Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds.

Importance: Cerebral small vessel disease (SVD) is associated with various cerebrovascular outcomes, but data on sex differences in SVD are scarce. Objective: To investigate whether the frequency, severity, and distribution of cerebral microbleeds (CMB), other SVD markers on magnetic resonance imaging (MRI), and outcomes differ by sex. Design, Setting, and Participants: This cohort study used pooled individual patient data from the Microbleeds International Collaborative Network, including patients from 38 prospective cohort studies in 18 countries between 2000 and 2018, with clinical follow-up of at least 3 months (up to 5 years). Participants included patients with acute ischemic stroke or transient ischemic attack with available brain MRI. Data were analyzed from April to December 2023. Main Outcomes and Measures: Outcomes of interest were presence of CMB, lacunes, and severe white matter hyperintensities determined on MRI. Additionally, mortality, recurrent ischemic stroke, and intracranial hemorrhage during follow-up were assessed. Multivariable random-effects logistic regression models, Cox regression, and competing risk regression models were used to investigate sex differences in individual SVD markers, risk of recurrent cerebrovascular events, and death. Results: A total of 20 314 patients (mean [SD] age, 70.1 [12.7] years; 11 721 [57.7%] male) were included, of whom 5649 (27.8%) had CMB. CMB were more frequent in male patients, and this was consistent throughout different age groups, locations, and in multivariable models (female vs male adjusted odds ratio [aOR], 0.86; 95% CI, 0.80-0.92; P < .001). Female patients had fewer lacunes (aOR, 0.82; 95% CI, 0.74-0.90; P < .001) but a higher prevalence of severe white matter hyperintensities (aOR, 1.10; 95% CI, 1.01-1.20; P = .04) compared with male patients. A total of 2419 patients (11.9%) died during a median (IQR) follow-up of 1.4 (0.7-2.5) years. CMB presence was associated with a higher risk of mortality in female patients (hazard ratio, 1.15; 95% CI, 1.02-1.31), but not male patients (hazard ratio, 0.95; 95% CI, 0.84-1.07) (P for interaction = .01). A total of 1113 patients (5.5%) had recurrent ischemic stroke, and 189 patients (0.9%) had recurrent intracranial hemorrhage, with no sex differences. Conclusions and Relevance: This cohort study using pooled individual patient data found varying frequencies of individual SVD markers between female and male patients, indicating potential pathophysiological differences in manifestation and severity of SVD. Further research addressing differences in pathomechanisms and outcomes of SVD between female and male patients is required.

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke.

BACKGROUND: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking. METHODS: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data. RESULTS: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P=4.34×10-8). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings. CONCLUSIONS: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

A Randomized Trial on Hemodynamic Optimization of Cerebral Perfusion after Successful Endovascular Therapy in Patients with Acute Ischemic Stroke (HOPE).

INTRODUCTION: In patients with acute ischemic stroke (AIS) secondary to intracranial large vessel occlusion, optimal blood pressure (BP) management following endovascular treatment (EVT) has not yet been established. The randomized trial on Hemodynamic Optimization of Cerebral Perfusion after Successful Endovascular Therapy in Patients with Acute Ischemic Stroke (HOPE) (clinicaltrials.gov id: NCT04892511) aims to demonstrate whether hemodynamic optimization using different systolic BP targets following EVT according to the degree of final recanalization, is more effective than currently recommended BP management in improving functional outcomes of patients with AIS. METHODS: HOPE is an investigator-initiated multicenter clinical trial with randomized allocation, open-label treatment, and blinded endpoint evaluation (PROBE). Patients with an anterior circulation AIS within 24 h of symptom onset, treated with EVT, and showing successful recanalization (mTICI ≥2b) at the end of the procedure, are equally allocated (1:1) to hemodynamic optimization according to the study protocol versus BP management according to current guidelines (≤180/105 mm Hg). The protocol includes two different targets of systolic BP depending on the recanalization status (mTICI = 2b: 140-160 mm Hg; mTICI = 2c/3: 100-140 mm Hg). The protocol is applied within the first 72 h and includes BP lowering as well as vasopressor therapies when needed. The primary outcome is the proportion of favorable outcome (modified Rankin Scale [mRS] 0-2) at 90 days. Secondary outcomes include the shift on the mRS score, neurological deterioration, symptomatic intracerebral hemorrhage, and mortality. CONCLUSION: The HOPE trial will provide new information on the safety and efficacy of different BP targets following EVT according to the degree of final recanalization in patients with AIS.

Influence of Hospital Type on Outcomes of Patients With Acute Spontaneous Intracerebral Hemorrhage: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Whether the outcome of patients with spontaneous intracerebral hemorrhage (ICH) differs depending on the type of hospital where they are admitted is uncertain. The objective of this study was to determine influence of hospital type at admission (telestroke center [TSC], primary stroke center [PSC], or comprehensive stroke center [CSC]) on outcome for patients with ICH. We hypothesized that outcomes may be better for patients admitted to a CSC. METHODS: This is a multicenter prospective observational and population-based study of a cohort of consecutively recruited patients with ICH (March 2020-March 2022). We included all patients with spontaneous ICH in Catalonia (Spain) who had a pre-ICH modified Rankin scale (mRS) score of 0-3 and who were admitted to the hospital within 24 hours of onset. We compared patients admitted to a TSC/PSC (n = 641) or a CSC (n = 1,320) and also analyzed the subgroup of patients transferred (n = 331) or not transferred (n = 310) from a TSC/PSC to a CSC. The main outcome was the 3-month mRS score obtained by blinded investigators. Outcomes were compared using adjusted ordinal logistic regression to estimate the common odds ratio (OR) and 95% CI for a shift in mRS scores. A propensity score matching (PSM) analysis was performed for the subgroup of transferred patients. RESULTS: Relevant data were obtained from 1961 of a total of 2,230 patients, with the mean (SD) age of 70 (14.1) years, and 713 (38%) patients were women. After adjusting for confounders (age, NIH Stroke Scale score, intraventricular hemorrhage, hematoma volume, and pre-ICH mRS score), type of hospital of initial admission (CSC vs TSC/PSC) was not associated with outcome (adjusted common OR 1.13, 95% CI 0.93-1.38). A PSM analysis indicated that transfer to a CSC was not associated with more favorable outcomes (OR 0.77, 95% CI 0.55-1.10; p = 0.16). DISCUSSION: In this population-based study, we found that, after adjusting for confounders, hospital types were not associated with functional outcomes. In addition, for patients who were transferred from a TSC/PSC to a CSC, PSM indicated that outcomes were similar to nontransferred patients. Our findings suggest that patient characteristics are more important than hospital characteristics in determining outcome after ICH. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03956485.

Early automated cerebral edema assessment following endovascular therapy: impact on stroke outcome.

BACKGROUND: Cerebral edema (CED) is associated with poorer outcome in patients with acute ischemic stroke (AIS). The aim of the study was to investigate the factors contributing to greater early CED formation in patients with AIS who underwent endovascular therapy (EVT) and its association with functional outcome. METHODS: We conducted a multicenter cohort study of patients with an anterior circulation AIS undergoing EVT. The volume of cerebrospinal fluid (CSF) was extracted from baseline and 24-hour follow-up CT using an automated algorithm. The severity of CED was quantified by the percentage reduction in CSF volume between CT scans (∆CSF). The primary endpoint was a shift towards an unfavorable outcome, assessed by modified Rankin Scale (mRS) score at 3 months. Multivariable ordinal logistic regression analyses were performed. The ∆CSF threshold that predicted unfavorable outcome was selected using receiver operating characteristic curve analysis. RESULTS: We analyzed 201 patients (mean age 72.7 years, 47.8% women) in whom CED was assessable for 85.6%. Higher systolic blood pressure during EVT and failure to achieve modified Thrombolysis In Cerebral Infarction (mTICI) 3 were found to be independent predictors of greater CED. ∆CSF was independently associated with the probability of a one-point worsening in the mRS score (common odds ratio (cOR) 1.05, 95% CI 1.03 to 1.08) after adjusting for age, baseline mRS, National Institutes of Health Stroke Scale (NIHSS), and number of passes. Displacement of more than 25% of CSF was associated with an unfavorable outcome (OR 6.09, 95% CI 3.01 to 12.33) and mortality (OR 6.72, 95% CI 2.94 to 15.32). CONCLUSIONS: Early CED formation in patients undergoing EVT was affected by higher blood pressure and incomplete reperfusion. The extent of early CED, measured by automated ∆CSF, was associated with worse outcomes.

Effects of Achieving Rapid, Intensive, and Sustained Blood Pressure Reduction in Intracerebral Hemorrhage Expansion and Functional Outcome.

BACKGROUND AND OBJECTIVES: The time taken to achieve blood pressure (BP) control could be pivotal in the benefits of reducing BP in acute intracerebral hemorrhage (ICH). We aimed to assess the relationship between the rapid achievement and sustained maintenance of an intensive systolic BP (SBP) target with radiologic, clinical, and functional outcomes. METHODS: Rapid, Intensive, and Sustained BP lowering in Acute ICH (RAINS) was a multicenter, prospective, observational cohort study of adult patients with ICH <6 hours and SBP ≥150 mm Hg at 4 Comprehensive Stroke Centers during a 4.5-year period. Patients underwent baseline and 24-hour CT scans and 24-hour noninvasive BP monitoring. BP was managed under a rapid (target achievement ≤60 minutes), intensive (target SBP <140 mm Hg), and sustained (target stability for 24 hours) BP protocol. SBP target achievement ≤60 minutes and 24-hour SBP variability were recorded. Outcomes included hematoma expansion (>6 mL or >33%) at 24 hours (primary outcome), early neurologic deterioration (END, 24-hour increase in NIH Stroke Scale score ≥4), and 90-day ordinal modified Rankin scale (mRS) score. Analyses were adjusted by age, sex, anticoagulation, onset-to-imaging time, ICH volume, and intraventricular extension. RESULTS: We included 312 patients (mean age 70.2 ± 13.3 years, 202 [64.7%] male). Hematoma expansion occurred in 70/274 (25.6%) patients, END in 58/291 (19.9%), and the median 90-day mRS score was 4 (interquartile range, 2-5). SBP target achievement ≤60 minutes (178/312 [57.1%]) associated with a lower risk of hematoma expansion (adjusted odds ratio [aOR] 0.43, 95% confidence interval [CI] 0.23-0.77), lower END rate (aOR 0.43, 95% CI 0.23-0.80), and lower 90-day mRS scores (aOR 0.48, 95% CI 0.32-0.74). The mean 24-hour SBP variability was 21.0 ± 7.6 mm Hg. Higher 24-hour SBP variability was not related to expansion (aOR 0.99, 95% CI 0.95-1.04) but associated with higher END rate (aOR 1.15, 95% CI 1.09-1.21) and 90-day mRS scores (aOR 1.06, 95% CI 1.04-1.10). DISCUSSION: Among patients with acute ICH, achieving an intensive SBP target within 60 minutes was associated with lower hematoma expansion risk. Rapid SBP reduction and stable sustention within 24 hours were related to improved clinical and functional outcomes. These findings warrant the design of randomized clinical trials examining the impact of effectively achieving rapid, intensive, and sustained BP control on hematoma expansion. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in adults with spontaneous ICH and initial SBP ≥150 mm Hg, lowering SBP to <140 mm Hg within the first hour and maintaining this for 24 hours is associated with decreased hematoma expansion.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Asymptomatic parenchymal haemorrhage following endovascular treatment: Impact on functional outcome in patients with acute ischaemic stroke.

BACKGROUND AND PURPOSE: In patients with acute ischaemic stroke (AIS), haemorrhagic transformation (HT) following endovascular treatment (EVT) is associated with poor functional outcome. However, the impact of asymptomatic HT, not linked to neurological deterioration in the acute phase, is unknown. We aimed to investigate the impact of asymptomatic PH1 (aPH1) and PH2 (aPH2) subtypes of HT on the functional outcome of patients treated with EVT. METHODS: We conducted a retrospective study of patients with AIS who were consecutively admitted to our comprehensive stroke centre between January 2019 and December 2022, and who underwent EVT. We collected clinical, radiological, and procedural data. HTs were categorized according to the Heidelberg classification. The primary outcome was the shift on the modified Rankin Scale (mRS) at 3 months of follow-up. We performed bivariate and multivariable ordinal regression analyses to test the association between aPH1/aPH2 and the primary outcome. RESULTS: We included 314 patients (mean age = 72.5 years [SD = 13.6], 171 [54.5%] women). We detected 54 (17.2%) patients with HT; 23 (7.3%) were classified as PH2 (11 asymptomatic) and 17 (5.4%) as PH1 (16 asymptomatic). The adjusted common odds ratio for aPH2 of worsening 1 point on the 3-month mRS was 3.32 (95% confidence interval = 1.16-9.57, p = 0.026). No association was observed for aPH1. aPH2 was also independently associated with lower odds of achieving a favourable outcome (mRS = 0-2). Neither aPH1 nor aPH2 was associated with mortality. CONCLUSIONS: In patients with AIS treated with EVT, aPH2 is independently associated with unfavourable functional outcome.

Clinical characteristics and outcome of amaurosis fugax due to transient retinal ischemia: Results from a contemporary cohort.

BACKGROUND: Whether presenting an episode of amaurosis fugax (AFx) increases the risk of ischemic stroke is controversial and there is a lack of consensus in the following management. We aimed to describe the clinical characteristics and prognosis of patients with AFx due to suspected transient retinal ischemia. METHODS: Observational, retrospective study of patients admitted in a Comprehensive Stroke Center with diagnosis of AFx due to suspected transient retinal ischemia between 2015 and 2020. Clinical characteristics and diagnostic-therapeutic data were collected, as well as recurrences (new episodes of amaurosis and/or ischemic strokes). Multivariable Cox regression analyses were performed to study factors associated with the risk of recurrence. RESULTS: We included 91 patients with a mean age of 67.9±14.8 years, 43(47.3%) were women. After the diagnostic workup 14(15.4%) AFx were attributed to an atherothrombotic etiology, 4(4.4%) cardioembolic source, 10(11%) other determined cause (TOAST-OC) and 63(69,2%) indeterminate etiology. 71(78%) patients started antiplatelet therapy and 2(2.2%) anticoagulant therapy. After a median follow-up of 3.5 years (IQR 1.8-5.2), at least one recurrence was recorded in eight (8.8%) patients (four new AFx and four cerebral infarctions). TOAST-OC (HR=9.66, 95% CI 2.41-38.70; p=0.001) and prior history of ischemic stroke (HR=4.21. 95% CI 1.01-17.66; p=0.049) were both independently associated with the risk of recurrence. CONCLUSIONS: In two out of three patients, AFx due to transient retinal ischemia was of undetermined cause. The risk of stroke recurrence after a first episode of AFx in our cohort was 8.8%. Patients with TOAST-OC etiology identified were at highest risk of recurrence.

Effect of Bypassing the Closest Stroke Center in Patients with Intracerebral Hemorrhage: A Secondary Analysis of the RACECAT Randomized Clinical Trial.

Importance: Prehospital transfer protocols are based on rapid access to reperfusion therapies for patients with ischemic stroke. The effect of different protocols among patients receiving a final diagnosis of intracerebral hemorrhage (ICH) is unknown. Objective: To determine the effect of direct transport to an endovascular treatment (EVT)-capable stroke center vs transport to the nearest local stroke center. Design, Setting, and Participants: This was a prespecified secondary analysis of RACECAT, a multicenter, population-based, cluster-randomized clinical trial conducted from March 2017 to June 2020 in Catalonia, Spain. Patients were evaluated by a blinded end point assessment. All consecutive patients suspected of experiencing a large vessel occlusion stroke (Rapid Arterial Occlusion Evaluation Scale [RACE] score in the field >4 on a scale of 0 to 9, with lower to higher stroke severity) with final diagnosis of ICH were included. A total of 1401 patients were enrolled in RACECAT with suspicion of large vessel occlusion stroke. The current analysis was conducted in October 2022. Intervention: Direct transport to an EVT-capable stroke center (n = 137) or to the closest local stroke center (n = 165). Main Outcomes and Measures: The primary outcome was tested using cumulative ordinal logistic regression to estimate the common odds ratio (OR) and 95% CI of the shift analysis of disability at 90 days as assessed by the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) in the intention-to-treat population. Secondary outcomes, included 90-day mortality, death or severe functional dependency, early neurological deterioration, early mortality, ICH volume and enlargement, rate of neurosurgical treatment, rate of clinical complications during initial transport, and rate of adverse events until day 5. Results: Of 1401 patients enrolled, 1099 were excluded from this analysis (32 rejected informed consent, 920 had ischemic stroke, 29 had transient ischemic attack, 12 had subarachnoid hemorrhage, and 106 had stroke mimic). Thus, 302 patients were included (204 [67.5%] men; mean [SD] age 71.7 [12.8] years; and median [IQR] RACE score, 7 [6-8]). For the primary outcome, direct transfer to an EVT-capable stroke center (mean [SD] mRS score, 4.93 [1.38]) resulted in worse functional outcome at 90 days compared with transfer to the nearest local stroke center (mean [SD] mRS score, 4.66 [1.39]; adjusted common OR, 0.63; 95% CI, 0.41-0.96). Direct transfer to an EVT-capable stroke center also suggested potentially higher 90-day mortality compared with transfer to the nearest local stroke center (67 of 137 [48.9%] vs 62 of 165 [37.6%]; adjusted hazard ratio, 1.40; 95% CI, 0.99-1.99). The rates of medical complications during the initial transfer (30 of 137 [22.6%] vs 9 of 165 patients [5.6%]; adjusted OR, 5.29; 95% CI, 2.38-11.73) and in-hospital pneumonia (49 of 137 patients [35.8%] vs 29 of 165 patients [17.6%]; OR, 2.61; 95% CI, 1.53-4.44) were higher in the EVT-capable stroke center group. Conclusions and Relevance: In this secondary analysis of the RACECAT randomized clinical trial, bypassing the closest stroke center resulted in reduced chances of functional independence at 90 days for patients who received a final diagnosis of ICH. Trial Registration: ClinicalTrials.gov Identifier: NCT02795962.

Ischaemic stroke patients present sex differences in gut microbiota.

BACKGROUND: Gut microbiota plays a role in the pathophysiology of ischaemic stroke (IS) through the bidirectional gut-brain axis. Nevertheless, little is known about sex-specific microbiota signatures in IS occurrence. METHODS: A total of 89 IS patients and 12 healthy controls were enrolled. We studied the taxonomic differences of the gut microbiota between men and women with IS by shotgun metagenomic sequencing. To evaluate the causal effect of several bacteria on IS risk, we performed a two-sample Mendelian randomisation (MR) with inverse-variance weighting (IVW) using genome-wide association analysis (GWAS) summary statistics from two cohorts of 5959 subjects with genetic and microbiota data and 1,296,908 subjects with genetic and IS data, respectively. RESULTS: α-Diversity analysis measured using Observed Species (p = 0.017), Chao1 (p = 0.009) and Abundance-based Coverage Estimator (p = 0.012) indexes revealed that IS men have a higher species richness compared with IS women. Moreover, we found sex-differences in IS patients in relation to the phylum Fusobacteria, class Fusobacteriia, order Fusobacteriales and family Fusobacteriaceae (all Bonferroni-corrected p < 0.001). MR confirmed that increased Fusobacteriaceae levels in the gut are causally associated with an increased risk of IS (IVW p = 0.02, ß = 0.32). CONCLUSIONS: Our study is the first to indicate that there are gut microbiome differences between men and women with IS, identifying high levels of Fusobacteriaceae in women as a specific risk factor for IS. Incorporating sex stratification analysis is important in the design, analysis and interpretation of studies on stroke and the gut microbiota.

Electronegative LDL Is Associated with Plaque Vulnerability in Patients with Ischemic Stroke and Carotid Atherosclerosis.

Owing to the high risk of recurrence, identifying indicators of carotid plaque vulnerability in atherothrombotic ischemic stroke is essential. In this study, we aimed to identify modified LDLs and antioxidant enzymes associated with plaque vulnerability in plasma from patients with a recent ischemic stroke and carotid atherosclerosis. Patients underwent an ultrasound, a CT-angiography, and an 18F-FDG PET. A blood sample was obtained from patients (n = 64, 57.8% with stenosis ≥50%) and healthy controls (n = 24). Compared to the controls, patients showed lower levels of total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B (apoB), apoA-I, apoA-II, and apoE, and higher levels of apoJ. Patients showed lower platelet-activating factor acetylhydrolase (PAF-AH) and paraoxonase-1 (PON-1) enzymatic activities in HDL, and higher plasma levels of oxidized LDL (oxLDL) and electronegative LDL (LDL(-)). The only difference between patients with stenosis ≥50% and <50% was the proportion of LDL(-). In a multivariable logistic regression analysis, the levels of LDL(-), but not of oxLDL, were independently associated with the degree of carotid stenosis (OR: 5.40, CI: 1.15-25.44, p < 0.033), the presence of hypoechoic plaque (OR: 7.52, CI: 1.26-44.83, p < 0.027), and of diffuse neovessels (OR: 10.77, CI: 1.21-95.93, p < 0.033), indicating that an increased proportion of LDL(-) is associated with vulnerable atherosclerotic plaque.

Automated scoring of collaterals, blood pressure, and clinical outcome after endovascular treatment in patients with acute ischemic stroke and large-vessel occlusion.

Introduction: We aimed to determine whether the degree of collateral circulation is associated with blood pressure at admission in acute ischemic stroke patients treated with endovascular treatment and to determine its prognostic value. Methods: We evaluated patients with anterior large vessel occlusion treated with endovascular treatment in a single-center prospective registry. We collected clinical and radiological data. Automated and validated software (Brainomix Ltd., Oxford, UK) was used to generate the collateral score (CS) from the baseline single-phase CT angiography: 0, filling of ≤10% of the occluded MCA territory; 1, 11-50%; 2, 51-90%; 3, >90%. When dichotomized, we considered that CS was good (CS = 2-3), or poor (CS = 0-1). We performed bivariate and multivariable ordinal logistic regression analysis to predict CS categories in our population. The secondary outcome was to determine the influence of automated CS on functional outcome at 3 months. We defined favorable functional outcomes as mRS 0-2 at 3 months. Results: We included 101 patients with a mean age of 72.1 ± 13.1 years and 57 (56.4%) of them were women. We classified patients into 4 groups according to the CS: 7 patients (6.9%) as CS = 0, 15 (14.9%) as CS = 1, 43 (42.6%) as CS = 2 and 36 (35.6%) as CS = 3. Admission systolic blood pressure [aOR per 10 mmHg increase 0.79 (95% CI 0.68-0.92)] and higher baseline NIHSS [aOR 0.90 (95% CI, 0.84-0.96)] were associated with a worse CS. The OR of improving 1 point on the 3-month mRS was 1.63 (95% CI, 1.10-2.44) favoring a better CS (p = 0.016). Conclusion: In acute ischemic stroke patients with anterior large vessel occlusion treated with endovascular treatment, admission systolic blood pressure was inversely associated with the automated scoring of CS on baseline CT angiography. Moreover, a good CS was associated with a favorable outcome.

A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype.

Background: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification. Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10-8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort. Results: We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension. Conclusion: The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.

Association of Plaque Inflammation With Stroke Recurrence in Patients With Unproven Benefit From Carotid Revascularization.

BACKGROUND AND OBJECTIVES: In pooled analyses of endarterectomy trials for symptomatic carotid stenosis, several subgroups experienced no net benefit from revascularization. The validated symptomatic carotid atheroma inflammation lumen-stenosis (SCAIL) score includes stenosis severity and inflammation measured by PET and improves the identification of patients with recurrent stroke compared with lumen-stenosis alone. We investigated whether the SCAIL score improves the identification of recurrent stroke in subgroups with uncertain benefit from revascularization in endarterectomy trials. METHODS: We did an individual-participant data pooled analysis of 3 prospective cohort studies (Dublin Carotid Atherosclerosis Study [DUCASS], 2008-2011; Biomarkers and Imaging of Vulnerable Atherosclerosis in Symptomatic Carotid Artery Disease [BIOVASC], 2014-2018; Barcelona Plaque Study, 2015-2018). Eligible patients had a recent nonsevere (modified Rankin Scale score ≤3) anterior circulation ischemic stroke/TIA and ipsilateral mild carotid stenosis (<50%); ipsilateral moderate carotid stenosis (50%-69%) plus at least 1 of female sex, age <65 years, diabetes mellitus, TIA, or delay >14 days to revascularization; or monocular loss of vision. Patients underwent coregistered carotid 18F-fluorodeoxyglucosePET/CT angiography (≤7 days from inclusion). The primary outcome was 90-day ipsilateral ischemic stroke. Multivariable Cox regression modeling was performed. RESULTS: We included 135 patients. All patients started optimal modern-era medical treatment at admission, and 62 (45.9%) underwent carotid revascularization (36 within the first 14 days and 26 beyond). At 90 days, 18 (13.3%) patients had experienced at least 1 stroke recurrence. The risk of recurrence increased progressively according to the SCAIL score (0.0% in patients scoring 0-1, 15.1% scoring 2-3, and 26.7% scoring 4-5; p = 0.04). The adjusted (age, smoking, hypertension, diabetes, carotid revascularization, antiplatelets and statins) hazard ratio for ipsilateral recurrent stroke per 1-point SCAIL increase was 2.16 (95% CI 1.32-3.53; p = 0.002). A score ≥2 had a sensitivity of 100% for recurrence. DISCUSSION: The SCAIL score improved the identification of early recurrent stroke in subgroups who did not experience benefit in endarterectomy trials. Randomized trials are needed to test whether a combined stenosis-inflammation strategy will improve selection for carotid revascularization when benefit is currently uncertain. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, in patients with recent anterior circulation ischemic stroke who do not benefit from carotid revascularization, the SCAIL score accurately distinguishes those at risk for recurrent ipsilateral ischemic stroke.

Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men.

BACKGROUND: Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. METHODS: We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. RESULTS: Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, P=1.34×10-2); the same tendency was observed in the second cohort (women=-0.57, men=0.79, P=0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (P<0.05), belonging to the immune effector process (P=1.54×10-6) and platelet degranulation (P<8.74×10-6) pathways. CONCLUSIONS: This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women.

Frequency, Predictors, Etiology, and Outcomes for Deep Intracerebral Hemorrhage without Hypertension.

OBJECTIVES: Some patients with deep intracerebral hemorrhage (ICH) have a transient hypertensive response and they may be erroneously classified as secondary to hypertension. We investigated frequency, risk factors, and outcomes for patients with deep ICH without hypertension. MATERIALS AND METHODS: We consecutively recruited patients with spontaneous ICH attending two Spanish stroke centers (January 2015-June 2019). Excluded were patients with lobar/infratentorial ICH and patients who died during hospitalization. We defined deep ICH without hypertension when the bleeding was in a deep structure, no requirement for antihypertensive agents during follow-up and no evident chronic hypertension markers evaluated by transthoracic echocardiography, 24 h ambulatory blood pressure monitoring and/or electrocardiography. We compared clinical, radiological, and 3-month functional outcome data for deep-ICH patients with hypertension versus those without hypertension. RESULTS: Of 759 patients with ICH, 219 (mean age 69.6 ± 15.4 years, 54.8% men) met the inclusion criteria and 36 (16.4%) did not have hypertension. Of these 36 patients, 19 (52.7%) had a transient hypertensive response. Independent predictors of deep ICH without hypertension were age (adjusted OR:0.94;95%CI:0.91-0.96) and dyslipidemia (adjusted OR:0.27;95% CI:0.08-0.85). One third of deep ICH without hypertension were secondary to vascular malformations. Favorable outcomes (modified Rankin Scale 0-2) were more frequent in patients with deep ICH without hypertension compared to those with hypertension (70.9% vs 33.8%; p < 0.001). CONCLUSION: Of patients with deep ICH, 16.4% were unrelated with hypertension, around half showed hypertensive response, and around a third had vascular malformations. We suggest studying hypertension markers and performing a follow-up brain MRI in those patients with deep ICH without prior hypertension.

Endothelial Progenitor Cells Count after Acute Ischemic Stroke Predicts Functional Outcome in Patients with Carotid Atherosclerosis.

OBJECTIVES: Circulating Endothelial Progenitor Cells (EPCs) predict cardiovascular outcomes in patients with coronary disease. However, the predictive value of EPCs after ischemic stroke is not well established. We aimed to study the prognostic role of EPCs in patients with acute ischemic stroke and carotid atherosclerosis, focusing on post-stroke functional outcome and stroke recurrences. MATERIALS AND METHODS: We studied consecutive adult patients with an acute (<7 days) anterior circulation ischemic stroke and carotid atherosclerosis. Cardioembolic strokes were excluded. We measured circulating EPCs by flow cytometry (CD34+/CD133+/KDR+) at inclusion (7±1 days after stroke) and at one year of follow-up. At three months and at one year we registered the modified Rankin Scale score, stroke recurrences and coronary syndromes during the follow-up. RESULTS: We studied 80 patients with a mean age of 74.3±10.4 years. We divided the population in tertiles according to the EPCs count. At three months we observed a favorable outcome in 25/36 (69.4%) patients in the lowest, 19/22 (86.4%) in the medium and 21/22 (95.5%) in the highest tercile (p=0.037). In the multivariable analysis a higher EPCs count was associated with favorable functional outcome after adjusting for age and baseline NIHSS score (OR=3.61, 95%CI 1.34-9.76; p=0.011). This association persisted at one year of follow-up. We did not find association between counts of EPCs and stroke recurrence. CONCLUSIONS: In patients with acute ischemic stroke and carotid atherosclerosis, a higher count of EPCs was associated with favorable functional outcome in the mid and long-term follow-up. Counts of EPCs did not predict stroke recurrences.

Impact of COVID-19 Infection on the Outcome of Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: We evaluated whether stroke severity, functional outcome, and mortality are different in patients with ischemic stroke with or without coronavirus disease 2019 (COVID-19) infection. METHODS: A prospective, observational, multicentre cohort study in Catalonia, Spain. Recruitment was consecutive from mid-March to mid-May 2020. Patients had an acute ischemic stroke within 48 hours and a previous modified Rankin Scale (mRS) score of 0 to 3. We collected demographic data, vascular risk factors, prior mRS score, National Institutes of Health Stroke Scale score, rate of reperfusion therapies, logistics, and metrics. Primary end point was functional outcome at 3 months. Favourable outcome was defined depending on the previous mRS score. Secondary outcome was mortality at 3 months. We performed mRS shift and multivariable analyses. RESULTS: We evaluated 701 patients (mean age 72.3±13.3 years, 60.5% men) and 91 (13%) had COVID-19 infection. Median baseline National Institutes of Health Stroke Scale score was higher in patients with COVID-19 compared with patients without COVID-19 (8 [3-18] versus 6 [2-14], P=0.049). Proportion of patients with a favourable functional outcome was 33.7% in the COVID-19 and 47% in the non-COVID-19 group. However, after a multivariable logistic regression analysis, COVID-19 infection did not increase the probability of unfavourable functional outcome. Mortality rate was 39.3% among patients with COVID-19 and 16.1% in the non-COVID-19 group. In the multivariable logistic regression analysis, COVID-19 infection was a risk factor for mortality (hazard ratio, 3.14 [95% CI, 2.10-4.71]; P<0.001). CONCLUSIONS: Patients with ischemic stroke and COVID-19 infection have more severe strokes and a higher mortality than patients with stroke without COVID-19 infection. However, functional outcome is comparable in both groups.

RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis.

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 × 10-8) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 × 10-8) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-ß, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.