Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct.

BACKGROUND: The role of endovascular therapy for acute stroke with a large infarction has not been extensively studied in differing populations. METHODS: We conducted a multicenter, prospective, open-label, randomized trial in China involving patients with acute large-vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower values indicating larger infarction) or an infarct-core volume of 70 to 100 ml. Patients were randomly assigned in a 1:1 ratio within 24 hours from the time they were last known to be well to undergo endovascular therapy and receive medical management or to receive medical management alone. The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability), and the primary objective was to determine whether a shift in the distribution of the scores on the modified Rankin scale at 90 days had occurred between the two groups. Secondary outcomes included scores of 0 to 2 and 0 to 3 on the modified Rankin scale. The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours after randomization. RESULTS: A total of 456 patients were enrolled; 231 were assigned to the endovascular-therapy group and 225 to the medical-management group. Approximately 28% of the patients in both groups received intravenous thrombolysis. The trial was stopped early owing to the efficacy of endovascular therapy after the second interim analysis. At 90 days, a shift in the distribution of scores on the modified Rankin scale toward better outcomes was observed in favor of endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval, 1.11 to 1.69; P = 0.004). Symptomatic intracranial hemorrhage occurred in 14 of 230 patients (6.1%) in the endovascular-therapy group and in 6 of 225 patients (2.7%) in the medical-management group; any intracranial hemorrhage occurred in 113 (49.1%) and 39 (17.3%), respectively. Results for the secondary outcomes generally supported those of the primary analysis. CONCLUSIONS: In a trial conducted in China, patients with large cerebral infarctions had better outcomes with endovascular therapy administered within 24 hours than with medical management alone but had more intracranial hemorrhages. (Funded by Covidien Healthcare International Trading [Shanghai] and others; ANGEL-ASPECT ClinicalTrials.gov number, NCT04551664.).

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis.

BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE-/- and Gsdmd-/- ApoE-/- mice, bone marrow transplantation, and AAV (adeno-associated virus serotype 9)-F4/80-shGSDMD (shRNA-GSDMD) were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd-/- attenuates the atherosclerotic lesion area in high-fat diet-fed ApoE-/- mice. We performed single-cell RNA sequencing of ApoE-/- and Gsdmd-/- ApoE-/- mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 (GSDMD inhibitor Y1) can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.

Disrupted pattern of rich-club organization in structural brain network from prediabetes to diabetes: A population-based study.

The network nature of the brain is gradually becoming a consensus in the neuroscience field. A set of highly connected regions in the brain network called "rich-club" are crucial high efficiency communication hubs in the brain. The abnormal rich-club organization can reflect underlying abnormal brain function and metabolism, which receives increasing attention. Diabetes is one of the risk factors for neurological diseases, and most individuals with prediabetes will develop overt diabetes within their lifetime. However, the gradual impact of hyperglycemia on brain structures, including rich-club organization, remains unclear. We hypothesized that the brain follows a special disrupted pattern of rich-club organization in prediabetes and diabetes. We used cross-sectional baseline data from the population-based PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study, which included 2218 participants with a mean age of 61.3 ± 6.6 years and 54.1% females comprising 1205 prediabetes, 504 diabetes, and 509 normal control subjects. The rich-club organization and network properties of the structural networks derived from diffusion tensor imaging data were investigated using a graph theory approach. Linear mixed models were used to assess associations between rich-club organization disruptions and the subjects' glucose status. Based on the graphical analysis methods, we observed the disrupted pattern of rich-club organization was from peripheral regions mainly located in frontal areas to rich-club regions mainly located in subcortical areas from prediabetes to diabetes. The rich-club organization disruptions were associated with elevated glucose levels. These findings provided more details of the process by which hyperglycemia affects the brain, contributing to a better understanding of the potential neurological consequences. Furthermore, the disrupted pattern observed in rich-club organization may serve as a potential neuroimaging marker for early detection and monitoring of neurological disorders in individuals with prediabetes or diabetes.

Associations of life's essential 8 with extent of multi-territorial atherosclerotic plaques and stenosis: a cross-sectional study.

BACKGROUND: Life's Essential 8 (LE8), the recently updated construct for quantifying cardiovascular health, is related to the risks of cardiovascular events. The present study aimed to evaluate associations of LE8 score with the multi-territorial extent of atherosclerosis in a community-dwelling population. METHODS: Data were derived from the baseline cross-sectional survey of the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in Lishui City. The LE8 included overall, medical and behavior LE8 scores, and were categorized as low (< 60), moderate (60-<80), and high (≥ 80) groups. Vascular magnetic resonance imaging was used to evaluate intracranial and extracranial arteries; thoracoabdominal computed tomography angiography to evaluate coronary, subclavian, aorta, renal, ilio-femoral arteries; and ankle-brachial index to evaluate peripheral arteries. The presence of atherosclerotic plaque or stenosis in any territory was defined as plaque or vascular stenosis with 1 territory affected or more in these arteries. The extent of atherosclerotic plaques or stenosis was assessed according to the number of these 8 vascular sites affected, and graded as four grades (none, single territory, 2-3 territories, 4-8 territories). RESULTS: Of 3065 included participants, the average age was 61.2 ± 6.7 years, and 53.5% were women (n = 1639). The moderate and high overall LE8 groups were associated with lower extent of multi-territorial plaques [common odds ratio (cOR) 0.44, 95% confidence interval (CI), 0.35-0.55; cOR 0.16, 95%CI, 0.12-0.21; respectively] and stenosis (cOR 0.51, 95%CI, 0.42-0.62; cOR 0.16, 95%CI, 0.12-0.21; respectively) after adjustment for potential covariates. Similar results were observed for medical LE8 score with the extent of multi-territorial plaques and stenosis (P < 0.05). We also found the association between behavior LE8 score and the extent of multi-territorial stenosis (P < 0.05). CONCLUSIONS: The higher LE8 scores, indicating healthier lifestyle, were associated with lower presence and extent of atherosclerotic plaque and stenosis in southern Chinese adults. Prospective studies are needed to further validate these findings.

Endovascular Treatment Versus Best Medical Management in Acute Basilar Artery Occlusion Strokes: Results From the ATTENTION Multicenter Registry.

BACKGROUND: The authors compare the effectiveness and safety of endovascular treatment (EVT) versus best medical management (BMM) in strokes attributable to acute basilar artery occlusion (BAO). METHODS: The present analysis was based on the ongoing, prospective, multicenter ATTENTION (Endovascular Treatment for Acute Basilar Artery Occlusion) trial registry in China. Our analytic sample comprised 2134 patients recruited at 48 sites between 2017 and 2021 and included 462 patients who received BMM and 1672 patients who received EVT. We performed an inversed probability of treatment weighting analysis. Qualifying patients had to present within 24 hours of estimated BAO. The primary clinical outcome was favorable functional outcome (modified Rankin Scale score, 0-3) at 90 days. We also performed a sensitivity analysis with the propensity score matching-based and the instrumental variable-based analysis. RESULTS: In our primary analysis using the inversed probability of treatment weighting-based analysis, there was a significantly higher rate of favorable outcome at 90 days among EVT patients compared with BMM-treated patients (adjusted relative risk, 1.42 [95% CI, 1.19-1.65]; absolute risk difference, 11.8% [95% CI, 6.9-16.7]). The mortality was significantly lower (adjusted relative risk, 0.78 [95% CI, 0.69-0.88]; absolute risk difference, -10.3% [95% CI, -15.8 to -4.9]) in patients undergoing EVT. Results were generally consistent across the secondary end points. Similar associations were seen in the propensity score matching-based and instrumental variable-based analysis. CONCLUSIONS: In this real-world study, EVT was associated with significantly better functional outcomes and survival at 90 days. Well-designed randomized studies comparing EVT with BMM in the acute BAO are needed. REGISTRATION: URL: www.chictr.org.cn; Unique identifier: ChiCTR2000041117.

Association of insulin resistance with intra- and extra-cranial atherosclerotic burden in the nondiabetic community population.

AIMS: Few population-based studies have investigated the association between insulin resistance and atherosclerotic burden in intra- and extra-cranial arteries. The purpose of this study is to explore the relationship between insulin resistance and intra- and extra-cranial atherosclerotic burden in community-based nondiabetic participants. METHODS: This is a cross-sectional analysis from a population-based prospective cohort-PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in China. The homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity indices (ISI0-120) were stratified by the quartiles, respectively. The atherosclerotic presence of plaques and burden was evaluated by high-resolution MRI. Binary or ordinal logistic regression was performed to assess the association between HOMA-IR or ISI0-120 and the presence and burden of atherosclerosis. RESULTS: Among the 2754 participants, the mean age was 60.9 ± 6.6 years, and 1296 (47.1%) were males. Compared with the lowest quartile of HOMR-IR, the highest quartile of HOMA-IR (indicating a higher level of insulin resistance) was associated with an increased presence of plaques (OR:1.54, 95% CI:1.14-2.08), and atherosclerotic burden (OR:1.53, 95%CI:1.14-2.07) in intracranial arteries. Meanwhile, we observed a similar relationship between HOMA-IR and the presence or burden in extracranial atherosclerosis. The first (indicating a higher level of insulin resistance) quartiles of ISI0-120 were associated with the intracranial plaques (Q1, OR:1.56, 95%CI:1.16-2.11) and atherosclerotic burden (Q1, OR:1.57, 95%CI:1.17-2.12), but not extracranial plaques or atherosclerotic burden, compared with the fourth quartile of ISI0-120. CONCLUSIONS: Insulin resistance was associated with an increased intra-and extra-cranial atherosclerotic burden in the nondiabetic elderly Chinese population.

Novel GSDMD inhibitor GI-Y1 protects heart against pyroptosis and ischemia/reperfusion injury by blocking pyroptotic pore formation.

Activation of gasdermin D (GSDMD) and its concomitant cardiomyocyte pyroptosis are critically involved in multiple cardiac pathological conditions. Pharmacological inhibition or gene knockout of GSDMD could protect cardiomyocyte from pyroptosis and dysfunction. Thus, seeking and developing highly potent GSDMD inhibitors probably provide an attractive strategy for treating diseases targeting GSDMD. Through structure-based virtual screening, pharmacological screening and subsequent pharmacological validations, we preliminarily identified GSDMD inhibitor Y1 (GI-Y1) as a selective GSDMD inhibitor with cardioprotective effects. Mechanistically, GI-Y1 binds to GSDMD and inhibits lipid- binding and pyroptotic pore formation of GSDMD-N by targeting the Arg7 residue. Importantly, we confirmed the cardioprotective effect of GI-Y1 on myocardial I/R injury and cardiac remodeling by targeting GSDMD. More extensively, GI-Y1 also inhibited the mitochondrial binding of GSDMD-N and its concomitant mitochondrial dysfunction. The findings of this study identified a new drug (GI-Y1) for the treatment of cardiac disorders by targeting GSDMD, and provide a new tool compound for pyroptosis research.

Association of metabolic dysfunction-associated fatty liver disease with systemic atherosclerosis: a community-based cross-sectional study.

BACKGROUND: Data are limited on the association of metabolic dysfunction-associated fatty liver disease (MAFLD) with systemic atherosclerosis. This study aimed to examine the relationship between MAFLD and the extent of atherosclerotic plaques and stenosis, and presence of polyvascular disease (PolyVD). METHODS: In this cross-sectional study, MAFLD was diagnosed based on the presence of metabolic dysfunction (MD) and fatty liver disease (FLD). MAFLD was divided into three subtypes: MAFLD with diabetes mellitus (DM), MAFLD with overweight or obesity (OW), as well as MAFLD with lean/normal weight and at least two metabolic abnormalities. Atherosclerosis was evaluated, with vascular magnetic resonance imaging for intracranial and extracranial arteries, thoracoabdominal computed tomography angiography for coronary, subclavian, aorta, renal, iliofemoral arteries, and ankle-brachial index for peripheral arteries. The extent of plaques and stenosis was defined according to the number of these eight vascular sites affected. PolyVD was defined as the presence of stenosis in at least two vascular sites. RESULTS: This study included 3047 participants, with the mean age of 61.2 ± 6.7 years and 46.6% of male (n = 1420). After adjusting for potential confounders, MAFLD was associated with higher extent of plaques (cOR, 2.14, 95% CI 1.85-2.48) and stenosis (cOR, 1.47, 95% CI 1.26-1.71), and higher odds of presence of PolyVD (OR, 1.55, 95% CI 1.24-1.94) as compared with Non-MAFLD. In addition, DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD (All P < 0.05). However, lean-MAFLD was only associated with the extent of atherosclerotic plaques (cOR, 1.63, 95% CI 1.14-2.34). As one component of MAFLD, FLD per se was associated with the extent of plaques and stenosis in participants with MAFLD. Furthermore, FLD interacted with MD to increase the odds of presence of systemic atherosclerosis (P for interaction ≤ 0.055). CONCLUSIONS: MAFLD and its subtypes of DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD. This study implicated that FLD might be a potential target of intervention for reducing the deleterious effects of MAFLD on systemic atherosclerosis.

Prevalence and Risk Factors of Cerebral Small Vessel Disease from a Population-Based Cohort in China.

INTRODUCTION: Cerebral small vessel disease (CSVD) is a significant burden of morbidity and mortality among elderly people around the world. Epidemiological data with complete CSVD evaluations and a large sample size in the general population are still limited. METHODS: Community-dwelling residents in Lishui city in China from the cross-sectional survey of the Polyvascular Evaluation for Cognitive Impairment and Vascular Events (PRECISE) study were included in this study from 2017 to 2019. All participants underwent 3 Tesla brain magnetic resonance images to assess CSVD imaging markers. Demographic and risk factor data were collected. The general and age-specific prevalence of lacune, confluent white matter hyperintensity (WMH), moderate-severe enlarged perivascular spaces (EPVS), cerebral microbleed (CMB), and total CSVD score (an ordinal scale from 0 to 4, counting the presence of four imaging markers of CSVD) was evaluated. Associations between vascular risk factors and these markers were analyzed by multivariable logistic regression. RESULTS: A total of 3,063 participants were enrolled. The mean age was 61.2 years and 46.5% were men. The most prevalent CSVD marker was confluent WMH (16.7%), followed by CMB (10.2%), moderate-severe EPVS in the basal ganglia (BG-EPVS) (9.8%), and lacune (5.6%). 30.5% of the participants have at least one of the four markers (total CSVD score ≥1 points). The prevalence of CSVD markers increases as age increases. Age and hypertension were independent risk factors for four CSVD markers and the total CSVD score. CONCLUSIONS: In this Chinese cohort with community-based adults aged 50-75 years, our findings showed a prevalence of 30.5% for CSVD. The most prevalent CSVD marker was confluent WMH, followed by CMB, moderate-severe BG-EPVS, and lacune. The risk factors for CSVD must be strictly screened and controlled in adults living in the community.

Association of intracranial atherosclerosis with cerebral small vessel disease in a community-based population.

BACKGROUND AND PURPOSE: The purpose of this study was to explore the relationship between intracranial atherosclerosis and cerebral small vessel disease (CSVD). METHODS: Community-dwelling residents of Lishui, China in the PRECISE (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) study were involved. Intracranial atherosclerosis was grouped by the severity of intracranial artery plaques with stenosis and burden. Four imaging markers including lacunes, white matter hyperintensity (WMH), cerebral microbleeds (CMBs), and perivascular spaces (PVS) as well as the CSVD burden scores were assessed. Logistic regression or ordinal logistic regression models with odds ratio (OR) or common OR (cOR) were used to estimate the relationship between intracranial atherosclerosis and CSVD markers and burdens. RESULTS: The mean age was 61.20 ± 6.68 years, and 1424 (46.52%) were men among 3061 participants included at baseline. Intracranial atherosclerotic burden was associated with the severity of the lacunes (OR = 4.18, 95% confidence interval [CI] = 1.83-9.58), modified WMH burden (cOR = 1.94, 95% CI = 1.01-3.71), presence of CMBs (OR = 2.28, 95% CI = 1.05-4.94), and CMB burden (OR = 2.23, 95% CI = 1.03-4.80). However, it was not associated with the WMH burden and PVS. Intracranial atherosclerotic burden was associated with CSVD burden (Wardlaw: cOR = 2.73, 95% CI = 1.48-5.05; Rothwell: cOR = 2.70, 95% CI = 1.47-4.95). The association between intracranial atherosclerosis and CSVD was obvious in participants with both anterior and posterior circulation artery stenosis. CONCLUSIONS: Based on a Chinese community population, there may be an association between intracranial atherosclerosis and CSVD, but its mechanism in relation to vascular risk factors still needs to be clarified.

Adherence to a healthy lifestyle and brain structural imaging markers.

Previous research has linked specific modifiable lifestyle factors to age-related cognitive decline in adults. Little is known about the potential role of an overall healthy lifestyle in brain structure. We examined the association of adherence to a healthy lifestyle with a panel of brain structural markers among 2,413 participants in PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in China and 19,822 participants in UK Biobank (UKB). A healthy lifestyle score (0-5) was constructed based on five modifiable lifestyle factors: diet, physical activity, smoking, alcohol consumption, and body mass index. Validated multimodal neuroimaging markers were derived from brain magnetic resonance imaging. In the cross-sectional analysis of PRECISE, participants who adopted four or five low-risk lifestyle factors had larger total brain volume (TBV; ß = 0.12, 95% CI: - 0.02, 0.26; p-trend = 0.05) and gray matter volume (GMV; ß = 0.16, 95% CI: 0.01, 0.30; p-trend = 0.05), smaller white matter hyperintensity volume (WMHV; ß = - 0.35, 95% CI: - 0.50, - 0.20; p-trend < 0.001) and lower odds of lacune (Odds Ratio [OR] = 0.48, 95% CI: 0.22, 1.08; p-trend = 0.03), compared to those with zero or one low-risk factors. Meanwhile, in the prospective analysis in UKB (with a median of 7.7 years' follow-up), similar associations were observed between the number of low-risk lifestyle factors (4-5 vs. 0-1) and TBV (ß = 0.22, 95% CI: 0.16, 0.28; p-trend < 0.001), GMV (ß = 0.26, 95% CI: 0.21, 0.32; p-trend < 0.001), white matter volume (WMV; ß = 0.08, 95% CI: 0.01, 0.15; p-trend = 0.001), hippocampus volume (ß = 0.15, 95% CI: 0.08, 0.22; p-trend < 0.001), and WMHV burden (ß = - 0.23, 95% CI: - 0.29, - 0.17; p-trend < 0.001). Those with four or five low-risk lifestyle factors showed approximately 2.0-5.8 years of delay in aging of brain structure. Adherence to a healthier lifestyle was associated with a lower degree of neurodegeneration-related brain structural markers in middle-aged and older adults.

Association of Serum Cystatin C With Cerebral Small Vessel Disease in Community-Based Population.

BACKGROUND: The aim of this study was to investigate the relationship between serum cystatin C levels and the presence and severity of cerebral small vessel disease (CSVD). METHODS: Community-dwelling residents in the Lishui city in China from the cross-sectional survey of the PRECISE (Poly-Vascular Evaluation for Cognitive Impairment and Vascular Events) cohort study were included in present study from 2017 to 2019. Total CSVD burden and modified total CSVD burden score, as well as the markers of CSVD on magnetic resonance imaging, including white matter hyperintensity, lacunes, cerebral microbleeds, and perivascular spaces, were assessed at baseline survey. Participants were divided into 4 groups according to the quartiles of cystatin C. The association of serum cystatin C with total CSVD burden and imaging markers was analyzed using ordinal or binary logistic regression models. Furthermore, 2-sample Mendelian randomization analysis was performed to investigate the genetically predicted effect of cystatin C on CSVD. RESULTS: A total of 3061 participants were included in this study. The mean age of the participants was 61.2±6.7 years, and 1637 (53.5%) were women. Higher level of cystatin C was associated with an increased total CSVD burden and modified total CSVD burden (Q4 versus Q1: common odds ratio [OR], 1.30 [95% CI, 1.03-1.64] and 1.32 [95% CI, 1.01-1.73]) after adjustment for covariates. Further, compared with the first quartile of cystatin C, subjects in the last quartile had higher risk of lacunes (OR, 1.99 [95% CI, 1.05-3.76]), modified white matter hyperintensity burden (common OR, 1.42 [95% CI, 1.07-1.90]), and moderate-to-severe perivascular spaces (OR, 2.15 [95% CI, 1.29-3.59]) but not cerebral microbleeds. The Mendelian randomization analysis showed that a genetically predicted higher cystatin C level was associated with increased risk of lacunar stroke (OR, 1.16 [95% CI, 1.06-1.27]). CONCLUSIONS: In this community-based study, we found a possible association between cystatin C and CSVD, especially for lacunes, that was independent of estimated glomerular filtration rate.

Associations of Life's Simple 7 With Cerebral Small Vessel Disease.

BACKGROUND: The purpose of this study is to examine the associations of Life's Simple 7 (LS7) with risks of cerebral small vessel disease (CSVD) and its magnetic resonance imaging markers. METHODS: Community-dwelling residents in Lishui city in China from the cross-sectional survey of the PRECISE study (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) were included in this study from 2017 to 2019. LS7 was analyzed as the total score, medical score (derived from the 3 metrics based on medical history and testing), and behavioral score (based on 4 metrics based on behaviors), and categorized as poor, intermediate, or ideal. A CSVD score or a modified CSVD score was derived from 4 magnetic resonance imaging markers (lacunes, microbleeds, perivascular spaces, and white matter hyperintensity) at baseline. Binary logistic regression or ordinal logistic regression model was used to estimate the relationship of LS7 scores with CSVD and magnetic resonance imaging markers. RESULTS: A total of 3061 participants were included in this study. Compared with poor total LS7 score, ideal LS7 total score was associated with reduced adjusted odds of higher CSVD score (common odds ratio [cOR], 0.73 [95% CI, 0.58-0.90]) and higher modified CSVD score (cOR, 0.78 [95% CI, 0.64-0.95]). Compared with poor LS7 medical score, ideal LS7 medical score was associated with reduced adjusted odds of higher CSVD score (cOR, 0.65 [95% CI, 0.53-0.80]) and higher modified CSVD score (cOR, 0.67 [95% CI, 0.56-0.81]). Higher total LS7 score and LS7 medical score were associated with a lower risk of white matter hyperintensities and lacunes. Higher LS7 behavioral score was associated with lower risk of lacunes. CONCLUSIONS: Ideal LS7 score, indicating excellent cardiovascular health, was associated with lower total CSVD burden. Optimizing the risk factors captured by LS7 may reduce the progression of CSVD.

Association of inflammatory markers with cerebral small vessel disease in community-based population.

BACKGROUND: This study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD). METHODS: A total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed. RESULTS: At baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05-1.70; cOR 1.28, 95% CI 1.02-1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00-1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25-3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14-2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16-2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08-1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20-2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04-1.39) and small vessel stroke (OR 1.21, 95% CI 1.06-1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p < 0.05). CONCLUSIONS: This community-based population study found a suggestive association between NC and CSVD, especially for BG-EPVS and lacune, and provided evidence supporting the prognostic significance of NC.

Association between triglyceride glucose index and atherosclerotic plaques and Burden: findings from a community-based study.

BACKGROUND: Insulin resistance is an important cause of cardiovascular events and cerebral infarction development. We aimed to investigate the association of the triglyceride glucose (TyG) index with atherosclerotic burden and plaques in coronary, intra- and extracranial arteries in participants with non-diabetes, and compared the results with that of the homeostasis model assessment of insulin resistance (HOMA-IR). METHODS: Participants without diabetes in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were included. We categorized participants by tertiles of the TyG index and the concordance/discordance of the TyG index and HOMA-IR. Discordance was defined as a TyG index equal to or greater than the median and HOMA-IR less than the median, or vice versa. The atherosclerosis plaques and burden in coronary, intra- and extracranial arteries were evaluated. The association of HOMA-IR and TyG index with the presence of atherosclerotic plaques and atherosclerotic burden was assessed by binary and ordinal logistic regression models, respectively. RESULTS: Among 2,719 included participants, the average age was 60.9 (± 6.6) years, and 53.0% were female. Both TyG index and HOMA-IR were associated with increased odds of coronary/intra- and extracranial atherosclerotic plaques and burden after adjustment for age, sex, currenting smoking and drinking (all P < 0.05). However, the association between HOMA-IR and intracranial atherosclerosis was not statistically significant after adjustment for all potential confounders. Discordantly high TyG index with HOMA-IR had a higher odd of extracranial plaque (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.04-1.71), extracranial atherosclerotic burden (common odds ratio [cOR]: 1.35, 95% CI 1.06-1.71), coronary plaque (OR: 1.30, 95% CI 1.01-1.68) and segment stenosis score (cOR: 1.39, 95% CI 1.09-1.78) as compared with concordantly low TyG index with HOMA-IR. The TyG index had a better net reclassification improvement ability than HOMA-IR for atherosclerotic plaques when adding to baseline model. CONCLUSION: Elevated TyG index was associated with increased odds of atherosclerosis in coronary/intra- and extracranial arteries. Compared with HOMA-IR, the TyG index was more strongly associated with intracranial atherosclerosis. Moreover, discordantly high TyG index with HOMA-IR was also important for atherosclerosis identification.

Elevated circulating levels of gasdermin D are related to acute myocardial infarction and pyrogptosis.

BACKGROUND: Acute myocardial infarction (AMI) is one of the leading contributors to morbidity and mortality worldwide, with a prevalence of nearly three million people, and more than one million deaths reported in the United States every year. Gasdermin D (GSDMD) is involved in the development of atherosclerosis as a key protein of proptosis. This study was designed to determine the potential relationship of GSDMD with AMI in Chinese patients. METHODS: One hundred patients with AMI and 50 controls were consecutively enrolled in this prospective observational study. GSDMD expression levels and other clinical variables in peripheral blood mononuclear cells (PBMCs) were measured upon admission to the hospital. All patients were followed up for 360 days, and the endpoint was considered the occurrence of major adverse cardiovascular events (MACE). RESULTS: GSDMD expression levels in the PBMCs of patients with AMI were significantly higher than those in the controls. Moreover, our analysis showed that GSDMD was an independent biomarker of AMI and had a promising diagnostic ability for it. Finally, the results suggested that high expression of GSDMD and diabetes increased the risk of MACE after AMI. CONCLUSIONS: This study indicated that the GSDMD expression level in PBMCs was elevated in AMI patients and was closely associated with the pyroptosis of AMI.

Effect of vitamin D supplementation on markers of cardiometabolic risk in children and adolescents: A meta-analysis of randomized clinical trials.

BACKGROUND AND AIMS: An increasing attention to the effect of vitamin D supplementation on cardiometabolic risk markers in children and adolescents has been gained recently. However, the results are inconsistent. Therefore, we conducted a meta-analysis to examine the effect of vitamin D supplementation on cardiometabolic risk markers in children and adolescents. METHODS AND RESULTS: Eligible randomized controlled trials (RCTs) were identified by searching PubMed, EMBASE and Web of Science. The results of this study are synthetized and reported in accordance with the PRISMA statement. GRADE system was used to assess the certainty of evidence. A total of 9 RCTs were identified and included in the meta-analysis. We found that vitamin D supplementation did not affect the changes of cardiometabolic risk markers including high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), body mass index (BMI), waist circumferences, systolic blood pressure (SDP) and diastolic blood pressure (DBP). However, vitamin D supplementation showed a beneficial effect on fasting glucose (MD, -1.54 mg/dl, 95% CI -2.98 to -0.10) and TG (MD, -24.76 mg/dl, 95% CI -37.66 to -11.86) in the sub-group analysis of total vitamin D supplementation ≥ 200,000 IU. CONCLUSIONS: Vitamin D supplementation appeared to have a beneficial effect on reducing fasting glucose and TG level when total vitamin D supplementation ≥200,000 IU but not HDL-C, LDL-C TC, blood pressure and waist circumferences levels in children and adolescents. Further studies are needed to address this issue.

Efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. METHODS: Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. RESULTS: In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. CONCLUSIONS: The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. TRIAL REGISTRATION: Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019.

Stress-Induced Hyperglycemia and Remote Diffusion-Weighted Imaging Lesions in Primary Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Stress-induced hyperglycemia (SIH) is the relative transient increase in glucose during a critical illness such as intracerebral hemorrhage (ICH) and is likely to play an important role in the pathogenesis of remote diffusion-weighted imaging (DWI) lesion (R-DWIL) in primary ICH. We sought to determine the association between SIH and the occurrence of R-DWILs. METHODS: We prospectively enrolled primary ICH patients within 14 days after onset from November 2016 to May 2018. In these patients, cerebral magnetic resonance imaging was performed within 14 days after ICH onset. R-DWIL was defined as a hyperintensity signal in DWI with corresponding hypointensity in apparent diffusion coefficient, and at least 20 mm apart from the hematoma. SIH was measured by stress-induced hyperglycemia ratio (SHR). SHR was calculated by fasting blood glucose (FBG) divided by estimated average glucose derived from glycosylated hemoglobin. The included patients were dichotomized into two groups by the 50th percentile of SHR, and named as SHR (-P50) group and SHR (P50+) group, respectively. We evaluated the association between SHR and R-DWIL occurrence using multivariable logistic regression modeling adjusted for potential confounders. RESULTS: Among the 288 patients enrolled, forty-six (16.0%) of them had one or more R-DWILs. Compared with the patients in the lower 50% of SHR (SHR [-P50]), the odds ratio (OR) [95% confidence interval (CI)] for the higher 50% of SHR (SHR [P50+]) group for R-DWIL occurrence was 3.13 (1.39-7.07) in the total population and 6.33 (2.19-18.30) in population absent of background hyperglycemia after adjusting for potential covariates. Similar results were observed after further adjusted for FBG. CONCLUSIONS: Our study demonstrated that SIH was associated with the occurrence of R-DWILs in patients with primary ICH within 14 days of symptom onset.

Inhibition of LncRNA-HRIM Increases Cell Viability by Regulating Autophagy Levels During Hypoxia/Reoxygenation in Myocytes.

Backgrund/Aims: Ischemia reperfusion (I/R) promotes the severity of cardiomyocyte injury. Long noncoding RNAs (LncRNAs) are key regulators in cardiovascular diseases. However, the association between LncRNAs and myocardial I/R injury has not been thoroughly characterized to date. We attempted to clarify the potential biological role of a LncRNA (E230034O05Rik), which we named hypoxia/reoxygenation (H/R) injury-related factor in myocytes (HRIM), by investigating the differential expression of LncRNAs between groups of myocytes exposed to either a normal level of oxygen or to H/R. METHODS: Microarray analysis was used to determine analyze the global differential expression of LncRNAs in H9c2 myocytes exposed either to a normal level of oxygen or to H/R. Target LncRNA levels were further verified in vitro and ex vivo by real-time polymerase chain reaction (qPCR). Cell viability was analyzed using the Cell Counting Kit-8 assay. Autophagy levels were confirmed by Western blotting, transmission electron microscopy, and autophagic double-labeled (mRFP-GFP-LC3) adenovirus analyses. RESULTS: Gene expression profiling revealed that 797 LncRNAs and 1898 mRNAs were differentially expressed in the H/R group compared with the normal oxygen group. Among these LncRNAs and mRNAs, 6 upregulated LncRNAs and 2 downregulated LncRNAs in the H/R group were selected and further validated by qPCR in vitro and ex vivo. Additionally, LncRNA-HRIM was inhibited by specific siRNAs in H9c2 myocytes exposed to H/R. The inhibition of LncRNA-HRIM by siRNA prevented cell death by suppressing excessive autophagic activity in myocytes, This finding suggests a detrimental role of LncRNA-HRIM in the regulation of I/R injury. CONCLUSIONS: LncRNAs are involved in H/R injury of H9c2 myocytes. Inhibition of LncRNA-HRIM increased cell viability by reducing autophagy in myocytes during H/R.