bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptation of Arterial Wall Viscosity to the Short‐Term Reduction of Heart Rate: Impact of Aging
Authors: Roca Frédéric , Iacob Michèle , Duflot Thomas , Donnadieu Nathalie , Thill Caroline , Bellien Jérémy , Joannides Robinson
Published: February 2022

Background

Changes in arterial wall viscosity, which dissipates the energy stored within the arterial wall, may contribute to the beneficial effect of heart rate (HR) reduction on arterial stiffness and cardiovascular coupling. However, it has never been assessed in humans and could be altered by aging. We evaluated the effect of a selective HR‐lowering agent on carotid arterial wall viscosity and the impact of aging on this effect.

Methods and Results

This randomized, placebo‐controlled, double‐blind, crossover study performed in 19 healthy volunteers evaluated the effects of ivabradine (5 mg BID, 1‐week) on carotid arterial wall viscosity, mechanics, hemodynamics, and cardiovascular coupling. Arterial wall viscosity was evaluated by the area of the hysteresis loop of the pressure‐lumen cross‐sectional area relationship, representing the energy dissipated (W
V
), and by the relative viscosity (W
V
/W
E
), with W
E
representing the elastic energy stored.

HR reduction by ivabradine increased W
V
and W
E
whereas W
V
/W
E
remained stable. In middle‐aged subjects (n=11), baseline arterial stiffness and cardiovascular coupling were less favorable, and W
E
was similar but W
V
and therefore W
V
/W
E
were lower than in youth (n=8). HR reduction increased W
V
/W
E
in middle‐aged but not in young subjects, owing to a larger increase in W
V
than W
E
. These results were supported by the age‐related linear increase in W
V
/W
E
after HR reduction (
P
=0.009), explained by a linear increase in W
V
.

Conclusion

HR reduction increases arterial wall energy dissipation proportionally to the increase in W
E
, suggesting an adaptive process to bradycardia. This mechanism is altered during aging resulting in a larger than expected energy dissipation, the impact of which should be assessed.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: 2015/077/HP. URL:
https://www
. eudract.ema.europa.eu; Unique identifier: 2015‐002060‐17.
Panax notoginsengSaponin Protects Against Diabetic Cardiomyopathy Through Lipid Metabolism Modulation
Authors: Zhang Chenyang , Zhang Bin , Zhang Xuelian , Wang Min , Sun Xiaobo , Sun Guibo
Published: February 2022

Background

People with diabetes are more likely to develop cardiovascular diseases. Lipotoxicity plays a key role in the development of diabetic cardiomyopathy.Panax notoginsengsaponin (PNS) has been used to treat diabetes and obesity. However, the role of PNS in diabetic cardiomyopathy remains unclear.

Methods and Results

Diabetic db/db mice received high‐dose (200 mg/kg per day) or medium‐dose (100 mg/kg per day) PNS by gavage for 12 weeks until week 36. Lipid accumulation and cardiac function in diabetic mice were detected and possible mechanisms involved were explored. PNS significantly improved body weight, body fat content, serum lipids, adipocytokines, and antioxidative function in db/db mice. Lipid accumulation in adipose tissue, liver, and heart were also alleviated by PNS treatment. Cardiac function and mitochondrial structure were also improved by PNS. H9c2 cells were treated with palmitate acid, and PNS pretreatment reduced lipid accumulation, mitochondrial reactive oxygen species, as well as improved mitochondrial membrane potential and mitochondrial oxygen consumption rate. Levels of proteins and expression of genes related to glucose and lipid metabolism, antioxidative function, and mitochondrial dynamics were also improved by PNS administration.

Conclusions

PNS attenuated heart dysfunction in diabetic mice by reducing lipotoxicity as well as modulating oxidative stress and improving mitochondrial function.
Abstract 101: Predicting Hematoma Expansion Using An Artificial Neural Network: An Exploratory Analysis Of The Atach 2 Trial
Authors: Kumar Arooshi , Frontera Jennifer , Yaghi Shadi , Qureshi Adnan I , Melmed Kara R
Published: February 2022

Introduction:
Hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) is a key predictor of poor prognosis and potentially amenable to treatment. Current clinical scoring models, radiological markers, and labs have limited ability to predict HE. This study aimed to create a more robust classification model to predict HE in patients with ICH using a deep learning algorithm, an artificial neural network (ANN).

Methods:
Data from the ATACH 2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage) was utilized. Variables included in the models were chosen as per literature consensus on salient factors associated with HE and clinical expertise. HE was defined as increase in either >33% or 6mL in hematoma volume in the first 24 hours. A multi-layer feedforward ANN was trained using the back-propagation method to minimize the loss function with 5-fold cross validation. 80% of patients were used for training and 20% for testing. The ANN was compared to a logistic regression model (GLM). Given the imbalance in patients with HE, AUPRC (area under the precision-recall curve), recall and precision were calculated for the respective models.

Results:
Of the 963 patients in the study (mean age 62±13.0, 38.5% female), 31% had hematoma expansion. The median [interquartile range (IQR)] initial hematoma volume was 10.5mm
3
[5.16 - 20.25], median admission SBP [IQR] was 200 [184-217], median platelet count [IQR] was 213 [178-256], median INR [IQR] was 1.0 [0.9-1.0], and median admission GCS [IQR] was 15 [13-15]. The GLM model had AUPRC of 0.38 with recall of 0.60 and precision of 0.38 in the testing cohort. The ANN training model demonstrated AUPRC of 0.92 with recall of 0.72 with precision of 0.39 during testing. Initial ICH volume, platelets, INR, and GCS had the highest feature importance.

Conclusion:
We developed an ANN to predict HE in ICH patients performing with improved sensitivity and similar positive predictive value when compared to GLM. We support that ANN can capture complex associations between variables not attainable in classic regression models. This model may help identify patients at risk for HE who warrant careful monitoring and aggressive treatment upfront including those suitable for clinical trials for treatments.
Abstract 107: Effect Of Intensive Blood Pressure Control On Incident Stroke Risk In Patients With Mild Cognitive Impairment
Authors: de Havenon Adam H , Sharma Richa , Falcone Guido J , Prabhakaran Shyam , Sheth Kevin N
Published: February 2022

Background:
Patients with mild cognitive impairment (MCI) are at higher risk of incident stroke, but the effect of intensive blood pressure (BP) control on that risk has not been explored.

Methods:
We performed a post-hoc analysis of the SPRINT trial and included patients with a baseline Montreal Cognitive Assessment (MoCA) score of 20-26 and without a prior history of stroke. The primary outcome was incident stroke (ischemic and hemorrhagic) during follow-up. We estimated the risk of our primary outcome by SPRINT randomization arm (intensive vs. standard BP control) and fit Cox models for the primary outcome, adjusting for patient age, race, sex, baseline blood pressure, atrial fibrillation, diabetes, and smoking. We also verified the proportional hazards assumption of our final model.

Results:
We included 5507 patients (mean age 67.8
+
9.4 years, 66.6% male, 59.5% non-Hispanic white, and 50.1% randomized to intensive BP control), of which 94/5507 (1.7%) had an incident stroke during a mean of 3.8±0.9 years of follow-up. The risk of incident stroke in patients randomized to intensive BP control was 37/2762 (1.3%) and to standard BP control was 57/2745 (2.1%). In the adjusted Cox model, the hazard ratio for incident stroke events with intensive BP control was 0.63 (95% CI 0.42-0.96, p=0.03). The Kaplan-Meier curve by randomization arm is seen in Figure 1.

Conclusion:
Although the SPRINT trial failed to show a reduction in stroke with intensive BP control for all subjects, those with MCI at baseline may benefit from intensive BP control to lower risk of incident stroke. Future trials of primary prevention of stroke or vascular cognitive impairment and dementia could benefit from enrichment using baseline biomarkers of elevated risk, such as mild cognitive impairment.
Abstract 108: Home Blood Pressure Telemonitoring-enhanced Versus Usual Post-acute Stroke Care In An Underserved Setting: The Telehealth After Stroke Care Pilot Randomized Clinical Trial
Authors: Naqvi Imama A , Strobino Kevin , Li Jessica , Schmitt Kevin , Garcon Marie , Li Hanlin , Arcia Adriana , Tom Sarah , Williams Olajide A , Cheung Ken , Kronish Ian M , Elkind Mitchell
Published: February 2022

Introduction:
Hypertension is the most important modifiable risk factor for recurrent stroke. However, it remains poorly controlled after stroke, especially among Black and Hispanic patients. Black and Hispanics have a higher prevalence of uncontrolled BP and limited access to care. Interventions that promote equitable access are needed to improve outcomes.

Aim:
We tested whether a randomized trial of post-acute stroke care that integrates nurse-supported home BP telemonitoring, tailored infographics, and video visits with a multidisciplinary team including pharmacy (Telehealth After Stroke Care (TASC intervention) was feasible.

Methods:
Acute stroke patients with hypertension were randomized prior to discharge to usual care or TASC. Usual care patients received a video visit with primary care at 1-2 weeks and stroke specialist at 6 and 12 weeks after discharge. TASC patients received a tablet that wirelessly transmits BP data to the electronic health record, supported by remote telehealth nurse monitoring along with BP infographics, developed through community participatory design, at first visit and pharmacist visits. Outcomes included recruitment feasibility, visit adherence, and retention. Generalized linear modeling was used to evaluate within-patient home BP change.

Results:
Of 67 eligible patients, 6 were discharged before recruitment, 8 refused and 3 engaged in other studies. Fifty enrolled patients included 44% Hispanic, 32% Black and 36% women with mean age 64.3 (±14.0) yrs. About half had ≤ a high school education and 30% had commercial insurance. Baseline SBP was similar in TASC (140 ± 19 mmHg) vs. usual care (142 ± 19 mmHg). Retention rate was higher in TASC vs. usual care (84% vs 64%, p=0.11). Adherence to video visits was also higher in TASC (91% vs 75%, p=0.14). SBP control was better in TASC (76% vs. 25%, p<0.01). At 12 weeks, home SBP declined by 16 ± 19 mmHg from baseline in TASC vs increased by 3 ± 24 mmHg (p<0.01) in usual care. SBP control in Black patients improved from 40% at baseline to 100% in TASC vs from 14% to 29% in usual care.

Conclusion:
Enhancing post-acute stroke care with home BP telemonitoring is a promising approach to improving hypertension control in an underserved setting that should be tested in a definitive randomized trial.
Abstract 11: Cardiac CT To Detect Cardiac Thrombi In Patients With Acute Ischemic Stroke: A Substudy Of Mind The Heart
Authors: Rinkel Leon A , Guglielmi Valeria , Beemsterboer Chiel , Groeneveld Nina-Suzanne , Lobé Nick , Boekholdt S. Matthijs , Bouma Berto , Muller Fenna , Beenen Ludo , Marquering Henk , Majoie Charles B , Roos Yvo , van Randen Adrienne , Planken Nils , Coutinho Jonathan
Published: February 2022

Background:
Cardiac thrombi are a major risk factor for ischemic stroke. We used cardiac CT to assess the prevalence of cardiac thrombi in acute ischemic stroke patients.

Methods:
This was a substudy of Mind the Heart, a prospective single-center cohort study in which consecutive adult patients with acute ischemic stroke underwent prospective ECG-gated cardiac CT during the initial stroke imaging protocol. Patients also underwent routine stroke work-up, including transthoracic echocardiography (TTE). Patients were included from May 2018 to November 2020. We compared patients with a cardiac thrombus on CT (defined as filling defect <100 Hounsfield’s Units) to those without a cardiac thrombus. Outcomes were functional outcome on the modified Rankin scale (mRS) and ischemic stroke recurrence at 90 days.

Results:
Of 452 included patients, cardiac CT detected 40 thrombi in 38 (8%) patients. Thrombi were located in the left atrial appendage in 31 (7%), left atrium in 2 (0.4%) and left ventricle in 7 (2%) patients. TTE, performed in 25 patients with a cardiac thrombus (median time CT to TTE 1 day), detected a thrombus in 2 patients (0.4%, both left ventricle thrombi). Patients with a cardiac thrombus more frequently had a history of atrial fibrillation (40% vs 15%), used anticoagulation (42% vs 16%), had a large vessel occlusion (58% vs 41%), had intracranial occlusions in multiple vascular territories (5% vs 0.5%) and had a higher baseline NIHSS (17 [IQR 6-22] vs 5 [IQR 2-3]). In total, 26/38 (68%) patients with a cardiac thrombus had a history of atrial fibrillation or had atrial fibrillation diagnosed during stroke work-up. At 90 days, 19/23 (83%) patients with a cardiac thrombus who were alive were treated with anticoagulation. Patients with a cardiac thrombus had worse functional outcome (median mRS 4 [IQR 2-6] vs 2 [IQR 1-4], p<0.01) and non-significantly more often had a recurrent ischemic stroke (8% vs 5%,p=0.61) than patients without a cardiac thrombus.

Conclusion:
Cardiac CT detected a cardiac thrombus in 1 in every 12 patients with acute ischemic stroke. These thrombi were rarely detected with TTE. Patients with cardiac thrombi more often had atrial fibrillation and severe neurological deficits. Functional outcome was worse in patients with cardiac thrombi.
Abstract 112: Roles Of Platelets In Aneurysm Formation And Rupture
Authors: Morgan Jordan , Kudo Daisuke , Sato Hiroki , Ai Jinglu , Lawton Michael , Hashimoto Tomoki N
Published: February 2022

Platelets were once exclusively connected to thrombus; however, they play more diverse roles. Platelets have been found to be mediators of adhesion and transmigration of leukocytes at sites of inflammation. Inflammation is emerging as a key factor in the formation and subsequent rupture of intracranial aneurysms. In the presence of endothelial damage as well as increased shear stress, platelets are activated and, thus, become capable of modulating inflammation. Both conditions are present at the site of intracranial aneurysm. Evaluation of ruptured and unruptured aneurysms have demonstrated the presence of thrombus intramurally and intraluminally. Furthermore, multiple cohort studies on the use of aspirin, an inhibitor of platelet aggregation, have shown a significant reduction in the incidence of aneurysmal rupture. We hypothesize that platelets promote the formation and rupture of intracranial aneurysm. To evaluate this hypothesis, c-mpl receptor knockout mice were used. These mice are thrombocytopenic due to impaired megakaryocyte function, making them an ideal model to test our hypothesis. Intracranial aneurysm was induced in mice by a combination of systemic hypertension and a single injection of elastase into the cerebrospinal fluid. The rate of aneurysm formation and rupture were used as endpoints. To evaluate systemic thrombocytopenia in study mice, platelet count in plasma samples was assessed. Platelets in c-mpl knockout mice were 85% lower than in wild-type controls (mean ± SD: 226*10
3
± 9*10
3
/μL vs 1438*10
3
± 183*10
3
/μL, P< 0.05). Formation rate of aneurysm was reduced in c-mpl knockout as opposed to wild-type counterparts (65% vs 87%, P<0.05). More importantly, there was also a reduction in rupture rate of aneurysms in c-mpl knockout compared to wild-type (45% vs 72%, P<0.05). Our findings show that systemic reduction of platelets results in a decreased rate of aneurysm formation and rupture. We plan to investigate more specific interactions at the site of intracranial aneurysm between platelets and leukocytes or endothelial factors. We aim to find the molecules mediating these interactions in hopes that a therapeutic target can be identified.
Abstract 113: Duration Between Stroke Onset And Presentation Over Time: A Population-based Study
Authors: Robinson David , Stanton Robert J , Ferioli Simona , Sucharew Heidi , Khoury Jane C , Haverbusch Mary , Adeoye Opeolu M , Jasne Adam , Slavin Sabreena , Star Michael , De Los Rios La Rosa Felipe , Walsh Kyle B , Demel Stacie L , Coleman Elisheva R , Martini Sharyl R , Alwell Kathleen , Mackey Jason , Mistry Eva , Woo Daniel , Kleindorfer Dawn O , Kissela Brett M
Published: February 2022

Background:
In acute stroke, reducing delays between symptom onset and treatment can improve outcomes. While in-hospital delays have been successfully reduced, pre-hospital delays have persisted. Public health campaigns have attempted to reduce these delays by increasing stroke symptom awareness, but it is unknown whether these efforts have improved the percentage of patients presenting early after symptom onset.

Methods:
We performed an analysis of the Greater Cincinnati/Northern Kentucky Stroke Study, a population-based study of all stroke patients in a large geographic area. We looked at the 2010 and 2015 study years. All stroke cases (ischemic and hemorrhagic) presenting to the 16 regional EDs were included. We examined the time between symptom onset and ED arrival times, dichotomized into ≤3.5 hours and >3.5 hours. In cases without a clear onset, estimates were derived using wake-up or last known well times. Comparisons were made using multivariable logistic regression.

Results:
Among 4633 total stroke patients, 1359 patients presented early (29%). Results of the multivariable analysis are shown in the
Table
. There was no improvement the rate of early presentation in 2015 (aOR 1.01, 95% CI 0.89-1.16). EMS utilization, night arrival, higher NIHSS scores, and better premorbid function were associated with early arrival. Patients who lived alone were less likely to arrive early.

Conclusion:
We found no evidence for improvement in the rate of early presentation over the years studied. Work is needed to address other barriers to early hospital arrival, including underutilization of EMS.
Abstract 119: The Effect Of Neuroprotectant NA1 On Early Infarct Growth Following Endovascular Therapy: The REPERFUSE-NA1 Study
Authors: Fladt Joachim , Guo Jen , Specht Jacinta , Chan Leona , d'Esterre Christopher , Hill Michael D , Demchuk Andrew M , Barber Philip A
Published: February 2022

Background:
Early infarct growth after endovascular therapy (EVT) may lead to unfavorable outcomes despite successful reperfusion. The REPERFUSE-NA1 study replicated the preclinical NA1 experiment by investigating the effect of NA1 on early DWI infarct growth in acute ischemic stroke patients receiving EVT.

Methods:
REPERFUSE-NA1 was a sub-study of the randomized controlled trial ESCAPE-NA1 (ClinicalTrialGov NCT02930018). Patients received MRI within 5 hours and 24 hours of EVT. The primary outcome was early diffusion weighted (DWI) infarct growth. The secondary outcome was region-specific DWI infarct growth in the white matter, cortical grey matter and basal ganglia.

Results:
A total of 71 patients was included, of whom 67 had sufficient MR imaging at 5h and 24h post-EVT. For patients who received NA1 compared to placebo, the median age (68.8 v 67.5), baseline NIHSS (15.5 v 16), time from symptom onset to reperfusion (161 v 167 minutes) and mTICI 2b-3 (94.4% v 94.3%) were statistically not different. Median DWI volumes post-EVT (5h) were 13.0 mL (IQR, 5.9-28.1) in NA1 and 13.3 mL (IQR, 3.1-27.0) in placebo. At 24h median DWI volumes increased to 22.6 mL (IQR, 11.2-63.4) in the NA1 group and 22.4 mL (IQR, 7.4-52.3) in the placebo group, equating to a 48.4% DWI volume growth in the NA1 group and a 66.0% growth in the placebo group. Median DWI volume growth was 55.1% for NA1 patients who received alteplase compared to 41.3% for NA1 patients who did not receive alteplase (p=0.65). In terms of region-specific infarct volumes, absolute growth was 2.27mL (IQR, 0.70-6.19) in the white matter, 3.93 mL (IQR, 0.18-12.40) in cortical grey matter, and 1.20 mL (IQR, 0.31-2.62) in basal ganglia in the overall cohort. Between the NA1 and the placebo groups, lesion growth in the white matter (1.96 mL v 2.77mL), cortical gray matter (3.93 mL v 4.07 mL) and basal ganglia (1.62 mL v 0.89 mL) did not differ significantly.

Conclusion:
There was substantial infarct growth early after EVT, with the largest absolute growth in cortical grey matter. No significant effect of NA1 on early infarct growth was observed.
Abstract 123: Carotid Artery Stenosis In Underrepresented Populations Defined By Factors Other Than Race/ethnicity: Results From All Of Us
Authors: Renedo Daniela , Acosta Julian , Sheth Kevin N , Matouk Charles , Falcone Guido J
Published: February 2022

Background:
While existing evidence points to differences in the prevalence of Carotid Artery Stenosis (CAS) across race/ethnic groups, these differences have not been fully studied in underrepresented populations defined by other factors. We leveraged the recently introduced NIH All of Us Research Program to test the hypothesis that CAS disproportionally affects underrepresented groups defined by factors other than race/ethnicity.

Methods:
We evaluated data from the All of Us Research Program. We conducted a cross-sectional analysis including study participants with available data from both baseline questionnaires and electronic health records. We ascertained CAS using validated ICD-9/10 codes and corresponding Observational Medical Outcomes Partnership codes. Following the conceptual framework provided by All of Us, we considered underrepresented groups defined not only by race/ethnicity but also by gender identity/sexual orientation, education and income. We fitted multivariable logistic regression models adjusting for vascular risk factors.

Results:
We included 203,813 study participants in the analysis (mean age 51.5 (SD 16.7), 124,735 (61%) were female). The prevalence of CAS in the overall cohort was 2.7% (n=5,420). For underrepresented groups defined by factors other than race/ethnicity, income <$35K USD (OR 1.16; 1.08-1.25; p<0.001) was associated with higher odds of CAS whereas having less than high school degree (OR 0.87; 0.75-1.00; p=0.05) was associated with lower odds of CAS in multivariable analyses. No significant differences were seen for sexual/gender minorities (p=0.95). For underrepresented groups defined by race/ethnicity, Black (OR 0.87; 95%CI 0.78-0.96; p=0.005) and Hispanic participants (OR 0.83; 95%CI 0.73-0.94; p=0.003) had lower odds of CAS.

Conclusions:
Among participants enrolled in the All of Us Research Program, lower income was associated with higher risk of CAS whereas Hispanic and Black race/ethnicity were associated with lower risk of CAS. These results underscore the importance of evaluating underrepresented groups beyond those defined by race/ethnicity and highlight the potential of the NIH All of Us Research Program to accelerate health disparities research on this topic.
Abstract 130: Real World Experience With Viz.AI Automated Large Vessel Occlusion Detection
Authors: Vitellas Carol A , Mannix Nicholas C , Nimjee Shahid M , Shujaat Mohammad T , Heaton Sharon , Lee Vivien H
Published: February 2022

Introduction:
Viz.AI LVO is an artificial-intelligence platform which analyzes brain computed tomography angiography (CTA) images in patients with suspected acute ischemic stroke (AIS) and sends an automated alert for suspected large vessel occlusions (LVO). The FDA cleared Viz.AI for LVO detection and Viz.AI reports high sensitivity and specificity (96.3% and 93.8%). We report our experience with Viz.AI LVO detection at our academic comprehensive stroke center (CSC).

Methods:
We performed a retrospective review of suspected stroke patients who had CTA ordered as a stroke code from September 2020 to December 2020. Data was collected on sex, age, Viz.AI LVO alert, and official Radiology review of CTA. Radiology read of CTA was considered gold standard. True negative was defined as Viz negative, Radiology negative. False positive was defined as Viz positive, Radiology negative. False negative was defined as Viz negative, Radiology positive. True positive was defined as Viz positive, Radiology positive. LVO was defined as occlusion of the intracranial carotid (ICAT) or MCA (M1 or M2 segment). Data was collected on performance of Viz.AI LVO alert, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results:
Among 282 consecutive suspected AIS patients with CTA analyzed by Viz.AI, the mean age was 61.9 years (range 19 to 96) and 152 (53.9%) were female. Viz LVO autodetection alerted for 60 patients (21.3%). Radiologist review reported 32 patients with LVO as follows: 12 (37.5%) M2, 16 (50%) M1, and 4 (12.5%) ICAT. The following were adjudicated: 219 true negatives, 31 false positive, 3 false negative, and 29 true positives. Sensitive was 90.6% and Specificity was 87.6%. PPV was 0.483 and NPV was 0.986. The 3 false negative patients all had M2 occlusions. The median time to alert was 10 min (range 7 to 656).

Conclusions:
In our series of AIS patients evaluated with CTA at an academic CSC, Viz.AI automated LVO detection performed well with a sensitivity of 90.6% and specificity of 87.5%, with a median time to alert of 10 minutes.
Abstract 132: Projections Of Endovascular Therapy-eligible Patients For The Us Population In 2021
Authors: Mistry Eva , Khoury Jane C , Kissela Brett , Kleindorfer Dawn O , Alwell Kathleen S , Jasne Adam , Ferioli Simona , De Los Rios La Rosa Felipe , Coleman Elisheva R , Demel Stacie L , Walsh Kyle B , SLAVIN Sabreena J , Star Michael , Haverbusch Mary , Mackey Jason , Woo Daniel , Heldner Mirjam , Fischer Urs M , Jadhav Ashutosh , Jovin Tudor G , Albers Gregory W , Nogueira Raul G , Khatri Pooja
Published: February 2022

Introduction:
Endovascular (EVT) eligibility estimates using population-based, NIH-funded Greater Cincinnati Northern Kentucky (GCNK) Stroke Study 2010 data have been reported. Given the evolving EVT landscape, we present updated estimates of annual EVT eligibility using the 2015 GCNK epidemiological data and extrapolate to the 2021 US census. We project the potential increase in eligible patients in the US for each possible expanded indication with a randomized trial currently planned/underway.

Methods:
We ascertained all hospitalized AIS patients ≥18 years old in 2015 using ICD-9 430-436; ICD-10 I60-I67, G45-G46 within GCNK population; all cases were physician-reviewed. Patients presenting within 0-5 hrs of last known well (LKW) were considered EVT eligible if they had a pre-stroke mRS<2, NIHSS ≥6 and ASPECTS ≥6. Those within 5-23 hrs of LKW were considered EVT-eligible if they had a pre-stroke mRS <3, NIHSS≥6, and favorable perfusion imaging. Expanded EVT eligible patients were defined as those with NIHSS <6, and pre-stroke mRS >1 (for 0-5 hrs) or ≥2 (for 5-23 hrs), or larger core. Estimates of vessel occlusion and favorable imaging were applied based on literature review and expert opinions. The derived estimates were age, race and sex-adjusted to the 2015 US adult population and extrapolated to 2021 population.

Results:
Among the 1.3 million total (1.05m adult) GCNK population in 2015, 2741 adults had an ischemic stroke and 2176 had data available for this analysis. A total of 1978 presented within 23 hrs of LKW, and 1233 within 0-5 hrs of LKW. Further results are outlined in the figure.

Conclusions:
It is estimated 18,484 adult patients in the US in 2021 meet strict EVT eligibility criteria. An estimated 15,699 patients with low NIHSS, 9621 with unfavorable imaging, and 28,107 with pre-stroke disability may become eligible for EVT in the future annually. US stroke systems should be optimized to handle all EVT-eligible stroke patients both now and in the future.
Abstract 136: Long-term Impact Of Aruba Trial On Management And Outcomes Of Unruptured Intracranial Arteriovenous Malformations
Authors: Patel Smit D , Hinman Jason D , Liebeskind David S , Saver Jeffrey L
Published: February 2022

Introduction:
The real-world evolution of management and outcomes of patients with unruptured cerebral arteriovenous malformations (AVMs) has not been well-delineated following the ARUBA trial findings of no general advantage of initial interventional (surgical/endovascular/radiotherapy) vs initial conservative medical therapy.

Methods:
We analyzed from 2009-2018 the National Inpatient Sample of all AVM admissions in the United States. Analyses were performed by year and for the dichotomized periods of pre-ARUBA (2009-2013)
vs.
post-ARUBA (2014-2018). Joinpoint regression models with permutation model selection delineated yearly trends in intervention rate in uAVMs.

Results:
Among a total of 72,812 uAVMs, 35,420 were in the post-ARUBA and 37,392 in the pre-ARUBA period. Median age was 53.3 in post-ARUBA
vs.
51.8 in the pre-ARUBA period (p=0.001) with no difference in female sex, 51.1% vs. 51.8% (p=0.44). The intervention rate was lower in the post- vs -pre-ARUBA period, 29.6% vs. 34.0% (p=0.006) (figure). Interventional rate decreased monotonically by -4.32% in the post-ARUBA period (figure). Among the post-ARUBA AVM patients, compared with pre-ARUBA, there were no differences in odds of in-hospital ischemic stroke [OR 1.05 (0.92-1.20), p=0.45] or in-hospital mortality [OR 0.88 (0.62-1.24), p=0.47] but the odds did increase for combined discharge to a facility or in-hospital mortality [OR 1.14 (1.02-1.28), p=0.020]. In addition, the frequency of admissions for ruptured AVMs accelerated in the post-ARUBA period (figure).

Conclusion:
Nationwide practice in management of unruptured AVMs changed substantially with the publication of the ARUBA trial, in a durable and increasing manner. Fewer admissions with interventional treatment of unruptured AVMs occurred and a corresponding increase in admission for ruptured AVMs transpired, as expected with a strategy of watchful waiting and treatment only after an index bleeding event.
Abstract 137: Dose-dependent Improvement In Stroke Outcomes Following Intra-arterial Mesenchymal Stem Cell Therapy In A Canine Endovascular Stroke Model
Authors: Thakkar Roshni , Watanabe Mitsuyoshi , Guada Luis , Bates Karen , Nishimura Kengo , Saini Vasu , Ramdas Kevin , Sidani Charif , Dong Chuanhui , Khan Aisha , Hare Joshua M , Yavagal Dileep R
Published: February 2022

Introduction:
Cell-based therapies for stroke remain under development and there is a lack of pre-clinical large animal data defining optimal dosing and delivery methods. Whereas safety and efficacy of intra-arterial (IA) mesenchymal stem cells (MSC) have been demonstrated in rodent models, large animal model are lacking, hampering advancement of the field and limiting mechanistic insights.

Methods:
An endovascular canine reversible Middle Cerebral Artery Occlusion (MCAO) model using a retractable platinum coil for 60-120 min was established. At 48-hour post-MCAO, allogeneic male canine MSCs (10-80 million) were delivered using a microcatheter in the ipsilateral upper cervical internal carotid artery of female canine subjects. Serial MRIs and neurological deficit scoring (NDS) were performed over 30 days. Animals were euthanized at15-30 d post-MCAO and brains were harvested for histology and molecular analyses.

Results:
There was a dose-dependent reduction of infarct volume on MRI associated with improved neurological scoring and corticospinal tract caliber on Diffusion Tensor Imaging over the range of 10, 20 and 40 million MSCs vs. PBS control. This dose-range was safe and did not result in worsening of stroke volume or behavioral outcomes. In contrast, 80 million IA MSCs led to a worsened neurological score immediately following the injection and an increase in the infarct volume at 4 days post injection.

Conclusion:
Together these findings establish a successful preclinical canine model of stroke in which dose-dependent efficacy of IA MSC therapy is demonstrated to reduce stroke size and augment DTI. These findings have important clinical implications in designing early-stage trials of IA delivery in humans.
Abstract 140: Real-world Efficacy Of Left Atrial Appendage Closure Versus Anticoagulation Therapy For Long-term Prevention Of Ischemic Stroke And All-cause Mortality Among Patients With Atrial Fibrillation
Authors: Meeks Jennifer , Pan Alan , Tannous Jonika , Bako Abdulaziz T , Potter Thomas , Khan Osman , Misra Vivek , Vahidy Farhaan S
Published: February 2022

Introduction:
There is limited data on real-world efficacy of left atrial appendage closure (LAAC) procedures compared to anticoagulants (AC) for stroke prevention among patients with atrial fibrillation (AF).

Methods:
We utilized a retrospective cohort of over 63 million patients from 51 healthcare organizations across 6 countries via a harmonized electronic medical record-based research data platform. Utilizing international classification of disease version 10 and current procedural terminology codes, adult (≥ 18 years) patients with AF (I48) were identified and grouped by treatment type (LAAC (33340, 02L73DK) vs AC (1015112, Z79.0, BL110)). Patients with a history of stroke prior to AC initiation or LAAC procedure were excluded. Subjects were followed for 5 years for incident ischemic stroke (I63), intracerebral hemorrhage (I61), and all-cause mortality. Treatment groups were propensity score matched by age, sex, race, ethnicity, and comorbidities. Risk ratio(RR) and 95% confidence intervals(CI) among unmatched and matched populations are reported.

Results:
Among a total of 1,980,130 AF patients; 1,374,013 were flagged for AC use and 8,004 were treated via LAAC. Treatment cohorts were propensity score matched by age, race, sex, hyperlipidemia, and hypertension resulting in an exact 1:1 matched cohort of 8,004 subjects, across all co-variates. In the matched population the mean (SD) age was 75.2 (8.05) years, 63.2% were male; 86.6% were white, 4.4% black, 0.89% Asian, and 3.5% Hispanic; with 64.4% hyperlipidemic and 79.2% hypertensive. Prior to matching, AC (vs. LAAC) was significantly associated with a higher 5-year risk of ischemic stroke, intracerebral hemorrhage, and all-cause mortality. The protective effect of LAAC (vs. AC) was maintained for 5-year risk of ischemic stroke (RR, CI: 0.68, 0.58 - 0.79) and all-cause mortality (RR, CI: 0.42, 0.39 - 0.45). However, the difference in 5-year risk for intracerebral hemorrhage for LAAC (vs. AC) was not statistically lower (RR, CI: 0.72, 0.50 - 1.05).

Conclusion:
Notwithstanding the possibility of residual confounding in our analyses, LAAC seems to be associated with a lower long-term risk of ischemic stroke and all-cause mortality as compared to AC treated AF patients in large real-world data.
Abstract 144: Glucagon-like Peptide-1 Receptor Agonists Reduce The Risk Of Ischemic Stroke
Authors: Goldstein Eric , Garg Gauri , Navarro Kayla , Wong Ka-ho , de Havenon Adam H
Published: February 2022

Background and Purpose:
Glucagon-like peptide-1 receptor agonists (GLP1-RA) are antihyperglycemic medications which may have a pleotropic benefit in reducing the risk of stroke. However, with ischemic stroke being the most common stroke subtype in diabetic individuals, it is currently unknown if this benefit remains present when evaluating ischemic stroke in isolation. The aim of this study was to identify whether GLP1-RA medications lower the risk of ischemic stroke.

Methods:
A 1:1 propensity score matched analysis of a retrospective cohort of patients from the TriNetX platform was performed with the outcome of ischemic stroke, defined with ICD-10-CM codes, during 5 years of follow-up. The exposure was prescription of a GLP1-RA, after which follow-up began. Subgroup propensity matched analyses were performed on individual GLP1-RA medications.

Results:
256,938 diabetic individuals prescribed a GLP1-RA were matched with an equal cohort of unexposed diabetics. Demographic and diabetic parameters were equally matched (mean age 57.4 years, 52.5% using insulin concurrently, mean hemoglobin A1c 8.3%). Composite ischemic stroke was lower in the GLP1-RA cohort (3.5%; 8,961/256,938 versus 5.8%; 14,806/256,938) with a risk ratio of 0.61 (95% 0.59-0.62), odds ratio of 0.59 (95% CI 0.58-0.61), hazard ratio of 0.71 (95% CI 0.60-0.87), without violation of the PH assumption (p=0.4). Rate of first-time incident stroke followed a similar pattern: (1.9%; 4,746/246,735 versus 3.3%; 8,044/241,891), risk ratio of 0.58 (95% CI 0.56 - 0.60), odds ratio of 0.57 (0.57 - 0.59), hazard ratio of 0.76 (0.67 - 0.86) with preservation of the PH assumption (p= 0.25). All four GLP1-RA medications lowered the event rate of ischemic stroke.

Conclusions:
In our study of a large cohort of adults with diabetes, the use of a GLP1-RA reduced the risk of ischemic stroke, consistent with post-hoc analyses of randomized controlled trials.
Abstract 151: Effects Of Tenecteplase On Acute Stroke Treatment Processes And Outcomes In A Large Community Cohort
Authors: Nguyen-huynh Mai N , Alexander Janet , Meighan Melissa M , Lee Catherine , Burnett Molly , Rao Vivek A , Bhopale Sunil , Hatton Joeffrey R , Sudhalkar Hemali , Klingman Jeffrey
Published: February 2022

Background:
Published data suggests tenecteplase (TNKase) is non-inferior to alteplase for acute ischemic stroke treatment. TNKase has certain advantages over alteplase including single-bolus administration. We evaluated TNKase performance in all acute stroke patients in a large integrated healthcare system.

Methods:
In 2016, we launched a standardized telestroke program for 21 certified stroke centers to include immediate video evaluation by a teleneurologist. In November 2020, we transitioned all centers to use TNKase for qualifying stroke patients presenting within 4.5 hours of last time known well. Selection criteria were the same as those for alteplase. Our study cohort included all potential acute stroke patients evaluated by telestroke. We compared the TNKase cohort treated during 12/1/20 - 3/31/21 to the alteplase cohort during 5/1/20 - 8/31/20. Assessment included demographics, mode of arrival, initial NIHSS, neuroimaging results, large vessel occlusion, rate of intracranial hemorrhage (ICH), discharge outcomes, percent with mRS (0-2) and mortality at 90 days with 95% CI.

Results:
Study cohort had 301 patients treated with TNKase and 248 patients with alteplase. Average age was about 70 years. Compared to alteplase, TNKase was associated significantly with faster door-to-needle (DTN) and door-in-door-out (DIDO) times [Table]. TNKase cohort had a larger percentage of stroke mimics. There was a trend of less symptomatic hemorrhage seen with TNKase. Multivariate model revealed that TNKase treatment was less likely to have 90-day mortality (OR=0.56, 95% CI 0.33-0.96, p=0.04). Percent 90-day favorable mRS score (0-2) was no different between the cohorts.

Conclusions:
We have successfully and safely transitioned to using TNKase for acute stroke treatment in our community setting. Compared to alteplase, TNKase cohort achieved faster DTN and DIDO times and less 90-day mortality. Further evaluation is needed to examine 90-day mRS in larger cohorts.
Abstract 152: Alarmingly Higher Risk Of Stroke Hospitalizations With Reduced Inpatient Mortality In Young Females (18-44 Years) And Associated Racial Disparities: A Nationwide Analysis 10-years Apart
Authors: Desai Rupak , Wiltshire Dwayne , Went Terry R , Jnaneswaran Geethu , Raju Athul Raj , Sultan Waleed , Asifali Roshna , Mohammad Aamer , Jain Akhil
Published: February 2022

Background:
Underrepresentation of females in clinical trials and paucity of data on young-onset stroke incited us to review two national cohorts a decade apart to assess the frequency and odds of stroke admissions and inpatient mortality and associated racial disparities in young females.

Methods:
We queried weighted data from the National Inpatient Sample (2017 & 2007) to identify stroke admissions in young females (18-44 years). Stroke admissions and mortality rates among young females were compared between different race groups for 2017 vs. 2007. Multivariable regression was performed to determine the difference in risk of stroke admissions and inpatient mortality with associated racial distinctions between 2017 & 2007.

Results:
Young women's stroke admissions from 2017 and 2007 increased from 0.3% (n=20009/7,746,732) in 2007 to 0.5% (n=28885/6,268,570) in 2017 (p<0.001). Adjusted analysis for covariates showed nearly 50% increased risk of stroke admissions in young women in 2017 vs 2007 (aOR:1.48; 95%CI:1.44-1.51, p<0.001). Comorbidities including hypertension, diabetes, vascular disease, obesity, smoking, atrial fibrillation were more prevalent in 2017 vs 2007 (p<0.001). Notwithstanding the increased admissions, inpatient mortality risk decreased by 35% in 2017 (aOR:0.65; 95%CI:0.60-0.71, p<0.001). Assessing racial disparities in young women, we found that white and Native Americans demonstrated the highest increase in stroke admissions, whereas Hispanic and Asian-Pacific Islanders did not show an improvement in survival odds in 2017 vs. 2007
[Figure 1]
.

Conclusion:
The risk of stroke admissions among young women increased nearly 50% in 2017 vs. 2007 with all races showing a rise in hospitalizations. Reassuringly, advanced therapeutics helped with the overall reduction of inpatient mortality; however, persistent racial disparities in survival odds warrant a more inclusive approach for primary preventive strides and healthcare delivery.
Abstract 16: Inhibiting Ezh2 Is Neuroprotective After Stroke In Aged Mice
Authors: Bu Fan , Min Jia-wei , El Hamamy Ahmad , Xu Yan , Qi Li , Koellhoffer Edward C , McCullough Louise , Li Jun
Published: February 2022

Introduction:
Ischemic stroke results in activation of microglia, which may polarize towards a pro-inflammatory (M1) phenotype and/or an anti-inflammatory (M2) phenotype. Enhancer of zeste homolog (EZH) 2 is a histone-lysine N-methyltransferase enzyme, a key modulator of microglia polarization. We here investigated whether microglial-specific deletion of EZH2 leads to a beneficial protective effect in stroke and microglial over-expressing microglial EZH2 exacerbates stroke outcome
in
vivo
.

Methods:
Aged male mice were subjected to 60-minutes middle cerebral artery stroke. Tamoxifen administration was started 30 days prior to stroke to induce genetic deletion of microglial EZH2 in CX3CR1-creER/EZH2-floxed mice. EZH2 floxed mice were used as controls. Microglial EZH2 over-expressing was performed using lentiviral vectors. Mice were sacrificed for immunohistochemistry and crystal violet staining (brain infarct assay) after behavior tests at 3 days after stroke.

Results:
The expression of microglial EZH2 was significantly abrogated with tamoxifen injection in KO mice compared to the control floxed mice (144±15.43 vs. 50.65±4.99 cells/mm
2
, P<0.01, N=5/each group). EZH2 deletion reduced brain infarct volume (29.27±2.23% vs. 6.07±0.88%, P<0.001, N=7/each group) and improved functional outcome assayed by adhesive removal test (59±13.1 seconds, N=7 in control vs. 26.28±4.1 seconds, N=12 in KO, P<0.01). Mechanistically, microglial EZH2 deletion led to a decrease in expression of M1 marker iNOS (170±14.78 vs. 76.65±11.38 cells/mm
2
, P<0.05, N=4/each group), an increase in M2 marker Arg1 (96.64±11.48 vs. 203.3±22.02 cells/mm
2
, P<0.05, N=4/each group) co-stained in microglia (Iba1). We additionally found over-expressing EZH2 in microglial cells exacerbated stroke outcome including performance in adhesive tape removal and hang-wire tests 3 days after stroke. We observed decreased Arg1 and increased iNOS in stroke mice with over-expression of EZH2 (n= 5/6, p=<0.05).

Conclusions:
Genetic deletion of EZH2 in microglia improved stroke outcome in aged while overexpression of EZH2 exacerbated stroke outcome. The effect of protective effect of EZH2 inhibition may be due to limiting microglial M1 polarization and enhancing M2 polarization.
Abstract 165: Age-specific Effects Of Maternal Gut Biome Influence Sex Dependent Changes In Offspring Weight, Behavior, And Depression
Authors: Blixt Frank W , Khan Romeesa , Honarpisheh Parisa , Blasco-Conesa Maria P , Ahnstedt Hilda , Ganesh Bhanu P , McCullough Louise
Published: February 2022

Background:
The gut-brain axis has recently become key in understanding stroke pathogenesis. The bidirectional communication between the gut and the brain are highly involved in the immune response to stroke. The effect of the aged biome, naturally occurring dysbiosis through the process of inflammaging, may have significant impact on offspring in terms of stroke risk factors.

Method:
Young (3-month) female wildtype C57B/6 mice were subjected to antibiotic treatment to clear their native gut biome and were then treated with fecal microbiome transplants from 3-month (M) control, 14M menopausal, and 18M reproductively senescent female mice, and were bred in our facility. Subsequent pups obtained were aged to 9 months followed by a battery of behavioral tests (novel object recognition (NORT), Y-maze, tail suspension, and open field test) and body weight measurements. Feces was collected periodically for 16s rRNA sequencing analysis.

Results:
Aged biome affected the female fecundity significantly (p=0.028, n=7/12) and the pup biome showed a significant sex specific difference in composition through 16s sequencing (p=0.009, n=7). Female pup from 14- or 18M biome mothers had consistently higher body weight from 21 days to 9 months of age compared to controls (p=0.183, n=6/9/13). Male pups from 18M biome dams showed significantly low body weight 2 months post birth (p=0.048, n= 7/10). Mothers that received 14M biome had overweight male offspring at 9 months of age (p=0.017. Cognitive assessment through NORT showed that female pups from mothers colonized with 14M biome had a significantly lower discrimination index compared to controls (p=0.045, n=6/9). Only male pups from 14M biome mothers showed a deficit in spatial cognition (p=0.018). Both males and females exhibited an early depressive phenotype compared to controls at 2 months of age (p=0.028), with female pups also exhibiting this phenotype at 9 months (p=0.018).

Conclusion:
Age of the maternal biome has a significant effect on its offspring’s health, specifically body weight, cognition, and depressive phenotype in a sex and time dependent manner. These effects correlate positively with stroke risk factors highlighting the importance of the microbiome as an epigenetic regulator of offspring health.