIP registry (Stroke Thromboembolism Registry of Imaging and Pathology), consecutive emboli retrieved during mechanical thrombectomy were stained using Martius Scarlett Blue and analyzed using machine learning software. We assessed proportions of red blood cells, fibrin, platelets, and white blood cells. Correlations between clot components and stroke pathogenesis (large artery atherosclerosis, cardioembolism, and stroke of undetermined pathogenesis) were assessed using SPSS22. Results- One hundred five patients were included. The proportion of platelet-rich clots (55.0% versus 21.2%; P=0.005) and percentage of platelet content (22.1±4.2% versus 13.9±14.2%; P=0.03) was significantly higher in the large artery atherosclerosis group compared with the cardioembolic group. The proportion of platelet-rich clots (50.0% versus 21.2%; P=0.024) was also significantly higher in the cryptogenic group compared with cardioembolic cases. Large artery atherosclerosis and cryptogenic cases had a similar proportion of platelet-rich clots (55.0% versus 50.0%; P=0.636). There was no significant difference between stroke pathogenesis and the other major clot components. Conclusions- High platelet content of emboli is associated with a large artery atherosclerosis etiology of large vessel occlusion.

Plasma miR-126 and miR-143 as Potential Novel Biomarkers for Cerebral Atherosclerosis.

BACKGROUND: Cerebral atherosclerosis is the most important mechanism for ischemic stroke. However, specific plasma biomarkers to assess atherosclerosis susceptibility are still lacking. Circulating miRNAs have been shown to be promising biomarkers for various pathologic conditions. We investigated whether plasma miR-126 and miR-143 could be used as biomarkers for identifying and evaluating cerebral atherosclerosis. Results showed that miR-143 and miR-126 might participate in the process of atherosclerosis and were minimally affected by cerebral infarction. Using Pearson correlation analysis, we showed that miR-126 and miR-143 were correlated with the presence and severity of cerebral atherosclerosis. The ability of miR-126 and miR-143 to differentiate atherosclerosis patients from healthy controls was demonstrated via a receiving operating characteristic curve with high specificity and sensitivity. Our data thus indicate that miR-126 and miR-143 may be potential specific biomarkers for atherosclerosis.

Differential Expression of Vascular Endothelial Growth Factor-A165 Isoforms Between Intracranial Atherosclerosis and Moyamoya Disease.

BACKGROUND: Vascular endothelial growth factor-A165 (VEGF-A165) has been identified as a combination of 2 alternative splice variants: proangiogenic VEGF-A165a and antiangiogenic VEGF-A165b. Intracranial atherosclerotic disease (ICAD) and moyamoya disease (MMD) are 2 main types of intracranial arterial steno-occlusive disorders with distinct capacities for collateral formation. Recent studies indicate that VEGF-A165 regulates collateral growth in ischemia. Therefore, we investigated if there is a distinctive composition of VEGF-A165 isoforms in ICAD and MMD. METHODS: Sixty-six ICAD patients, 6 MMD patients, and 5 controls were enrolled in this prospective study. ICAD and MMD patients received intensive medical management upon enrollment. Surgery was offered to 9 ICAD patients who had recurrent ischemic events, 6 MMD patients, and 5 surgical controls without ICAD. VEGF-A165a and VEGF-A165b plasma levels were measured at baseline, within 1 week after patients having surgery, and at 1, 3, and 6 months after treatment. RESULTS: A significantly higher baseline VEGF-A165a/b ratio was observed in MMD compared to ICAD (P = .016). The VEGF-A165a/b ratio increased significantly and rapidly after surgical treatment in ICAD (P = .026) more so than in MMD and surgical controls. In patients with ICAD receiving intensive medical management, there was also an elevation of the VEGF-A165a/b ratio, but at a slower rate, reaching the peak at 3 months after initiation of treatment (baseline versus 3 months VEGF-A165a/b ratio, P = .028). CONCLUSIONS: Our study shows an increased VEGF-A165a/b ratio in MMD compared to ICAD, and suggests that both intensive medical management and surgical revascularization elevate the VEGF-A165a/b ratio in ICAD patients.

A Preliminary Study of the Association between Apolipoprotein E Promoter Methylation and Atherosclerotic Cerebral Infarction.

AIM: To investigate association of Apolipoprotein E (ApoE) gene promoter methylation with atherosclerotic cerebral infarction (ACI) in the Han Chinese population. METHODS: Twenty-six ACI patients (the case group) and 26 healthy (the control group) were recruited randomly from Henan Han nationality population, from April 2016 to August 2016. Bisulfite pyrosequencing technology was used to examine the role of the aberrant gene promoter methylation in ACI in Han Chinese population. Especially, we used the odds ratio and 95% confidence interval (95% CI) method to elevate the correlation between ApoE Promoter Methylation and ACI. RESULTS: The case group was significantly more likely to have hypertension and carotid atherosclerotic plaques (Table 1). The case group had significantly lower levels of high-density lipoprotein cholesterol (HDL-C), folate, and higher levels of homocysteine (Table 2). We observed that ACI patients (n = 26) had significantly higher methylation levels at cytosine-phosphate-guanine (CpG) 14 and CpG16 compared with controls (n = 26) (Table 3). Importantly, our results indicated a significant association between ApoE promoter methylation and ACI (OR = 16.146; 95% CI, 1.154-225.832; P* < .05; P*: adjusted for age, gender, carotid atherosclerotic plaque, hypertension, HDL-C, homocysteine, and folate) (Table 4). CONCLUSIONS: Our study indicates that ApoE promoter methylation may be associated with ACI in Han Chinese people.

Decreased Antiatherogenic Protein Levels are Associated with Aneurysm Structure Alterations in MR Vessel Wall Imaging.

OBJECTIVE: Thickened intracranial aneurysm wall with atherosclerotic remodeling is a part of its degenerative scenario. Current magnetic resonance (MR)-vessel wall imaging enables the detection of atherosclerotic wall thickening as aneurysm wall enhancement. The purpose of this study was to examine the correlation between identified atherosclerotic remodeling in vessel wall imaging, and systemic atherosclerosis-related risk factors. METHODS: A total of 39 aneurysms in 38 consecutive patients scheduled to undergo microsurgical clipping or endovascular coiling of intracranial aneurysms were prospectively evaluated. All patients underwent aneurysm MR-vessel wall imaging and the presence of aneurysm wall enhancement on contrast-enhanced vessel wall imaging was evaluated. The relationship between aneurysm wall enhancement and patient demographic data, aneurysm morphology and atherosclerosis-related risk factors including blood laboratory data were assessed. RESULTS: Aneurysm wall enhancement was detected in 19 of 39 intracranial aneurysms (48.7%). The maximum diameter of the intracranial aneurysm (P < .01), apolipoprotein A2 (P < .01) and apolipoprotein C2 (P = .01) was significantly associated with the presence of aneurysm wall enhancement. In multivariate logistic regression analyses, the maximum diameter of the intracranial aneurysm (odds ratio: 1.67, 95% confidence interval: 1.17-3.05) and decreased apolipoprotein A2 (odds ratio: 0.62, 95% confidence interval: 0.34-0.97) was significantly correlated with aneurysm wall enhancement. CONCLUSIONS: Rather than atherosclerotic factors, antiatherogenic proteins reduction was associated with aneurysm wall enhancement in vessel wall imaging. To elucidate antiatherogenic factors might to help find out promoting factor of unruptured intracranial aneurysms instability.

Study of the Inflammatory Mechanisms in Hyperhomocysteinemia on Large-Artery Atherosclerosis Based on Hypersensitive C-Reactive Protein-A Study from Southern China.

OBJECTIVE: To study the inflammatory mechanism of hyperhomocysteinemia on large-artery atherosclerosis based on hypersensitive C-reactive protein in patients. METHODS: In all, 153 inpatients and 1357 physical examinees were selected. The levels of homocysteine were compared between the carotid/intracranial artery stenosis group and the nonstenosis group, between the carotid artery unstable plaque group and the nonplaque group, and between the intima-media thickness (IMT) greater than or equal to 1 group and the normal IMT group. The hypersensitive C-reactive protein levels were compared between the lacunar infarction (LI) group and the nonstroke control group and between the unstable plaque group and the nonplaque group. RESULTS: Homocysteine level was significantly higher in the carotid/intracranial artery stenosis group than in the nonstenosis group, in the LI group than in the inpatient nonstroke group, and in the IMT greater than or equal to 1 group than in the normal IMT group. The hypersensitive C-reactive protein level was significantly higher in the LI group than in the nonstroke group and in the unstable plaque group than in the nonplaque group. CONCLUSIONS: Hyperhomocysteinemia may aggravate the development of IMT, carotid atherosclerotic plaque instability, and carotid/intracranial artery stenosis by increasing inflammation, ultimately leading to the occurrence of LI. Hyperhomocysteinemia-induced inflammation mechanism warrants further study.

Serum Aldosterone Is Associated with Cerebral Artery Atherosclerosis and Calcification.

BACKGROUND AND PURPOSE: Elevated serum aldosterone concentration is known to be linked with elevated risk of cerebrovascular events as a result of vascular senescence. We studied the association between serum aldosterone concentration and cerebral arteriosclerosis status involving cerebral atherosclerosis burden and cerebral vascular calcification. METHODS: A total of 207 patients (mean age = 62.40 ± 10.54, 70 female patients) admitted with acute ischemic stroke from a single center-based stroke registry were included in the study. The participants were categorized into 4 groups in accordance to the serum aldosterone concentration. Cerebral atherosclerosis burden was derived as the stenosis degree of main intracranial arteries, and cerebral artery calcification was investigated from the cavernous portions of both internal carotid arteries from brain computed tomography angiography. RESULTS: The median aldosterone was 146.00 pg/mL; interquartile range was 133.18-172.10 pg/mL. Advanced intracranial atherosclerosis was present in 134 patients (64.7%) and advanced intracranial arterial calcification was present in 77 patients (37.2%). The prevalence of cerebral atherosclerosis burden and cerebral artery calcification showed increasing tendency through the aldosterone quartiles. Multivariable logistic regression analysis including age, sex, vascular risk factors, estimated glomerular filtration rate and aldosterone quartiles disclosed that the highest serum aldosterone quartile was an independent predictor of advanced intracranial atherosclerosis (odds ratio, 5.07; 95% confidence interval, 1.82-14.17; Ptrend = .001) and advanced intracranial arterial calcification (odds ratio, 6.24; 95% confidence interval, 2.03-19.22; Ptrend = .001). CONCLUSIONS: An increased serum aldosterone concentration was independently associated with intracranial atherosclerosis burden and arterial calcification. Future studies should investigate whether aldosterone antagonists prevent stroke in at risk population.

Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study.

BACKGROUND AND PURPOSE: Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR). METHODS: Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance-weighted MR was used to obtain the causal estimates. Inverse-variance-weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias. RESULTS: A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04-1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10-1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67-0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes. CONCLUSIONS: LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.

Antiangiogenesis and medical therapy failure in intracranial atherosclerosis.

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and the one with the worst prognosis. In this study, we assessed the hypothesis that the balance of circulating pro- and antiangiogenic factors plays a role in the evolution of the disease and can be used as a potential marker for the disease course and a target for treatment. Seventy-four patients with severe ICAD were enrolled in this prospective observational study, medically optimized, and followed for 6 months. Thirteen pro- and eight antiangiogenic factors were measured in the participants' serum using a sandwich multiplex ELISA. Angiogenic profiles were calculated using principal component analysis. We tested the association between angiogenic profiles and recurring cerebrovascular events despite intensive medical therapy, disability at 6 months after enrollment, and angiographic neovascularization in patients who failed medical treatment and underwent indirect revascularization surgery. There is a strong association between a functionally antiangiogenic profile and recurrent stroke or TIA in patients with ICAD (OR = 7.2, CI 2.4-34.4). Multivariable regression analysis showed that this antiangiogenic profile was also associated with poor functional status after 6 months (p = 0.002), independent from other clinical features such as history of previous stroke, diabetes, and age. In patients who failed medical management and underwent indirect revascularization surgery, high endostatin and angiostatin levels were also associated with low angiographic neovascularization (p = 0.02). The results of this study point to the striking importance of antiangiogenesis as a determinant of ICAD patient prognosis and suggest a possible new target for therapy.

Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation.

L5, the most electronegative and atherogenic subfraction of low-density lipoprotein (LDL), induces platelet activation. We hypothesized that plasma L5 levels are increased in acute ischemic stroke patients and examined whether lectin-like oxidized LDL receptor-1 (LOX-1), the receptor for L5 on endothelial cells and platelets, plays a critical role in stroke. Because amyloid ß (Aß) stimulates platelet aggregation, we studied whether L5 and Aß function synergistically to induce prothrombotic pathways leading to stroke. Levels of plasma L5, serum Aß, and platelet LOX-1 expression were significantly higher in acute ischemic stroke patients than in controls without metabolic syndrome (P < .01). In mice subjected to focal cerebral ischemia, L5 treatment resulted in larger infarction volumes than did phosphate-buffered saline treatment. Deficiency or neutralizing of LOX-1 reduced infarct volume up to threefold after focal cerebral ischemia in mice, illustrating the importance of LOX-1 in stroke injury. In human platelets, L5 but not L1 (the least electronegative LDL subfraction) induced Aß release via IκB kinase 2 (IKK2). Furthermore, L5+Aß synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IκBα, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effects were blocked by inhibiting IKK2, LOX-1, or nuclear factor-κB (NF-κB). Injecting L5+Aß shortened tail-bleeding time by 50% (n = 12; P < .05 vs L1-injected mice), which was prevented by the IKK2 inhibitor. Our findings suggest that, through LOX-1, atherogenic L5 potentiates Aß-mediated platelet activation, platelet aggregation, and hemostasis via IKK2/NF-κB signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies.

Plasma homocysteine levels and intracranial plaque characteristics: association and clinical relevance in ischemic stroke.

BACKGROUND: Elevated plasma homocysteine (Hcy) is an independent risk factor for ischemic stroke. This study aimed to evaluate the association between Hcy levels and intracranial plaque characteristics and to investigate their clinical relevance in ischemic stroke. METHODS: Ninety-four patients with intracranial atherosclerosis (ICAS) were enrolled. Plasma Hcy levels were measured. Intracranial plaque characteristics including plaque enhancement, stenosis ratio, T2 and T1 hyperintense components were assessed on high-resolution magnetic resonance imaging. Logistic regression model was constructed to analyze the association between high Hcy levels and plaque characteristics, and their synergistic effects to predict the likelihood for ischemic stroke, while adjusting for demographics and traditional atherosclerotic risk factors. RESULTS: Elevated Hcy level was associated with strong plaque enhancement independently of age, sex, serum creatinine levels and other atherosclerotic risk factors ((P < 0.001, OR 6.00, 95% confidence interval [CI] 2.28-15.74). Both strong plaque enhancement (P = 0.026, OR 5.63, 95% CI 1.23-25.81) and high Hcy level (P = 0.018, OR 6.20, 95% CI 1.36-28.26) were correlated with acute ischemic stroke. The combination of them strengthened the ability to stratify the likelihood for ischemic stroke, with an improved area under the receiver operating characteristic curve (AUC) of 0.871, significantly higher than that of strong plaque enhancement (0.755) and high Hcy level (0.715) alone (P < 0.05 for both). CONCLUSIONS: High Hcy level appears to have association with intracranial strong plaque enhancement. The combined assessment of plasma Hcy levels and plaque enhancement may improve ischemic stroke risk stratification.