Reexamination of the Embolic Stroke of Undetermined Source Concept.

Occult atrial fibrillation (AF) is a leading cause of stroke of unclear cause. The optimal approach to secondary stroke prevention for these patients remains elusive. The term embolic stroke of undetermined source (ESUS) was coined to describe ischemic strokes in which the radiographic features demonstrate territorial infarcts resembling those seen in patients with confirmed sources of embolism but without a clear source of embolism detected. It was assumed that patients with ESUS had a high rate of occult AF and would benefit from treatment with direct oral anticoagulants, which are at least as effective as vitamin K antagonists for secondary stroke prevention in patients with AF, but with a much lower risk of intracerebral hemorrhage. Two recent large randomized trials failed to show superiority of direct oral anticoagulants over aspirin in ESUS patients. These findings prompt a reexamination of the ESUS concept, with the goal of improving specificity for detecting patients with a cardioembolic cause. Based on the negative trial results, there is renewed interest in the role of long-term cardiac monitoring for AF in patients who fit the current ESUS definition, as well as the clinical implication of detecting AF. Ongoing trials are exploring these questions. Current ESUS definitions do not accurately detect the patients who should be prescribed direct oral anticoagulants, potentially because occult AF is less common than expected in these patients and/or anticoagulants may be less beneficial in patients with ESUS but no AF than they are for patients with stroke with established AF. More specific criteria to identify patients who may be at higher risk for occult AF and reduce their risk of subsequent stroke have been developed and are being tested in ongoing clinical trials.

Recovery of Hypoxic Regions in a Rat Model of Microembolism.

OBJECTIVES: Endovascular treatment (EVT) has become the standard of care for acute ischemic stroke. Despite successful recanalization, a limited subset of patients benefits from the new treatment. Human MRI studies have shown that during removal of the thrombus, a shower of microclots is released from the initial thrombus, possibly causing new ischemic lesions. The aim of the current study is to quantify tissue damage following microembolism. MATERIALS AND METHODS: In a rat model, microembolism was generated by injection of a mixture of polystyrene fluorescent microspheres (15, 25 and 50 µm in diameter). The animals were killed at three time-points: day 1, 3 or 7. AMIRA and IMARIS software was used for 3D reconstruction of brain structure and damage, respectively. CONCLUSIONS: Microembolism induces ischemia, hypoxia and infarction. Infarcted areas persist, but hypoxic regions recover over time suggesting that repair processes in the brain rescue the regions at risk.

von Willebrand Factor Antigen, von Willebrand Factor Propeptide, and ADAMTS13 in Carotid Stenosis and Their Relationship with Cerebral Microemboli.

BACKGROUND: The relationship between von Willebrand factor antigen (VWF:Ag), VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio, ADAMTS13 activity, and microembolic signal (MES) status in carotid stenosis is unknown. METHODS: This prospective, multicenter study simultaneously assessed plasma VWF:Ag levels, VWFpp levels and ADAMTS13 activity, and their relationship with MES in asymptomatic versus symptomatic moderate-to-severe (≥50-99%) carotid stenosis patients. One-hour transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES+ve or MES-ve. RESULTS: Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the "early phase" (≤4 weeks) and 37 patients in the "late phase" (≥3 months) after transient ischemic attack (TIA)/ischemic stroke. VWF:Ag levels were higher (p = 0.049) and VWFpp/VWF:Ag ratios lower (p = 0.006) in early symptomatic than in asymptomatic patients overall, and in early symptomatic versus asymptomatic MES-ve subgroups (p ≤0.02). There were no intergroup differences in VWFpp expression or ADAMTS13 activity (p ≥0.05). VWF:Ag levels and ADAMTS13 activity decreased (p ≤ 0.048) and VWFpp/VWF:Ag ratios increased (p = 0.03) in symptomatic patients followed up from the early to late phases after TIA/stroke. Although there were no differences in the proportions of symptomatic and asymptomatic patients with blood group O, a combined analysis of early symptomatic and asymptomatic patients revealed lower median VWF:Ag levels in patients with blood group O versus those without blood group O (9.59 vs. 12.32 µg/mL, p = 0.035). DISCUSSION: VWF:Ag expression, a marker of endothelial ± platelet activation, is enhanced in recently symptomatic versus asymptomatic carotid stenosis patients, including in MES-ve patients, and decreases with ADAMTS13 activity over time following atherosclerotic TIA/ischemic stroke.

Standardized Fabrication Method of Human-Derived Emboli with Histologic and Mechanical Quantification for Stroke Research.

BACKGROUND: As access to patient emboli is limited, embolus analogs (EAs) have become critical to the research of large vessel occlusion (LVO) stroke and the development of thrombectomy technology. To date, techniques for fabricating standardized human blood-derived EAs are limited in the variety of compositions, and the mechanical properties relevant to thrombectomy are not quantified. METHODS: EAs were made by mixing human banked red blood cells (RBCs), plasma, and platelet concentrate in 10 different volumetric percentage combinations to mimic the broad range of patient emboli causing LVO strokes. The samples underwent histologic analysis and tensile testing to mimic the pulling action of thrombectomy devices, and were compared to patient emboli. RESULTS: EAs had histologic compositions of 0-96% RBCs, 0.78%-92% fibrin, and 2.1%-22% platelets, which can be correlated with the ingredients using a regression model. At fracture, EAs elongated from 81% to 136%, and the ultimate tensile stress ranged from 16 to 949 kPa. These EAs' histologic compositions and tensile properties showed great similarity to those of emboli retrieved from LVO stroke patients, indicating the validity of such EA fabrication methods. EAs with lower RBC and higher fibrin contents are more extensible and can withstand higher tensile stress. CONCLUSIONS: EAs fabricated and tested using the proposed new methods provide a platform for stroke research and pre-clinical development of thrombectomy devices.

Predictive value of free fatty acid levels in embolic stroke of undetermined source: A retrospective observational study.

The present study aimed to investigate the predictive value of free fatty acid (FFA) in embolic stroke of undetermined source (ESUS) according to the presence of potential embolic sources (PES) after extensive etiologic evaluation.This was a retrospective observational study based on a single-center registry from January 2011 to July 2017. Stroke subtypes were determined through laboratory findings, brain, and angiographic imaging, carotid ultrasonography, transthoracic echocardiography, and 24-hour Holter monitoring. If ESUS was suspected, transesophageal echocardiography was additionally performed. Patients were classified into ESUS with PES and ESUS without PES. PES included mitral annular calcification, mitral valve prolapse, patent foramen ovale, atrial septal aneurysm, spontaneous echo contrast, ventricular aneurysm, and high-risk plaques of aortic arch, or carotid bulb. We compared clinical and laboratory findings between the two groups.Of a total of 110 ESUS patients, 61 patients (55.5%) had no PES. Patients with ESUS without PES had higher levels of serum FFA, systolic blood pressure, diastolic blood pressure (DBP), and left atrial (LA) enlargement compared with those of ESUS with PES. Multivariable analysis demonstrated that the FFA level, DBP, and LA volume index were associated with ESUS without PES [odds ratio (OR) 1.038, 95% confidence interval (CI) 1.019-1.058 for FFA/10 µEq/L, OR 1.414, 95% CI 1.037-1.928 for DBP/10 mm Hg, and OR 1.073, 95% CI 1.009-1.141 for LA volume index].Higher levels of FFA, DBP, and LA volume index are associated with ESUS without PES, highlighting the need to identify the role of these markers in ESUS through further large-scale, multi-center and prospective studies.

High-Sensitivity Cardiac Troponin T for Risk Stratification in Patients With Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Optimal secondary prevention for patients with embolic stroke of undetermined source (ESUS) remains unknown. We aimed to assess whether high-sensitivity cardiac troponin T (hs-cTnT) levels are associated with major vascular events and whether hs-cTnT may identify patients who benefit from anticoagulation following ESUS. METHODS: Data were obtained from the biomarker substudy of the NAVIGATE ESUS trial, a randomized controlled trial testing the efficacy of rivaroxaban versus aspirin for secondary stroke prevention in ESUS. Patients were dichotomized at the hs-cTnT upper reference limit (14 ng/L, Gen V, Roche Diagnostics). Cox proportional hazard models were computed to explore the association between hs-cTnT, the combined cardiovascular end point (recurrent stroke, myocardial infarction, systemic embolism, cardiovascular death), and recurrent ischemic stroke. RESULTS: Among 1337 patients enrolled at 111 participating centers in 18 countries (mean age 67±9 years, 61% male), hs-cTnT was detectable in 95% and at/above the upper reference limit in 21%. During a median follow-up of 11 months, the combined cardiovascular end point occurred in 68 patients (5.0%/y, rivaroxaban 28 events, aspirin 40 events; hazard ratio, 0.67 [95% CI, 0.41-1.1]), and recurrent ischemic stroke occurred in 50 patients (4.0%/y, rivaroxaban 16 events, aspirin 34 events, hazard ratio 0.45 [95% CI, 0.25-0.81]). Annualized combined cardiovascular end point rates were 8.2% (9.5% rivaroxaban, 7.0% aspirin) for those above hs-cTnT upper reference limit and 4.8% (3.1% rivaroxaban, 6.6% aspirin) below with a significant treatment modification (P=0.04). Annualized ischemic stroke rates were 4.7% above hs-cTnT upper reference limit and 3.9% below, with no suggestion of an interaction between hs-cTnT and treatment (P=0.3). CONCLUSIONS: In patients with ESUS, hs-cTnT was associated with increased cardiovascular event rates. While fewer recurrent strokes occurred in patients receiving rivaroxaban, outcomes were not stratified by hs-cTn results. Our findings support using hs-cTnT for cardiovascular risk stratification but not for decision-making regarding anticoagulation therapy in patients with ESUS. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Antithrombotic Treatment of Embolic Stroke of Undetermined Source: RE-SPECT ESUS Elderly and Renally Impaired Subgroups.

Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the impact of age, renal function (both predefined), and dabigatran dose (post hoc) on the rates of recurrent stroke and major bleeding. Methods- RE-SPECT ESUS was a multicenter, randomized, double-blind trial of dabigatran 150 or 110 mg (for patients aged ≥75 years and/or with creatinine clearance 30 to <50 mL/minute) twice daily compared with aspirin 100 mg once daily. The primary outcome was recurrent stroke. Results- The trial, which enrolled 5390 patients from December 2014 to January 2018, did not demonstrate superiority of dabigatran versus aspirin for prevention of recurrent stroke in patients with embolic stroke of undetermined source. However, among the population qualifying for the lower dabigatran dose, the rate of recurrent stroke was reduced with dabigatran versus aspirin (7.4% versus 13.0%; hazard ratio, 0.57 [95% CI, 0.39-0.82]; interaction P=0.01). This was driven mainly by the subgroup aged ≥75 years (7.8% versus 12.4%; hazard ratio, 0.63 [95% CI, 0.43-0.94]; interaction P=0.10). Stroke rates tended to be lower with dabigatran versus aspirin with declining renal function. Risks for major bleeding were similar between treatments, irrespective of renal function, but with a trend for lower bleeding rates with dabigatran versus aspirin in older patients. Conclusions- In subgroup analyses of RE-SPECT ESUS, dabigatran reduced the rate of recurrent stroke compared with aspirin in patients qualifying for the lower dose of dabigatran. These results are hypothesis-generating. Aspirin remains the standard antithrombotic treatment for patients with embolic stroke of undetermined source. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

Independent Prognostic Value of MRproANP (Midregional Proatrial Natriuretic Peptide) Levels in Patients With Stroke Is Unaltered Over Time.

Background and Purpose- MRproANP (midregional proatrial natriuretic peptide) is known to be independently associated with cardioembolic stroke cause and to improve risk stratification for 90-day mortality when measured within 24 to 72 hours after symptom onset in patients with acute ischemic stroke. However, the optimal time point for assessment remains unclear. This study aimed to evaluate prognostic utility of MRproANP at different time points during the first 5 days of hospitalization in patients with acute ischemic stroke. Methods- Samples of MRproANP were collected on admission (<72 hours after onset) and at multiple time points during the first 5 days of hospitalization in 348 consecutively enrolled patients with acute ischemic stroke. The prognostic value for 90-day mortality, 90-day functional outcome, and the association with cardioembolic stroke cause was assessed regarding the time of measurement, and change over time was modeled using generalized estimating equations. Results- MRproANP levels modestly decease over the initial 5 days but remain highly predictive for cardioembolic stroke cause (odds ratio, 9.75 [95% CI, 3.2-29]; 10.62 [95% CI, 3.4-33.3]; 10.8 [95% CI, 3.1-37.1]; 19.4 [95% CI, 5.49-68.7] on admission, day 1, 3 and 5) and 90-day mortality (odds ratio, 59.4 [95% CI, 7.4-480.7]; 78.3 [95% CI, 7.9-772.6]; 14.5 [95% CI, 1.4-145]; 19.81 [95% CI, 2.7-143.4] on admission, day 1, 3, and 5). Change over time does not significantly modify the prognostic value of MRproANP (P=0.65 and P=0.56 for the interaction term in the multivariate model). Conclusions- Independent prognostic value of MRproANP remains unaltered in the acute phase of stroke at least up to 5 days; repeated measurements do not improve the prognostic value.

An Embolic Stroke in a Patient With PROC p.Lys193del.

We report a 58-year-old woman who suddenly developed brain infarction with weakness of the left lower extremity and left perioral dysesthesia during postoperative tamoxifen therapy for breast cancer and prednisolone therapy for rheumatoid arthritis. Diffusion-weighted images detected multiple areas of hyperintensity in the posterior circulation system of the brain. Despite extensive examinations, we could not identify any embolic sources except hypoplasia of the right vertebral artery. We found decreased activity of protein C against its antigen level (activity: 59% versus antigen: 122%) with enhanced activity of coagulation factor VIII (178%) and von Willebrand factor (285%). DNA sequencing identified trinucleotide deletion of the PROC gene leading to 1 amino acid deletion at Lys-193 (p.Lys193del). We speculate that the PROC gene polymorphism may have participated in tamoxifen- and prednisolone- associated hypercoagulable state, leading to development of an embolic stroke in this patient.

Atrial Cardiopathy and Nonstenosing Large Artery Plaque in Patients With Embolic Stroke of Undetermined Source.

Background and Purpose- Atrial cardiopathy and atherosclerotic plaque are two potential mechanisms underlying embolic strokes of undetermined source (ESUS). The relationship between these two mechanisms among ESUS patients remains unclear. A better understanding of their association may inform targeted secondary prevention strategies. Methods- We examined the association between atrial cardiopathy and atherosclerotic plaque in the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), which enrolled 7213 patients with recent ESUS during 2014 to 2017. For this analysis, we included patients with data on left atrial dimension, location of brain infarction, and cervical large artery plaque. The variables of primary interest were left atrial diameter and cervical plaque ipsilateral to brain infarction. Secondary markers of atrial cardiopathy were premature atrial contractions on Holter monitoring and newly diagnosed atrial fibrillation. For descriptive purposes, left atrial enlargement was defined as ≥4.7 cm. Multivariable logistic regression was used to examine the association between atrial cardiopathy markers and ipsilateral plaque after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, current smoking, and hyperlipidemia. Results- Among 3983 eligible patients, 235 (5.9%) had left atrial enlargement, 939 (23.6%) had ipsilateral plaque, and 94 (2.4%) had both. Shared risk factors for left atrial enlargement and ipsilateral plaque were male sex, white race, hypertension, tobacco use, and coronary artery disease. Despite shared risk factors, increasing left atrial dimension was not associated with ipsilateral plaque after adjustment for covariates (odds ratio per cm, 1.1 [95% CI, 1.0-1.2]; P=0.08). We found no consistent associations between secondary markers of atrial cardiopathy and ipsilateral plaque. Conclusions- In a large population of patients with ESUS, we did not observe a notable association between atrial cardiopathy and atherosclerotic plaque, and few patients had both conditions. These findings suggest that atrial cardiopathy and atherosclerotic plaque may be distinct, nonoverlapping risk factors for stroke among ESUS patients.

D-dimer and C-reactive Protein as Potential Biomarkers for Diagnosis of Trousseau's Syndrome in Patients with Cerebral Embolism.

BACKGROUND: Differentiating stroke due to Trousseau's syndrome from other types of cerebral embolism is challenging, especially in patients with occult cancer. The current study aimed to determine predicting factors and biomarkers of stroke due to Trousseau's syndrome. METHODS: This retrospective study comprised 496 consecutive patients with acute cerebral embolism, including 19, 85, 310, and, 82 patients with stroke due to Trousseau's syndrome, artery-to-artery embolism, cardioembolic stroke, and embolic stroke with undetermined source, respectively. All patients were evaluated within 72 hours of onset. The clinical characteristics, laboratory findings, and patterns on diffusion-weighted magnetic resonance imaging (DWI) were compared among the groups. RESULTS: Plasma D-dimer and C-reactive protein (CRP) levels were significantly higher in the Trousseau's syndrome than in the other causes of cerebral embolism. Multivariate analyses demonstrated that female sex, multiple lesions on DWI, high D-dimer and CRP levels, and low platelet and low brain natriuretic peptide levels were independent predictors that could distinguish Trousseau's syndrome from the other causes of cerebral embolism. The cutoff values of D-dimer and CRP to identify stroke due to Trousseau's syndrome was 2.68 µg/mL fibrinogen equivalent units and .29 mg/dL, respectively. CONCLUSIONS: The elevated D-dimer and CRP levels on admission in addition to specific clinical features may be useful for diagnosis of Trousseau's syndrome in patients with cerebral embolism.

The role of haematological traits in risk of ischaemic stroke and its subtypes.

Thrombosis and platelet activation play a central role in stroke pathogenesis, and antiplatelet and anticoagulant therapies are central to stroke prevention. However, whether haematological traits contribute equally to all ischaemic stroke subtypes is uncertain. Furthermore, identification of associations with new traits may offer novel treatment opportunities. The aim of this research was to ascertain causal relationships between a wide range of haematological traits and ischaemic stroke and its subtypes. We obtained summary statistics from 27 published genome-wide association studies of haematological traits involving over 375 000 individuals, and genetic associations with stroke from the MEGASTROKE Consortium (n = 67 000 stroke cases). Using two-sample Mendelian randomization we analysed the association of genetically elevated levels of 36 blood cell traits (platelets, mature/immature red cells, and myeloid/lymphoid/compound white cells) and 49 haemostasis traits (including clotting cascade factors and markers of platelet function) with risk of developing ischaemic (AIS), cardioembolic (CES), large artery (LAS), and small vessel stroke (SVS). Several factors on the intrinsic clotting pathway were significantly associated (P < 3.85 × 10-4) with CES and LAS, but not with SVS (e.g. reduced factor VIII activity with AIS/CES/LAS; raised factor VIII antigen with AIS/CES; and increased factor XI activity with AIS/CES). On the common pathway, increased gamma (γ') fibrinogen was significantly associated with AIS/CES. Furthermore, elevated plateletcrit was significantly associated with AIS/CES, eosinophil percentage of white cells with LAS, and thrombin-activatable fibrinolysis inhibitor activation peptide antigen with AIS. We also conducted a follow-up analysis in UK Biobank, which showed that amongst individuals with atrial fibrillation, those with genetically lower levels of factor XI are at reduced risk of AIS compared to those with normal levels of factor XI. These results implicate components of the intrinsic and common pathways of the clotting cascade, as well as several other haematological traits, in the pathogenesis of CES and possibly LAS, but not SVS. The lack of associations with SVS suggests thrombosis may be less important for this stroke subtype. Plateletcrit and factor XI are potentially tractable new targets for secondary prevention of ischaemic stroke, while factor VIII and γ' fibrinogen require further population-based studies to ascertain their possible aetiological roles.

Arterial Stiffness and Indices of Left Ventricular Diastolic Dysfunction in Patients with Embolic Stroke of Undetermined Etiology.

PURPOSE: The study is aimed at identifying echocardiographic and circulating biomarkers as well as hemodynamic indices of embolic stroke of undetermined etiology (ESUS) in patients aged <65. METHODS: We prospectively investigated 520 patients with confirmed ischemic stroke and selected those 65 patients who were diagnosed with ESUS (age 54 (47-58) years, 42% male). An additional 36 without stroke but with a similar risk profile were included as a control group (age 53 (47-58) years, 61% male). All patients underwent echocardiography, noninvasive assessment of hemodynamic parameters using a SphygmoCor tonometer (AtCor Med., Australia), and measurements of selected biomarkers. RESULTS: ESUS patients and controls were well matched for baseline characteristics including blood pressure and left ventricular ejection fraction (LVEF). Compared to controls, patients with ESUS had lower mean early diastolic (E') and systolic (S') mitral annular velocities and a higher ratio of the peak velocity of early diastolic transmitral flow to the peak velocity of early diastolic mitral annular motion (all p < 0.01). The peak velocity flow in the late diastole (A wave) value and LV mass indexed to the body surface area (LVMI) (g/m2) were higher in the ESUS group than in the control group (both p < 0.01). The isovolumetric relaxation time (IVRT) was longer and the mean left atrial volume index (LAVI) was higher in ESUS patients compared to the control group. Parameters of arterial stiffness such as augmentation pressure, augmentation index, and augmentation index adjusted to a heart rate of 75 bpm (AIx75) were higher in ESUS patients compared to controls (p < 0.05). Patients in the ESUS group had higher levels of asymmetric dimethylarginine, interleukin 6, and N-terminal probrain natriuretic peptide (NT-proBNP, all p < 0.05) than those in the control group. In multivariate analysis, the following factors were significantly associated with the presence of ESUS: AIx75 (odds ratio (OR) 1.095, 95% confidence interval (CI) 1.004-1.194; p = 0.04), IVRT (OR 1.045, 95% CI: 1.009-1.082; p = 0.014), LAVI (OR 1.3, 95% CI: 1.099-1.537; p = 0.002), and NT-proBNP (OR 1.003, 95% CI: 1.001-1.005; p = 0.005). CONCLUSIONS: Increased arterial stiffness and indices of diastolic dysfunction as well as a higher NT-proBNP level are significantly associated with ESUS. These parameters require further scrutiny over time to understand their impact on the development of symptomatic heart failure. The ClinicalTrials.gov identifier is NCT03377465.

Plasma Osteoprotegerin Correlates with Stroke Severity and the Occurrence of Microembolic Signals in Patients with Acute Ischemic Stroke.

BACKGROUND: Instability of atherosclerotic plaques is associated with the occurrence of stroke. Microembolic signals (MESs) are an indicator of unstable plaque. A relationship between plasma osteoprotegerin (OPG) and ischemic stroke has already been identified. The aim of this study was to investigate whether plasma OPG levels have a relationship with MESs and to evaluate the feasibility of OPG as a biomarker of stroke severity and occurrence of MESs. METHODS: Our study consisted of 127 patients with large artery atherosclerosis stroke and 56 controls. Patients were classified into subgroups based on stroke severity and the occurrence of MESs. MES-monitoring was performed for 60 min using transcranial Doppler within 72 h of stroke onset. Stroke severity at admission was assessed by the National Institutes of Health Stroke Scale. RESULTS: Plasma OPG levels were significantly associated with stroke, MESs, and stroke severity at admission (adjusted OR [95% CI]: 1.002 [1.001-1.003] p < 0.001; 1.002 [1.001-1.003] p = 0.001; 1.001 [1.000-1.002] p = 0.028). When plasma OPG levels were used to determine the stroke severity, the area under the receiver-operating characteristic curve (AUC) was 0.734 (95% CI: 0.625-0.843) based on a cutoff value of 1998.44 pg/ml; the sensitivity and specificity of this test were 80.6% and 65.6%, respectively. Furthermore, when the levels of OPG were used to distinguish the presence of MESs, the AUC was 0.766 (95% CI: 0.672-0.860); the cutoff value was 2107.91 pg/ml. The sensitivity of this cutoff value was 68.8% and the specificity was 73.7%. CONCLUSIONS: Plasma OPG levels correlate with stroke severity and the occurrence of MESs.

Platelet-Rich Emboli in Cerebral Large Vessel Occlusion Are Associated With a Large Artery Atherosclerosis Source.

Background and Purpose- Nearly 30% of large vessel occlusion acute ischemic stroke clots are from an unknown source. We assessed histological clot composition in a series of patients with large vessel occlusion and investigated correlations between clot composition and stroke pathogenesis. Methods- As part of the multi-institutional STRIP registry (Stroke Thromboembolism Registry of Imaging and Pathology), consecutive emboli retrieved during mechanical thrombectomy were stained using Martius Scarlett Blue and analyzed using machine learning software. We assessed proportions of red blood cells, fibrin, platelets, and white blood cells. Correlations between clot components and stroke pathogenesis (large artery atherosclerosis, cardioembolism, and stroke of undetermined pathogenesis) were assessed using SPSS22. Results- One hundred five patients were included. The proportion of platelet-rich clots (55.0% versus 21.2%; P=0.005) and percentage of platelet content (22.1±4.2% versus 13.9±14.2%; P=0.03) was significantly higher in the large artery atherosclerosis group compared with the cardioembolic group. The proportion of platelet-rich clots (50.0% versus 21.2%; P=0.024) was also significantly higher in the cryptogenic group compared with cardioembolic cases. Large artery atherosclerosis and cryptogenic cases had a similar proportion of platelet-rich clots (55.0% versus 50.0%; P=0.636). There was no significant difference between stroke pathogenesis and the other major clot components. Conclusions- High platelet content of emboli is associated with a large artery atherosclerosis etiology of large vessel occlusion.

Circulating Microparticles in Patients with Symptomatic Carotid Disease Are Related to Embolic Plaque Activity and Recent Cerebral Ischaemia.

BACKGROUND AND PURPOSE: In order to assess the association of microparticles derived from activated platelets (PMP) or endothelial cells (EMP) with risk markers for recurrent embolic events in patients with symptomatic carotid artery disease, we studied the associations between PMP/EMP and three risk markers: plaque haemorrhage (PH), micro-embolic signals and cerebral diffusion abnormalities. METHODS: Patients with recently symptomatic high-grade carotid artery stenosis (60-99%, 42 patients, 31 men; mean age 75 ± 8 years) and 30 healthy volunteers (HV, 11 men; mean age 56 ± 12 years) were prospectively recruited. Patients were characterised by carotid magnetic resonance imaging (presence of PH [MRI PH]), brain diffusion MRI (cerebral ischaemia [DWI+]) and transcranial Doppler ultrasound (micro-embolic signals [MES+]). PMP and EMP were classified by flow cytometry and expressed as log-transformed counts per microlitre. RESULTS: MES+ patients (n = 18) had elevated PMP (MES+ 9.61 ± 0.57) compared to HV (8.80 ± 0.73; p < 0.0001) and to MES- patients (8.55 ± 0.85; p < 0.0001). Stroke patients had elevated PMP (9.49 ± 0.64) and EMP (6.13 ± 1.0) compared to non-stroke patients (PMP 8.81 ± 0.73, p = 0.026, EMP 5.52 ± 0.65, p = 0.011) and HV (PMP 8.80 ± 0.73, p = 0.007, and EMP 5.44 ± 0.47, p = 0.006). DWI+ patients (n = 16) showed elevated PMP (DWI+ 9.53 ± 0.64; vs. HV, p = 0.002) and EMP (DWI+ 5.91 ± 0.99 vs. HV 5.44 ± 0.47; p = 0.037). Only PMP but not EMP were higher in DWI+ versus DWI- patients (8.67 ± 0.90; p = 0.002). No association was found between PMP and EMP with MRI PH. CONCLUSIONS: PMP and EMP were associated with stroke and recent cerebrovascular events (DWI+) but only PMP were also associated with ongoing (MES+) thrombo-embolic activity suggesting a differential biomarker potential for EMP to index cerebral ischaemia while PMP may predict on-going thrombo-embolic activity.

Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study.

OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

Microembolic Signals is Associated With Insulin Resistance Among Acute Ischemic Stroke Patients.

BACKGROUND: Microembolic signals (MES) and insulin resistance (IR) is common in patients with acute ischemic stroke (AIS). Patients with active MES tend to be more seriously ill and prone to aggravating disease progression. IR is an important risk factor for stroke which has been found to be associated with the severity of stroke. This study aims to investigate the clinical correlation between intracranial MES and IR in AIS patients. METHODS: A total of 119 patients with AIS were enrolled in this study. The IR index (HOMA-IR) was calculated according to the homeostasis model and divided into 4 levels, where IR was defined by HOMA-IR index in the top quartile (Q4). Transcranial Doppler Sonography was performed in all patients within 72 hours after the stroke onset to monitor arterial MES in the lesion side of the brain for 30 minutes. RESULTS: It is found that the positive rate of MES increased with the increase of IR level. The positive rate of MES in IR group was 55.2% (16/29), and that in non-IR group was 32.2% (29/90). In addition, HOMA-IR in patients with MES- were significantly lower than those in patients with MES+ (1.6 [Interquartile range: 0.9-2.5] compared with 2.2 [Interquartile range: 1.3-4.1], P < .05).In multiple logistic regression analysis, we calculated the OR of MES as compared with the HOMA-IR. The result of OR value is 1.38 (95% confidence interval: 1.05-1.82, P = .02). CONCLUSIONS: IR is positively related to MES in patients with AIS. Higher level of IR might contribute to plaque destabilization and the formation of MES, which finally leading to the occurrence of stroke.

Succinate links atrial dysfunction and cardioembolic stroke.

OBJECTIVE: To determine whether altered metabolic profiles represent a link between atrial dysfunction and cardioembolic (CE) stroke, and thus whether underlying dysfunctional atrial substrate may contribute to thromboembolism risk in CE stroke. METHODS: A total of 144 metabolites were measured using liquid chromatography-tandem mass spectrometry in plasma samples collected within 9 hours of stroke onset in 367 acute stroke patients. Stroke subtype was assigned using the Causative Classification of Stroke System, and CE stroke (n = 181) was compared to non-CE stroke (n = 186). Markers of left atrial dysfunction included abnormal atrial function (P-wave terminal force in lead V1, PTFV1 >4,000 µV·ms), left atrial enlargement on echocardiography, and frank atrial fibrillation on ECG. Stroke recurrence risk was assessed using CHADS2 and CHA2DS2-VASc scores. Associations between metabolites and CE stroke, atrial dysfunction, and stroke recurrence risk were evaluated using logistic regression models. RESULTS: Three tricarboxylic acid metabolites-succinate (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.36-2.15, p = 1.37 × 10-6), α-ketoglutarate (OR 1.62, 95% CI 1.29-2.04, p = 1.62 × 10-5), and malate (OR 1.58, 95% CI 1.26-1.97, p = 2.57 × 10-5)-were associated with CE stroke. Succinate (OR 1.36, 95% CI 1.31-1.98, p = 1.22 × 10-6), α-ketoglutarate (OR 2.14, 95% CI 1.60-2.87, p = 2.08 × 10-8), and malate (OR 2.02, 95% CI 1.53-2.66, p = 1.60 × 10-7) were among metabolites also associated with subclinical atrial dysfunction. Of these, succinate was also associated with left atrial enlargement (OR 1.54, 95% CI 1.23-1.94, p = 1.06 × 10-4) and stroke recurrence based on dichotomized CHADS2 (OR 2.63, 95% CI 1.68-4.13, p = 3.00 × 10-6) and CHA2DS2-VASc (OR 2.43, 95% CI 1.60-3.68, p = 4.25 × 10-6) scores. CONCLUSIONS: Metabolite profiling identified changes in succinate associated with CE stroke, atrial dysfunction, and stroke recurrence, revealing a putative underlying link between CE stroke and energy metabolism.