Machine Learning-Based Etiologic Subtyping of Ischemic Stroke Using Circulating Exosomal microRNAs.

Ischemic stroke is a major cause of mortality worldwide. Proper etiological subtyping of ischemic stroke is crucial for tailoring treatment strategies. This study explored the utility of circulating microRNAs encapsulated in extracellular vesicles (EV-miRNAs) to distinguish the following ischemic stroke subtypes: large artery atherosclerosis (LAA), cardioembolic stroke (CES), and small artery occlusion (SAO). Using next-generation sequencing (NGS) and machine-learning techniques, we identified differentially expressed miRNAs (DEMs) associated with each subtype. Through patient selection and diagnostic evaluation, a cohort of 70 patients with acute ischemic stroke was classified: 24 in the LAA group, 24 in the SAO group, and 22 in the CES group. Our findings revealed distinct EV-miRNA profiles among the groups, suggesting their potential as diagnostic markers. Machine-learning models, particularly logistic regression models, exhibited a high diagnostic accuracy of 92% for subtype discrimination. The collective influence of multiple miRNAs was more crucial than that of individual miRNAs. Additionally, bioinformatics analyses have elucidated the functional implications of DEMs in stroke pathophysiology, offering insights into the underlying mechanisms. Despite limitations like sample size constraints and retrospective design, our study underscores the promise of EV-miRNAs coupled with machine learning for ischemic stroke subtype classification. Further investigations are warranted to validate the clinical utility of the identified EV-miRNA biomarkers in stroke patients.

The Impact of age and outcomes of high-risk patients on carotid revascularization.

OBJECTIVES: To validate the accuracy of high-risk criteria for carotid endarterectomy (CEA) and analyze the correlation between age and outcome of CEA and carotid artery stenting (CAS) in risk groups. METHODS: We reviewed a prospectively managed vascular surgery database in a single tertiary referral center, and 2482 internal carotid arteries (ICAs) had undergone carotid revascularization from November 1994 to December 2021. To validate high-risk criteria for CEA, patients were classified as high risk (Hr) and normal risk (Nr). Subgroup analysis was performed with patients older or younger than 75 years to investigate the relationship between age and outcome in each group. Primary endpoints were 30-day outcomes including stroke, death, stroke/death, myocardial infraction (MI), and major adverse cardiovascular events (MACEs). RESULTS: A total of 2345 ICAs in 2256 patients were enrolled. The number of patients in the Hr group was 543 (24%) and the number in the Nr group was 1713 (76%). CEA and CAS were performed on 1384 (61%) and 872 (39%) patients, respectively. The 30-day stroke/death rate was higher with CAS than CEA in both the Hr (1.1% vs. 3.9%, p = 0.032) and Nr (1.2% vs. 6.9%, p < 0.001) groups. In unmatched logistic regression analysis of the Nr group (n = 1778), the rate of 30-day stroke/death (OR, 5.575; 95% CI, 2.922-10.636; p < 0.001) was higher for CAS than CEA. In propensity score matching of the Nr group, the rate of 30-day stroke/death (OR, 5.165; 95% CI, 2.391-11.155; p < 0.001) was also higher for CAS than CEA. In the age <75 subgroup of the Hr group (n = 428), CAS was associated with higher 30-day stroke/death (OR, 14.089; 95% CI, 1.314-151.036; p = 0.029). In the age ≥75 subgroup of the Hr (n = 139), there was no difference in 30-day stroke/death between CEA and CAS. In the age <75 subgroup of the Nr group (n = 1318), 30-day stroke/death (OR, 6.300; 95% CI, 2.797-14.193; p < 0.001) was higher in CAS. In the age ≥75 subgroup of the Nr group (n = 460), 30-day stroke/death (OR, 6.468; 95% CI, 1.862-22.471; p = 0.003) was higher in CAS. CONCLUSIONS: In patients older than 75 years in the Hr group, there were relatively poor 30-day treatment outcomes in both CEA and CAS. Alternative treatment is needed that can expect better outcomes in older high-risk patients. In the Nr group, CEA has a significant benefit compared with CAS, and CEA should be recommended more to these patients.

Atherosclerotic Burden and Vascular Risk in Stroke Patients With Atrial Fibrillation.

Background and Purpose: Data on the effect on vascular outcomes of concomitant atherosclerotic vascular disease (ASVD) with atrial fibrillation (AF) after stroke are limited. This study evaluated the effect of ASVD with AF versus AF only on the risk of vascular events. Methods: We retrospectively analyzed a prospectively registered multicenter database involving 3213 stroke patients with AF. ASVD included extracranial atherosclerosis measured in the proximal portion of the internal carotid artery, intracranial atherosclerosis (all ≥50% stenosis), coronary artery disease, and peripheral artery disease and was categorized into 4 strata depending on the number of ASVDs (0, 1, 2, and 3­4). The independent associations of ASVD with major adverse cardiovascular events, stroke, and all-cause death were assessed. Results: A total of 2670 patients were included (mean age, 73.5±9.8 years; median CHA2DS2-VASc score, 5; interquartile range, 4−6). During the follow-up (mean, 1.7 years), a total of 672 (25.2%) major adverse cardiovascular events, 170 (6.4%) stroke events, and 501 (18.8%) all-cause deaths were noted. The adjusted hazard ratio for major adverse cardiovascular events versus no ASVD was 1.25 (95% CI, 1.00­1.56) for ASVD 1, 1.34 (95% CI, 1.02­1.76) for ASVD 2, and 1.93 (95% CI, 1.24­2.99) for ASVD 3­4. The adjusted hazard ratio for all-cause death versus no ASVD was 1.32 (1.01­1.74), 1.47 (1.06­2.03), and 2.39 (1.47­3.89), respectively. Among ASVD components, the presence of symptomatic or asymptomatic extracranial atherosclerosis was a more potent predictor of major adverse cardiovascular events (1.27 [1.05­1.54]) and all-cause death (1.45 [1.17­1.81]). Conclusions: ASVD burden with AF can be a cumulative marker of a high risk for untoward vascular outcomes. Among ASVD components, extracranial atherosclerosis seems to have a predominant effect.

Pre-Admission CHADS2 and CHA2DS2-VASc Scores on Early Neurological Worsening.

BACKGROUND: Stroke risk scores (CHADS2 and CHA2DS2-VASc) not only predict the risk of stroke in atrial fibrillation (AF) patients, but have also been associated with prognosis after stroke. OBJECTIVE: The aim of this study was to evaluate the relationship between stroke risk scores and early neurological deterioration (END) in ischemic stroke patients with AF. METHODS: We included consecutive ischemic stroke patients with AF admitted between January 2013 and December 2015. CHADS2 and CHA2DS2-VASc scores were calculated using the established scoring system. END was defined as an increase ≥2 on the total National Institutes of Health Stroke Scale (NIHSS) score or ≥1 on the motor NIHSS score within the first 72 h of admission. RESULTS: A total of 2,099 ischemic stroke patients with AF were included. In multivariable analysis, CHA2DS2-VASc score (adjusted odds ratio [aOR] = 1.17, 95% confidence interval [CI] = 1.04-1.31) was significantly associated with END after adjusting for confounders. Initial NIHSS score, use of anticoagulants, and intracranial atherosclerosis (ICAS) were also found to be closely associated with END, independent of the CHA2DS2-VASc score. Multivariable analysis stratified by the presence of ICAS demonstrated that both CHA2DS2-VASc (aOR = 1.20, 95% CI = 1.04-1.38) and CHADS2 scores (aOR = 1.24, 95% CI = 1.01-1.52) were closely related to END in only patients with ICAS. In patients without ICAS, neither of the risk scores were associated with END. CONCLUSIONS: High CHA2DS2-VASc score was associated with END in ischemic stroke patients with AF. This close relationship is more pronounced in patients with ICAS.

White matter hyperintensity determines ischemic stroke severity in symptomatic carotid artery stenosis.

INTRODUCTION: The aim of this study is to investigate the influence of white matter hyperintensity (WMH) on stroke severity and prognosis in patients with symptomatic carotid artery stenosis. METHODS: Patients with symptomatic carotid artery stenosis were retrieved from the Samsung Medical Center stroke registry from January 2011 to December 2016. Stroke severity was categorized into three levels according to National Institutes of Health Stroke Scale (NIHSS): transient ischemic attack (TIA) or transient symptoms with infarction (TSI), mild stroke, and moderate to severe stroke. WMH volume was measured with medical image processing and visualization. The clinical outcome was assessed using the modified Rankin scale on the 90th day from which the latest onset of the neurological symptom. Logistic regression was used to predict stroke severity, and ordinal regression was used to compare the clinical outcome. RESULTS: Among 158 patients, the numbers of patients with TIA or TSI, mild stroke, and moderate to severe stroke were 48 (30.4%), 59 (37.3%), and 51 (32.3%), respectively. The larger WMH volume was associated with moderate to severe strokes (TIA/TSI vs. moderate to severe strokes, odds ratio (OR) 2.318, 95% confidence interval (CI) 1.194-4.502, p = 0.007; mild vs. moderate to severe strokes, OR 1.972, 95% CI 1.118-3.479, p = 0.013). Patients with larger volume of WMH showed poorer clinical outcome (cutoff value: 9.71 cm3, OR 2.099, 95% CI 1.030-4.311, p = 0.042). CONCLUSION: Our study showed that larger WMH volume is associated with more severe stroke and poorer prognosis in patients with symptomatic carotid artery stenosis.

Luminal and Wall Changes in Intracranial Arterial Lesions for Predicting Stroke Occurrence.

BACKGROUND AND PURPOSE: Luminal imaging (degree of stenosis) currently serves as the gold standard to predict stroke recurrence and guide therapeutic strategies in patients with intracranial large artery diseases (ILADs). We comparatively evaluated the importance of vessel wall and luminal changes in predicting stroke occurrence. METHODS: Consecutive patients with ILAD in the proximal middle cerebral artery or distal internal carotid artery without proximal sources of embolism from the carotid and heart underwent time-of-flight magnetic resonance angiography, high-resolution magnetic resonance imaging, and the ring finger protein 213 (RNF213) gene variant test. Patients were followed up for >3 months. RESULTS: Of the 675 patients, 241 (35.7%) had atherosclerotic ILAD and 434 (64.3%) showed nonatherosclerotic ILAD (315 [46.7%] moyamoya disease cases and 119 [17.6%] dissection cases). The RNF213 variant was detected in 74.9%, 33.6%, and 3.4% patients with moyamoya disease, atherosclerosis, and dissection, respectively. Three hundred (44.4%) patients had asymptomatic ILAD, whereas 375 (55.6%) patients had symptomatic ILAD. Multivariate analysis showed that vessel enhancement and etiological subtypes, not degree of stenosis, determined by high-resolution magnetic resonance imaging and RNF213 gene variant analysis were independently associated with symptomatic ILAD. The presence of the RNF213 variant was also independently associated with recurrent cerebrovascular events. CONCLUSIONS: This study demonstrates the prevalence of nonatherosclerotic ILAD in East Asian patients with ILAD. Unlike luminal changes, wall changes determined by high-resolution magnetic resonance imaging and presence of the RNF213 variant could predict stroke occurrence in patients with ILADs.

Perfusion recovery on TTP maps after endovascular stroke treatment might predict favorable neurological outcomes.

OBJECTIVES: Early recanalization and adequate collateral blood flow are surrogates for functional recovery in endovascular stroke treatment (EVT). We evaluated the prognostic value of pre- and immediate post-thrombectomy perfusion-weighted magnetic resonance imaging (PWI) parameters. METHODS: Consecutive patients with acute ischemic stroke who underwent EVT were enrolled. Lesion volumes and their corresponding changes on diffusion-weighted (DWI) and PWI were assessed. Outcome was measured with modified Rankin Scale (mRS) at 90 days, and early neurological improvement (> 8 points improvement on National Institutes of Health Stroke Scale [NIHSS] or 0 to 1) at 7 days. RESULTS: Fifty-two patients were enrolled. After control of initial NIHSS and recanalization status, post-thrombectomy time-to-peak (TTP) hypoperfused volume and TTP hypoperfused volume change remained independent predictors of favorable functional outcome (odds ratio [OR] = 0.13, 95% confidence interval [CI] = 0.03-0.54, p = 0.005; OR = 1.018, 95% CI = 1.00-1.03, p = 0.017), and early neurological improvement (OR = 0.20, 95% CI 0.07-0.58, p = 0.003; OR = 1.02, 95% CI = 1.00-1.03, p = 0.010). The areas under the curve of post-thrombectomy TTP hypoperfused volume and TTP hypoperfused volume change were 0.90 and 0.82 (cutoff 68 mL and 56 mL) for favorable outcome and 0.86 and 0.82 (cutoff 76 mL and 58 mL) for early neurological improvement, which had better prognostic values than other MR parameters and recanalization grades. CONCLUSIONS: These results suggest a large amount of perfusion recovery on TTP is associated with favorable outcome as well as early neurological improvement after EVT, and may be a useful prognostic marker. KEY POINTS: • A large amount of perfusion recovery on TTP map is associated with favorable outcome and early neurological improvement after EVT. • The best cutoff value for favorable functional outcome was 68 mL for post-EVT TTP hypoperfused volume and 56 mL decrease for TTP hypoperfused volume. • Amount of perfusion recovery on TTP map has better performance on the prediction of favorable functional recovery and early neurological improvement than other diffusion- and perfusion-weighted MRI parameters and recanalization grades.

Circulating DNAs, a Marker of Neutrophil Extracellular Traposis and Cancer-Related Stroke: The OASIS-Cancer Study.

Background and Purpose- The role of circulating neutrophil extracellular traps (NETs) in cancer-related stroke is unknown. Methods- We conducted a prospective cohort study to test whether NETs are increased in cancer-related stroke and whether elevated NETs levels are associated with coagulopathy, assessed using D-dimer levels (≥2 µg/mL). Plasma DNA and nucleosome were assessed as NET-specific biomarkers. Results- In total, 138 patients were recruited; 38 patients had cancer-related stroke (active cancer and acute cryptogenic embolic stroke), 33 patients were healthy-controls, 27 patients were cancer-controls (active cancer but no stroke), and 40 patients were stroke-controls (acute ischemic stroke but no cancer). Plasma DNA and nucleosome levels were significantly elevated in cancer-related stroke patients than in healthy-controls (P<0.05). These levels were correlated with the D-dimer levels (P<0.01). In multiple regression analyses, increased plasma DNA levels were associated with cancer-related stroke (odds ratio=11.65 for highest quartile; 95% CI, 3.199-42.46) and D-dimer levels of ≥2 µg/mL (odds ratio=19.09 for highest quartile; 95% CI, 4.143-87.95) after adjusting for possible confounders. Conclusions- Increased circulating DNA levels were associated with cancer-related stroke, suggesting that NETosis is one of the molecular mechanisms of cancer-related stroke. Further long-term follow-up studies in large cohorts are needed to confirm the role of NET-specific biomarkers.

Admission Diffusion-Weighted Imaging Lesion Volume in Patients With Large Vessel Occlusion Stroke and Alberta Stroke Program Early CT Score of ≥6 Points: Serial Computed Tomography-Magnetic Resonance Imaging Collateral Measurements.

Background and Purpose- We hypothesized that the pial collateral status at the time of presentation could predict the infarct size on magnetic resonance imaging in patients with similar degrees of early ischemic changes on computed tomography. We tested the association between serial changes in collateral status and infarct volume defined on diffusion-weighted imaging (DWI) in patients with large vessel occlusion and small core. Methods- Consecutive patients who were candidates for endovascular treatment (Alberta Stroke Program Early CT Score [ASPECTS] of ≥6 points) and who underwent both pretreatment multiphasic computed tomography angiography (mCTA) and multimodal magnetic resonance imaging were enrolled. The baseline early ischemic changes and collateral status were determined using both mCTA and magnetic resonance imaging-based collateral maps. Multivariable linear regression was used to evaluate adjusted estimates of the effect of collateral status on predicting MR DWI lesion volume before endovascular treatment. Results- Of 65 patients (39 men; median age, 76 years; median ASPECTS, 8 points [range, 6-10]), 10 (15.4%), 8 (12.3%), and 47 (72.3%) presented poor, intermediate, and good collaterals on mCTA, respectively. After adjusting for the initial stroke severity, ASPECTS, time to DWI, and mismatch volume, the mCTA collateral grade was the only factor independently associated with the DWI lesion volume (ß=-35.657, SE mean=3.539; P<0.0001). An excellent correlation between the mCTA- and magnetic resonance imaging-based collateral grades was observed (matching grade seen in 92.3%), suggesting a collateral status persistence during the hyperacute stroke phase. Conclusions- The mCTA assessed collateral adequacy is the sole predictor of eventual DWI lesion volume before endovascular treatment. The added value of collateral assessment in early ischemic changes and large vessel occlusion for decision-making regarding more aggressive revascularizations requires further evaluation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03234634 and NCT02668627.

Evaluation of Diffusion Lesion Volume Measurements in Acute Ischemic Stroke Using Encoder-Decoder Convolutional Network.

Background and Purpose- Automatic segmentation of cerebral infarction on diffusion-weighted imaging (DWI) is typically performed based on a fixed apparent diffusion coefficient (ADC) threshold. Fixed ADC threshold methods may not be accurate because ADC values vary over time after stroke onset. Deep learning has the potential to improve the accuracy, provided that a large set of correctly annotated lesion data is used for training. The purpose of this study was to evaluate deep learning-based methods and compare them with commercial software in terms of lesion volume measurements. Methods- U-net, an encoder-decoder convolutional neural network, was adopted to train segmentation models. Two U-net models were developed: a U-net (DWI+ADC) model, trained on DWI and ADC data, and a U-net (DWI) model, trained on DWI data only. A total of 296 subjects were used for training and 134 for external validation. An expert neurologist manually delineated the stroke lesions on DWI images, which were used as the ground-truth reference. Lesion volume measurements from the U-net methods were compared against the expert's manual segmentation and Rapid Processing of Perfusion and Diffusion (RAPID; iSchemaView Inc) analysis. Results- In external validation, U-net (DWI+ADC) showed the highest intraclass correlation coefficient with manual segmentation (intraclass correlation coefficient, 1.0; 95% CI, 0.99-1.00) and sufficiently high correlation with the RAPID results (intraclass correlation coefficient, 0.99; 95% CI, 0.98-0.99). U-net (DWI+ADC) and manual segmentation resulted in the smallest 95% Bland-Altman limits of agreement (-5.31 to 4.93 mL) with a mean difference of -0.19 mL. Conclusions- The presented deep learning-based method is fully automatic and shows a high correlation of diffusion lesion volume measurements with manual segmentation and commercial software. The method has the potential to be used in patient selection for endovascular reperfusion therapy in the late time window of acute stroke.

Association of Cancer Cell Type and Extracellular Vesicles With Coagulopathy in Patients With Lung Cancer and Stroke.

BACKGROUND AND PURPOSE: Coagulopathy is an important cause of stroke in cancer patients. However, underlying mechanisms and clinical factors related to coagulopathy remain unclear. We hypothesized that certain characteristics of cancer affect coagulopathy in patients with lung cancer and ischemic stroke. METHODS: Consecutive patients with active lung cancer and acute ischemic stroke were prospectively studied. Volume and pattern of acute brain infarcts and plasma levels of circulating tumor extracellular vesicles (EVs) were measured using flow cytometry. In vitro experiments investigated the pathophysiological mechanisms underlying cancer-associated coagulopathy. RESULTS: Of 114 patients, 95 (83.3%) had an adenocarcinoma cell type and 95 (83.3%) had distant metastasis. Acute brain infarct volumes were larger and circulating EV levels were higher in patients with an adenocarcinoma cell type than in those with other cell types. The presence of metastasis was not associated with infarct volume or circulating EV levels. Coagulation assays demonstrated dose-dependent shorter clotting times after treatment with EVs from adenocarcinoma cell lines than with the use of EVs from squamous cell carcinoma. These findings were confirmed by coagulation assays using circulating EVs from patients with adenocarcinoma and stroke and from those with conventional stroke mechanisms. CONCLUSIONS: Our findings indicate that cancer cell type is associated with circulating EV levels and coagulopathy in patients with lung cancer and stroke.

Cav-1 (Caveolin-1) and Arterial Remodeling in Adult Moyamoya Disease.

Background and Purpose- Moyamoya disease (MMD) is a unique cerebrovascular occlusive disease characterized by progressive stenosis and negative remodeling of the distal internal carotid artery (ICA). We hypothesized that cav-1 (caveolin-1)-a protein that controls the regulation of endothelial vesicular trafficking and signal transduction-is associated with negative remodeling in MMD. Methods- We prospectively recruited 77 consecutive patients with MMD diagnosed via conventional angiography. Seventeen patients with intracranial atherosclerotic stroke and no RNF213 mutation served as controls. The outer distal ICA diameters were examined using high-resolution magnetic resonance imaging. We evaluated whether the degree of negative remodeling in the patients with MMD was associated with RNF213 polymorphism, cav-1 levels, or various clinical and vascular risk factors. We also investigated whether the derived factor was associated with negative remodeling at the cellular level using the tube formation and apoptosis assays. Results- The serum cav-1 level was lower in the patients with MMD than in the controls (0.47±0.29 versus 0.86±0.68 ng/mL; P=0.034). The mean ICA diameter was 2.48±0.98 mm for the 126 affected distal ICAs in patients with MMD and 3.84±0.42 mm for the asymptomatic ICAs in the controls ( P<0.001). After adjusting for confounders, cav-1 levels (coefficient, 1.018; P<0.001) were independently associated with the distal ICA diameter in patients with MMD. In vitro analysis showed that cav-1 downregulation suppressed angiogenesis in the endothelial cells and induced apoptosis in the smooth muscle cells. Conclusions- Our findings suggest that cav-1 may play a major role in negative arterial remodeling in MMD.

Burden of Intracranial Atherosclerosis Is Associated With Long-Term Vascular Outcome in Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: Ischemic stroke patients often have intracranial atherosclerosis (ICAS), despite heterogeneity in the cause of stroke. We tested the hypothesis that ICAS burden can independently reflect the risk of long-term vascular outcome. METHODS: This was a retrospective cohort study analyzing data from a prospective stroke registry enrolling consecutive patients with acute ischemic stroke or transient ischemic attack. A total of 1081 patients were categorized into no ICAS, single ICAS, and advanced ICAS (ICAS ≥2 different intracranial arteries) groups. Primary and secondary end points were time to occurrence of recurrent ischemic stroke and composite vascular outcome, respectively. Study end points by ICAS burden were compared using Cox proportional hazards models in overall and propensity-matched patients. RESULTS: ICAS was present in 405 patients (37.3%). During a median 5-year follow-up, recurrent stroke and composite vascular outcome occurred in 6.8% and 16.8% of patients, respectively. As the number of ICAS increased, the risk for study end points increased after adjustment of potential covariates (hazard ratio per 1 increase in ICAS, 1.19; 95% confidence interval, 1.01-1.42 for recurrent ischemic stroke and hazard ratio, 1.18; 95% confidence interval, 1.05-1.33 for composite vascular outcome). The hazard ratios (95% confidence interval) for recurrent stroke and composite vascular outcome in patients with advanced ICAS compared with those without ICAS were 1.56 (0.88-2.74) and 1.72 (1.17-2.53), respectively, in the overall patients. The corresponding values in the propensity-matched patients were 1.28 (0.71-2.30) and 1.95 (1.27-2.99), respectively. CONCLUSIONS: ICAS burden was independently associated with the risk of subsequent composite vascular outcome in patients with ischemic stroke. These findings suggest that ICAS burden can reflect the risk of long-term vascular outcome.

Infarct Pattern and Collateral Status in Adult Moyamoya Disease: A Multimodal Magnetic Resonance Imaging Study.

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals, called moyamoya vessels. Although hemodynamic studies have been applied in MMD patients, the mechanisms of stroke in MMD are still unclear. The present study evaluated the infarct pattern and collateral status using multimodal magnetic resonance imaging in MMD patients. METHODS: Adult MMD patients with acute ischemic stroke were prospectively recruited, and infarct pattern on diffusion-weighted imaging was evaluated. A collateral flow map, derived from magnetic resonance perfusion-weighted imaging data, was generated through automatic postprocessing, and collateral status was assigned into 3 grades. Transcranial Doppler monitoring was performed to detect microembolic signals in selected patients. RESULTS: A total of 67 hemispheres (31 patients with bilateral and 5 patients with unilateral MMD) were analyzed. Most patients (83.7%) showed embolic pattern and rarely deep (9.3%) or hemodynamic infarct pattern (7.0%) on diffusion-weighted imaging. Most cases (86%) showed good collateral status, and few patients with acute infarcts of embolic pattern showed poor collateral status (n=7). One third (31.6%) of patients who underwent transcranial Doppler monitoring showed microembolic signals. CONCLUSIONS: In the studied population of adult MMD patients, embolic phenomenon played an important role in ischemic stroke. Therapeutic strategies against thromboembolism, as well as collateral enhancing strategies targeting improvement of hemodynamic status or increased washout of emboli, are warranted.

Distinct Roles of Endothelial Dysfunction and Inflammation in Intracranial Atherosclerotic Stroke.

BACKGROUND/AIMS: The aim of the study was to evaluate the differential roles of endothelial dysfunction and inflammation in intracranial atherosclerotic stroke (ICAS). METHODS: We prospectively recruited 262 patients with acute cerebral infarcts caused by ICAS and 75 individuals with no history of stroke as controls. Markers of endothelial dysfunction (asymmetric dimethylarginine, ADMA) and inflammation (lipoprotein-associated phospholipase A2, Lp-PLA2) were measured. Acute ischemic lesions were measured in terms of their size, composition, and patterns. Subclinical microangiopathy (degree of leukoaraiosis) and macroangiopathy (presence/number of asymptomatic stenoses) were graded in each patient. RESULTS: Compared to normal controls, serum levels of ADMA (0.69 ± 0.14 vs. 0.47 ± 0.10, p < 0.001) and Lp-PLA2 (138.1 ± 116.8 vs. 19.0 ± 58.0, p < 0.001) were elevated in patients with ICAS. A high ADMA serum level was associated with greater prevalence of preclinical microangiopathy and macroangiopathy. Contrastingly, an elevated serum Lp-PLA2 level was associated with larger ischemic lesions, a greater number of lesions, and a larger cortical pattern. CONCLUSIONS: Endothelial dysfunction and inflammation have distinct effects in ICAS patents; endothelial dysfunction is associated with the underlying micro- and macro-atherosclerotic burden, whereas inflammation is associated with acute infarct volume and pattern.

Implications of CHA2DS2-VASc Score in Stroke Patients with Atrial Fibrillation: An Analysis of 938 Korean Patients.

BACKGROUND AND AIMS: The aim of this study was to investigate the stroke mechanisms and associated conditions influencing the decision regarding stroke thromboprophylaxis in patients with atrial fibrillation (AF) plus ischemic stroke, according to the CHA2DS2-VASc score. METHODS: We evaluated 938 consecutive patients with a diagnosis of AF plus transient ischemic attack/ischemic stroke. Based on the CHA2DS2-VASc scores, patients were stratified as score 0 or 1 (n = 151), score 2 (n = 146), score 3 (n = 213), score 4 (n = 185), or score ≥5 (n = 243). RESULTS: Patients with a higher CHA2DS2-VASc score were more likely to have noncardioembolic stroke mechanism (p = 0.001). Large-artery atherosclerosis causing stenosis >50% was more frequently observed in the high CHA2DS2-VASc group (p < 0.001). Coronary artery disease and the use of antiplatelet agents were more prevalent in the higher group (p < 0.001). A high CHA2DS2-VASc score was associated with a higher frequency of cerebral microbleeds and a higher Fazekas grade for leukoaraiosis (p < 0.001). The HAS-BLED score was correlated with the CHA2DS2-VASc score (γ = 0.650; p < 0.001). CONCLUSIONS: A higher CHA2DS2-VASc score is associated with noncardioembolic mechanisms of stroke and with a higher risk of bleeding. Strategies to treat macro/microangiopathy such as use of statin for plaque stabilization, as well as oral anticoagulants with a lower bleeding risk, are needed in these patients.

Genetic and Non-Genetic Factors Affecting the Quality of Anticoagulation Control and Vascular Events in Atrial Fibrillation.

BACKGROUND: Warfarin has a narrow therapeutic window. We hypothesized that genetic factors related to warfarin metabolism (CYP2C9) and activity (VKORC1) would show stronger associations than modifiable factors with the quality of anticoagulation control and risks for thromboembolism and hemorrhage. METHODS: In this retrospective cohort analysis, clinical and genetic data were collected from 380 patients with atrial fibrillation (AF) who were followed for an average observation period of 4 years. We evaluated the factors associated with time in therapeutic range (TTR, international normalized ratio [INR]: 2-3) and vascular events (either thromboembolic or hemorrhagic), including both genetic (CYP2C9 and VKORC1 genotype) and modifiable factors (anticoagulation service and warfarin dose assessment interval). RESULTS: The genotypic frequency of CYP2C9*3 (rs1057910) was 9.5% and that of VKORC1 1173C>T (rs9934438) was 16.3%. TTR showed dependence on VKORC1 polymorphism: TTR was higher in carriers of the VKORC1 1173C>T than of the VKORC1 TT genotype (61.7 ± 16.0% versus 56.7 ± 17.4%, P = .031). Multivariate testing showed that the VKORC1 genotype and anticoagulation service were independently related to labile INRs (TTR <65%). Vascular events were observed in 66 patients (18.4%) during the study period. A Cox proportional hazard model showed that the use of anticoagulation service and patients' characteristics, such as AF-thromboembolic risk (CHA2DS2-VASc score: Congestive heart failure, Hypertension, Age 75 years or older, Diabetes mellitus, previous Stroke or transient ischemic attack, Vascular disease, Age 65 to 74 years, female) and consequence (neurologic disability), but not genetic factors, were independently associated with vascular events. CONCLUSIONS: Both genetic factor (VKORC1 genotype) and clinical efforts (anticoagulation service) influenced the quality of anticoagulation control. However, clinical events were more strongly associated with patient characteristics and clinical efforts than with genetic factors.

Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding. RESULTS: Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77-1.35; P=0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P=0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group. CONCLUSIONS: Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00814268.

Predicting Collateral Status With Magnetic Resonance Perfusion Parameters: Probabilistic Approach With a Tmax-Derived Prediction Model.

BACKGROUND AND PURPOSE: Good collateral flow is an important predictor for favorable responses to recanalization therapy and successful outcomes after acute ischemic stroke. Magnetic resonance perfusion-weighted imaging (MRP) is widely used in patients with stroke. However, it is unclear whether the perfusion parameters and thresholds would predict collateral status. The present study evaluated the relationship between hypoperfusion severity and collateral status to develop a predictive model for good collaterals using MRP parameters. METHODS: Patients who were eligible for recanalization therapy that underwent both serial diffusion-weighted imaging and serial MRP were enrolled into the study. A collateral flow map derived from MRP source data was generated through automatic postprocessing. Hypoperfusion severity, presented as proportions of every 2-s Tmax strata to the entire hypoperfusion volume (Tmax≥2 s), was compared between patients with good and poor collaterals. Prediction models for good collaterals were developed with each Tmax strata proportion and cerebral blood volumes. RESULTS: Among 66 patients, 53 showed good collaterals based on MRP-based collateral grading. Although no difference was noted in delays within 16 s, more severe Tmax delays (Tmax16-18 s, Tmax18-22 s, Tmax22-24 s, and Tmax>24 s) were associated with poor collaterals. The probability equation model using Tmax strata proportion demonstrated high predictive power in a receiver operating characteristic analysis (area under the curve=0.9303; 95% confidence interval, 0.8682-0.9924). The probability score was negatively correlated with the volume of infarct growth (P=0.030). CONCLUSIONS: Collateral status is associated with more severe Tmax delays than previously defined. The present Tmax severity-weighted model can determine good collaterals and subsequent infarct growth.

A novel magnetic resonance imaging approach to collateral flow imaging in ischemic stroke.

OBJECTIVE: Dedicated magnetic resonance (MR) imaging (MRI) sequences for evaluation of collaterals can be generated using MR perfusion (MRP) source data. We compared a novel collateral flow imaging technique with digital subtraction angiography (DSA) for determining collateral circulation in acute stroke and evaluated the ability of MR-based collateral flow maps to predict outcomes after recanalization therapy. METHODS: Consecutive patients who were candidates for endovascular treatment were enrolled. A collateral flow map derived from MRP source data was generated by manual or automatic postprocessing. Collateral grading based on the collateral flow map was performed and compared with grading based on DSA. Clinical and radiological outcomes were evaluated according to MR-based collateral grading and early reperfusion (ER) status. RESULTS: There was good correlation between MRI-based and DSA-based collateral grades (weighted κ-coefficient = 0.70). Collateral status and achievement of ER were the 2 main determinants of a favorable functional outcome and neurological improvement, in addition to infarct growth. Regardless of achievement of ER, better collaterals were significantly associated with a lower modified Rankin score at day 90 (p < 0.001 for trend in both ER(-) and ER(+) ). Most symptomatic intracranial hemorrhages occurred in patients with a poor collateral grade and ER(+) , whereas no patient with excellent collaterals suffered symptomatic intracranial hemorrhage or died. INTERPRETATION: MRI techniques to assess collaterals are rapidly being developed, and may provide insight into collateral perfusion. The combination of collateral images derived from pretreatment MRP source data and reperfusion status is a robust predictor of outcomes in acute ischemic stroke.