bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 139: Which Cell Populations Within The Mononuclear Fraction Of Bone Marrow Contribute To The Beneficial Effects Of Autologous Bone Marrow Cell Therapy For Stroke
Authors: Yang Bing , Strong Roger , Schaar Krystal , xi Xiaopei , Savitz Sean
Published: March 2022

Background:
Bone marrow derived mononuclear cells (MNCs) enhance recovery after acute stroke in animal models and clinical trials are testing MNCs in stroke patients. MNCs are composed of a mixture of various cell populations. We aimed to determine which cell populations within MNCs contribute to their beneficial effects in stroke.

Methods:
Male SV129 mice were subjected to transient CCAo/MCAo for 90 minutes. After 24hrs, animals were randomly assigned to 6 groups: 1) Saline; 2) Whole MNCs; 3) MNCs depleted of lymphoid cells; 4) MNCs depleted of myeloid cells; 5) MNCs depleted erythroid cells; 6) MNCs depleted of stem cells (n=5 per group). Bone marrow was harvested and MNCs were isolated. In group 2, the whole MNC fraction was dosed at 1.5 million cells per animal IV. The amount of cells administered in groups 3 to 5 was the same dose of MNCs as in group 2 minus the specific fraction depleted. At day 3 after stroke, all animals were sacrificed. Serum was collected for Multiplex assay. Brains were harvested to evaluate the infarction sizes with TTC.

Results:
MNCs reduced infarct maturation compared with saline. The depletion of lymphoid, myeloid, or stem cell populations from the whole fraction of MNCs significantly attenuated or abolished the cytoprotective effect. Only the depletion of erythroid cells had no effect on lesion size. In addition, animals treated with MNCs have a profound effect on a range of inflammatory cytokines. Serum IL-1β is reduced while IL-10 is increased. The depletion of different fractions of cells changes the inflammatory profile, e.g., an increase in IL-1β and a decrease in IL-10 when lymphoid cells were depleted.

Conclusions:
Different cell subpopulations from different lineages within MNCs are required to reduce infarct maturation in the post-ischemic brain. We are determining if depletion of these different fractions has an impact on behavioral outcomes. In addition, IL-10 may be an important cytokine underlying the cytoprotective effects of MNCs.
Abstract 143: Classification of Stroke Sub-types by Race-Ethnicities in the Stroke Genetics Network with Causative Classification System
Authors: Katsnelson Michael J , Rundek Tatjana , Sacco Ralph , Worrall Bradford B , Meschia James F , Ay Hakan , Woo Daniel , Brown Robert D , Rosand Jonathan , McArdle Patrick , Wassertheil-Smoller Sylvia , Kaplan Robert , Arsava Ethem M , Anderson Christopher D , Helenius Johanna , Biffi Alessandro , Kittner Steven ,   NINDS Stroke Genetics Network (SiGN) Investigators
Published: March 2022

Objectives:
Genetic and environmental influences contribute to differences in ischemic stroke phenotype across race-ethnic groups. The Causative Classification System (CSS) is an ischemic stroke phenotype characterization tool developed for etiological and causative classification. The CCS phenotypes across ethnic groups were analyzed and compared.

Methods:
The NINDS
S
troke
G
enetics
N
etwork (SiGN) is a large consortium aimed at identifying subtype-specific ischemic stroke susceptibility genes. Over 12,000 subjects at 22 sites across US and Europe were enrolled, with CSS locally adjudicated. Central CCS quality control was performed on all participants. Analysis was performed on 7,674 patients with complete workups.

Findings:
Significant ethnic differences were found in stroke etiology across ethnic groups (p <0.0001) with large artery atherosclerosis present most commonly in Asians, cardioembolic sources among Caucasian Europeans, and lacunar strokes among African Americans. African Americans were the youngest ethnic cohort analyzed (see Table 1).

Conclusion:
Significant differences in stroke subtypes are present across ethnic groups. Future genetic analyses may contribute to our understanding of these differences.
Abstract 144: Southern Diet Pattern Increases Risk Of Stroke While Plant-based Pattern Decreases Risk Of Stroke in the REGARDS Study
Authors: Judd Suzanne E , Gutierrez Orlando , Kissela Brett M , Howard George , Locher Julie , Howard Virginia J , Newby P K , Shikany James M
Published: March 2022

Background:
Diet is one of many potential factors proposed to explain racial and regional differences in stroke. We examined prospectively the association of diet patterns with risk of stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

Methods:
Between 2003-2007, REGARDS enrolled black and white Americans aged 45 years or older. A two-stage analytic approach was employed. First, principle components analysis was used to assess underlying diet patterns using 56 food groups for 20,480 participants who completed the Block98 food frequency questionnaire. Second, participant scores (divided into quartiles) on these patterns were then considered as predictors of incident stroke using Cox regression. The factor analysis identified five dietary patterns: “Convenience” (Chinese and Mexican foods, pasta, pizza), “Plant-based” (fruits, vegetables, legumes), and “Southern” (fried foods, organ meats, sweetened beverages), “Sweets/Fats” (desserts, added sugars, sweet snacks) and “Alcohol/Salads” (alcohol, fats, vegetables).

Results:
Participants with a higher adherence to the Southern dietary pattern were more likely to reside in the Southeast (comparing Q4 to Q1: 64% vs 48%) and experienced a 41% increased risk of stroke (comparing Q4 to Q1: HR=1.41; 95% CI = 1.07, 1.85). In contrast, higher adherence to the Plant-based pattern was association with a 29% reduction in stroke risk (comparing Q4 to Q1: HR=0.71; 95% CI = 0.55, 0.91). The trend across quartiles was <0.001 indicating a dose response for adherence to each pattern. Adding socio-economic status, smoking, physical activity and total energy (calories) intake to the models attenuated the association but the direction remained the same and persisted in sub-group analysis examining only ischemic strokes. The Convenience, Sweets, and Alcohol patterns were not associated with stroke risk.

Discussion:
The present study suggests that foods common to Southern cuisine such as fried foods and sweetened beverages may increase the risk of stroke while diets rich in legumes, fruits, vegetables, and fish may reduce stroke risk. Interventions focusing on increasing plant-based foods and fish while reducing fried foods and sweetened beverages are needed.
Abstract 149: Endothelial NADPH Oxidase 4 Worsens Ischemic Stroke by Suppressing eNOS Activity
Authors: Arimura Koichi , Ago Tetsuro , Nishimura Ataru , Kuroda Junya , Sugimori Hiroshi , Kamouchi Masahiro , Sasaki Tomio , Kitazono Takanari
Published: March 2022

NADPH oxidase (Nox) family proteins are a major source of reactive oxygen species (ROS) and play various important roles in immune systems, arteriosclerosis, angiogenesis and aging. We have previously demonstrated that among the Nox proteins, Nox4 is abundantly expressed and is a major source of ROS in endothelial cells; however, its roles in endothelial cells are not fully understood. In the present study, we investigated the roles of endothelial Nox4 in brain ischemia, using mice with endothelial cell-specific Nox4 overexpression (Tg-EC-Nox4) and cultured human brain microvascular endothelial cells (HMEC) overexpressing Nox4.

Nox4 was abundantly expressed and was significantly upregulated in response to hypoxia at O2 1% (2.0-fold increase, p<0.001) in HMEC. Immunofluorescent double staining demonstrated that in a middle cerebral occlusion model (MCAO) of wild type mice, Nox4 was markedly upregulated in endothelial cells in peri-infarct area. We subjected Tg-EC-Nox4 mice and their littermates to either transient (ischemia 90 min and reperfusion) or permanent MCAO. Triphenyltetrazolium chloride staining demonstrated that infarct volume at 1 day after MCAO was significantly larger in Tg-EC-Nox4 than wild-type mice in both the models (transient MCAO: 151 %, permanent MCAO: 132 %, p<0.05). We overexpressed Nox4 by adenovirus in HMEC. In the endothelial cells overexpressing Nox4, angiopoietin-2 (Ang-2) was drastically upregulated (30-fold increase, p<0.0001) at mRNA levels and the phosphorylation of Akt at Ser-473 (47 %, p<0.01) and endothelial nitric oxide synthase (eNOS) at Ser-1177 (43 %, p<0.01) were significantly attenuated. Treatment with Ang-2 suppressed the phosphorylation of Akt and eNOS induced by angiopoietin-1 in a dose-dependent manner in HMEC. Consistently, Ang-2 mRNA was significantly increased (2.0-fold, p<0.05), and the phosphorylation of Akt (37 %, p<0.05) and eNOS (41 %, p=0.12) were suppressed in the ischemic hemisphere of Tg-EC-Nox4, compared to those of wild-type mice. In conclusion, the overexpression of endothelial Nox4 may increase infarct volume by suppressing eNOS activity through the upregulation of Ang-2 in brain ischemia.
Abstract 15: EMS In-Field Acute Stroke Severity Screening for Preferential Triage to a Comprehensive Stroke Center in Orlando, Florida
Authors: Allen Evan , Banerjee Paul , Lovec-Theobald Rhonda , Richards Donald , Husty Todd , Qureshi Adnan I
Published: March 2022

Background:
The Brain Attack Coalition identified Comprehensive Stroke Centers (CSCs) to play a critical role in coordinating acute stroke care within a geographic region. Severe acute stroke patients may benefit from CSC specific interventions (neurosurgical or endovascular interventions) but are often transported to Primary Stroke Centers (PSC’s) lacking CSC specific interventions. A Critical determinant of the value of EMS preferential CSC triage with occasional bypass of PSC’s is the rate of utilization of CSC specific interventions among these patients.

Methods:
We retrospectively evaluated combined data from two different EMS groups in two different counties using in-field modified versions of two different stroke severity scales designed to predict the presence of a large vessel occlusion: the 3 Item Stroke Scale (3I-SS) and the Los Angeles Motor Scale (LAMS). During the years 2007-2012 patients with the most severe suspected acute strokes were transported to a single CSC. We calculated the rate of utilization of CSC specific interventions and the length of stay based on in-field stroke severity scores.

Results:
On average, this EMS preferential CSC triage policy resulted in a combined total of 12 more patients transported to the CSC each month by EMS from these two counties. Of the 526 patients preferentially CSC triaged 77 (15%) received a CSC specific intervention. The odds of receiving a CSC specific intervention were higher among patients with higher LAMS scores of 4-5 (30 of 143 patients) compared to those with scores of 1-3 (0 of 26 patients, Odds ratio =3.84, 95% CI =1.2-12.15). The mean length of stay was higher among patients with higher LAMS scores of 4 and 5 (8.2 days, 95% CI 7-9.4) compared to those with lower LAMS scores of 1-3 (4.3 days, 95% CI 3.2-5.4).

Conclusions:
Our results support the ability of EMS to identify patients in-field with severe stroke-like symptoms that may require CSC specific intervention. PSC’s, CSC’s and EMS should collaboratively insure that these patients receive rapid evaluation for and prompt access to CSC specific interventions.
Abstract 156: SAMMPRIS Angiography Discloses Hemodynamic Effects of Intracranial Stenosis: Computational Fluid Dynamics of Fractional Flow
Authors: Liebeskind David S , Fong Albert K , Scalzo Fabien , Lynn Michael J , Derdeyn Colin P , Fiorella David J , Cloft Harry J , Chimowitz Marc I , Feldmann Edward ,   for the SAMMPRIS Investigators
Published: March 2022

Background:
Pressure gradients across an intracranial stenosis, or fractional flow (FF), may identify the hemodynamic significance of symptomatic lesions. Computational fluid dynamic (CFD) simulations on 3D morphology of such lesions can calculate these pressure gradients and model effects of systemic physiology interacting with these lesions, such as hypotension and induced hypertension. We studied SAMMPRIS angiography to calculate FF across symptomatic intracranial stenoses and modeled the downstream effect of systemic blood pressure (BP) fluctuations.

Methods:
Conventional angiography of symptomatic intracranial stenoses in the SAMMPRIS trial was converted from biplanar images to a 3D geometric mesh. CFD simulations were conducted with Ansys CFX on a Cray supercomputer to calculate FF derived from distal/proximal pressure gradients for each of 3 inflow conditions: normal BP (120/80 mm Hg), hypotension (90/60 mm Hg) and hypertension (180/120 mm Hg). Abnormal FF was defined as ≤ 0.8 during diastole to define hemodynamic significance of a stenosis.

Results:
407 patients with 70-99% symptomatic stenosis had conventional angiography with biplanar views available for 3D reconstruction in 249, and CFD simulations in 188 (25 VA, 45 BA, 32 ICA, 86 MCA). Under simulated normal inflow conditions (120/80 mm Hg), only 76/188 (40%) cases had low FF.

During simulated hypertension, FF improved to normal in 10/188 (5%) cases. Simulated hypotension caused FF to worsen from normal in 12/188 (6%) cases. Other hemodynamic parameters including shear stress could also be calculated and visually depicted in all cases.

Conclusions:
CFD and hemodynamic modeling of FF can be retrospectively performed after 3D conversion of biplanar angiogram views. FF estimates predict that only 40% of severe (70-99%) symptomatic intracranial stenoses are hemodynamically significant. Systemic BP fluctuations can be modeled during phases of the cardiac cycle to show downstream flow changes.
Abstract 157: Validation Of Quantitative Eeg In The Assessment Of Cerebral Vasodilatory Reserve In Patients With Severe Stenosis Of Intracranial Internal Carotid Or Middle Cerebral Artery
Authors: rathakrishnan rahul , yeo leonard L , Ahmad Aftab , Seow Phillip , sinha arvind , sharma vijay
Published: March 2022

Background and aim:
Estimation of cerebral vasodilatory reserve (CVR) provides important information about the adequacy of autoregulatory mechanisms in patients with severe steno-occlusive disease of intracranial internal carotid (ICA) or middle cerebral artery (MCA). Acetazolamide-challenged HMPAO-SPECT (Az-SPECT) is an established method of assessing CVR. Owing to the high cost and some radiation exposure, it cannot serve as the primary screening tool to select high-risk patients. Transcranial Doppler (TCD), often used as a screening tool, may be limited by insufficient temporal acoustic windows in a considerable proportion of patients. Quantitative electroencephalography (QEEG) monitors electrical brain activity with excellent temporal resolution. This pilot study aimed to study the feasibility of QEEG in assessing CVR in our cohort of ICA or MCA stenosis and its correlation with Az-SPECT.

Methods:
Consecutive symptomatic patients with severe steno-occlusive disease of ICA/MCA and impaired CVR on Az-SPECT were evaluated with QEEG. QEEG was recorded during breath-holding and hyperventilation, with 5minutes rest in between. The composite alpha index (CAI), which unifies fluctuations in alpha band power and its variablility, was calculated. An inter-hemispheric difference of more than 50% was deemed significant, with lower CAI indicating impaired CVR. Each modality was independently evaluated, with each cerebral hemispheres graded as having either impaired or preserved CVR.

Results:
14 patients (10 males, mean age 59yrs, range 42-73years) were included. There was good correlation between the grades assigned to each hemisphere based on QEEG and SPECT. (Spearman’s correlation, r=0.67, p=0.008).

Conclusion:
Our preliminary data suggests that QEEG reliably detects impaired CVR in patients with severe intracranial stenosis. It may be used as a primary screening tool in patients unsuitable for TCD evaluations or as a complementary test in identifying patients at high-risk for cerebral ischemia and candidates for possible revascularization procedures.
Abstract 159: Symptomatic MCA Plaque Enhancement on High Resolution MRI
Authors: Ryu Chang-Woo , Lee Kyung Jin , Jahng Geon-Ho
Published: March 2022

Objective
High-resolution MRI (HR-MRI) is the useful modality to evaluate the characteristics of intracranial arterial atherosclerotic plaque. The purpose of this study was to evaluate the relationship between the enhancement of middle cerebral artery (MCA) plaque on post-contrast HR-MRI and ischemic stroke.

Materials and methods
Thirty four patients (19 females, 15 males, mean age: 69.0 years ± 12.1) with isolated MCA stenosis of 50% or more were enrolled in this study. Post-contrast axial 3 dimensional T1-weighted VISTA sequence (TR, 350 ms; TE, 19.51 ms; matrix, 360x299; field of view, 113x180; section thickness, 1 mm; total scan time, 3 min 4 sec) was acquired for assessment of the plaque enhancement. The subjects were divided into two groups (symptomatic or asymptomatic), based on the presence of recent ischemic stroke in the same ipsilateral MCA territory as the MCA stenosis. The signal intensity of plague in the stenotic segment and the CSF were measured by ROI on T1-VISTA. It is subdivided the MCA stenosis into moderate stenosis and severe stenosis by the stenotic degree of 80%. The plaque-to-CSF contrast ratio, the stenotic degree, and the clinical parameters (age, sex, atherosclerotic risk factors, ESR) between two groups were compared. Multivariate logistic regression analysis was used to test for the association of contrast ratio, stenotic degree, and the clinical parameters with ischemic stroke.

Results
Twenty patients had symptomatic MCA stenosis, and 14 patients had asymptomatic lesion. The plaque-to-CSF contrast ratio was a statistically significant difference between the symptomatic group (mean 5.29 ± 1.78) and asymptomatic group (3.67 ± 1.38). In the multivariate logistic regression analysis, the plaque-to-CSF contrast ratio was the only independent factor for ischemic stroke (OR=7.5, P<0.05).

Conclusion
The results of our study showed that the enhancement of plaques were significantly higher in symptomatic groups than in asymptomatic groups. It is assumed that the enhancement of symptomatic plaques could be related with the vulnerability.
Abstract 165: Is Sooner Better When It Comes To Carotid Artery Stenting In Patients With Transient Ischemic Attach (tia) Or Minor Stroke: Prospective Observational Study
Authors: Kass-Hout Tareq , Dumont Travis , Mokin maxim , Kass-Hout omar , Wach MIchael , Snyder Kenneth , Siddiqui Adnan , Levy Elad
Published: March 2022

Background:
Patients with symptomatic carotid artery stenosis presenting with TIA or minor stroke have a risk of recurrent devastating stroke of 21% within 2weeks and 32% within 12 weeks. Efficacy of early endarterectomy (CEA) has already been proven. However, data on ideal timing of Carotid Artery Stenting (CAS) is still lacking.

Methods:
A prospective observational cohort of elective endovascular procedures at our hospital was queried for consecutive cases of internal carotid artery stenting for minor symptomatic atherosclerotic stenosis inclusive of the years 2009-2011. A total of 438 patients were studied with the primary outcome measured as a combined incidence of major perioperative complications (stroke, Myocardial Infarction MI or death) at 90 days from procedure time, was compared between patients based on timing of procedure relative to onset of symptoms. Patients were stratified into four treatment groups: those treated urgently (0-2 days), early (3-7 days), routinely (8-14 days), or late (15-90 days). Incidence of the primary outcome was compared between groups using the Fisher’s exact test (SAS software, Cary NC).

Results:
Stent implantation was successful in all cases (100%). Combined incidence of major perioperative complications of stroke, MI or death at 90 days was 7% in the urgently treated group 0-2 days (10 out of 143), 11% in the early treated group 3-7 days (10 out of 110), 3% in the routinely treated group 8-14 days (3 out of 100) and 7% in the late treatment group 15-90 days (6 out of 85). Mortality was only reported in the urgently treated group and it was as high as 3% (5 out of 143).

Conclusion:
Little data is available regarding urgent carotid stenting post minor stroke or TIA. Out data suggest that the safest period to perform carotid artery stenting in symptomatic atherosclerotic stenosis is between 8-14 days with a rate of all combined major perioperative complications as low as 3%. Randomized and double-blinded trial is warranted to study this further.
Abstract 172: Vascular Predictors Of Cognitive Impairment In Patients With And Without Cardiovascular Disease: Results From Nhanes 1998-2001.
Authors: Gutierrez Jose , Lazar Ronald M , Marshall Randolph S
Published: March 2022

Objective:
To assess predictors of cognitive dysfunction in a nationwide sample of adults 60 years or older with and without cardiovascular disease (CVD)

Methods:
In non-institutionalized US adults randomly selected to participate in the National Health and Nutrition Examination Survey (NHANES), we used the survey-collected digit symbol substitution test (DSST) score as a surrogate of cognitive function. Stratified analysis was performed to sort out the effects of CVD and vascular risk factors on the DSST score. Univariate logistic regression was used to identify significant associations that were used to create an adjusted multivariate analysis.

Results:
The studied sample included 1607 participants, mean age 70.1 ± 0.3 years, 43% men, 85% Non-Hispanic Whites, 7% Hispanic and 5% non-Hispanic Black. Vascular risk factors included hypertension (HTN) in 68%, Diabetes (DM) in 16%, Dyslipidemia in 75%, and current smoking in 12%. Cardiovascular disease was reported in 20.8% -- 3.2 % stroke, 16.5 % cardiac disease and 1.1% both. In univariate analysis, statistically significant predictors of a lower DSS score were age (β -0.92 per year), Hispanic and Non-Hispanic Black ethnicities compared to non-Hispanic whites (β -18.1 and β -15.0, respectively), HTN (β -6.1), DM (β -7.6) and CVD (β -7.5); greater education and income both predicted higher DSS scores (β 9.7 and 5.3, respectively). Multivariate analysis confirmed all associations with the exception of HTN (β -1.4, P=0.08). In this adjusted model, both stroke and cardiac disease were independent predictors of lower DSS score (β -5.3 and -2.2, respectively). Stratifying by CVD status using the same multivariate model, DM was the only modifiable vascular risk factor predicting lower DSS score in those without CVD (β -4.8, P=0.001), whereas HTN was associated with lower DSST score only in those who reported having CVD (β -4.6, P=0.05).

Conclusion:
We confirmed the deleterious effects of HTN and DM on cognition in this nationwide sample, but showed that DM was associated with worse cognition in those without reported CVD, while HTN had a significant negative impact on cognition only in those who already had CVD. The mechanisms underlying these differential associations need further study.
Abstract 184: Irradiation Induces Gene Expression Changes In Cultured Murine Brain Endothelial Cells
Authors: Raoufi-Rad Newsha , Duong Hong , Stoodley Marcus
Published: March 2022

Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins and are the leading cause of hemorrhagic stroke in children and young adults. Treatment of large and deep AVMs remains challenging, therefore new and safe treatment methods are required. Our hypothesis is that stereotactic radiosurgery can be used to selectively alter AVM endothelial cell phenotype, allowing targeted molecular therapies that spare normal vessels. This study examined the post-radiation time course of gene expression changes of potential molecular targets. A murine brain endothelial cell culture (bEnd.3) was treated with 25 Gy using a linear accelerator; non-irradiated cells were used as controls. Quantitative real-time PCR was used to measure the relative gene expression at 1, 6, 12, 24, 48, 72, 96, 120, 144, and 168 h after radiation. Genes encoding for intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were found to be significantly up-regulated post irradiation (p<0.0001), with the maximum level of gene expression for ICAM-1 being evident at 144 h (9-fold) and for VCAM-1 at 120 h (23-fold). Additionally, leukocyte-endothelial cell adhesion molecule 2 (E-selectin) and leukocyte-endothelial cell adhesion molecule 3 (P-selectin) showed significantly increased gene expression at 24 h with 1.5-fold (p<0.001) and 2-fold (p<0.0001) increases respectively. These data support the hypothesis that stereotactic radiosurgery can significantly alter endothelial cell phenotype in AVMs, potentially enabling the use of ligand-based molecular targeting therapies such as the stimulation of thrombosis for AVM treatment.
Abstract 188: Clinical Factors Associated with Lesion Count in Familial Cerebral Cavernous Malformation Type 1 Patients with the Common Hispanic Mutation
Authors: Choquet Hélène , Nelson Jeff , Pawlikowska Ludmila , Akers Amy , Baca Beth , Khan Yasir , Hart Blaine , Morrison Leslie , Kim Helen
Published: March 2022

Introduction:
Cerebral Cavernous Malformations (CCMs) are clusters of abnormally enlarged, capillary cavities that can lead to hemorrhages, seizures, neurological deficits and death. Familial CCM type 1 (CCM1) is caused by mutations in KRIT1 and is characterized by multiple lesions that vary widely among patients. The factors that influence variability in lesion count within patients with the same gene mutation are not known. The purpose of this study was to identify clinical factors associated with lesion count among familial CCM1 patients who all carry the common Hispanic mutation (CCM1-CHM).

Methods:
As a part of the Brain Vascular Malformation Consortium (BVMC) study, we reviewed detailed clinical and neuroimaging data on 137 CCM1-CHM patients from 34 families with at least two members and 35 singletons. We performed a cross-sectional analysis of clinical factors and lesion count using linear regression analysis, adjusting for covariates and standard errors for clustering within families.

Results:
Sixty-three percent of patients were symptomatic at presentation with a mean age ± standard deviation (SD) at CCM diagnosis of 30.8 ± 18.7 years (range: 0.32-70.9). The main clinical symptom leading to diagnosis was hemorrhage (24%); others included seizure (21%), headache (24%), and focal neurologic deficit (4%). Lesion count (range: 0-713; mean ± SD: 63.7 ± 124.4) was highly variable among CCM1-CHM patients and positively correlated with increasing age (P<0.001). Prevalence of cardiovascular co-morbidities was: 40% for obesity, 11% for diabetes, 20% for hypertension and 19% for hyperlipidemia. Obesity was significantly associated with a 47% lower lesion count (P=0.006) in multivariate analysis adjusting for age (P<0.001), male gender (P=0.024), symptomatic presentation (P=0.144) and other cardiovascular co-morbidities.

Conclusions:
Hispanic familial CCM1-CHM patients present with a wide range in lesion count. Older age, male gender and absence of obesity may be predictors of higher lesion count. Further work is needed to elucidate how these factors influence lesion burden and determine associations with clinical outcomes.
Abstract 189: ARUBA - A Randomised Trial Of Unruptured Brain Avms
Authors: Stapf C , Moskowitz A J , Parides M K , Moquete E , Moy C S , Vicaut E , Mohr J P ,   and the international ARUBA investigators
Published: March 2022

RATIONALE:
Current invasive treatment for brain arteriovenous malformations (AVMs) is varied and includes endovascular procedures, neurosurgery, and radiotherapy. However, no controlled treatment data for any comparison of treatments, immediate or deferred, on the benefit of preventive therapy for unruptured brain AVMs have yet been performed.

DESIGN:
ARUBA is an international, multicenter, randomized, controlled, open, prospective clinical trial.

SAMPLE SIZE:
400 patients (1:1 random assignment).

POPULATION STUDIED:
Patients aged ≥18 years, diagnosed with an unruptured brain AVM considered by the local investigators to be suitable for attempted eradication.

Outcome measures:
The primary outcome is the composite event of death from any cause or stroke (hemorrhage or infarction confirmed by imaging). Clinical outcome status will be measured by the Rankin Scale, NIHSS, SF-36, and EuroQol.

INTERVENTIONS:
Patients are randomly assigned to best possible invasive therapy (medical management plus endovascular, surgical, and/or radiation therapy ) versus medical management alone. Patients will be followed for 5-10 years from randomisation.

PRIMARY AIM:
To determine whether a strategy of medical management alone is superior to invasive therapy for preventing the composite outcome of death from any cause or stroke (symptomatic haemorrhage or infarction) in the treatment of unruptured BAVMs.

SECONDARY AIM:
To determine whether treatment of unruptured BAVMs by medical management alone decreases the risk of death or clinical impairment (Rankin Score >/= 2) at 5 years post-randomization compared to invasive therapy.

TRIAL STATUS:
More than 200 patients have been enrolled worldwide.

SPONSOR:
NIH/NINDS (
NCT00389181
)

CONTACT:
jpm10@columbia.edu (www.arubastudy.org)
Abstract 192: Stroke in the WARCEF Trial
Authors: Pullicino Patrick , Thompson JLP , Sacco Ralph L , Sanford Alexandra R , Qian Min , Mohr JP , Homma Shunichi ,   for the WARCEF Investigators
Published: March 2022

Background
The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference between warfarin and aspirin in heart failure patients in sinus rhythm for the outcome of first to occur of 84 ischemic strokes (IS), 7 intracerebral hemorrhages or 531 deaths. Pre-specified secondary analysis showed a 48% HR reduction (p=0.005) in IS risk for warfarin vs. aspirin. We examined this IS benefit for warfarin in post-hoc analyses.

Methods
We used the Wilcoxon rank sum test, stratified by prior IS or TIA, to compare the distributions of mRS among warfarin and aspirin IS patients in WARCEF. Median (md) scores and interquartile ranges (IQR) are shown for warfarin and aspirin arms, respectively. We used Fisher’s exact test to compare the effect of warfarin vs. aspirin on fatal IS; a stratified exact test to compare proportions of severe (mRS 3-5) IS; and stratified Poisson regression to compare IS subtypes.

Results
Twenty-nine (2.5%) of 1142 patients on warfarin and 55 (4.7%) of 1163 on aspirin had IS. The warfarin IS rate (0.72 per 100 patient years [/100PY]) was lower than for aspirin (1.36/100PY). There were no differences between warfarin and aspirin IS patients in baseline mRS (md 1, IQR, 2, N=29 vs. md 1, IQR 2, N=55); fatal IS (3/29, 10.3% vs. 6/55, 10.9%, p=1.0), or post-IS (after 90+30 days) mRS (md 2, IQR 3, n=23 vs. md 2, IQR 3, n=48, p=0.437). There were also no differences between warfarin and aspirin in change from baseline to post-IS mRS (md 1, IQR 3, n=23 vs. md 1, IQR 3, n=48, p=0.884). Cardioembolic IS was significantly less frequent on warfarin than on aspirin (9 [0.22/100PY] vs. 22 [0.55/100PY], p=0.012). The warfarin arm showed trends to fewer severe (mRS 3-5) IS (3/23 [13.0%] vs. 16/48 [33.3%], p=0.086) and a lower rate of IS of potential cardioembolic etiology (15 [0.37/100PY] vs. 27 [0.67/100PY] p=0.063). There was no difference between warfarin and aspirin in rate of non-cardioembolic IS (5 [0.12/100PY] vs. 6 [0.15/100PY], p=0.768).

Conclusions
Warfarin appears superior to aspirin in reducing the frequency of cardioembolic IS in heart failure patients in sinus rhythm. This is supported by trends to lower frequencies of severe IS and potentially cardioembolic IS in patients on warfarin compared to aspirin.
Abstract 208: No Independent Association Between Extended-Release Niacin (ERN) Therapy and Ischemic Stroke in Patients with Established Cardiovascular Disease: A Detailed Analysis from the AIM HIGH Trial
Authors: Teo Koon , Goldstein Larry B , Chaitman Bernard R , Grant Shannon , Weintraub William S , Anderson David C , Sila Cathy A , Cruz-Flores Salvador , Padley Robert J , Kostuk William J , Anderson Todd J , Boden William E
Published: March 2022

Background:
Statins reduce cardiovascular (CV) events and stroke by 20-25% in both patients with established cardiovascular disease (CVD) and in asymptomatic patients at high risk for CVD. Meta-analyses also show that niacin reduces major CV events by 25% and stroke by 27%. In AIM HIGH, which evaluated the addition of extended-release niacin (ERN) to simvastatin in patients with established CV disease and low baseline levels of HDL-C, we observed an unexpected increased rate of ischemic stroke in those randomized to ERN. The present analysis explores possible reasons for the observed numerical excess of ERN-associated stroke.

Methods and Results:
Among 3,414 patients (85% male; mean age: 64±9 years) randomized to simvastatin + ERN (1,500-2,000mg/day or matching placebo to achieve an on-treatment LDL-C target of 40-80mg/dL), there was no difference in the trial’s composite primary endpoint at a mean 36-month follow-up. This included 50 fatal or non-fatal ischemic strokes, of which 18 (1.85%) occurred in the placebo arm and 32 (2.3%) in the niacin arm (age-adjusted HR 1.78; 95% CI 1.00-3.17, p=0.050). Multivariate step-wise analyses showed strong associations between ischemic stroke risk and age > 65 (HR 3.60 95% CI 1.83-7.09, p=0.0002) and history of stroke/TIA/carotid disease (HR 2.19 95% CI 1.23-3.90, p=0.0075), a moderate association with Lp(a) (HR 2.80, 95%CI 1.25 - 6.27, p=.012 comparing the middle to the lowest tertile), but an insignificant association between ischemic stroke and ERN (HR 1.74 95% CI .97-3.11, p=0.063).

Conclusion:
Although there was a numerical excess in ischemic strokes associated with the addition of ERN to simvastatin, the number of events was small and multivariable analysis accounting for known risk factors revealed no significant association between niacin treatment and subsequent ischemic stroke risk.
Abstract 21: Should Aphasic Ischemic Stroke Patients Undergo Pre-procedural Intubation prior to Endovascular Treatment?
Authors: Hassan Ameer E , Adil Malik M , Zacharatos Haralabos , Rahim Basit , Chaudhry Saqib A , Tekle Wondwossen G , Grigoryan Mikayel , Qureshi Adnan I
Published: March 2022

Background:
Current practice in the endovascular treatment of acute ischemic stroke includes pre-procedural intubation of aphasic stroke patients to ensure immobility during the procedure. Multiple series have shown that pre-procedural intubation for endovascular procedures leads to a higher rate of poor outcomes mandating a critical review of such ancillary interventions.

Objective:
To compare outcomes in acute ischemic stroke patients with aphasia of various severities undergoing endovascular treatment with or without pre-procedural intubation.

Methods:
All endovascularly treated acute ischemic stroke patients were identified through a prospective database maintained from two comprehensive stroke centers over a 6 year period. Patients’ risk factors, type of aphasia, and pre-procedural intubation status were obtained. The rate of unexpected intubation in patients without pre-procedural intubation was ascertained. The rates of poor outcome at discharge (modified Rankin score [mRS] of≥3) and intracerebral hemorrhage (ICH) were compared between those who did or did not undergo pre-procedural intubation after adjustment for age, gender, admission NIHSS score, diabetes mellitus, and cigarette smoking.

Results:
A total of 120 patients with aphasia were identified; with 60 (50%) patients intubated prior to the revascularization procedure. Among the remaining patients who were not intubated prior to the procedure 21 (35%), 31 (52%), and 8 (13%) had global, expressive, and receptive aphasia, respectively. We identified 6 (10%) patients who required intra-procedural intubation. The odds of any ICH (odds ratio [OR] 6.3, 95% confidence interval [CI] 1.6-24.0) and in-hospital mortality [OR 9.3, 95% CI 2.7-31.0] were significantly higher among those who underwent pre-procedural intubation after adjusting for potential confounders. The rates of favorable outcomes at discharge were significantly lower among patients who underwent pre-procedural intubation [OR 0.1, 95% CI 0.04-0.2].

Conclusions:
Endovascular revascularization among aphasic, acute ischemic stroke patients should be attempted without intubation, in an effort to reduce intra-procedural complications, such as ICH and death.
Abstract 210: Stroke-Related Specific Mortality and Influencing Factors in Patients with Atrial Fibrillation in the RE-LY Trial
Authors: Le Heuzey Jean-Yves , Marijon Eloi , Connolly Stuart , Brueckmann Martina , Yang Sean , Pogue Janice , Eikelboom John , Ezekowitz Michael , Themeles Ellison , Wallentin Lars , Yusuf Salim
Published: March 2022

Background:
Atrial fibrillation (AF) is associated with increased mortality, but the specific causes of death and their predictors have not been described.

Methods and results:
The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial randomized 18,113 patients (71.5 ± 9 years, 64% males, CHADS
2
score 2.1 ± 1) to receive dabigatran or warfarin. Median follow-up was 2 years and complete follow-up was achieved in 99.9% of patients. All deaths were categorized by the investigators using pre-specified definitions followed by central adjudication. Overall, 1,371 deaths occurred (annual mortality rate of 3.84%, 95% CI 3.64-4.05). Cardiovascular death (sudden cardiac death [SCD] and progressive heart failure) accounted for 37.4% of all deaths, whereas stroke and hemorrhage-related represented only 9.8% of the total mortality. When examining causes of death according to dabigatran or warfarin, dabigatran only significantly affected stroke/hemorrhage-related mortality (RR 0.71, 95% CI 0.51-0.98,
P
= 0.04). The strongest independent predictor of cardiovascular death was heart failure (HR 2.45, 95% CI 2.10-2.88,
P
< 0.0001), of stroke-related deaths was non-fatal major hemorrhage (HR 4.35, 95% CI 2.58-7.34,
P
< 0.0001) and of hemorrhage-related deaths was non-fatal stroke (HR 3.80, 95% CI 1.07-13.5,
P
= 0.039).

Conclusions:
Among AF patients under antithrombotics, the majority of death (up to 90%) is due to causes other than stroke and bleeding. These results emphasize the need to identify interventions other than effective anticoagulation, which target SCD and progressive heart failure deaths in order to substantially reduce overall mortality, in AF patients.

Clinical trial registration:
(
http://www.clinicaltrials.gov
): Unique identifier
NCT00262600
.
Abstract 211: GAMES (Glyburide Advantage in Malignant Edema and Stroke) Pilot Study
Authors: Sheth Kevin N , Kimberly W. T , Elm Jordan , Yarbrough Karen , O'Connor Sydney , Hammer Maxim , Kane April , Busl Katharina , Cole Terry , Yoo Albert J , Jacobson Sven , Stern Barney
Published: March 2022

Introduction:

Malignant infarction is characterized by the formation of cerebral edema, and decompressive craniectomy (DC) is the only proven therapy. The NC (Ca-ATP) channel, regulated by the SUR1 receptor, is blocked by the sulfonylurea drug glyburide, which attenuates brain water content in preclinical models of large stroke. A phase I study has been safely completed. We assessed the hypothesis that a pilot study of RP-1127 (Glyburide for Injection) in patients at high risk for malignant infarction was safe and feasible.

Methods:

The objective of this four-center prospective, open label, phase IIa trial was to assess the safety and feasibility of treating severe anterior circulation ischemic stroke patients with RP-1127, whether or not treated with IV rtPA. The study enrolled patients with a baseline MRI DWI lesion between 82 cm3 and 210 cm3, age 18-80 years, and time from symptom onset to drug infusion of ≤ 10 hours. Patients received a RP-1127 bolus followed by continuous infusion for 72 hours.

Results:

Recruitment of 10 patients was completed within 9.6 months. The mean initial DWI lesion volume was 102 ± 23 cm3. There were no serious adverse events related to the drug. The incidence of malignant edema was 20%, compared to 88% in a prospective observational study with DWI ≥82 cm3. Further, 8/10 patients did not require any bolus osmotherapy or DC. The mean increase in ipsilateral hemisphere volume was 50±33 cm3 compared to historical controls of 71.5±27 cm3. The proportion of 30 day mRS ≤ 4 was 90% compared to 23.8% (at 12 months) in control patients from a pooled analysis of DC trials.

Conclusions:

These findings suggest that a Phase II trial for patients at risk of malignant infarction is feasible and will provide important insights into the safety and potential efficacy of RP-1127.
Abstract 212: Estrogen Protects against Aneurysmal Rupture Through Estrogen Receptor-beta in Ovariectomized Mice
Authors: Tada Yoshiteru ,   The Univ of Tokushima, Wada Kosuke , Makino Hiroshi , Liang Elena I , Murakami Shoko , Kudo Mari , Shimada Kenji ,   The Univ of Tokushima, Kitazato Keiko T ,   The Univ of Tokushima, Nagahiro Shinji , Hashimoto Tomoki
Published: March 2022

Introduction

Epidemiological studies suggest that estrogen has protective effects against the formation and rupture of intracranial aneurysms. Post-menopausal women are at a higher risk for aneurysmal rupture. In our mouse model of intracranial aneurysms, aneurysmal rupture occurs at a high incidence and results in neurological symptoms. We hypothesized that estrogen or stimulation of estrogen receptors (ERs) is protective against aneurysmal rupture in ovariectomized female mice. We also sought to determine the role of ER subtypes on aneurysmal rupture.

Methods

All female mice received bilateral ovariectomy. Intracranial aneurysms were induced using a combination of a single injection of elastase into the cerebrospinal fluid and deoxycorticosterone acetate (DOCA) salt hypertension. Six days after aneurysm induction, we started 2-week treatment with vehicle (n=19), 17β-estradiol (n=17) with (n=14) or without ER antagonist, ERα agonist (n=12), or ERβ agonist (n=15). Nitric oxide synthase (NOS) inhibitor (L-NAME, n=15) was used to determine roles of NOS in ER mediated prevention of aneurysmal rupture. Aneurysmal rupture was detected by neurological symptoms.

Results

17β-estradiol (E2) reduced rupture rates in ovariectomized female mice (P < 0.05). ER antagonist reversed the protective effect of E2 on the aneurysmal rupture (P < 0.05). While ERα agonist did not prevent aneurysmal rupture, ERβ agonist reduced the rupture rate (P < 0.05). Inhibition of NOS by L-NAME abolished the protective effects of ERβ agonist on aneurysmal rupture (P < 0.05) (Figure).

Conclusion

These findings suggest that estrogen protects against aneurysmal rupture through ERβ activation. In addition, the protective effect of estrogen through ERβ is dependent on NOS. ERβ an NOS may be used as therapeutic targets for the prevention of aneurysmal rupture in post-menopausal women
Abstract 213: The Probability of Ischemic Stroke Therapeutic Targets at Extended Time Windows
Authors: Warach Steven , Luby Marie , Davis Lisa A , Merino José G , Hsia Amie W , Jesser Christine , Robertson Henry T , Latour Lawrence L
Published: March 2022

BACKGROUND.

A contributing factor in the decreased efficacy of thrombolysis over time may be a decrease in the probability of the therapeutic target, but this has not been well studied. Detection of therapeutic targets beyond 4.5 hr is the premise for reperfusion trials at extended time windows. We quantified the relationship of time from onset to the probability of detection of therapeutic targets.

METHODS.

We analyzed a consecutive series of 1103 ischemic stroke patients with NIHSS > 3 and an MRI within 24 hr from last known well. Potential therapeutic targets were occlusion on MRA (ARTERY), M1 or M2 occlusion (MCAO), focal ischemia on perfusion MRI (PERFUSION), and diffusion-perfusion mismatch (MISMATCH). Logistic regression models evaluated hours from onset, NIHSS, age, and sex as predictors of target.

RESULTS.

ARTERY, PERFUSION, and MISMATCH probabilities decreased over time (p < 0.0001) at approximately 1% per hour. More severe strokes increased the probability of detection by about 1% per NIHSS point. Logistic regression model found significant relationships of MISMATCH to hours, NIHSS, MCAO, and the interaction of NIHSS X MCAO (Table). MCAO patients had higher probabilities of MISMATCH, which decreased more rapidly over time (Graph). The probability of MISMATCH can be estimated by the logistic regression model: e.g., MCAO and NIHSS 12 at 9 hr = 78%; MCAO and NIHSS 14 at 20 hr = 47%.

CONCLUSION.

The probability of potential targets of reperfusion therapy declines over the first 24 hours from stroke onset. A substantial proportion of patients have a target beyond the proven time window for thrombolytic therapy, and the proportion can be estimated by the logistic regression model.
Abstract 23: African American Women Delay in Stroke Treatment Seeking
Authors: Miller Elaine T , Harris Adelaide
Published: March 2022

Despite decades of research on stroke awareness and prevention targeting Americans in the U.S., research focusing on African American Woman (AAW) has remained limited. Pilot Study’s Specific Aims were:

Determine AAW’s knowledge of major signs and symptoms of TIA and stroke.

Determine AAW’s knowledge of major risk factors for TIA and stroke

Identify the major factors affecting AAW’s delay in seeking treatment when a TIA or stroke is suspected.

Theoretical Framework:
The Common Sense Model was the guiding framework that provided the structure for identifying and interpreting the AAW’s perceptions and actions.

Sample:
A convenience sample of 203 AAW ranging in age from 20-91 (M=55) were obtained through local churches. Educational levels were 42.3% college graduates, 24% some college, 15.8% technical training, and remaining high school graduates. Thirty percent were either married or single and remaining divorced or widowed).

Design and methodology:
In this descriptive study after obtaining informed consent, participants completed a demographic form and an instrument assessing their knowledge of TIA and stroke signs and symptoms, major risk factors, treatment seeking behavior, and major factors affecting treatment seeking. The study instrument had content validity and a Cronbach alpha reliability of .76.

Results:
With regard to stroke symptoms, weakness and ability to speak were identified 85% and 87% respectively, while visual disturbances were selected 71% of the time. Shortness of breath and chest pain were also incorrectly identified 50% of the time as major symptoms. Ninety-six percent knew hypertension was a major risk factor as cigarette smoking (78%), and being African American (75%). Fewer than 20% knew being male was a risk factor. The first action for 97% of the participants who suspected a TIA or stroke was calling 911. The major factors identified as being linked to actually calling 911 were the signs/symptoms of speaking difficulties (F=3.08, p =.003), weakness F=4.53, p=.004), the risk factors of high cholesterol (F=4.56, p=.04), diabetes (F=4.2, p=.006) and obesity (F=4.07, p<.008) in that order. Building upon these study findings a larger longitudinal study will be designed with an educational intervention component.