Hemodynamic Impairment of Blood Pressure and Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Stenosis.

BACKGROUND: Hemodynamic impairment of blood pressure may play a crucial role in determining the mechanisms of stroke in symptomatic intracranial atherosclerotic stenosis). We aimed to elucidate this issue and assess the impacts of modifications to blood pressure on hemodynamic impairment. METHODS: From the Third China National Stroke Registry III, computed fluid dynamics modeling was performed using the Newton-Krylov-Schwarz method in 339 patients with symptomatic intracranial atherosclerotic stenosis during 2015 to 2018. The major exposures were translesional systolic blood pressure (SBP) drop and poststenotic mean arterial pressure (MAP), and the major study outcomes were cortex-involved infarcts and borderzone-involved infarcts, respectively. Multivariate logistic regression models and the bootstrap resampling method were utilized, adjusting for demographics and medical histories. RESULTS: In all, 184 (54.3%) cortex-involved infarcts and 70 (20.6%) borderzone-involved infarcts were identified. In multivariate logistic model, the upper quartile of SBP drop correlated with increased cortex-involved infarcts (odds ratio, 1.92 [95% CI, 1.03-3.57]; bootstrap analysis odds ratio, 2.07 [95% CI, 1.09-3.93]), and the lower quartile of poststenotic MAP may correlate with increased borderzone-involved infarcts (odds ratio, 2.07 [95% CI, 0.95-4.51]; bootstrap analysis odds ratio, 2.38 [95% CI, 1.04-5.45]). Restricted cubic spline analysis revealed a consistent upward trajectory of the relationship between translesional SBP drop and cortex-involved infarcts, while a downward trajectory between poststenotic MAP and borderzone-involved infarcts. SBP drop correlated with poststenotic MAP negatively (rs=-0.765; P<0.001). In generating hemodynamic impairment, simulating blood pressure modifications suggested that ensuring adequate blood pressure to maintain sufficient poststenotic MAP appears preferable to the reverse approach, due to the prolonged plateau period in the association between the translesional SBP drop and cortex-involved infarcts and the relatively short plateau period characterizing the correlation between poststenotic MAP and borderzone-involved infarcts. CONCLUSIONS: This research elucidates the role of hemodynamic impairment of blood pressure in symptomatic intracranial atherosclerotic stenosis-related stroke mechanisms, underscoring the necessity to conduct hemodynamic assessments when managing blood pressure in symptomatic intracranial atherosclerotic stenosis.

Effect of Postoperative Prolonged sedation with Dexmedetomidine after successful reperfusion with Endovascular Thrombectomy on long-term prognosis in patients with acute ischemic stroke (PPDET): study protocol for a randomized controlled trial.

BACKGROUND: Endovascular thrombectomy (EVT) is a standard treatment for acute ischemic stroke (AIS) with large vessel occlusion. Hypertension and increased blood pressure variability within the first 24 h after successful reperfusion are related to a higher risk of symptomatic intracerebral hemorrhage and higher mortality. AIS patients might suffer from ischemia-reperfusion injury following reperfusion, especially within 24 h. Dexmedetomidine (DEX), a sedative commonly used in EVT, can stabilize hemodynamics by inhibiting the sympathetic nervous system and alleviate ischemia-reperfusion injury through anti-inflammatory and antioxidative properties. Postoperative prolonged sedation for 24 h with DEX might be a potential pharmacological approach to improve long-term prognosis after EVT. METHODS: This single-center, open-label, prospective, randomized controlled trial will include 368 patients. The ethics committee has approved the protocol. After successful reperfusion (modified thrombolysis in cerebral infarction scores 2b-3, indicating reperfusion of at least 50% of the affected vascular territory), participants are randomly assigned to the intervention or control group. In the intervention group, participants will receive 0.1~1.0 µg/kg/h DEX for 24 h. In the control group, participants will receive an equal dose of saline for 24 h. The primary outcome is the functional outcome at 90 days, measured with the categorical scale of the modified Rankin Scale, ranging from 0 (no symptoms) to 6 (death). The secondary outcome includes (1) the changes in stroke severity between admission and 24 h and 7 days after EVT, measured by the National Institute of Health Stroke Scale (ranging from 0 to 42, with higher scores indicating greater severity); (2) the changes in ischemic penumbra volume/infarct volume between admission and 7 days after EVT, measured by neuroimaging scan; (3) the length of ICU/hospital stay; and (4) adverse events and the all-cause mortality rate at 90 days. DISCUSSION: This randomized clinical trial is expected to verify the hypothesis that postoperative prolonged sedation with DEX after successful reperfusion may promote the long-term prognosis of patients with AIS and may reduce the related socio-economic burden. TRIAL REGISTRATION: ClinicalTrials.gov NCT04916197. Prospectively registered on 7 June 2021.

NIR-II responsive PEGylated MoO2 nanocrystals with LSPR for efficient photothermal and photodynamic performance enhancement.

Phototherapy, including photothermal and photodynamic therapy, has gained extensive attention in the tumor treatment field recently, while synergistic therapy can significantly improve curative effects. However, a complicated photo-responsive nanosystem, different excitation wavelengths, and low tissue depth hindered its actual application. Herein, single near-infrared responsive PEGylated defective MoO2 nanocrystals were fabricated by a green hydrothermal method. The photothermal and photodynamic performances of the samples were presented in detail under a safe power of 1064 nm (NIR-II, 1.0 W cm-2). Interestingly, the photodynamic properties were prompted by the localized surface plasmon resonance (LSPR) photothermal effect obviously, and the collaborative enhancement mechanism was explored in depth. Subsequently, the in vitro cytotoxicity was evaluated on the 4T1 cancer cells under NIR-II irradiation. This work may provide guidance for the facile fabrication of TMOs for NIR-II responsive and enhanced dual-modal phototherapy.

U-shaped association between low-density lipoprotein cholesterol levels and risk of all-cause mortality mediated by post-stroke infection in acute ischemic stroke.

During the acute stage of ischemic stroke, it remains unclear how to interpret the low low-density lipoprotein cholesterol (LDL-C) level. We aimed to evaluate the association between LDL-C levels, post-stroke infection, and all-cause mortality. 804,855 ischemic stroke patients were included. Associations between LDL-C levels, infection, and mortality risk were estimated by multivariate logistic regression models and displayed by restricted cubic spline curves. Mediation analysis was performed under counterfactual framework to elucidate the mediation effect of post-stroke infection. The association between LDL-C and mortality risk was U-shaped. The nadir in LDL-C level with the lowest mortality risk was 2.67 mmol/L. Compared with the group with LDL-C = 2.50-2.99 mmol/L, the multivariable-adjusted odds ratio for mortality was 2.22 (95% confidence intervals (CI): 1.77-2.79) for LDL-C <1.0 mmol/L and 1.22 (95% CI: 0.98-1.50) for LDL-C ≥5.0 mmol/L. The association between LDL-C and all-cause mortality was 38.20% (95% CI: 5.96-70.45, P = 0.020) mediated by infection. After stepwise excluding patients with increasing numbers of cardiovascular risk factors, the U-shaped association between LDL-C and all-cause mortality and the mediation effects of infection remained consistent with the primary analysis, but the LDL-C interval with the lowest mortality risk increased progressively. The mediation effects of infection were largely consistent with the primary analysis in subgroups of age ≥65 years, female, body mass index <25 kg/m2, and National Institutes of Health Stroke Scale ≥16. During the acute stage of ischemic stroke, there is a U-shaped association between LDL-C level and all-cause mortality, where post-stroke infection is an important mediating mechanism.

Low LDL-C level and intracranial haemorrhage risk after ischaemic stroke: a prospective cohort study.

BACKGROUND AND PURPOSE: The Treat Stroke to Target trial has confirmed the benefit of targeting low-density lipoprotein cholesterol (LDL-C) of <1.8 mmol/L in patients who had an ischaemic stroke (IS). However, haemorrhagic risk brought by this target level (<1.8 mmol/L) or even lower level (<1.4 mmol/L) of LDL-C should also be concerned. In this study, we aimed to demonstrate whether low LDL-C could increase the intracranial haemorrhage risk following IS. METHODS: Patients who had an IS from China Stroke Center Alliance programme with complete baseline information were prospectively enrolled. 793 572 patients who had an IS were categorised into 6 groups according to LDL-C level (<1.40 mmol/L, 1.40-1.79 mmol/L, 1.80-2.59 mmol/L, 2.60-2.99 mmol/L, 3.00-4.89 mmol/L, ≥4.90 mmol/L). The study outcome was defined as intracranial haemorrhage identified during hospitalisation. Logistic regression model was used to examine the association between different LDL-C levels and risk of intracranial haemorrhage. RESULTS: Compared with patients of LDL-C=1.80-2.59 mmol/L, both subgroups of LDL-C<1.40 mmol/L and LDL-C=1.40-1.79 mmol/L showed significantly higher risk of intracranial haemorrhage (OR=1.26, 95% CI=1.18 to 1.35; OR=1.22, 95% CI=1.14 to 1.30, respectively). Interaction effect was found to exist between the subgroups of intravenous thrombolytic therapy (p=0.04), rather than the subgroups of age, sex and body mass index. Moreover, the sensitivity analyses indicated that even patients who had an IS with minor stroke still suffered from the increased intracranial haemorrhage risk related to low LDL-C level. CONCLUSIONS: Among patients who had an IS, the low LDL-C level (<1.4 mmol/L or <1.8 mmol/L) at baseline is associated with increased risk of intracranial haemorrhage during acute stage. While actively lowering LDL-C level for patients who had an IS, clinicians should also concern about the haemorrhagic risk associated with low LDL-C level.

Nontraditional Risk Factors for Residual Recurrence Risk in Patients with Ischemic Stroke of Different Etiologies.

BACKGROUND AND OBJECTIVE: With the popularization of guideline-based secondary prevention based on traditional risk factors, rates of stroke recurrence reduced greatly after ischemic stroke (IS) or transient ischemic attack (TIA), but the residual risk still exists. We aim to evaluate which IS subtype benefits the most from the current secondary prevention and to evaluate nontraditional risk factors for residual recurrence risk of different IS etiologies. METHODS: The study included IS/TIA patients who participated in both biomarker substudy and imaging substudy of the Third China National Stroke Registry. We used 5 guideline-recommended interventions (antiplatelet, statins, anticoagulant, antihypertensive, and antidiabetic therapies) to document the performance of secondary prevention care. Residual risk was defined as the risk of stroke recurrence despite adherence to these 5 guideline-based secondary prevention strategies. Risk factors associated with stroke recurrence were analyzed by using Cox regression models. RESULTS: In total, 9,733 patients were included in this study. At 3 months, 4,186 (43.0%) patients adhered to 5 secondary prevention strategies, and the residual risk of recurrence was 5.1%. According to Trial of Org 10172 in Acute Stroke Treatment subtypes, cardioembolism benefited the most from current secondary prevention (relative risk reduction: 65.2%), followed by large-artery atherosclerosis (LAA) (29.0%) and small-artery occlusion (SAO) (20.0%). Despite adhering to secondary prevention strategies, high sensitivity C-reactive protein, interleukin-6 (IL-6) levels, and impaired renal function were independent risk factors for the residual recurrence risk of LAA subtype, while IL-6 and trimethylamine N-oxide significantly contributed to the residual risk of SAO subtype. CONCLUSIONS: LAA and SAO subtypes own the specific nontraditional risk factors while inflammation is a common risk factor for residual recurrence risk of both.

Effects of individual and integrated cumulative burden of blood pressure, glucose, low-density lipoprotein cholesterol, and C-reactive protein on cardiovascular risk.

AIM: This study aimed to demonstrate the impact of cumulative burden of cardiovascular risk factors (CVRFs) on risk of cardiovascular events (CVEs). METHODS AND RESULTS: A total of 34 959 participants were enrolled who participated in the four surveys during 2006-2013. Cumulative CVRF burden was calculated as number of years (2006-2013) multiplied by the values of CVRFs including systolic blood pressure, fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), and high-sensitive C-reactive protein (hs-CRP). The primary outcome was defined as the CVE during 2012-2017, including ischaemic stroke, myocardial infarction, and all-cause mortality. During 4.62 (±0.71) years follow-up on average, there were 2118 (6.06%) CVE, including 847 (2.42%) ischaemic stroke, 221 (0.63%) myocardial infarction, and 1185 (3.39%) all-cause mortality. Higher cumulative burden of individual CVRF was significantly associated with increased risk of outcomes, except for LDL-C for all-cause mortality, FBG for myocardial infarction, and hs-CRP for ischaemic stroke. In Cox proportional hazards model, compared with the group, of the lower quartile of integrated cumulative burden, the hazard ratio (95% confidence intervals) of the upper quartile was 2.45 (2.03-2.94) for CVE, 3.65 (2.68-4.96) for ischaemic stroke, 4.51 (2.19-9.27) for myocardial infarction, and 1.73 (1.36-2.21) for all-cause mortality. CONCLUSION: We demonstrated the correlation between cumulative burden of CVRFs and cardiovascular risk, except for cumulative burden of hs-CRP and ischaemic stroke. Thus, our study suggests the necessity to extend the observation duration of CVRFs in order to elucidate the life-course cumulative effect.

Application of Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping Score for Efficacy of Clopidogrel: Secondary Analysis of the CHANCE Trial.

BACKGROUND AND PURPOSE: The age, body mass index, chronic kidney disease, diabetes, and genotyping (ABCD-GENE) score is a validated risk score integrating CYP2C19 genotypes with clinical risk factors influencing clopidogrel response that would allow the more precise identification of subjects at risk for high platelet reactivity and adverse clinical outcomes. Our objective was to further verify application of the ABCD-GENE score and investigate appropriate cutoff value in patients with minor stroke or transient ischemic attack. METHODS: In this post-analysis of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), the ABCD-GENE score was calculated for all patients enrolled in this study. By using the proposed cutoff of 10, patients were stratified as being at high risk for high platelet reactivity or not. We further categorized the ABCD-GENE score to 0 to 5, 6 to 24, and >24 to investigate the cutoff value of this scale in clinical application. Stroke recurrence at 3 months was considered as the primary outcome. RESULTS: Among a total of 2923 patients with minor stroke/transient ischemic attack, there were 2273 (77.76%) with ABCD-GENE score <10 and 650 (22.24%) patients with ABCD-GENE score ≥10. Compared with the aspirin alone, hazard ratios (95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 0.70 (0.54-0.91) and 0.76 (0.46-1.24), among patients of ABCD-GENE scores <10 and ABCD-GENE scores ≥10, respectively. Stratified analyses by ABCD-GENE score 0 to 5, 6 to 24, and >24, hazard ratios of the clopidogrel-aspirin therapy for stroke recurrence were 0.57 (95% CI, 0.38-0.85), 0.78 (0.58-1.06), and 1.20 (0.44-3.28) (P value for trend=0.0052). CONCLUSIONS: Among Chinese minor stroke/transient ischemic attack population, the efficacy of clopidogrel-aspirin therapy was decreased in patients with higher ABCD-GENE score. Our study suggests that CYP2C19 genotypes and clinical risk factors can be integrated by ABCD-GENE score to estimate the efficacy of clopidogrel-aspirin therapy.

Serum Cystatin C Predicts Stroke Clinical Outcomes at 1 Year Independent of Renal Function.

Objective: Serum cystatin C (CysC) is a sensitive marker of renal function to predict cardiovascular diseases. We aimed to investigate the predictive value of CysC for clinical outcomes independent of renal function in patients with acute ischemic stroke (AIS). Methods: We measured serum CysC levels in 10,256 AIS patients from Third China National Stroke Registry (CNSR-III). The primary outcome was a combination of all-cause mortality and major disability (modified Rankin scale score, 3-6). Secondary outcomes included stroke recurrence and combined vascular events at 1 year. Outcomes were analyzed using logistic regression and Cox proportional hazards models, respectively. Results: The median CysC of included patients was 0.95 mg/l (interquartile range, 0.83-1.10 mg/l). A U-shaped association was observed between CysC and primary outcome (all-cause mortality or major disability) [quartile (Q)1 vs. Q2: adjusted odds ratio (aOR) 1.29, 95% CI 1.06-1.58, p = 0.012; Q3 vs. Q2: aOR 1.12, 95% CI 0.93-1.35, p = 0.242; Q4 vs. Q2: aOR 1.35, 95% CI 1.10-1.65, p = 0.004]. A similar trend also existed in "preserved renal function" patients. Adding CysC to a model containing conventional risk factors improved the model performance with integrated discrimination improvement (IDI) of 0.13% (p = 0.016) and net reclassification index (NRI) of 13.10% (p <0.001) for primary outcome. No significant association was observed for stroke recurrence or combined vascular event rate in different CysC quartiles. Conclusions: CysC showed a U-shaped correlation with 1-year stroke clinical outcome, suggesting that serum CysC may not only be a simple candidate marker of renal function.

Cumulative burden of lipid profiles predict future incidence of ischaemic stroke and residual risk.

OBJECTIVES: Incident ischaemic stroke (IS) risk may increase not only with lipids concentration but also with longer duration of exposure. This study aimed to investigate the impact of cumulative burden of lipid profiles on risk of incident IS. METHODS: A total of 43 836 participants were enrolled who participated in four surveys during 2006-2013. Individual cumulative lipid burden was calculated as number of years (2006-2013) multiplied by the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglyceride (TG), respectively. The primary outcome was defined as the incident IS during 2012-2017. RESULTS: During 4.67 years (±0.70 years) follow-up on average, we identified 1023 (2.33%) incident IS. Compared with respective reference groups, the HRs (95% CIs) of the upper tertile in cumulative TG burden, cumulative LDL-C burden, cumulative TC burden and cumulative non-HDL-C burden were 1.26 mmol/L (1.02-1.55 mmol/L), 1.47 mmol/L (1.25-1.73 mmol/L), 1.33 mmol/L (1.12-1.57 mmol/L) and 1.51 mmol/L (1.28-1.80 mmol/L) for incidence of IS, respectively. However, this association was not significant in cumulative HDL-C burden and IS (HR: 1.09; 95% CI: 0.79 to 1.52), after adjustment for confounding variables. Among 16 600 participants with low cumulative LDL-C burden, HRs (95% CI) for TC, TG, non-HDL-C and HDL-C with IS were 1.63 mmol/L (1.03-2.57 mmol/L), 1.65 mmol/L (1.19-2.31 mmol/L), 1.57 mmol/L (1.06-2.32 mmol/L) and 0.98 mmol/L (0.56-1.72 mmol/L), respectively. CONCLUSIONS: We observed the correlation between cumulative burden of lipid profiles, except for cumulative burden of HDL-C, with the risk of incident IS. Cumulative burden of TC, TG and non-HDL-C may still predict IS in patients with low cumulative LDL-C burden. TRIAL REGISTRATION NUMBER: ChiCTR-TNRC-11001489.

Ambulatory blood pressure profile and stroke recurrence.

OBJECTIVES: To establish a new ambulatory blood pressure (ABP) parameter (24-hour ABP profile) and evaluated its performance on stroke outcome in ischaemic stroke (IS) or transient ischaemic attack (TIA) patients. METHODS: The prospective cohort consisted of 1996 IS/TIA patients enrolled for ABP monitoring and a 3-month follow-up for stroke recurrence as outcome. Profile groups of systolic blood pressure (SBP) were identified via an advanced functional clustering method, and the associations of the profile groups and conventional ABP parameters with stroke recurrence were examined in a Cox proportional hazards model. RESULTS: Three discrete profile groups (n=604, 781 and 611 in profiles 1, 2 and 3, respectively) in 24-hour ambulatory SBP were identified. Profile 1 resembled most to the normal diurnal blood pressure pattern; profile 2 also dropped at night, but climbed earlier and with higher morning surge; while profile 3 had sustained higher nocturnal SBP without significant nocturnal SBP decline. The incidence of stroke recurrence was 2.9%, 3.9% and 5.5% in profiles 1, 2 and 3, respectively. After adjustment for covariates, profile 3 was significantly associated with higher risk of stroke recurrence with profile 1 as reference (HR 1.76, 95% CI: 1.00 to 3.09), while no significant difference was observed between profiles 2 and 1 (HR 1.22, 95% CI: 0.66 to 2.25). None of conventional ABP parameters showed significant associations with the outcome. CONCLUSIONS: Ambulatory 24-hour SBP profile is associated with short-term stroke recurrence. Profiles of ABP may help improve identification of stroke recurrence by capturing the additive effects of individual ABP parameters.

Effect of Low Diastolic Blood Pressure to Cardiovascular Risk in Patients With Ischemic Stroke or Transient Ischemic Attacks Under Different Systolic Blood Pressure Levels.

Background: In the context of recently updated strategies of pressure management, there is a paucity of evidence on the effect of diastolic blood pressure (DBP) level on adverse events among stroke patients. This study aimed to examine the effect of low DBP (<60 mmHg) under different levels of systolic blood pressure (SBP) on the risk of composite events and stroke recurrence among patients with ischemic stroke (IS) or transient ischemic attack (TIA). Material and Methods: This study was conducted in 2,325 patients with IS or TIA. DBP values were categorized into <60, 60-70, 70-80 (reference), 80-90, and ≥90 mmHg in the main sample and were further categorized as <60 and ≥60 mmHg (reference) when patients were stratified according to SBP levels (<140, <130, and <120 mmHg). The outcomes were defined as recurrent stroke and cumulative composite events (defined as the combination of nonfatal myocardial infarction, nonfatal congestive heart failure, and death) at 1 year. Results: During 1 year of follow-up, a total of 95 composite events and 138 stroke recurrences were identified. The patients with low DBP showed a significantly higher risk of composite events [hazard ratio (HR) = 4.86, 95% confidence interval (CI) = 2.54-8.52], especially the elderly patients (≥60 years); however, this result was not observed for stroke recurrence (HR = 0.90, 95% CI = 0.46-1.74). With the reduction of the SBP levels, the proportion of patients with low DBP increased (6.87, 12.67, and 34.46%), and the risk for composite events persisted. Conclusions: Along with the new target levels of SBP suggested by updated criteria, there is a trend for DBP to be reduced to a harmfully low level, which was associated with an increased risk of composite events among patients with IS or TIA.

Impact of Infection on the Risk of Recurrent Stroke Among Patients With Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Infection occurs commonly in patients with acute ischemic stroke. We aimed to investigate the association of infection with short- and long-term risk of recurrent stroke in patients with ischemic stroke. METHODS: Data were derived from ischemic stroke patients in 2 stroke registries: the CSCA (Chinese Stroke Center Alliance) program recorded medical data during hospitalization, and the CNSR-III (Third China National Stroke Registry) recorded the medical data during hospitalization and finished 1-year follow-up. Associations of infection (pneumonia or urinary tract infection) during hospitalization with recurrent stroke in short (during hospitalization) and long term (since 30 days to 1 year after stroke onset) were analyzed. Short-term outcomes were analyzed with logistic models and long-term outcomes with Cox models. RESULTS: In the CSCA (n=789 596), the incidence of infection during hospitalization reached 9.6%. Patients with infection had a higher risk of stroke recurrence during hospitalization compared with patients without infection (10.4% versus 5.2%; adjusted odds ratio, 1.70 [95% CI, 1.65-1.75]; P<0.0001). In the CNSR-III (n=13 549), the incidence of infection during hospitalization was 6.5%. Infection during hospitalization was significantly associated with short-term risk of recurrent stroke (7.4% versus 3.9%; adjusted odds ratio, 1.40 [95% CI, 1.05-1.86]; P=0.02) but not with long-term risk of recurrent stroke (7.2% versus 5.2%; adjusted hazard ratio, 1.16 [95% CI, 0.88-1.52]; P=0.30). CONCLUSIONS: Infection was an independent risk factor for high risk of early stroke recurrence during hospitalization, but we have not found its sustained effect on long-term recurrent risk in patients with acute ischemic stroke.

The impact of the cumulative burden of LDL-c and hs-CRP on cardiovascular risk: a prospective, population-based study.

BACKGROUND: This study aims to demonstrate the impact of the cumulative burden of low density lipoprotein-cholesterol (cumLDL-c) and high sensitivity C-reactive protein (cumhs-CRP) on cardiovascular risk. RESULTS: During the 4.62 (±0.70) years of follow-up, 2,148 (5.92%) participants had MACE. Both of cumLDL-c and cumhs-CRP were independent risk factors for MACE. In participants without cumLDL-c during 2006-2013, the participants with cumhs-CRP had higher MACE risk during the subsequent 5 years, than those without cumhs-CRP (hazard ratio [HR]: 1.24, 95% confidence interval [CI]:1.04-1.47). In addition, cumhs-CRP correlated with MACE in a cumhs-CRP level-dependent pattern. CONCLUSION: This study validated the effects of residual inflammation risk in patients with low LDL-c Level in a general population, using long-term burdens of hs-CRP or LDL-c other than a single time-point level. METHOD: The Kailuan study is a prospective, population-based study began in 2006. These total 36,421 participants completed 4 measurements of hs-CRP and LDL-c biennially from 2006-2013. Cumhs-CRP or cumLDL-c levels were calculated as the number of interval years multiplied by the Δhs-CRP (more than 2.0 mg/L) or ΔLDL-c (more than 2.6 mmol/L). Outcomes measured during follow-up (2012-2017) were defined as major adverse cardiac events (MACE), including ischemic stroke, myocardial infarction, and all-cause mortality.

Combined impact of body mass index and glycemic control on the efficacy of clopidogrel-aspirin therapy in patients with minor stroke or transient ischemic attack.

BACKGROUND: A single index of body mass index (BMI) may not fully address its impact on anti-platelet therapy. We aimed to elucidate the combined impact of BMI and dysglycemia expressed by glycated albumin (GA) on efficacy of clopidogrel-aspirin therapy among minor stroke (MS) or transient ischemic attack (TIA) patients. RESULTS: Patients with overweight/obesity and low GA levels still benefited from clopidogrel-aspirin therapy for stroke recurrence (Hazard ratio [HR]: 0.48, 95 % confidence interval [CI]: 0.28-0.82), so did those with high GA levels but low/normal weight (HR: 0.67, 95 % CI: 0.45-0.99). However, patients with both overweight/obesity and high GA levels did not benefit from clopidogrel-aspirin therapy (HR: 0.89, 95 % CI: 0.59-1.33). CONCLUSIONS: Compared with aspirin alone, efficacy of clopidogrel-aspirin therapy for stroke still exists in overweight/obesity patients with normal glycemic control. METHODS: In Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial, 3044 patients with available baseline GA were recruited. Low/normal weight and overweight/obesity were defined as BMI < 25 kg/m2 and ≥ 25 kg/m2, respectively. Elevated and low GA levels were defined as GA levels > 15.5 % and ≤ 15.5 %, respectively. The primary outcome was stroke recurrence during the 90-day follow-up.

Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation.

The NLRP3 inflammasome is a core component of innate immunity, and dysregulation of NLRP3 inflammasome involves developing autoimmune, metabolic, and neurodegenerative diseases. Potassium efflux has been reported to be essential for NLRP3 inflammasome activation by structurally diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Thus, the molecular mechanisms underlying potassium efflux to activate NLRP3 inflammasome are under extensive investigation. Here, we review current knowledge about the distinction channels or pore-forming proteins underlying potassium efflux for NLRP3 inflammasome activation with canonical/non-canonical signaling or following caspase-8 induced pyroptosis. Ion channels and pore-forming proteins, including P2X7 receptor, Gasdermin D, pannexin-1, and K2P channels involved present viable therapeutic targets for NLRP3 inflammasome related diseases.

Efficacy of Clopidogrel-Aspirin Therapy for Stroke Does Not Exist in CYP2C19 Loss-of-Function Allele Noncarriers With Overweight/Obesity.

Background and Purpose- The role of dual-antiplatelet therapy with clopidogrel plus aspirin has been demonstrated to substantially decrease the risk of recurrent stroke among patients with minor stroke and transient ischemic attack. We aimed to determine whether the efficacy of clopidogrel-aspirin therapy among patients with minor stroke / transient ischemic attack was influenced by the stratification of CYP2C19 genotype and body mass index (BMI). Methods- CYP2C19 loss-of-function allele (LoFA) carriers were defined as patients with either LoFA of *2 or *3. Low/normal weight and overweight/obesity was defined as BMI <25 and ≥25 kg/m2, respectively. Primary outcome was defined as stroke recurrence at 3 months. Results- In a total of 2933 patients, there were 1726 (58.8%) LoFA carriers and 1275 (43.5%) patients with overweight/obesity (BMI ≥25 kg/m2). Stratified analyses by LoFA carrying status and BMI, hazard ratios (hazard ratios 95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 0.90 (0.60-1.36), 0.87 (0.56-1.35), 0.65 (0.39-1.09), and 0.40 (0.22-0.71) among subgroups of LoFA carriers with overweight/obesity, LoFA carriers with low/normal weight, LoFA noncarriers with overweight/obesity, and LoFA noncarriers with low/normal weight, respectively, with P=0.049 for interaction. Conclusions- Efficacy of clopidogrel-aspirin therapy in reducing the risk of stroke recurrence is not present in CYP2C19 LoFA noncarriers with overweight/obesity. Our study suggests that BMI significantly influences the correlation between CYP2C19 genotype and efficacy of clopidogrel-aspirin therapy. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00979589.

Uric Acid Contributes to Obesity-Paradox of the Outcome of Ischemic Stroke.

Background: The mechanism of obesity paradox in stroke is not clear. This study aimed to investigate whether uric acid (UA) contributes to obesity-stroke outcome paradox. Material and Methods: The study cohort consisted of 1,984 IS patients recruited in the ACROSS-China study. Serum UA and BMI were measured at admission. Low and high BMI groups were defined by the threshold of 24, and low and high UA by the age- and sex-specific median. Poor outcomes were defined as modified Rankin scale score ≥3 in 1 year after onset. Results: UA was significantly and positively correlated with BMI. Lower levels of UA and BMI were significantly associated with higher risk of poor outcomes. Incidence of the poor outcome was 34.5, 29.4, 27.7, and 23.5% in the BMI/UA groups of low/low, high/low, low/high and high/high, respectively, with p = 0.001 for trend. The association between low UA and poor outcome was significant in lower BMI groups (odds ratio = 1.36, p = 0.006 in quartile 1 and 1.28, p = 0.021 in quartile 2), but the odds ratios were not significant in the BMI quartile 3 and 4 groups, with p = 0.038 for trend. The adverse effect of lower UA was significant in males, but not in females, with p = 0.006 for sex difference. Conclusions: These findings suggest that low UA and low BMI have a joint effect on poor outcomes in IS patients. Across BMI categories, uric acid is differentially associated with functional outcome after stroke. This effect of low UA in the low BMI groups may be one of the mechanisms underlying the obesity-stroke paradox of the outcome in IS patients.

Risk Profile of Ischemic Stroke Caused by Small-Artery Occlusion vs. Deep Intracerebral Hemorrhage.

Background: Small-artery occlusion (SAO) subtype accounts for a quarter of the cases of ischemic stroke and is mainly caused by pathological changes in cerebral small vessels, which also involve in deep intracerebral hemorrhage (dICH). However, the factors that drive some cases to SAO and others to dICH remained incompletely defined. Material and Methods: This study is a cross-sectional study from the China National Stroke Registry that included consecutive patients with ischemic stroke or intracerebral hemorrhage between August 2007 and September 2008. We compared the risk profile between the two subgroups using multivariable logistic regression. Results: A total of 1,135 patients with SAO stroke and 1,125 dICH patients were included for analyses. Generally, patients with SAO stroke were more likely to be male (odds ratio = 0.74, confidence interval = 0.58-0.94) and have diabetes (0.30, 0.22-0.40), higher atherogenic lipid profiles, higher body mass index (0.96, 0.94-0.99), higher waist/height ratio (0.12, 0.03-0.48), higher platelet count (0.84, 0.77-0.91), and higher proportion of abnormal estimated glomerular filtration rate (<90, ml/min/1.73 m2) (0.77, 0.62-0.95). Conversely, patients with dICH were more likely to have higher blood pressure parameters, inflammation levels (white blood cell count: 1.61, 1.48-1.76; high sensitivity C-reactive protein: 2.07, 1.36-3.16), and high-density lipoprotein-c (1.57, 1.25-1.98). Conclusions: The risk profile between SAO stroke and dICH were different. Furthermore, despite of traditional indexes, waist/height ratio, platelet count, inflammation levels, lipid profile, and estimated glomerular filtration rate also play important roles in driving arteriolosclerosis into opposite ends.