Acute Ischemic Stroke Subjects Research Articles

Flow cytometry-based peripheral blood analysis as an easily friendly tool for prognostic monitoring of acute ischemic stroke: a multicenter study.

Acute ischemic stroke (AIS) is a leading cause of mortality, severe neurological and long-term disability world-wide. Blood-based indicators may provide valuable information on identified prognostic factors. However, currently, there is still a lack of peripheral blood indicators for the prognosis of AIS. We aimed to identify the most promising prognostic indicators and establish prognostic models for AIS. 484 subjects enrolled from four centers were analyzed immunophenotypic indicators of peripheral blood by flow cytometry. Least absolute shrinkage and selection operator (LASSO) regression was applied to minimize the potential collinearity and over-fitting of variables measured from the same subject and over-fitting of variables. Univariate and multivariable Cox survival analysis of differences between and within cohorts was performed by log-rank test. The areas under the receiving operating characteristic (ROC) curves were used to evaluate the selection accuracy of immunophenotypic indicators in identifying AIS subjects with survival risk. The prognostic model was constructed using a multivariate Cox model, consisting of 402 subjects as a training cohort and 82 subjects as a testing cohort. In the prospective study, 7 immunophenotypic indicators of distinct significance were screened out of 72 peripheral blood immunophenotypic indicators by LASSO. In multivariate cox regression, CTL (%) [HR: 1.18, 95% CI: 1.03-1.33], monocytes/μl [HR: 1.13, 95% CI: 1.05-1.21], non-classical monocytes/μl [HR: 1.09, 95% CI: 1.02-1.16] and CD56high NK cells/μl [HR: 1.13, 95% CI: 1.05-1.21] were detected to decrease the survival probability of AIS, while Tregs/μl [HR:0.97, 95% CI: 0.95-0.99, p=0.004], BM/μl [HR:0.90, 95% CI: 0.85-0.95, p=0.023] and CD16+NK cells/μl [HR:0.93, 95% CI: 0.88-0.98, p=0.034] may have the protective effect. As for indicators' discriminative ability, the AUC for CD56highNK cells/μl attained the highest of 0.912. In stratification analysis, the survival probability for AIS subjects with a higher level of Tregs/μl, BM/μl, CD16+NK cells/μl, or lower levels of CD56highNK cells/μl, CTL (%), non-classical monocytes/μl, Monocytes/μl were more likely to survive after AIS. The multivariate Cox model showed an area under the curve (AUC) of 0.805, 0.781 and 0.819 and 0.961, 0.924 and 0.982 in the training and testing cohort, respectively. Our study identified 7 immunophenotypic indicators in peripheral blood may have great clinical significance in monitoring the prognosis of AIS and provide a convenient and valuable predictive model for AIS.

Abstract 011: Endovascular therapy for acute ischemic stroke utilizing SOFia Aspiration System as first line Technique (SOFAST)

Introduction Mechanical thrombectomy using stent retrievers and aspiration techniques has emerged as the standard of care for patients with acute ischemic stroke (AIS) secondary to emergent large vessel occlusion (LVO). This study intended to collect real‐world clinical evidence on the safety and effectiveness of endovascular treatment of AIS using the SOFIA Flow Plus 6F aspiration catheter. The primary endpoint was the proportion of subjects achieving mTICI ≥2b. Secondary endpoints included good functional outcomes (mRS 0‐2) at Day 90, revascularization time, first line and first pass mTICI ≥2b, occurrence of procedure‐related SAEs, vasospasm involving the accessed vascular tree, embolization to new territories (ENTs), symptomatic intracerebral hemorrhage (sICH) within 24 hours and mortality at Day 90. Methods SOFAST was a prospective, multicenter, single‐arm, observational post‐market study. The enrolled subjects were ≥21 and ≤85 years with large vessel (ICA or MCA) proximal occlusion, pre‐morbid mRS ≤1, baseline NIHSS ≥5, and for whom groin puncture was within 8 hours of symptom onset. A total of 108 patients were enrolled and treated using aspiration thrombectomy with SOFIA 6F as the first line treatment device. Patients were followed at 24 hours, 7 days/discharge, and 90 days post‐procedure. Cerebral angiography was performed pre‐ and post‐procedure. Clinical assessments included the NIHSS and mRS scales. All neurological, device‐related, and procedure‐related AEs and deaths were adjudicated by independent medical reviewers. Angiographic and other imaging data was adjudicated by an independent core laboratory. Results A total of 108 subjects were enrolled (mean age 62.7 years, 50% men) with a median NIHSS of 15.5. Of 108 subjects, 97.2% (105/108), 85.2% (92/108) and 55.6% (60/108) achieved mTICI ≥2b, ≥2c and =3 revascularization, respectively. With first line aspiration using SOFIA 6F, 87.0%, 79.6% and 52.8% achieved mTICI ≥2b, ≥2c and =3 revascularization, respectively. Median number of passes was one (range 1‐3). First pass rate of mTICI 2c or 3 using SOFIA 6F was 70.4%, of which 50.9% patients achieved mTICI score of 3. Mean duration from groin puncture to initial clot contact was 13.0 min and to successful revascularization was 17.9 min. Good functional outcome was achieved in 66.7% (72/108) of subjects at Day 90 (mRS 0‐2), procedure‐related SAEs occurred in 2.8% (3/108) of subjects and sICH in 0.9% (1/108) of subjects within 24 hours. Procedural vasospasm was recorded in in 9.3% (10/108) of subjects, and mortality in 7.4% (8/108) subjects at Day 90 (none related to the study device). No ENTs occurred. Conclusion In SOFAST study, mTICI ≥2b revascularization was achieved in the majority of patients at the end of all procedures (97.2%) and with first line treatment (87.0%) with a large fraction of these subjects achieving mTICI ≥2c following the first SOFIA 6F pass (70.4%). Durations from groin puncture to clot contact and successful revascularization were relatively short. The study presented high rates of good functional outcome at Day 90 and low rates of safety events. In summary, the study provides encouraging evidence of the safety and effectiveness of the SOFIA 6F device for aspiration thrombectomy in acute ischemic stroke subjects.

The expression levels of circulating miR-140-3p, miR-130a-3p, and miR-320b as diagnostic biomarkers in acute ischemic stroke.

Plasma miRNAs can characterize several diseases, including acute ischemic stroke (AIS), which is noninvasive and currently affordable in most laboratories worldwide. We aimed to demonstrate plasma miR-140-3p, miR-130a-3p, and miR-320b as diagnostic biomarkers in AIS.GSE110993 and GSE86291 datasets were analyzed to obtain plasma differentially expressed miRNAs between AIS and healthy control subjects (HCs). We further applied RT-qPCR for the validation in 85 AIS patients and 85 HCs. Receiver operating characteristic (ROC) curve were conducted to evaluate their diagnostic utility in AIS. Correlation was analyzed between DEmiRNAs and clinical and laboratory parameters, as well as inflammatory markers. The plasma levels of miR-140-3p, miR-130a-3p, and miR-320b were found to be consistently altered in both GSE110993 and GSE86291 datasets. In comparison to HCs, AIS patients at admission exhibited lower levels of miR-140-3p and miR-320b and higher level of miR-130a-3p in their plasma. The ROC analysis revealed that plasma miR-140-3p, miR-130a-3p, and miR-320b had area under the curve values of 0.790, 0.831, and 0.907, respectively. When combined, these miRNAs showed superior discriminatory power with a sensitivity of 91.76% and specificity of 95.29%. Plasma miR-140-3p and miR-320b negatively correlated glucose levels and inflammatory markers (IL-6, MMP-2, MMP-9, and VEGF) in AIS patients. Conversely, plasma miR-130a-3p levels were positively associated with glucose levels and these markers. Plasma miR-140-3p, miR-130a-3p, and miR-320b levels varied significantly among AIS patients with different NIHSS scores. Plasma miR-140-3p, miR-130a-3p, and miR-320b had high diagnostic value in AIS patients, which were correlated with inflammation and severity in stroke.

Abstract TP49: The Pupillary Light Reflex Detects Large Vessel Occlusion

Introduction: The pupillary light reflex (PLR) is a well-validated biomarker for neurologic monitoring and a decision-making tool for traumatic brain injury patients. We studied a machine learning-based mobile pupillometry platform in patients with acute ischemic stroke (AIS) with a large-vessel occlusion (LVO) prior to thrombectomy, compared to healthy volunteers. Methods: Pupillometry measurements were conducted with a mobile pupillometry platform (PupilScreen) and a digital infrared pupillometer (NeurOptics) for both pre-thrombectomy AIS subjects and healthy volunteers at an academic medical center. To correct for subject age differences, comparisons used the absolute inter-eye difference in each parameter for each subject by measuring the right:left (R:L) eye ratio absolute distance away from 1. Inter-eye difference means across subjects between AIS and healthy cohorts were analyzed for PLR changes in the presence of acute LVO using a t-test for independent means. Results: Seven AIS patients (4 female, 3 male; 1 Hispanic, 6 Caucasian; mean age 60.9 years) and 32 healthy patients (19 female, 13 male; 1 Hispanic, 2 African American, 3 Native American, 5 Asian, 21 Caucasian; mean age 34.4) were enrolled. All LVOs were of the middle cerebral artery, with 3 on the left and 4 on the right. NPi value was above 3 (briskly reactive) for all subjects. However, the smartphone pupillometer demonstrated a statistically significant (p<0.05) increase in mean inter-eye differences for maximum diameter (mean inter-eye difference of 0.14 vs 0.03), minimum diameter (0.21 vs 0.03), and percent change (0.23 vs 0.05). The mean inter-eye differences were lateralized to the side of the LVO for maximum and minimum diameters (right LVO, max pre vs post R:L 0.95 vs 1.0, min 0.91 vs 0.98) (left LVO, max 0.98 vs 0.96, min 1.15 vs 0.93), and were increased in latency and mean constriction velocity whereas they were decreased in maximum constriction velocity and mean dilation velocity, but this was not statistically significant in this cohort. Conclusions: Patients with AIS from LVO demonstrate inter-eye differences in PLR parameters, and mobile pupillometry could be used as a pre-intervention biomarker of AIS in future study. Further investigation in a larger cohort is necessary.

Abstract 356: Phospholipid Profile Of Cerebral Thrombi In Acute Ischemic Stroke

Background and Purpose: The University of Washington Clot Bank (UWCB) has established a tissue banking protocol optimized for “omic” analysis for cerebral thrombi retrieved during standard-of-care thrombectomy. Thrombi from cerebral arteries of acute ischemic stroke (AIS) patients are a novel resource that allow for the evaluation of lipid biological markers present at the time of ictus. The pathophysiological processes following AIS are complex, and involve ischemia, inflammation, and disturbances of lipid metabolism. The purpose of this study was to characterize the lipid profile from cerebral thrombi in AIS patients. Methods: The UWCB study is a non-probability, convenience sampling of adult subjects (> 18 years of age) who undergo thrombectomy for vascular occlusion. Lipidomics analysis was performed using LC-MS of untargeted lipids on thrombi taken from cerebral arteries of AIS subjects who underwent thrombectomy. Random forest, a supervised machine learning method, was employed to identify lipids associated with cerebral thrombi. Results: Five subjects (age = 53 ± 26.4, 3 males) were included from the UWCB registry. The most common comorbid conditions were atrial fibrillation (40%) and hypertension (40%). The top 10 metabolites identified from the random forest analysis, were of phosphatidylethanolamine molecular species. Phospholipids are involved in structural and functional integrity of cellular membranes and mediate host inflammatory responses. They are a key component of bacterial membranes. Changes in the structure or function of membrane phospholipids of host or relevant human microbiota may lead to alterations in membrane permeability and contribute to pathology of diseases such as neurodegeneration. Conclusion: An untargeted LC-MS lipidomics approach was used to identify lipids in cerebral thrombi at the time of mechanical thrombectomy. The top 10 lipids present in cerebral thrombi were identified, which included significant concentrations of phosphatidylethanolamine species. Because phospholipids play a key regulatory role in complex downstream cellular function, these findings may be of great significance in understanding AIS pathophysiology that has the potential to inform personalized preventive strategies.

Physiological Aspects of Plasma Osmolarity and its Association with the Clinical Severity of Ischemic Stroke Evaluated with the NIHSS: A Cross-sectional Study

BACKGROUND: Ischemic stroke is one of the leading causes of mortality and disability worldwide. Recent studies have observed that some physiological factors play a pivotal role in determining stroke severity, which can be assessed using the National Institutes of Health Stroke Scale (NIHSS) score. Hydration status is one of the most frequently studied physiological factors and can be evaluated by measuring plasma osmolarity levels. However, studies regarding the association between plasma osmolarity and stroke severity remain scarce. AIM: This study aimed to investigate the association between increased blood plasma osmolarity levels and the NIHSS scores in patients with acute ischemic stroke. METHODS: This cross-sectional study obtained medical records of subjects aged 18–80 years old who were diagnosed with their first acute ischemic stroke from January to March 2021 at the Siloam Hospitals Lippo Village Tangerang in Indonesia. RESULTS: The NIHSS scores of patients with acute ischemic stroke were observed to have a moderate positive correlation with plasma osmolarity (p = 0.004, r = 0.309). Patients with an elevated plasma osmolarity had higher NIHSS scores than those with normal levels of plasma osmolarity (8.52 ± 5.01 vs. 6.03 ± 3.72). CONCLUSIONS: Higher levels of plasma osmolarity among acute ischemic stroke subjects correlated positively with increased NIHSS scores on admission.

Abstract WMP120: Vascular Risk Factor Reduction Is Associated With Corneal Nerve Regeneration In Patients With Tia And Ischemic Stroke

Background and Purpose: Vascular risk factors are associated with transient ischemic attack (TIA), acute ischemic stroke (AIS) and corneal nerve damage. We have assessed if an improvement in vascular risk factors in patients with TIA and AIS is associated with corneal nerve regeneration. Methods: Patients with TIA or AIS and control subjects underwent assessment of clinical and vascular risk factors and corneal confocal microscopy (CCM) at baseline and 1-year follow up. Results: Eighty-one patients with TIA (n=28), AIS (n=53) and control subjects (n=56) were studied. Systolic blood pressure (SBP)( P =0.000), diastolic blood pressure (DBP) ( P =0.000) and HbA1 c (P=0.000) were significantly higher and HDL ( P =0.000), corneal nerve fiber length (CNFL) (P=0.000), corneal nerve fiber density (CNFD) (P=0.000) and corneal nerve branch density (CNBD) (P=0.003) were significantly lower in patients with TIA/AIS compared to controls. At follow up, there was a significant decrease in triglycerides (-0.37 mmol/l, P=0.005), total cholesterol (-1.12 mmol/l, P=0.000); LDL-cholesterol (-1.08 mmol/l, P=0.000), SBP (-24.76 mmHg, P=0.000), DBP (-14.24 mmHg, P=0.000) and HbA1 c (-0.50 mmol/l, P=0.027) and an increase in HDL (0.10 mmol/l, P=0.010), CNFL (1.48 mm/mm 2 , P=0.018), CNFD (1.66 no./mm 2 , P=0.024), and CNBD (26.90 no./mm 2 , P=0.000). The improvement in lipids and blood pressure was associated with an increase in corneal nerve parameters ( P <0.05). Conclusions: An improvement in vascular risk factors in patients with TIA or AIS is associated with corneal nerve regeneration. CCM could be used to assess the effectiveness of risk factor reduction in patients with TIA or AIS.

Inhibition of HDAC3 and ATXN3 by miR-25 prevents neuronal loss and ameliorates neurological recovery in cerebral stroke experimental rats.

HDAC3 plays important role in regulating memory and plasticity of neurons. We studied the role of miR-25 against HDAC3-induced neuronal injury in acute ischemic stroke. Subjects reported for acute stroke were included in the study. The rat model of middle cerebral artery occlusion was developed and received miR-25 agomir and antagomir treatments via intra-cerebroventricular injection. The brain tissues were processed and neuronal cells were isolated and submitted to oxygen glucose derivation-mediated injury. mRNA levels were studied by RT-PCR and protein levels by ELISA method. TUNEL and nuclear protein staining was done to find the ischemic area. Behavioral studies were carried out by Morris water maze test and beam balance test. Results suggested a significant increase in plasma miR-25 levels observed in acute ischemic stroke subjects. The levels of miR-25 were increased in the tissues of infarcted area of brain tissues of rats. However, the expression of miR-25 decreased in neuronal cells but increased in supernatant post-oxygen glucose deprivation. The treatment of miR-25 agomir decreased the infarct volume and apoptosis of neurons in MCAO rats, and it also improved the plasticity of neurons and axons, down-regulated ATXN3 and HDAC3 levels, and improved acetyl-H3K9 expression. In vitro outcomes suggested that miR-25 inhibited HDAC3 neurons and modulated the oxygen glucose deprivation injury in neurons. The treatment of RGFP966 increased the acetyl-H3K9 levels and prevented the miR-25 antagomir-induced injury. The study suggested miR-25 as an important predicting biomarker in acute ischemia injury. KEY POINTS: • HDAC3 is key regulator for neuronal health. • miR-25 was overexpressed in acute ischemic stroke condition. • miR-25 inhibits loss of neurons and provides neuronal recovery in animal model of stroke via inhibiting HDAC3 and ATXN3.

Prediction of recurrent stroke among ischemic stroke patients with atrial fibrillation: Development and validation of a risk score model.

There is currently no validated risk prediction model for recurrent events among patients with acute ischemic stroke (AIS) and atrial fibrillation (AF). Considering that the application of conventional risk scores has contextual limitations, new strategies are needed to develop such a model. Here, we set out to develop and validate a comprehensive risk prediction model for stroke recurrence in AIS patients with AF. AIS patients with AF were collected from multicenter registries in South Korea and Japan. A developmental dataset was constructed with 5648 registered cases from both countries for the period 2011‒2014. An external validation dataset was also created, consisting of Korean AIS subjects with AF registered between 2015 and 2018. Event outcomes were collected during 1 year after the index stroke. A multivariable prediction model was developed using the Fine-Gray subdistribution hazard model with non-stroke mortality as a competing risk. The model incorporated 21 clinical variables and was further validated, calibrated, and revised using the external validation dataset. The developmental dataset consisted of 4483 Korean and 1165 Japanese patients (mean age, 74.3 ± 10.2 years; male 53%); 338 patients (6%) had recurrent stroke and 903 (16%) died. The clinical profiles of the external validation set (n = 3668) were comparable to those of the developmental dataset. The c-statistics of the final model was 0.68 (95% confidence interval, 0.66 ‒0.71). The developed prediction model did not show better discriminative ability for predicting stroke recurrence than the conventional risk prediction tools (CHADS2, CHA2DS2-VASc, and ATRIA). Neither conventional risk stratification tools nor our newly developed comprehensive prediction model using available clinical factors seemed to be suitable for identifying patients at high risk of recurrent ischemic stroke among AIS patients with AF in this modern direct oral anticoagulant era. Detailed individual information, including imaging, may be warranted to build a more robust and precise risk prediction model for stroke survivors with AF.

Small dense low-density lipoprotein cholesterol is strongly associated with NIHSS score and intracranial arterial calcification in acute ischemic stroke subjects

Intracranial artery calcification (IAC) is an important risk factor for cerebral infarction and a key biomarker for intracranial artery stenosis. Small dense low-density lipoprotein cholesterol (sd-LDL-c) was independently associated with increased cardiovascular events and coronary calcification. Our study assessed whether sd-LDL-c is an independent factor for IAC in acute ischemic stroke (AIS) patients. This cross-sectional study involved a total of 754 patients with AIS (mean age: 65 ± 13.2 years). All the patients had received brain computed tomography angiography (CTA) examination to evaluate IAC. Serum sd-LDL-c levels and other biochemical parameters were analyzed. Admission NIHSS score and mRS score at discharge were collected. After 60-days 85 patients died during hospitalization and follow-up. Partial correlation analysis showed that serum sd-LDL-c levels were associated with admission NIHSS score and IAC score after adjusted age and gender. Logistic regression analysis showed that serum sd-LDL-c levels independently predicted NIHSS scores (β = 1.537, 95%CI: 0.134-2.878, p = 0.042) and IAC scores (β = 1.355, 95%CI: 0.319-2.446, p = 0.015). The average level of sd-LDL-c in patients who died was also significantly increased compared to survival patients (1.04 ± 0.59 vs 0.88 ± 0.44 mmol/L, p = 0.017). However, multivariate logistic regression analysis showed serum sd-LDL-c levels could not predict all-cause mortality and prognosis in AIS patients. Our study found that sd-LDL-c as a strong atherogenic lipid particle can independently predict admission NIHSS scores and the severity of cerebral artery calcification in AIS patients. However, its prognostic value in AIS patients still needs further study in the future.

Abstract WP120: Welcoming the New Kid on the Block; The Phase IIb Prospective, Randomized, Open-Label, Blinded Endpoint (PROBE) Study of NanO 2 TM Neuroprotection in Large Vessel Strokes

Background: NVX-208 (NanO 2 TM ) was recently examined in a completed randomized, placebo-controlled and double-blinded dose escalation Phase Ib/II safety trial in acute ischemic stroke (AIS) patients and was found to be safe in all dosage levels. Exploratory aims indicated early treatment in the highest NanO 2 TM dose cohort improved clinical outcomes of early NIHSS and 90-day mRS. In the current Phase 2b protocol, NanO 2 TM ’s enhanced oxygen delivery from the blood to tissue will be examined in early AIS subjects with large vessel occlusions (LVO). LVO patients will provide the optimal assessment for NanO 2 TM to maintain penumbra tissue viability. The Phase 2b primary objective will be to assess functional recovery and subject independence. Drug information: NanO 2 TM is an emulsion of 2% dodecafluoropentane (DDFP) in stabilizers (sucrose, PEG-Telomer-B) and phosphate buffered saline (pH 7.0) that is a highly efficient fluorocarbon oxygen transporter. Compared to previously developed fluorocarbon oxygen carriers, NanO 2 TM carries far more oxygen per gram of fluorocarbon. Because DDFP is not metabolized, almost 100% of administered doses was recovered in the subject’s breath as DDFP. Hypothesis: NanO 2 TM given early to subjects with LVO ischemic stroke will maintain penumbra tissue viability. Methods: Phase 2b study sites will include multiple stand-alone and hub and spoke systems located across the United States. Central IRB and safety monitors will provide oversight and support coverage. Key methodology includes providing early first dosage administration of NanO 2 TM or placebo (study treatment) to identify and consent LVO AIS subjects with viable penumbra. For drip and ship patients, second and third doses will be given en route or after arrival at the hub hospital and after revascularization procedures, respectively. Following the third dose, all subjects will receive study treatment dosing out to 24 hours, each dose at 90 minute intervals. 24-hour imagery assessments will confirm infarct volume. All final angiograms and 24-hour imaging data will be sent to core labs for blinded confirmatory review. Subject recovery and independence will be assessed throughout the study to 90 days. Conclusion: Study projected start date is early to mid-2020.

Association between Serum Gamma-glutamyl transferase and Intracranial Arterial Calcification in Acute Ischemic Stroke Subjects

Intracranial artery calcification (IAC) is an important risk factor for cerebral infarction and a key biomarker for intracranial artery stenosis. Gamma-glutamyl transferase (GGT) has been independently associated with increased cardiovascular events and coronary calcification. Our study assessed whether GGT is an independent factor for IAC in acute ischemic stroke (AIS) patients. This cross-sectional study involved a total of 754 patients with AIS (mean age: 65 ± 13.2 years). All the patients had received brain computed tomography angiography (CTA) examination to evaluate IAC. Further, serum GGT levels and other biochemical parameters were analyzed. The average GGT level in patients who died was also significantly increased (37.0 ± 26.8 vs 29.0 ± 21.5 U/L, p = 0.012). Partial correlation analysis showed that serum GGT levels were associated with NIHSS score at admission after adjustment for age and gender was considered (r = 0.150, p = 0.001). Logistic regression analysis showed that serum GGT levels independently predicted all-cause mortality (OR = 1.036, 95% CI: 1.014–1.060, p = 0.002), NIHSS scores (β = 0.051, 95% CI: 0.020–0.082, p = 0.001) and IAC scores (β = 0.006, 95% CI: 0.003–0.014, p = 0.005) in male patients. Each SD (standard deviation) increase of serum GGT levels was also associated with risk of all-cause mortality (OR = 2.272, 95% CI: 1.364–3.787, P = 0.002). GGT levels in patients with severe IAC were significantly elevated (37.6 ± 33.6 vs 28.6 ± 19.2, p < 0.001). However, serum GGT levels could not independently predict the severity of IAC in AIS patients. Our study identified that serum GGT levels were significantly elevated in patients who died, and the GGT levels had a certain association with the risk of death and IAC in male patients.

Abstract TMP8: High Flow Normobaric Oxygen (NBO) Therapy Provides Effective Neuroprotection After Endovascular Recanalization in Acute Ischemic Stroke

Introduction: Recent advancements in endovascular thrombectomy for large vessel acute ischemic stroke (AIS) have achieved longer intervention time windows (16-24 h) and higher rates of revascularization (71%). Despite improvements, 40% of patients still have severe disability [modified Rankin scale (mRS): 3-5] with 15% mortality. Thus, adjuncts to improve clinical outcomes after endovascular recanalization need to be explored. NBO has long been recognized as a potential adjuvant therapy in AIS. Previous clinical trials have failed to demonstrate efficacy, while vessel recanalization was not assessed in the trials. The present study was performed to determine whether administration of NBO after endovascular recanalization conveys a clinical benefit. Methods: In this single-center prospective study (ChiCTR-INR-17013685), all AIS patients with large vessel occlusion who underwent endovascular recanalization (TICI≥1) were recruited between January 2016 to June 2018. Patients received NBO therapy by Venturi mask (FiO2 50%, 15 L/min) or routine low-dose oxygen supplementation (3 L/min) for 6 h, immediately after vessel recanalization. Clinical outcome measures, including NIIHSS scores, mRS scores, and mortality, as well as the incidence of symptomatic intracerebral hemorrhage (ICH) were recorded. Results: 138 AIS subjects (69 randomized to NBO) were analyzed. Average NIHSS score at stroke onset were similar (17.7±5.1 in NBO;17.8±5.1 with control, p=0.89). There were no significant differences in other baseline characteristics either. Mild disability (mRS 0-3) in patients in the NBO group (78%) was significantly higher (p=0.04) than in control (61%) at 90 days. Severe disability (mRS 3-5) was equal in both groups (30 v. 26%, p=0.706), while mortality in the NBO group (9%) was largely decreased (p=0.016) compared to control (25%). Additionally, 61% (n=42) of patients in the NBO group were functionally independent (mRS 0-2) compared to 49% (n=34) in control, although this difference did not reach a significant level (p=0.231). ICH was low in both groups (3 vs 7%, p=0.44). Conclusion: The utilization of NBO following endovascular revascularization appears to be safe and may enhance the therapeutic effect of endovascular thrombectomy in AIS.

Prognostic value of global left atrial peak strain in patients with acute ischemic stroke and no evidence of atrial fibrillation.

Prognostic stratification of acute ischemic stroke (AIS) patients without atrial fibrillation (AF) remains a challenge. Two-dimensional speckle tracking echocardiography (2D-STE) has recently been introduced for dynamic evaluation of left atrial function. However only few data are actually available regarding the application of 2D-STE in AIS patients. The aim of our study was to assess the prognostic role of global left atrial peak strain (GLAPS), measured by 2D-STE, in AIS patients without AF history. Eighty-five AIS patients (mean age 74.1 ± 12.1 years, 49 males) with normal sinus rhythm on ECG and without AF history were enrolled in the prospective study. All patients underwent a complete echocardiographic study with 2D-STE. At 1year follow-up, we evaluated the occurrence of a composite endpoint of all-cause mortality plus cardiovascular re-hospitalizations. GLAPS was markedly reduced in AIS patients (15.71 ± 4.70%), without any statistically significant difference between the stroke subtypes. At 1-year follow-up, 14 deaths and 17 hospital readmissions were detected in AIS subjects. On a multivariate Cox model, variables independently associated with the occurrence of the composite endpoint were the "Rankin in" Scale (HR 1.69, p = 0.001), GFR (HR 0.98, p = 0.03) and the GLAPS value (HR 0.78, p < 0.0001). A GLAPS value ≤ 15.5% predicted the composite endpoint with sensitivity of 100% and specificity of 80%. A GLAPS value ≤ 15.5% reflects a more advanced atrial cardiomyopathy and might provide a reliable and useful prognostic risk stratification of AIS patients without AF history.

Elevated C-reactive Protein and Depressed High-density Lipoprotein Cholesterol are Associated with Poor Function Outcome After Ischemic Stroke.

C-reactive protein is an established marker of inflammation that can impair the protective function of High Density Lipoprotein Cholesterol (HDL-C). The combined effect of Creactive protein and HDL-C on long-term outcomes in patients with stroke remains uncertain. A total of 3124 acute ischemic stroke subjects from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) were included in this analysis. Participants were divided into four groups according to CRP and HDL-C levels on admission. The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at one year after stroke. Compared to participants with low CRP/ high HDL-C, adjusted odd ratios for primary outcome for those with low CRP /low HDL-C, high CRP /high HDL-C and high CRP /low HDL-C were 1.06(0.81-1.39),1.78(1.31-2.41) and 2.03(1.46-2.80), respectively, after multiple adjustments. Adding serum CRP and HDL-C status to a model containing conventional stroke risk factors significantly improve risk reclassification for the combined outcome of death and major disability (NRI: 6.85%, P=0.005; IDI: 2.57%, P=0.002). Moreover, no interaction was observed between CRP and HDL-C in relation to stroke outcomes (P-interaction >0.05 for all). High CRP with low HDL-C levels was associated with death and major disability within one year after ischemic stroke. The findings suggest that the ischemic patients with both high CRP and low HDL-C should be treated with reducing CRP and promoting HDL-C levels.

Prognostic Value of White Blood Cell in Acute Ischemic Stroke Patients.

It is unclear whether white blood cell on admission has a prognosis value on ischemic stroke and whether its function is affected by other inflammation factors. We hypothesized that elevated white blood cell is associated with stroke severity and 3-month mortality after acute ischemic stroke. A total of 3891 acute ischemic stroke subjects from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) were included in this analysis. Participants were divided into four groups according to quartiles of white blood cell on admission (cutoff points for the quintiles: 5.60×109/L,6.83×109/L,8.50×109/L). The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 3 months. Secondary outcomes were major disability, death, and vascular events, respectively. After adjustment for major conventional risk factors, elevated white blood cell on admission was associated with poor primary and secondary outcomes after acute ischemic stroke. Compared with the lowest quartile, the ORs (95% CIs) for the highest quartile were 1.79 (1.37-2.91) and 1.62 (1.21-3.55) for primary outcome in model 1 and model 2. In addition, there was a linear association between white blood cell and primary outcome at 3-months (P for linear trend = 0.001). This analysis indicated that elevated white blood cell on admission is associated with 3-months poor prognosis in ischemic stroke patients independently of other inflammation factors. The results emphasize the need for further research on the application of anti-inflammatory therapy.

Determining the joint effect of obesity and diabetes on functional disability at 3-months and on all-cause mortality at 1-year following an ischemic stroke

BackgroundObesity and diabetes mellitus, or diabetes, are independently associated with post-ischemic stroke outcomes (e.g., functional disability and all-cause mortality). Although obesity and diabetes are also associated with post-ischemic stroke outcomes, the joint effect of obesity and diabetes on these post-ischemic stroke outcomes has not been explored previously. The purpose of the current study was to explore whether the effect of obesity on post-ischemic stroke outcomes differed by diabetes status in a cohort of acute ischemic stroke subjects with at least a moderate stroke severity.MethodsData from the Interventional Management of Stroke (IMS) III clinical trial was analyzed for this post-hoc analysis. A total of 656 subjects were enrolled in IMS III and were followed for one year. The joint effects of obesity and diabetes on functional disability at 3-months and all-cause mortality at 1-year were examined.ResultsOf 645 subjects with complete obesity and diabetes information, few were obese (25.74%) or had diabetes (22.64%). Obese subjects with diabetes and non-obese subjects without diabetes had similar odds of functional disability at 3-months following an ischemic stroke (adjusted common odds ratio, 1.038, 95% CI: 0.631, 1.706). For all-cause mortality at 1-year following an ischemic stroke, obese subjects with diabetes had a similar hazard compared with non-obese subjects without diabetes (adjusted hazard ratio, 1.005, 95% CI: 0.559, 1.808). There was insufficient evidence to declare a joint effect between obesity and diabetes on either the multiplicative scale or the additive scale for both outcomes.ConclusionsIn this post-hoc analysis of data from the IMS III clinical trial of acute ischemic stroke patients with at least a moderate stroke severity, there was not sufficient evidence to determine that the effect of obesity differed by diabetes status on post-ischemic stroke outcomes. Additionally, there was not sufficient evidence to determine that either factor was independently associated with all-cause mortality. Future studies could differentiate between metabolically healthy and metabolically unhealthy patients within BMI categories to determine if the effect of obesity on post-stroke outcomes differs by diabetes status.

Prognostic significance of hs-CRP in acute ischemic stroke patients

Background: Stroke, a serious neurological disease is a major cause of death and disability throughout world. The pathophysiology of stroke involves inflammatory pathways, oxidative damage, apoptosis, angiogenesis and neuroprotection. High sensitivity C - reactive protein (hs-CRP) is associated with atherosclerosis and predict incident stroke in many patients. Objective of present study was to find out change in pattern of hs-CRP in acute ischemic stroke (AIS) patients during 3-months follow up and its prognostic significance.Methods: Single centre prospective cross-sectional time bound study. 256 were screened and 130 meet the inclusion and exclusion criteria, of which 100 gave informed consent and 80 patients completed the study at 3 months. Demographic, clinical parameters including NIHSS scoring, biochemical analysis was collected at enrolment, discharge and at end of the study.Results: hs-CRP levels in AIS increased significantly (within 24 hours of stroke) and continued to increase further at discharge, while decreased significantly during 3 months follow up. &gt;7mg/dl hs-CRP at admission had 3.5 fold higher risk of mortality. Age &gt;60 years, metabolic syndrome, hyperlipidemic, SBP &gt;160mmHg and hs-CRP &gt; 7 mg/dL increases relative risk in AIS stroke patients by 1.42, 1.09, 1.11, 1.577 and 3.23 fold respectively.Conclusions: hs-CRP increased significantly in AIS patients during 1st weeks of stroke with subsequent gradual decrease by the end of 3 months, the severity scoring system could determine prognosis on admission to ICU while hs-CRP is the main factor determining short as well as long term prognosis. We recommend serial measurements of hs-CRP for prognostication in AIS subjects.

Aging alters the immunological response to ischemic stroke

The peripheral immune system plays a critical role in aging and in the response to brain injury. Emerging data suggest inflammatory responses are exacerbated in older animals following ischemic stroke; however, our understanding of these age-related changes is poor. In this work, we demonstrate marked differences in the composition of circulating and infiltrating leukocytes recruited to the ischemic brain of old male mice after stroke compared to young male mice. Blood neutrophilia and neutrophil invasion into the brain were increased in aged animals. Relative to infiltrating monocyte populations, brain-invading neutrophils had reduced phagocytic potential, and produced higher levels of reactive oxygen species and extracellular matrix-degrading enzymes (i.e., MMP-9), which were further exacerbated with age. Hemorrhagic transformation was more pronounced in aged versus young mice relative to infarct size. High numbers of myeloperoxidase-positive neutrophils were found in postmortem human brain samples of old (> 71 years) acute ischemic stroke subjects compared to non-ischemic controls. Many of these neutrophils were found in the brain parenchyma. A large proportion of these neutrophils expressed MMP-9 and positively correlated with hemorrhage and hyperemia. MMP-9 expression and hemorrhagic transformation after stroke increased with age. These changes in the myeloid response to stroke with age led us to hypothesize that the bone marrow response to stroke is altered with age, which could be important for the development of effective therapies targeting the immune response. We generated heterochronic bone marrow chimeras as a tool to determine the contribution of peripheral immune senescence to age- and stroke-induced inflammation. Old hosts that received young bone marrow (i.e., Young → Old) had attenuation of age-related reductions in bFGF and VEGF and showed improved locomotor activity and gait dynamics compared to isochronic (Old → Old) controls. Microglia in young heterochronic mice (Old → Young) developed a senescent-like phenotype. After stroke, aged animals reconstituted with young marrow had reduced behavioral deficits compared to isochronic controls, and had significantly fewer brain-infiltrating neutrophils. Increased rates of hemorrhagic transformation were seen in young mice reconstituted with aged bone marrow. This work suggests that age alters the immunological response to stroke, and that this can be reversed by manipulation of the peripheral immune cells in the bone marrow.

Long-term outcomes of acute ischemic stroke patients treated with endovascular thrombectomy: A real-world experience

Background and purposeLong-term follow-up of large trials have confirmed the superiority of endovascular thrombectomy (ET) for treating acute ischemic stroke (AIS). However, it is still unknown whether these results can be generalized to clinical practice. In this study, we aimed to determine the long-term outcomes of AIS post-ET in the real-world clinical practice. MethodsThis observational study is based on a single-center prospective registry study. AIS patients were treated with second-generation stent retrievers from December 2012 to April 2016. The primary outcome was modified Ranks scale (mRS) at the time of the latest assessment. Favorable outcome was defined as mRS scores 0–2, and the unfavorable outcome was defined as mRS scores 3–6. ResultsEighty-nine AIS subjects with large artery occlusion in anterior circulation undergoing ET were eligible for analysis. Median follow-up duration was 20 months (interquartile range 6–32), and 47 subjects (53%) achieved favorable outcome whereas 17 subjects (19%) were functional dependence and 25 subjects (28%) died. Independent predicators for long-term unfavorable outcome were higher baseline National Institutes of Health Stroke Scale (NIHSS) score (odd ratio:1.21;95% confidence interval 1.09–1.35; p < 0.001) and symptomatic intracerebral hemorrhage (sICH) (odd ratio:16.45;95% confidence interval 1.34–193.44; p = 0.026). More subjects of large-artery-atherosclerosis underwent permanent intracranial stenting (22%vs.10%) as compared with those of cardioembolism, while subjects of cardioembolism were more likely to experience sICH (13%vs.8%) and died (32%vs.16%). ConclusionsOver half of AIS patients can achieve favorable long-term outcomes post-ET. Higher baseline NIHSS scores and sICH are independently associated with unfavorable outcome. Overall, clinical practice in this single canter can replicate the long-term outcomes from the published endovascular clinical trials.