bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 651: Autophagic Cholesterol Metabolism in Macrophages with Lysosome Dysfunction
Authors: Netherland-Van Dyke Courtney , Romer Carrie E , Jerome W G
Published: June 2021

Extensive cholesterol accumulation in human macrophages inhibits lysosome function; a key attribute of many late-stage atherosclerosis foam cells. Lipophagy (a specialized form of autophagy) delivers lipids, like cholesteryl esters, to lysosomes where the esters are hydrolyzed to unesterified cholesterol which can be utilized in membranes or effluxed from the cell. Lipophagy has been shown to be an important pathway in foam cell sterol metabolism. We investigated what occurs to lipophagy when lysosome function is disrupted by excess cholesterol. Does autophagy continue? Does autophagy transport lipid to non-functioning lysosomes and thus contribute to overall lysosomal dysfunction and lysosomal sterol accumulation? In macrophages with dysfunctional lysosomes, how does inhibition of autophagy effect overall sterol balance and macrophage function?. We incubated human macrophages with aggregated LDL to produce macrophages with various degrees of lysosome dysfunction (confirmed by lysosome pH measurement and cholesteryl ester hydrolysis). To assess the role of lipophagy in changes in cellular sterol metabolism, we compared lipid metabolism as lysosomes became more dysfunctional and also with identical cells in which autophagy was inhibited with vinblastin. Increases in lysosome dysfunction did not alter the constitutive rate of autophagy as measured by proteins critical to autophagosome assembly (Atg7, Atg5, p62, LC3) and visualization of autophagosomes. Moreover, autophagy targeted lipid droplet material to lysosomes as indicated by the progressive accumulation of perilipin 2 in lysosomes and a significant decrease in lysosome cholesteryl ester content when autophagy was inhibited. In cells with normal functioning lysosomes, inhibition of autophagy increased total cell sterol levels. However, in cells where lysosomal dysfunction was prominent, lysosomal levels of sterol decreased and efflux of cholesterol was slightly enhanced when autophagy was inhibited. Our data indicates that lipophagy continues in the face of lysosome dysfunction and autophagy-delivered cholesteryl ester can exacerbate overall lysosome sterol accumulation and macrophage dysfunction when foam cell sterol is excessive.
Abstract 086: Secondary Prevention of Cardiovascular Disease in Patients With Type 2 Diabetes: International Insights From the TECOS Trial
Authors: Pagidipati Neha J , Navar Ann Marie , Pieper Karen S , Green Jennifer B , Bethel M. A , Armstrong Paul W , Josse Robert G , McGuire Darren K , Lokhnygina Yuliya , Cornel Jan H , Halvorsen Sigrun , Strandberg Timo E , Delibasi Tuncay , Holman Rury R , Peterson Eric D ,   on behalf of the TECOS Study Group
Published: June 2021

Background:
Intensive risk factor modification significantly improves outcomes for patients with diabetes and cardiovascular disease (CVD). However, the degree to which secondary prevention treatment targets are achieved in international clinical practice is unknown.

Methods:
Attainment of 5 secondary prevention targets—aspirin use, lipid control (low-density lipoprotein cholesterol (LDL-C) <70 mg/dL or statin therapy), blood pressure control (<140 mmHg systolic, <90 mmHg diastolic), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and non-smoking status—was evaluated among 14,671 patients from 38 countries with diabetes and known CVD at entry into TECOS. Logistic regression was used to evaluate the association between individual and regional factors and target achievement.

Results:
Overall, 29.9% of patients with diabetes and CVD had all 5 secondary prevention measures at target. North America had the highest proportion (41.2%), whereas Western Europe, Eastern Europe, and Latin America had proportions of approximately 25%. The likelihood of having individual prevention components at target also varied by region: compared with North America, individuals in all other regions were less likely to have blood pressure at goal, and individuals in Eastern Europe and Latin America were less likely to have LDL-C at target or to be on statin therapy (see Figure). Overall, blood pressure control (57.9%) had the lowest overall attainment while non-smoking status had the highest (89%).

Conclusions:
On a global scale, significant opportunities exist to improve the quality of cardiovascular secondary prevention care among patients with diabetes and CVD, which in turn could lead to reduced risk of downstream cardiovascular events.
Abstract 207: Burden of Cardiovascular Disease (CVD) on Economic Cost. Comparison of Outcomes in US and Europe
Authors: Giedrimiene Dalia , King Rachel
Published: June 2021

CVD is a major cause of morbidity and mortality worldwide, responsible for nearly a third of all deaths. In US, 85.6 million Americans are living with CVD, including 15.5 million with coronary heart disease (CHD). Heart disease (HD) specifically is responsible for approximately one in every seven American deaths, taking 370,213 lives per year. Perhaps even more striking than CHD’s mortality is its preventability. The CDC estimates that 34% of deaths caused by HD could potentially be prevented with modifiable risk factors including hypertension, hyperlipidemia, diabetes, smoking, poor diet, and sedentary lifestyle. By comparing the mortality of CVD and CHD in the US, Europe, and the United Kingdom (UK), we aim to gain a better understanding of the CVD burden and economic cost.

Methods:
We conducted a literature review of the most recent epidemiological data for US, Europe, and UK to compare mortality due to CVD and CHD between these three regions. Data sources for US include the AHA and CDC. Data for Europe was obtained from the European Society of Cardiology, following the World Health Organization’s definition of 53 states as the European region. The UK is included as it was considered independently in this study. Data for the UK was published by the British Heart Foundation.

Results:
The comparison of data shows that high mortality is evident in all represented countries and regions with a highest percent of CVD of total deaths in Europe as compared to US (45% vs 30.8%) and CHD (20% vs 14.2%). Very similar findings according annual mortality are evident comparing US to UK for CVD (30.8% vs 28%) and for CHD (14.2% vs 13%). The treatment for CVD is increasing over time, with prescriptions and operations costs around 6.8 billion in England, the majority spend on secondary care. CDC data in US show that Americans suffer 1.5 million heart attacks and strokes each year, which contributes more than $320 billion in annual healthcare costs and lost productivity. By 2030, this cost is projected to rise to $818 billion, while lost productivity costs to $275 billion.

Conclusions:
Although there is some variation between Europe as a group of 53 countries compared to the US and UK, it is clear that CVD has a major impact on mortality in all three regions studied. Improved prevention of CVD, including heart disease, has the potential to save lives around the globe and to reduce economic burden.
Abstract P233: Diabetic Cardiomyopathy is Reversed by Increased Mitochondrial Bioenergetics Due to PGC-1α Activation by EET Treatment of Obese Mice
Authors: Cao Jian , McClung John A , Singh Shailendra P , Bellner Lars , Waldman Maayan , Schragenheim Joseph , Arad Michael , Hochhauser Edith , Shapiro Joseph I , Abraham Nader
Published: June 2021

Introduction:
Obesity and diabetes are associated with progressive cardiac fibrosis that, sequentially, results in diastolic dysfunction, reduced contractility, and ultimately heart failure. Contributing factors include hyperglycemia, insulin resistance, mitochondrial dysfunction, and a reduction in AMPK signaling. PGC-1α activates mitochondrial biogenesis and oxidative phosphorylation and is decreased in patients with diabetes mellitus (DM). We hypothesize that an epoxyeicosatrienoic acids (EETs) agonist (EET-A) will increase PGC-1α levels in a db mouse model of DM attenuate cardiomyopathy, and prevent heart failure.

Methods:
Db mice (4-wks), were allowed to acclimatize for 16-wks and were then divided into 3 treatment groups for an additional 16 wks: A) control, B) EET-A 1.5mg/100g BW 2 weeks and C) EET-A-Ln-PGC-1α shRNA. Ln-PGC-1α shRNA suppressed PGC-1α protein in heart tissue by 40-50%. Oxygen consumption (VO
2
), and blood glucose was determined. Heart tissues were harvested to measure PGC-1α, HO-1, pAMPK, PGC-1α, echocardiographic fractional shortening, mitochondrial oxidative phosphorylation (OXPHOS) and mitofusion protein markers.

Results:
All mice developed heart failure by the end of 16 weeks and were characterized by a decrease in myocardial contractility, an increase in insulin resistance and blood pressure, decreased VO
2
, the appearance of mitochondria dysfunction and a decrease in AMPK and downstream PGC-1α signaling. Mice treated with EET-A demonstrated an increase in PGC-1α levels, improved mitochondrial function and oxidative phosphorylation (p<0.01 vs control), increased NO bioavailability (p<0.05 vs control), and normalization of glucose metabolism, insulin levels, VO
2
and LV systolic function (p<0.05 vs control). All of these findings were suppressed by PGC-1α inhibition which was accompanied by the onset of even more severe LV dysfunction than in the control group.

Conclusion:
Increased EET levels result in activation of PGC-1α-HO-1 which reverses diabetes induced insulin resistance, mitochondrial dysfunction, and cardiomyopathy. EET may have potential as a powerful agent for therapeutic application in the treatment of diabetic cardiomyopathy.
Chronic Inhibition of Toll‐Like Receptor 9 Ameliorates Pulmonary Hypertension in Rats
Authors: Ishikawa Tomohito , Abe Kohtaro , Takana‐Ishikawa Mariko , Yoshida Keimei , Watanabe Takanori , Imakiire Satomi , Hosokawa Kazuya , Hirano Mayumi , Hirano Katsuya , Tsutsui Hiroyuki
Published: June 2021

Background

Recent accumulating evidence suggests that toll‐like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension.

Methods and Results

A rat model of monocrotaline‐induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline‐exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and
interleukin‐6
mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline‐exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF‐κB activation and
interleukin‐6
mRNA levels to a similar extent. In the short‐term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF‐κB activation and
interleukin‐6
mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline‐exposed rats.

Conclusions

TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF‐κB‒IL‐6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.
Hospital Variation in 30‐Day Readmissions Following Transcatheter Aortic Valve Replacement
Authors: Kolte Dhaval , Kennedy Kevin , Wasfy Jason H. , Jena Anupam B. , Elmariah Sammy
Published: June 2021

Background

Data on hospital variation in 30‐day readmission rates after transcatheter aortic valve replacement (TAVR) are limited. Further, whether such variation is explained by differences in hospital characteristics and hospital practice patterns remains unknown.

Methods and Results

We used the 2017 Nationwide Readmissions Database to identify hospitals that performed at least 5 TAVRs. Hierarchical logistic regression models were used to examine between‐hospital variation in 30‐day all‐cause risk‐standardized readmission rate (RSRR) after TAVR and to explore reasons underlying hospital variation in 30‐day RSRR. The study included 27 091 index TAVRs performed across 325 hospitals. The median (interquartile range) hospital‐level 30‐day RSRR was 11.9% (11.1%–12.8%) ranging from 8.8% to 16.5%. After adjusting for differences in patient characteristics, there was significant between‐hospital variation in 30‐day RSRR (hospital odds ratio, 1.59; 95% CI, 1.39–1.77). Differences in length of stay and discharge disposition accounted for 15% of the between‐hospital variance in RSRRs. There was no significant association between hospital characteristics and 30‐day readmission rates after TAVR. There was statistically significant but weak correlation between 30‐day RSRR after TAVR and that after surgical aortic valve replacement, percutaneous coronary intervention, acute myocardial infarction, heart failure, and pneumonia (
r
=0.132–0.298;
P
<0.001 for all). Causes of 30‐day readmission varied across hospitals, with noncardiac readmissions being more common at the bottom 5% hospitals (ie, those with the highest RSRRs).

Conclusions

There is significant variation in 30‐day RSRR after TAVR across hospitals that is not entirely explained by differences in patient or hospital characteristics as well as hospital‐wide practice patterns. Noncardiac readmissions are more common in hospitals with the highest RSRRs.
Abstract 134: A Telephone Approach for Sceening for Stroke RIsk: The REGARDS Telephone Stroke Risk Score
Authors: Howard George , McClure Leslie A , Moy Claudia S , Kleindorfer Dawn O , Long D. L , Cushman Mary , Safford Monika , Meadows Luke , Flaherty Matthew , Howard Virginia J ,   the REasons for Geograhic And Racial Differences in Stroke (REGARDS) Study
Published: June 2021

Introduction:
The ability to identify a stroke/TIA-free population at high risk for stroke is important for risk assessment in the general population, and also a critical step to make a primary stroke prevention trial feasible. The standard for risk stratification is the Framingham Stroke Risk Score (FSRS); however, its use requires a clinic visit for blood pressure and ECG assessment, and laboratory measurement of glucose levels. The feasibility of a primary prevention trial would be greatly enhanced by a brief interview, potentially conducted over the telephone or web, to identify a high-risk population.

Methods:
A general population sample consisting of 23,983 REGARDS participants aged 45+ who reported being stroke and TIA free at baseline was characterized on 11 self-reported characteristics: age, race, sex, self-reported diagnosis of medical conditions (hypertension, diabetes, atrial fibrillation, and myocardial infarction), smoking, previous stroke symptoms, self-reported general health, and education. Participants were followed for incident stroke, with associations assessed by proportional hazards.

Results:
Over an average follow-up of 8.2 years, 564 incident strokes occurred. The self-reported characteristics were strongly related to stroke risk (see table), and proved marginally more predictive of stroke risk (c-statistic = 0.7268; 95% CI: 0.7078 - 0.7459) than the FSRS (c-statistic = 0.7222; 95% CI: 0.7025 - 0.7419). The annual stroke risk was 1.4% (95% CI: 1.2 - 1.7) for those in the highest decile of the telephone risk score. The Spearman correlation between the FSRS and the REGARDS telephone risk score was 0.848 (95% CI: 0.844 - 0.851).

Discussion:
The REGARDS Telephone Stroke Risk Score can be calculated using data collected over the telephone, at a web site, or in person. It can identify a population at high risk for stroke as well as the FSRS clinic-based assessment can, making it an efficient stroke risk assessment tool.
Abstract 154: Genetic Variants in
CETP
That Increase HDL Levels also Increase Risk of Intracerebral Hemorrhage
Authors: Falcone Guido J , Phuah Chia-Ling , Radmanesh Farid , Peloso Gina M , Meschia James F , Selim Magdy , Brown Devin L , Worrall Bradford B , Silliman Scott L , Tirschwell David L , Jimenez-Conde Jordi , Klijn Catharina J , Sudlow Catherine L , Rannikmae Kristiina , Pezzini Alessandro , Norrving Bo , Montaner Joan , Lindgren Arne , Slowik Agnieszka , Kidwell Chelsea S , Kittner Steven J , Langefeld Carl D , Abecasis Goncalo , Willer Cristen J , Kathiresan Sekar , Woo Daniel , Rosand Jonathan , Anderson Christopher D ,   Global Lipids Genetics Consortium,   International Stroke Genetics Consortium
Published: June 2021

Introduction:
In observational studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of spontaneous intracerebral hemorrhage (ICH). Common DNA sequence variants within the
cholesteryl ester transfer protein
(
CETP
) gene decrease CETP protein activity and increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development to combat coronary artery disease.

Hypothesis:
Common
CETP
DNA sequence variants associated with higher HDL-C also increase risk for ICH.

Methods:
We performed a two-stage case-control genetic association study in Caucasians. The discovery phase utilized data on 12 independent loci within
CETP
(+/- 50 kilobases) from 3 genome-wide association studies of ICH. Replication involved direct genotyping in 5 additional studies. We also constructed a genetic risk score with 7 independent
CETP
variants and tested it for association with HDL-C and ICH risk. We used principal component analysis to account for population structure and a Bonferroni-adjusted p<0.004 (12 tests) to declare statistical significance.

Results:
The discovery phase included 1149 ICH cases (43% lobar hemorrhages) and 1238 controls. Twelve variants were nominally associated (p<0.05) with ICH, with the strongest association at the rs173539 locus (Figure 1: OR 1.25, 95%CI 1.11-1.41; p=6.0x10
-4
) and no heterogeneity across studies (I
2
=0%). This association was replicated in 1625 cases (43% lobar hemorrhages) and 1845 controls (OR 1.12, 95%CI 1.02-1.24; p=0.03). A genetic score of independent
CETP
variants known to increase HDL-C by ~2.85 mg/dL was strongly associated with ICH risk (OR 1.86, 95%CI 1.44-2.40; p=1.4x10
-6
).

Conclusion:
Genetic variants in
CETP
associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in
CETP
inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes is warranted.
Abstract 166: One-month Modified Rankin Scale (mRS) Score Predicts Five-year Disability, Death, Quality-of-Life, and Healthcare Costs in Ischaemic Stroke: A Prospective Cohort Study
Authors: Ganesh Aravind , Luengo-Fernandez Ramon , Wharton Rose M , Gutnikov Sergei A , Silver Louise E , Mehta Ziyah , Rothwell Peter M ,   on behalf of the Oxford Vascular Study
Published: June 2021

Background:
Outcome in acute stroke trials is often based on short-term mRS, but there are few data from prospective population-based studies on how this measure translates into long-term outcomes. We evaluated the relationship between 1-month mRS and 5-year disability, death, quality of life, and healthcare cost in a population-based cohort study.

Methods:
In 3-month survivors of ischaemic stroke in the Oxford Vascular Study (2002-2014), we used logistic regression to determine predictors of 5-year death/disability, including mRS score at 1 month, age, and sex. The analyses were repeated for different subgroups, including thrombectomy-eligible, atrial fibrillation-related, and lacunar strokes. Hospital resource use and institutionalization data up to 31 August 2015 were collected, and mean censor-adjusted costs were reported with 95% CIs from 1000 bootstrap estimates. A general gamma linear model was used with 1-month mRS controlling for age, sex, and comorbidities. 5-year quality-adjusted life expectancies (QALE) generated from survival data and EQ-5D-derived utility scores were stratified by 1-month mRS.

Results:
Among 1,425 survivors, mRS score was a strong independent predictor of 5-year death/disability, with a step-change from mRS 2 to 3: adjusted odds ratio for mRS 3-5 vs 0-2: 35.57, 95%CI 17.40-72.71, p<0.0001. This step-change was also seen for 5-year mortality: adjusted hazard ratio for mRS 3-5 vs 0-2: 1.84, 95%CI 1.59-2.14, p<0.0001. Trends were consistent across the stroke subgroups. mRS score was the only independent predictor of 5-year healthcare costs (p<0.0001) aside from age, again with a step-change from mRS 2 to 3: £8,817.67 (95%CI 6,207.98-10,688.86) vs 29,692.73 (95%CI 21,117.18-31,367.53). 5-year QALE dropped incrementally with rising mRS: mRS=0 - 3.47 (95%CI 3.25-3.66); 1 - 2.91 (2.77-3.04); 2 - 2.64(2.46-2.81); 3 - 1.72 (1.52-1.91); 4 - 1.23 (1.03-1.45); 5 - 0.31 (0.02-0.76).

Conclusions:
Our results reaffirm the practice in acute stroke trials of using short-term mRS as the primary outcome measure. The step change between mRS 2 and 3 for both death/disability and healthcare costs supports the traditional dichotomous outcome, but the incremental drop in QALE with each mRS grade shows that ordinal analysis is also valid.
Abstract 18: External Validation of the RACE Scale After Its Implementation in the Stroke Code Protocol in Catalonia
Authors: Perez de la Ossa Natalia , Abilleira Sonia , Ribó Marc , Monica Millan , Cardona Pere , Urra Xabier , Rodríguez-Campello Ana , Martí-Fábregas Joan , Purroy Francisco , Serena Joaquín , Cánovas David , Garcés Moisés , Krupinski Jurek , Ustrell Xavier , Saura Júlia , Gorchs Montse , Carrera David , Jiménez Xavier , Dávalos Antoni ,   Catalan Stroke Code and Reperfusion Consortium (Cat-SCR)
Published: June 2021

Introduction:
We aimed to revalidate the RACE scale as a pre-hospital tool to identify patients with large vessel occlusion (LVO) and patients receiving endovascular treatment (EVT) after its implementation in the Stroke Code protocol of Catalonia (7.5 M inhabitants).

Methods:
We used data from the CICAT registry (Feb to Jun 2016), a government-mandated, prospective, hospital-based dataset that includes all Stroke Code activations. CICAT is linked to the EMS database to capture information about the pre-hospital care. RACE score, pre-hospital and in-hospital delays, final diagnostic, presence of LVO (TICA, MCA M1 or M2, tandem or basilar occlusion) and revascularization treatment were registered. Sensitivity, specificity and area under the curve (AUC) to identify LVO and patients receiving EVT were calculated for the pre-established cut off RACE≥5.

Results:
From the 1600 stroke code activations we included in the study the 962 patients in which the RACE scale was available (60%). The RACE scale showed a strong correlation with the NIHSS evaluated at hospital arrival (r=0.74, p<0.001). Distribution of final diagnosis and median RACE scores were: ischemic with LVO (22.1%), RACE 7 [5-8], ischemic without LVO (29.3%), RACE 3 [2-5], hemorrhagic(17.8%), RACE 6 [4-7], mimic(21.0%), RACE 2 [1-4] and transient ischemic attack(9.7%), RACE 3 [1-5]. A RACE cut-off score ≥5 showed sensitivity 0.80 and specificity 0.63 to detect LVO (AUC 0.78, Youden index 0.45), similar to results obtained in the validation study. In patients with RACE≥5 the rates of LVO (42% Vs 9%;p<0.001) and EVT (21% Vs 6%;p<0.001) were significantly higher than in patients with RACE<5.

Conclusion:
This large validation study performed after implementation of the RACE scale in the real clinical practice in the region of Catalonia confirms RACE accuracy to identify candidates to EVT. A RACE score ≥5 detected 77% of patients that finally underwent EVT confirming the scale as a valuable tool at the prehospital level.
Abstract 31: The Association Between Baseline Ischemic Core Volume and Benefit of Endovascular Thrombectomy in Pooled Data from Six Randomized Trials
Authors: Campbell Bruce C , Majoie Charles B , Menon Bijoy K , Goyal Mayank , Dippel Diederik W , Demchuk Andrew , Dávalos Antoni , Liebeskind David S , Brown Scott , Sharma Gagan , van der Lugt Aad , San Román Luis , Muir Keith W , White Philip , Saver Jeffrey L , Jovin Tudor G , Hill Michael D , Mitchell Peter J ,   HERMES Collaborators
Published: June 2021

Background and purpose:
Patients estimated to have a large irreversibly injured ischemic core are sometimes excluded from reperfusion therapies. We examined the association between estimated core volume and thrombectomy outcomes.

Methods:
Patient-level CT perfusion (CTP) and clinical data were pooled from trials comparing endovascular thrombectomy with standard care in anterior circulation ischemic stroke: MR CLEAN, EXTEND IA, ESCAPE, SWIFT PRIME, REVASCAT and PISTE. Ischemic core volume was estimated using relative cerebral blood flow <30% of normal brain (RAPID automated software, IschemaView). The primary outcome was the 90 day modified Rankin scale (mRS), adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modeling with a random effect for trial incorporated in all models.

Results:
Of 1352 patients, pre-treatment CTP was assessable in 539 after exclusion of 27 patients (12 severe motion, 2 no lesion within coverage, 2 contrast bolus failure, 11 data corruption during transfer from site). There were 264 allocated to endovascular thrombectomy and 275 to control. Baseline characteristics were similar between endovascular and control patients with CTP, median core 9.6 mL (IQR 2.4-26 mL) and with the overall trial demographics. Larger estimated core volume was associated with lower probability of independent outcome (mRS 0-2) in endovascular (OR 0.87 95%CI 0.80-0.95) and control patients (OR 0.85 95%CI 0.77-0.93, core*treatment interaction p=0.62) and increased disability: utility scores derived from mRS reduced by 2% (95%CI 1-4%) per 10mL increase in core volume for both endovascular and control patients (core*treatment interaction p=0.79). However, patients with >70mL core (median 100 mL, IQR 82-144mL) still benefitted from thrombectomy: ordinal mRS cOR 7.0 (2.6 -18.9) and the number needed to treat (NNT) remained stable across the spectrum of core volumes (point estimate NNT<10 for mRS 0-2 and NNT<3 for improvement in at least 1 mRS level).

Conclusions:
Increasing estimated core volume was independently associated with worse outcome but endovascular thrombectomy remained effective versus standard care even in patients with large core who otherwise met eligibility for these trials.
Abstract 52: Contributors to the Rural Excess in Stroke Mortality: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Howard George , Kleindorfer Dawn O , Long D. L , Cushman Mary , Howard Virginia J ,   for the REasons for Geographic And Racial Differences in Stroke (REGARDS) Investigators
Published: June 2021

Introduction:
One NIH goal is to investigate the US nationwide rural-urban health disparities; however, few studies provide data to help understand the 30% higher rural stroke mortality. It is unknown if the higher stroke mortality is attributable to a higher incidence of stroke, or to a higher case fatality, in rural regions. Further, the role of risk factors or SES status in higher incidence or case-fatality is unknown.

Methods:
REGARDS participants stroke-free at baseline (n = 25,090) were stratified by Rural-Urban Commuting Area strata: urban, large rural city/town, or small rural town or isolated region. Participants were followed for incident stroke, and case fatality was defined as death within 30-days of a stroke. Difference in incident stroke was assessed using proportional hazards analysis, and case-fatality by logistic regression, each considered after adjustment for demographic factors, further adjustment for risk factors, and further adjustment for SES.

Results:
Over an average follow-up of 8.2 years, 1,060 incident strokes occurred, of which 160 died within 30 days. Risk of incident stroke increased with rurality (p = 0.016), with a hazard 1.21-times (95% CI: 1.00 - 1.46) higher in large rural cities/towns, and 1.24-times (95% CI: 1.00 - 1.54) higher in small rural towns or isolated regions (see table). Adjustment for risk factors and SES attenuated the estimated risk by 50%, and the association became non-significant. There was no evidence of a higher case-fatality from stroke in rural regions (p > 0.46).

Discussion:
The higher stroke mortality in rural regions appears to be attributable to higher stroke incidence, and not to higher case-fatality. Higher stroke incidence in rural regions is partially attributable to a worse risk factor profile and lower SES. Efforts to reduce rural disparity in stroke mortality should focus on preventive strategies, especially those relevant to risk factor development and control, and/or mitigating the impact of lower SES.
Abstract 73: Risk of Paradoxical Embolism (RoPE) Score Stratification of Pooled Pfo Closure Clinical Trial Data: Lack of Evidence for Improvement in Patient Selection for Closure
Authors: Thaler David E , Dahabreh Issa J , Ruthazer Robin , Furlan Anthony J , Reisman Mark , Carroll John D , Saver Jeffrey L , Smalling Richard W , Jüni Peter , Mattle Heinrich P , Meier Bernhard , Kent David M ,   The RoPE Investigators
Published: June 2021

Introduction:
The Risk of Paradoxical Embolism (RoPE) Score can disaggregate patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) into those who are more likely to have a pathogenic PFO (high RoPE score) than an incidental PFO (low RoPE score). Those with
higher
RoPE scores have a
lower
risk of recurrent stroke and different recurrence predictors compared to those with low RoPE scores.

Hypotheses:
Patients with high RoPE scores benefit more from PFO closure than patients with low RoPE scores. Patients with high RoPE scores
and
risk factors for recurrence should benefit even more.

Methods:
The RoPE score was created from a database of CS patients with known PFO status to estimate stratum-specific PFO-attributable fraction and recurrence rates. Variables that predict stroke recurrence in high RoPE score groups (atrial septal aneurysm, history of stroke/TIA prior to index event) were added – the “RoPE Recurrence Score.” Using pooled individual patient data from all 3 RCTs of PFO closure vs. medical therapy (ITT populations; stroke outcome) we tested the ability of the scores to predict the heterogeneity of response to assigned treatment.

Results:
The mean RoPE score was significantly higher (6.8 vs. 6.3) with smaller variance (Stdev 1.5 vs. 1.9) in the pooled RCT population than in the original RoPE cohort (p<0.0001). Hazard ratios favoring closure were 0.82 (0.42-1.59, p=0.56) in the low RoPE score (<7) group and 0.31 (0.11-0.85, p=0.02) in the high RoPE score (≥7) group but the interaction p-value was not significant (p=0.12). The RoPE Recurrence score did not improve the prediction of treatment response (low score HR=0.65 (0.31-1.37), p=0.26; high score HR=0.58 (0.26-1.26), p=0.17; interaction p=0.82).

Conclusion:
As expected, the HR favoring closure trended lower in the high RoPE score group in the RCTs but missed statistical significance. The RoPE Recurrence score did not improve the prediction. This may be due to the narrow distribution of relatively high RoPE scores amongst RCT patients and so a low power to detect heterogeneity of treatment effect. Given that PFO closure can only prevent PFO-related recurrences, the treatment effect may also have been obscured by including recurrent strokes with non-PFO-related mechanisms.
Abstract 92: Detection of Radiologic and Laboratory Features of Cerebral Amyloid Angiopathy in Patients with Alzheimer’s Disease
Authors: Fotiadis Panagiotis , Becker John A , Schwab Kristin , Rosand Jonathan , Viswanathan Anand , Sperling Reisa , Johnson Keith A , Greenberg Steven M , Gurol M. Edip ,   Alzheimer’s Disease Neuroimaging Initiative
Published: June 2021

Background:
Patients with Cerebral Amyloid Angiopathy (CAA) have posterior vascular amyloid deposition and lower Amyloid Beta (Aβ) levels when compared to Alzheimer’s Disease (AD). We hypothesized that similar findings would be observed in AD patients with strictly lobar microbleeds (LMB) and/or cortical superficial siderosis (cSS) attributable to CAA [CAA-AD], when compared to AD with no hemorrhagic lesion [NH-AD].

Methods:
We reviewed brain MRIs of patients with AD who had T2*-, FLAIR and 3D T1-weighted MRI as well as Florbetapir PET, CSF Aβ-42 and tau levels, and APOE status within the ADNI database. We compared the demographics, quantitative imaging and lab findings of CAA-AD to NH-AD.

Results:
The CAA-AD (n=51) and NH-AD (n=85) groups were balanced for age, gender and history of hypertension (all p>0.2). The APOE4 was more frequently present in the CAA-AD group (78% vs 60%, p=0.038), no difference for APOE2 (p=0.41). Patients with CAA-AD had higher WMH volume (0.73 vs 0.49 % intracranial volume [ICV], p=0.035) and higher occipital-to-global Florbetapir ratio (0.98 vs 0.94, p=0.02) but similar mean cortical Florbetapir uptake (1.38 vs 1.36, p=0.57), cortical thickness (2.22 vs 2.20 mm, p=0.38), and hippocampal volume (0.37 vs 0.38 % of ICV, p=0.24) when compared to NH-AD. In a multivariable regression model that included all variables above, higher occipital-to-global Florbetapir ratio (p=0.009) and presence of APOE4 (p=0.002) were associated with CAA-AD, higher WMH (p=0.097) showed a trend. In 117 patients with CSF data, CAA-AD (n=46) had lower Aβ-42 (127 vs 140 pg/ml, p=0.038) but similar tau levels (131 vs 136 pg/ml, p=0.68) when compared to NH-AD. Lower Aβ-42 was associated with CAA-AD (p=0.024) in the relevant multivariate regression model.

Conclusions:
Over one-third of patients with AD displayed subtle hemorrhagic lesions in a CAA-pattern on MRI. When compared to NH-AD, they have higher occipital Florbetapir uptake suggesting vascular amyloid binding and lower CSF Aβ-42 levels that might be related to sequestering of amyloid in cortical vessel walls. These results support the possibility that advanced CAA commonly accompanies clinically diagnosed AD, contributing to dementia pathogenesis and potentially affecting clinical treatment decisions.
Abstract TMP16: Efficacy and Safety of Ticagrelor in Relation to Time to Loading Dose in the SOCRATES Trial
Authors: Molina Carlos A , Johnston S C , Amarenco Pierre , Albers Gregory W , Denison Hans , Easton J D , Evans Scott R , Held Peter , Jonasson Jenny , Ladenvall Per , Minematsu Kazuo , Röther Joachim , Wang Yongjun , Wong KS L ,   SOCRATES Steering Committee and Investigators
Published: June 2021

Background:
The risk of recurrent ischemia is high in the acute period after transient ischemic attack (TIA) and minor stroke. Therefore, event rates and treatment effects may vary in relation to time to loading dose (TLD) of antiplatelet treatment. We aimed to explore safety and efficacy of ticagrelor in relation to TLD from the onset of the index event.

Methods:
In the SOCRATES trial (NCT01994720), we randomized 13,199 patients with a non-cardioembolic, non-severe ischemic stroke or high-risk TIA to ticagrelor (180 mg loading dose on day 1, followed by 90 mg twice daily for days 2-90) or aspirin (300 mg on day 1, followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. Ticagrelor was not found to be superior to aspirin in reducing the rate of the primary composite endpoint of stroke, myocardial infarction, or death at 90 days. Patients were categorized according to TLD as <12 h and ≥12h from index event for this pre-specified exploratory analysis. The primary endpoint was time to the occurrence of stroke, myocardial infarction, or death within 90 days. The first secondary endpoint was ischemic stroke, with major bleeding serving as the primary safety endpoint.

Results:
TLD was <12 h in 4,403 (33.4%) and ≥12 h in 8,723 (66.1%). Among TLD <12 h patients, the primary endpoint occurred in 147/2196 (6.7%) patients randomized to ticagrelor and in 184/2207 (8.3%) randomized to aspirin (HR 0.79; 95% CI 0.64-0.98, p=0.036); ischemic stroke was less frequent in those treated with ticagrelor (6.0% vs 7.5%, HR 0.79; 95% CI 0.63-0.99, p=0.041). Among patients with TLD ≥12 h, there were no differences in the treatment groups for the primary endpoint (6.7 vs 7.0%) or for ischemic stroke (5.8% vs 6.2%). There were no significant treatment-by-TLD interactions. Major bleeding was comparable in TLD <12 h patients (0.5% vs 0.7%, p=0.25) and TLD ≥12 h (0.5% vs 0.5%, p=0.95) on ticagrelor and aspirin, respectively.

Conclusion:
In this pre-specified exploratory analysis, ticagrelor showed a greater treatment effect over aspirin in patients with TLD <12 h, although the interaction terms for treatment by TLD were not significant. Event rates for primary and secondary endpoints tended to be higher in patients randomized <12 h. Major bleeding was unrelated to TLD.
Abstract TMP20: Efficacy and Safety of Ticagrelor in Relation to Prior Aspirin Usage in the SOCRATES Trial
Authors: Wong K.S. L , Amarenco Pierre , Albers Gregory W , Denison Hans , Easton J D , Evans Scott R , Held Peter , Jonasson Jenny , Kasner Scott E , Ladenvall Per , Minematsu Kazuo , Molina Carlos A , Wang Yongjun , Johnston S C ,   SOCRATES Steering Committee and Investigators
Published: June 2021

Background:
In the SOCRATES study (NCT01994720), addition of ticagrelor to patients on aspirin treatment before randomization may confer the effect of dual antiplatelet therapy as the antiplatelet effect of aspirin persists for more than a week. We aimed to explore safety and efficacy of ticagrelor in this pre-specified group of patients who had received aspirin prior to randomization.

Methods:
We randomized 13,199 patients with a non-cardioembolic, non-severe ischemic stroke or high-risk transient ischemic attack (TIA) to ticagrelor (180mg loading dose on day 1 followed by 90mg twice daily for days 2-90) or aspirin (300mg on day 1 followed by 100mg daily for days 2-90) within 24 hours of symptom onset. The prior aspirin group consisted of patients who had received aspirin within 7 days before randomization. The primary endpoint was the time to the occurrence of stroke, myocardial infarction, or death within 90 days.

Results:
The 4,232 patients with prior aspirin usage were older, had more vascular risk factors and vascular disease than the 8,967 patients with no prior aspirin usage. In the prior aspirin group, a primary endpoint occurred in 138/2,130 (6.5%) patients randomized to ticagrelor and in 177/2,102 (8.3%) patients randomized to aspirin (HR 0.76; 95% CI, 0.61-0.95, P=0.016) while for the non-aspirin group in 304/4,459 (6.9%) patients randomized to ticagrelor and in 320/4,508 (7.1%) patients randomized to aspirin (HR 0.96; 95%CI, 0.82-1.12, P=0.59). There was no significant treatment-by-prior-aspirin interaction (P=0.098). Major bleeding occurred in 0.7% of patients randomized to ticagrelor and in 0.4% randomized to aspirin (HR 1.58; 95% CI 0.68-3.65, P=0.28) in the prior aspirin group.

Conclusion:
In this pre-specified exploratory analysis, ticagrelor showed a numerically greater treatment effect over aspirin in patients taking prior aspirin, although the interaction for treatment by prior aspirin was not statistically significant. Further study is needed to evaluate the combination of ticagrelor and aspirin in patients with minor stroke/TIA.
Abstract TMP36: Diabetes Mellitus Prevents The Complete Recanalization In Patients With Middle Cerebral Artery Occlusion
Authors: Aoki Junya , Kimura Kazumi , Morita Naomi , Harada Masafumi , Metoki Norifumi , Tateishi Yohei , Todo Kenichi , Yamagami Hiroshi , Hayashi Koji , Terasawa Yuka , Fujita Koji , Yamamoto Nobuaki , Deguchi Ichiro , Tanahashi Norio , Inoue Takeshi , Iwanaga Takeshi , Kaneko Nobuyuki , Mitsumura Hidetaka , Iguchi Yasuyuki , Ueno Yasushi , Kuramoto Yoji , Ogata Toshiyasu , Fujimoto Shigeru , Mitomi Mutsumi , Nagahiro Shinji ,   YAMATO study group
Published: June 2021

Introduction:
The mechanism of the unfavorable outcome in diabetic patients treated with intravenous thrombolysis (tPA therapy) is still uncertain. We investigated the relationship of diabetes mellitus with early and delayed recanalization after tPA therapy.

Methods:
Data on 165 patients from the prospective randomized control study, evaluated the efficacy of combined tPA and Edaravone therapy, were retrospectively analyzed. All patients had the middle cerebral occlusion before t-PA therapy. Based on a history of diabetes mellitus or hemoglobin A1c level of ≥6.5% on admission, all patients were classified into diabetes (D) or non-diabetes (ND) groups. The presence of arterial recanalization was assessed at 2 points: 1) early recanalization, defined as at least partial recanalization <50% within 2 h after tPA therapy; and 2) delayed complete recanalization at 24 h.

Results:
Among the 165 (96 men; median age, 78 [69-85] years) patients, 33 (20%) patients were classified into the D group. Age, initial NIHSS score, DWI-ASPECTS, proximal occlusion, and the onset to needle time were not different between the 2 groups (p=0.118, 0.607, 0.586, 0.258, 0.238). Early recanalization was similarly observed in the D and ND groups (61% vs. 51%, p=0.435). However, complete recanalization at 24 h was significantly infrequent in the D group (13% vs. 44%, p=0.002). This tendency was consistent in patients with as well as without early recanalization. Regarding patients with early recanalization, 4 (22%) of the 18 patients in the D group and 34 (58%) of the 59 patients in the ND group had complete recanalization at 24 h (p=0.014). Among those without early recanalization, none (0%) of the 13 patients with the D group had complete recanalization at 24 h, while 18 (30%) of the 60 patients achieved it (p=0.029). By the multivariate regression analysis, diabetes mellitus was the independent negative factor for complete recanalization at 24 h (OR 0.17, 95%CI: 0.05-0.54, p=0.002). At 3 months, there is an increased mortality rate in the D group (19% vs. 6%, p=0.038).

Conclusion:
Diabetes mellitus was an indicator of no complete recanalization at 24 h regardless of the early recanalization. This may explain the mechanism of the unfavorable outcome in patients with diabetes mellitus.
Abstract TMP77: Race and Sex Differences in tPA Utilization Among Older Ischemic Stroke Patients
Authors: Lyerly Michael , Vahidy Farhaan , Donnelly John , Booth Katrina , Albright Karen C
Published: June 2021

Introduction:
The risk of ischemic stroke doubles for each decade beyond the age of 55. While disparities, particularly racial disparities, have been described for many aspects of acute stroke care, these disparities have not been well characterized among older adults. The purpose of this analysis was to evaluate potential differences in IV-tPA utilization among acute ischemic stroke (AIS) patients aged ≥65 years.

Methods:
We used the Nationwide Inpatient Sample (NIS) to examine primary AIS diagnosis discharges (ICD-9 codes 433.x1, 434.x1 and 436) from US hospitals over 2006-2011, among those aged ≥ 65 years. Utilization of IV-tPA was identified using procedure code 99.10. Multivariate logistic regression was conducted to determine age and race associations with IV tPA utilization.

Results:
Over the 6 year study period, we identified 1.5 million ischemic stroke discharges, with 3.9% receiving IV-tPA. Compared to discharges who did not receive treatment, those receiving IV-tPA were less likely to be female and black. The odds of women receiving IV-tPA were 10% lower than men. After adjusting for demographics, insurance, and medical comorbidities, the odds of women receiving IV-tPA were still 5% lower (Table). When compared to non-black discharges, older blacks were at 25% lower odds of receiving IV-tPA. After adjusting for demographics, insurance and medical comorbidities, older blacks were at 22% lower odds of receiving IV-tPA (Table).

Conclusions:
Among older Americans, women and blacks have lower odds of being treated with IV-tPA, even after adjusting for age, insurance and comorbidities. A greater understanding of the reasons for these unexplained differences in the fastest growing proportion of our population is needed.
Abstract TMP82: National Stroke Registry is Feasible and Improves Stroke Care and Training in Nigeria: A Pilot Experience
Authors: Akinyemi Rufus , Adebayo Philip , Owolabi Lukman , Obiako Reginald , Wahab Kolawole , Olugbo Obiabo , Akpa Onoja , Melikam Sylvia , Akinyemi Joshua , Komolafe Morenikeji , Olowoyo Paul , Chukwuonye Ijezie , Ovbiagele Bruce , Owolabi Mayowa
Published: June 2021

Introduction:
There is data - driven evidence showing that stroke registries improve tracking, documentation and the quality of care for acute stroke patients in centres across all continents except Africa where data is lacking. We report findings from a pilot multi - centre stroke registry in Nigeria.

Methods:
A World Federation of Neurology/World Stroke Organization (WFN/WSO) supported stroke training programme collaborated with NIH - funded Stroke Investigative Research and Education Network (SIREN) Project to develop a web-based multicenter acute stroke registry in 13 tertiary hospitals across Nigeria. All suspected cases of stroke were recorded in a Stroke Log and CT- confirmed cases were entered into a case report form and a web-based platform (RedCAP). A one hour focus group discussion (FGD) was conducted among 7 site neurologists to evaluate the impact of the pilot programme on stroke care and training.

Results:
Over a 21 month period (October 2014 - June 2016), 1686 suspected cases of stroke were logged into the stroke log while 1391 brain - CT confirmed cases of stroke were logged onto RedCAP. Across all sites; mean age(SD) was 60.1 (14.2) years, 57.1% male, 78.9% had at least primary education, 67.5%, 31.0% and 1.5% had ischemic, hemorrhagic and ischemic stroke with hemorrhagic transformation respectively, 51.8% were admitted with severe stroke, hypertension was the dominant risk factor (78.7% of cases) and 21.8% died within 7 days. An FGD to evaluate impact showed improved stroke awareness, better CT rate, reduced time to CT, reduced short term mortality, improved training and competence of interns and residents, development of stroke multidisciplinary teams and better job satisfaction among site neurologists.

Conclusion:
A pilot multicenter national stroke registry is feasible and improves stroke care, training and neurologist job satisfaction in Nigeria.