tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.

RATIONALE: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation. OBJECTIVE: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke. METHODS AND RESULTS: Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. CONCLUSIONS: Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.

Predictors of Atrial Fibrillation Development in Patients With Embolic Stroke of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial.

BACKGROUND: A proportion of patients with embolic stroke of undetermined source have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of the risk for development of AF is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke attributable to underlying AF. 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) provides an opportunity to assess predictors for developing AF and associated recurrent stroke. METHODS: RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) were found to develop AF reported as an adverse event or using cardiac monitoring per standard clinical care. Univariable and multivariable regression analyses were performed to define predictors of AF. RESULTS: In the multivariable model, older age (odds ratio for 10-year increase, 1.99 [95% CI, 1.78-2.23]; P<0.001), hypertension (odds ratio, 1.36 [95% CI, 1.03-1.79]; P=0.0304), diabetes (odds ratio, 0.74 [95% CI, 0.56-0.96]; P=0.022), and body mass index (odds ratio for 5-U increase, 1.29 [95% CI, 1.16-1.43]; P<0.001) were independent predictors of AF during the study. In a sensitivity analysis restricted to 1117 patients with baseline NT-proBNP (N-terminal prohormone of brain natriuretic peptide) measurements, only older age and higher NT-proBNP were significant independent predictors of AF. Performance of several published predictive models was assessed, including HAVOC (AF risk score based on hypertension, age ≥75 years, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, and coronary artery disease) and CHA2DS2-VASc (stroke risk score based on congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, previous stroke, transient ischemic attack or thromboembolism [doubled], vascular disease, age 65 to 74 years, and sex category [female]) scores, and higher scores were associated with higher rates of developing AF. CONCLUSIONS: Besides age, the most important variable, several other factors, including hypertension, higher body mass index, and lack of diabetes, are independent predictors of AF after embolic stroke of undetermined source. When baseline NT-proBNP was available, only older age and elevation of this biomarker were predictive of subsequent AF. Understanding who is at higher risk of developing AF will assist in identifying patients who may benefit from more intense, long-term cardiac monitoring. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

Angiotensin-Converting Enzyme 2 Activity Is Associated With Embolic Stroke of Undetermined Source.

[Figure: see text].

d-dimer Level as a Predictor of Recurrent Stroke in Patients With Embolic Stroke of Undetermined Source.

Background and Purpose: This study aimed to investigate the value of d-dimer levels in predicting recurrent stroke in patients with embolic stroke of undetermined source. We also evaluated the underlying causes of recurrent stroke according to d-dimer levels. Methods: A total of 1431 patients with undetermined source were enrolled in this study and divided into quartiles according to their baseline plasma d-dimer levels. The primary outcome measure was the occurrence of recurrent stroke (ischemic or hemorrhagic) in the year following the stroke event. Results: The risk of recurrent stroke increased significantly with the increasing d-dimer quartile (log-rank P=0.001). Patients in the higher d-dimer quartiles had a higher probability of recurrent embolic stroke because of covert atrial fibrillation, hidden malignancy, or undetermined sources. Most recurrent strokes in Q3 and Q4 were embolic but not in Q1 or Q2. Multivariate analysis revealed that patients in Q3 and Q4 had a significantly increased risk of recurrent stroke compared with those in Q1 (hazard ratio, 3.12 [95% CI, 1.07−9.07], P=0.036; hazard ratio, 7.29 [95% CI, 2.59−20.52], P<0.001, respectively; Ptrend<0.001). Binary analyses showed a significant association between a high d-dimer level above normal range and the risk of recurrent stroke (hazard ratio, 2.48 [95% CI, 1.31−4.70], P=0.005). In subgroup analyses, a high d-dimer level was associated with a significantly higher risk of recurrent stroke in men than in women (P=0.039). Conclusions: Our findings suggest that d-dimer levels can be a useful risk assessment biomarker for predicting recurrent stroke, especially embolic ischemic stroke, in patients with undetermined source.

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.

Thrombectomy for Treatment of Acute Stroke in the COVID-19 Pandemic.

This commentary will focus on the role of thrombectomy for the treatment of embolic stroke during the 2019 novel coronavirus disease (COVID-19). We will begin with review of recently promulgated guidelines for use of thrombectomy in COVID-19-associated stroke. We will then survey the reported experience of thrombectomy applied to treatment of large-vessel occlusion (LVO) stroke in COVID-19. We will conclude by discussing unusual challenges confronted by neuro-interventionalists seeking to perform thrombectomy in COVID-19 patients with acute LVO stroke.

Pinocembrin attenuates hemorrhagic transformation after delayed t-PA treatment in thromboembolic stroke rats by regulating endogenous metabolites.

Hemorrhagic transformation (HT) is a common serious complication of stroke after thrombolysis treatment, which limits the clinical use of tissue plasminogen activator (t-PA). Since early diagnosis and treatment for HT is important to improve the prognosis of stroke patients, it is urgent to discover the potential biomarkers and therapeutic drugs. Recent evidence shows that pinocembrin, a natural flavonoid compound, exerts anti-cerebral ischemia effect and expands the time window of t-PA. In this study, we investigated the effect of pinocembrin on t-PA-induced HT and the potential biomarkers for HT after t-PA thrombolysis, thereby improving the prognosis of stroke. Electrocoagulation-induced thrombotic focal ischemic rats received intravenous infusion of t-PA (10 mg/kg) 6 h after ischemia. Administration of pinocembrin (10 mg/kg, iv) prior t-PA infusion significantly decreased the infarct volume, ameliorated t-PA-induced HT, and protected blood-brain barrier. Metabolomics analysis revealed that 5 differential metabolites in the cerebral cortex and 16 differential metabolites in serum involved in amino acid metabolism and energy metabolism were significantly changed after t-PA thrombolysis, whereas pinocembrin administration exerted significant intervention effects on these metabolites. Linear regression analysis showed that lactic acid was highly correlated to the occurrence of HT. Further experiments confirmed that t-PA treatment significantly increased the content of lactic acid and the activity of lactate dehydrogenase in the cerebral cortex and serum, and the expression of monocarboxylate transporter 1 (MCT 1) in the cerebral cortex; pinocembrin reversed these changes, which was consistent with the result of metabolomics. These results demonstrate that pinocembrin attenuates HT after t-PA thrombolysis, which may be associated with the regulation of endogenous metabolites. Lactic acid may be a potential biomarker for HT prediction and treatment.

The Utility of the Markers of Coagulation and Hemostatic Activation Profile in the Management of Embolic Strokes of Undetermined Source.

BACKGROUND: Potential causes of embolic stroke of undetermined source (ESUS) include occult malignancy, venous thrombosis (VTE) with paradoxical embolism, and hypercoagulable disorders. Given the association of markers of coagulation and hemostatic activation (MOCHA) with these causes, the objective of this study was to validate the utility of the MOCHA profile in identifying the underlying cause of stroke. METHODS: We prospectively identified ESUS patients from January 1, 2017 to December 1, 2019 who underwent MOCHA profile (plasma d-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrin monomer) testing. Abnormal MOCHA profile was defined as ≥ 2 abnormal markers. New diagnoses of malignancy, VTE, hypercoagulable disorders and recurrent stroke were identified during routine clinical follow-up. RESULTS: Of 236 ESUS patients, 104 (44%) patients had an abnormal MOCHA profile. In multivariable analyses the number of MOCHA abnormalities was significantly associated with malignancy, VTE, and hypercoagulable disorders (OR 2.59, CI 95% 1.78-3.76, p<0.001). Sensitivity, specificity, positive predictive value, and negative predictive value of an abnormal MOCHA profile for the combined outcome of malignancy, VTE, and hypercoagulability was 96%, 62%, 23%, and 99% respectively. DISCUSSION: The MOCHA profile was able to identify ESUS patients more likely to have malignancy, VTE, and hypercoagulable disorders during follow-up. Our results show that a normal MOCHA profile in ESUS patients can effectively rule out these potential causes of ESUS.

Nonstenotic Carotid Plaque in Embolic Stroke of Undetermined Source: Interplay of Arterial and Atrial Disease.

BACKGROUND AND PURPOSE: Approximately one-sixth of all ischemic strokes are attributable to embolic stroke of undetermined source (ESUS). Recent analyses suggest that atrial cardiopathy and nonstenotic carotid plaque (nsCP) may represent 2 distinct underlying causes in patients with ESUS, although both diseases share common risk factors and are pathophysiologically intertwined. In this study, we, therefore, aimed to search for associations between nsCP and markers of atrial remodeling and function in patients with embolic stroke. METHODS: Sixty-eight patients with ESUS or atrial fibrillation (AF)-related stroke proven by imaging who underwent comprehensive echocardiographic studies, including measurements of left atrial function and remodeling, were considered. Patients with ESUS underwent a follow-up of at least 1 year after index stroke. For 20 patients with ESUS, NT-proBNP (N-terminal pro-B-type natriuretic peptide) values were available. Presence of nsCP was evaluated considering Duplex sonography and computed tomography angiography and was further categorized in possibly or probably symptomatic nsCP. RESULTS: ESUS patients with nsCP tended to have higher values of septal and lateral total atrial conduction times (P=0.071 and P=0.072, respectively), left atrial volume index (P=0.077), and revealed significantly higher strain rates during early diastole (P=0.013) as well as higher NT-proBNP values (P=0.010) than ESUS patients without nsCP. Moreover, septal total atrial conduction time was significantly longer in ESUS patients with possibly symptomatic nsCP compared with those without (P=0.015). Comparison of ESUS with AF patients revealed significantly higher proportions of nsCP (P=0.010), possibly symptomatic nsCP (P=0.037), and probably symptomatic nsCP (P=0.036) in patients with atrial fibrillation-related stroke. In the regression analysis adjusted for vascular risk factors probably symptomatic nsCP remained significantly associated with AF (P=0.048, odds ratio: 4.46 [95% CI, 1.02-19.56]). CONCLUSIONS: Presence of nsCP is associated with AF and markers of left atrial disease in patients with embolic stroke. Therefore, a thorough evaluation regarding atrial cardiopathy and AF in patients with ESUS should not be restricted if nsCP are found, even if high-risk plaque characteristics are evident.

Increased plasma levels of N-terminal pro-B-type natriuretic peptide as biomarker for the diagnosis of cardioembolic ischaemic stroke.

BACKGROUND: Despite comprehensive study, the aetiology of stroke is not identified in 35% of cases. AIMS: We conducted a study to assess the diagnostic capacity of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the identification of ischaemic stroke of cardioembolic origin. The secondary purpose of the study was to evaluate the prognostic value of NT-proBNP for predicting 90-day all-cause mortality. METHODS: We designed a prospective observational study including patients hospitalised due to stroke between March 2019 and March 2020. Blood samples were collected on admission to the emergency department and serum NT-proBNP levels were determined. Statistical analysis was performed using a bivariate logistic regression model and receiver operating characteristic (ROC) and Kaplan-Meier curves. Statistical significance was established at p<.05. RESULTS: The study included 207 patients with first ischaemic stroke. Plasma NT-proBNP levels were significantly higher (p<.001) in the cardioembolic stroke group (2069pg/mL±488.5). ROC curves showed that NT-proBNP>499pg/mL was the optimum value for diagnosing cardioembolic ischaemic stroke (sensitivity, 82%; specificity, 80%). Moreover, plasma NT-proBNP levels>499pg/mL were independently associated with cardioembolic stroke (OR: 9.881; p=.001). Finally, NT-proBNP>1500pg/mL was useful for predicting 90-day mortality (sensitivity, 70%; specificity, 93%). CONCLUSIONS: NT-proBNP was independently associated with cardioembolic stroke and should be quantified in blood tests within 24h of stroke onset. High plasma levels (>499pg/mL) may indicate an underlying cardioembolic cause, which should be further studied, while NT-proBNP >1500pg/mL was associated with increased 90-day mortality.

Mendelian Randomization and Bayesian Colocalization Analysis Implicate Glycoprotein VI as a Potential Drug Target for Cardioembolic Stroke in South Asian Populations.

BACKGROUND: Circulating plasma proteins are clinically useful biomarkers for stroke risk. We examined the causal links between plasma proteins and stroke risk in individuals of South Asian ancestry. METHODS AND RESULTS: We applied proteome-wide Mendelian randomization and colocalization approaches to understand causality of 2922 plasma proteins on stroke risk in individuals of South Asian ancestry. We obtained genetic instruments (proxies) for plasma proteins from the UK Biobank (N=920). Genome-wide association studies summary data for strokes (N≤11 312) were sourced from GIGASTROKE consortium. Our primary approach involved the Wald ratio or inverse-variance-weighted methods, with statistical significance set at false discovery rate <0.1. Additionally, a Bayesian colocalization approach assessed shared causal variants among proteome, transcriptome, and stroke phenotypes to minimize bias from linkage disequilibrium. We found evidence of a potential causal effect of plasma GP6 (glycoprotein VI) levels on cardioembolic stroke (odds ratio [OR]Wald ratio=2.53 [95% CI, 1.59-4.03]; P=9.2×10-5, false discovery rate=0.059). Generalized Mendelian randomization accounting for correlated single nucleotide polymorphisms (SNPs), with the P value threshold at P<5×10-8 and clumped at r2=0.3, showed consistent direction of effect of GP6 on cardioembolic stroke (ORgeneralized inverse-variance-weighted=2.21 [95% CI, 1.46-3.33]; P=1.6×10-4). Colocalization analysis indicated that plasma GP6 levels colocalize with cardioembolic stroke (posterior probability=91.4%). Multitrait colocalization combining transcriptome, proteome, and cardioembolic stroke showed moderate to strong evidence that these 2 traits colocalize with GP6 expression in the coronary artery and brain tissues (multitrait posterior probability>50%). The potential causal effect of GP6 on cardioembolic stroke was not significant in European populations (ORinverse-variance-weighted=1.08 [95% CI, 0.93-1.26]; P=0.29). CONCLUSIONS: Our joint Mendelian randomization and colocalization analyses suggest that genetically predicted GP6 is potentially causally associated with cardioembolic stroke risk in individuals of South Asian ancestry. As genetic data on individuals of South Asian ancestry increase, future Mendelian randomization studies with larger sample size for plasma GP6 levels should be implemented to further validate our findings. Additionally, clinical studies will be necessary to verify GP6 as a therapeutic target for cardioembolic stroke in South Asians.

The role of the D-dimer to fibrinogen ratio in the classification of cardioembolism and atherosclerotic stroke.

BACKGROUND: The D-dimer-to-fibrinogen ratio (DFR) is a good indicator of thrombus activity in thrombotic diseases, but its clinical role in acute ischaemic stroke (AIS) patients with different etiologies has not been studied. We evaluated the diagnostic value of the DFR for different subtypes of AIS. METHODS: We conducted a single-center retrospective study of 269 patients with AIS who were referred to our stroke center within 4.5 h from Jan 2017 to Oct 2019. Coagulation data including DFRs were compared among the different stroke subtypes, and a separate retrospective validation sample was utilized to evaluate the prediction efficiency of the DFR for subtype diagnosis. RESULTS: A higher DFR was observed in patients with cardioembolism than in those with large artery atherosclerosis (LAA) (odds ratio (OR) per 0.1 increase of the DFR: 1.49 [1.01-2.18]) after we adjusted for vascular risk factors. The diagnostic value of the DFR for detecting cardioembolism (AUC = 0.722, 95 % CI = 0.623-0.820) exceeded that of isolated D-dimer or fibrinogen. The validation sample (n = 117) further supported the notion that a diagnosis of cardioembolism was more common in patients with a DFR > 0.11 (multivariable risk ratio = 3.11[1.33-7.31], P = 0.009). CONCLUSION: High DFRs were associated with cardioembolism in patients with AIS. The utilization of DFR can be beneficial for distinguishing a cardiac embolic source from atherosclerotic stroke.

BNP on Admission Combined with Imaging Markers of Multimodal CT to Predict the Risk of Cardioembolic Stroke.

Background: The aim of the study was to find the potential roles of B-type natriuretic peptide (BNP) and imaging markers on distinguishing cardioembolic (CE) stroke from non-CE stroke, so as to provide useful information for making individualized endovascular treatment (EVT) plan for the patients with acute ischemic stroke (AIS). Methods: The patients with unilateral anterior circulation large vessel occlusion who underwent EVT between March 2016 and December 2021 were analyzed in this study, retrospectively. The risk factors, laboratory test indicators, imaging parameters, and other factors were compared between the CE group and non-CE group. Logistic regression was used to analyze the risk factors of CE stroke. ROC curves were used to assess the values of different parameters on distinguishing CE stroke from non-CE stroke. The relationships between BNP and imaging parameters were assessed using the Spearman correlation analysis. Results: 160 patients were enrolled in the study and divided into the CE group (n = 66) and non-CE group (n = 94). BNP (odds ratio (OR) = 1.004; 95% CI, 1.001-1.009; p = 0.038), MMR (OR = 0.736; 95% CI, 0.573-0.945; p = 0.016), NIHSS (OR = 1.150; 95% CI, 1.022-1.294; p = 0.020), and AF (OR = 556.968; 95% CI, 51.739-5995.765; p < 0.001) were the independent predictive factors of CE stroke. The area under the curve (AUC) of BNP and mismatch ratio (MMR) were 0.846 (95% CI (0.780-0.898), p < 0.001) and 0.636 (95% CI (0.633-0.779), p < 0.001), respectively. The cut-off value of BNP was 249.23 pg/mL with the sensitivity of 74.24% and the specificity of 82.98%. BNP combined with MMR improved the predictive value for CE stroke. The AUC of the combination was 0.858 with the sensitivity of 84.85% and the specificity of 73.40%. BNP was correlated with 4D CTA collateral score, MMR, clot burden score, final infarct volume, infarct core volume, and ischemic penumbra volume (all, p < 0.05). Conclusion: BNP on admission combined with MMR is valuable for the risk prediction of CE stroke, which will promote the further screening of the high-risk patients with CE stroke and provide more diagnostic information for clinicians.

BNP combined with echocardiographic parameters to predict the risk of cardioembolic stroke.

BACKGROUND: Previous studies have found that BNP and some indicators of cardiac structure and function are closely associated with atrial fibrillation, so we aim to investigate the potential role of BNP and echocardiographic parameters to identify the acute ischemic stroke with atrial fibrillation patients who have high risks of cardioembolic stroke based on it. METHODS: 436 AIS patients were divided into an AF group and non-AF group on the basis of the electrocardiogram and Holter results. Then we compared vascular risk factors, laboratory test indicators, and echocardiographic parameters among different groups. RESULTS: AIS with AF group had significantly higher age, CHD, previous medication, creatinine, d-dimer, fibrinogen, CRP, BNP, LAD, LVDd, LVDs and lower cholesterol, triglyceride, LDL and ejection fraction than the non-AF group (P < 0.05). Increased BNP, LAD, LVDd, LVDs and ejection fraction reduction were independent risk factors to predict cardioembolic stroke. BNP and LAD could be the two most effective indicators of the high risk of cardioembolic stroke. The area under the curve (AUC) of BNP and LAD were 0.791 [95%CI (0.743-0.838), p < 0.001), 0.786 [95%CI (0.739-0.833), p < 0.001]. The combined score we designed improved the prediction effect of single-indicator. The AUC of it was 0.822 with a sensitivity of 69.5% and specificity of 83.9%.There was an apparent positive correlation between BNP and LAD in AIS patients (r = 0.327, P < 0.001). CONCLUSION: BNP combined with echocardiographic parameters has outstanding value to predict the risk of cardioembolic stroke, especially for BNP and LAD.

Atrial Fibrillation After Ischemic Stroke Detected by Chest Strap-Style 7-Day Holter Monitoring and the Risk Predictors: EDUCATE-ESUS.

AIM: This study aimed to investigate the diagnostic yield of 7-day Holter monitoring for detecting covert atrial fibrillation (AF) in patients with recent embolic stroke of undetermined source (ESUS) and to identify the pre-entry screening biomarkers that had significant associations with later detection of AF (clinicaltrials.gov. NCT02801708). METHODS: A total of 206 patients who have recent ESUS without previously documented AF underwent Holter electrocardiography using a chest strap-style monitor. External validation of biomarkers predictive of AF was performed using 83 patients with ESUS who were implanted with insertable cardiac monitors. RESULTS: The 7-day Holter monitoring started at a median of 13 days after the onset of stroke. AF was detected in 14 patients, and three of these showed a single AF episode lasting ＜2 min. The median time delay to the first documented AF was 50 h. Each of serum brain natriuretic peptide ≥ 66.0 pg/mL (adjusted odds ratio 5.23), atrial premature contractions (APCs) ≥ 345 beats (3.80), and APC short runs ≥ 13 (5.74) on 24-h Holter prior to the 7-day Holter showed a significant association with detection of AF, independent of age and physiological findings in this derivation cohort, and all of these showed a significant association in the validation cohort (adjusted odds ratio 6.59, 7.87, and 6.16, respectively). CONCLUSIONS: In recent ESUS patients, the detection rate of AF using the 7-day Holter monitoring was 6.8% (95% CI 4.1%-11.1%). Brain natriuretic peptide, APC count, and APC short runs in the standard clinical workup seemed to be predictors of covert AF.

The relation between aortic arch branching types and the location of large vessel occlusion in cardioembolic stroke.

Cardiac embolism is the leading etiology of ischemic strokes. There are arguments about the left-right propensity of cardioembolic strokes.This study aimed to reveal the relationship between the different aortic arch types and the location of large vessel occlusion (LVO) in cardioembolic stroke.We retrospectively identified all patients with acute ischemic stroke admitted to our comprehensive stroke center who had medium- to high-risk cardioembolicsources according to the TOAST classification.Only those with LVO and available images of the aortic arch were included. Patients were classified into 3 groups according to the aortic arch types: Type I (n = 44), Type II (n = 105), Type III (n = 36).The thrombus was divided into large thrombus or small thrombus based on the location of LVO.Overall, left-sided strokes (50.8%) were almost equal to right-sided (49.2%). There was a growing tendency for the percentage of left-sided infarcts with advancement of the aortic arch types either in the total cases or in the atrial fibrillation cases, with no statistical difference between the 3 aortic arch types.In type III aortic arch, left-sided strokes (69.0%) were twice than right-sided (31%) in large thrombus (P < 0.05), while right-sided strokes (85.7%) were more common than left-sided (14.3%) in small thrombus (P < 0.05).Conversely, in type Ⅰ and II aortic arches, left-sided strokes were more common than right-sided in small thrombus, while right-sided strokes were more common than left-sided in large thrombus (P < 0.05). The left-right propensity of cardioembolic stroke is related to the proximity of clot lodging in different aortic arch types.

Cardioembolic Ischemic Stroke Gene Expression Fingerprint in Blood: a Systematic Review and Verification Analysis.

An accurate etiological classification is key to optimize secondary prevention after ischemic stroke, but the cause remains undetermined in one third of patients. Several studies pointed out the usefulness of circulating gene expression markers to discriminate cardioembolic (CE) strokes, mainly due to atrial fibrillation (AF), while only exploring them in small cohorts. A systematic review of studies analyzing high-throughput gene expression in blood samples to discriminate CE strokes was performed. Significantly dysregulated genes were considered as candidates, and a selection of them was validated by RT-qPCR in 100 patients with defined CE or atherothrombotic (LAA) stroke etiology. Longitudinal performance was evaluated in 12 patients at three time points. Their usefulness as biomarkers for AF was tested in 120 cryptogenic strokes and 100 individuals at high-risk for stroke. Three published studies plus three unpublished datasets were considered for candidate selection. Sixty-seven genes were found dysregulated in CE strokes. CREM, PELI1, and ZAK were verified to be up-regulated in CE vs LAA (p = 0.010, p = 0.003, p < 0.001, respectively), without changes in their expression within the first 24 h after stroke onset. The combined up-regulation of these three biomarkers increased the probability of suffering from CE stroke by 23-fold. In cryptogenic strokes with subsequent AF detection, PELI1 and CREM showed overexpression (p = 0.017, p = 0.059, respectively), whereas in high-risk asymptomatic populations, all three genes showed potential to detect AF (p = 0.007, p = 0.007, p = 0.015). The proved discriminatory capacity of these gene expression markers to detect cardioembolism even in cryptogenic strokes and asymptomatic high-risk populations might bring up their use as biomarkers.

Inflammatory and stress markers predicting pneumonia, outcome, and etiology in patients with stroke: Biomarkers for predicting pneumonia, functional outcome, and death after stroke.

OBJECTIVE: Prognosis of stroke is negatively affected by complications, in particular stroke-associated pneumonia (SAP). We hypothesized that inflammatory and stress biomarkers predict SAP during hospitalization and outcome 3 months after stroke. METHODS: We pooled the clinical data of 2 acute stroke studies with identical assessment: the STRoke Adverse outcome is associated WIth NoSoKomial Infections (STRAWINSKI) and PREDICT studies. Measurement of biomarkers (ultrasensitive procalcitonin [PCTus]; midregional pro-adrenomedullin; midregional pro-atrial natriuretic peptide [MRproANP]; ultrasensitive copeptin [CPus]; C-terminal pro-endothelin) was performed from serum samples drawn on the first 4 days of hospital admission. RESULTS: The combined cohort consists of 573 cases with available backup samples to perform the analysis. SAP was associated with increased admission and maximum levels of all biomarkers. Furthermore, all biomarkers were associated with death and correlated with functional outcome 3 months after stroke. The multivariate logistic regression model retained ultrasensitive CPus and PCTus beyond clinical risk factors for predicting SAP, improving the receiver operating characteristic area under the curve (AUC) from 0.837 to 0.876. In contrast, the biomarkers did not improve the prediction of death and functional outcome in the multivariate model. Cardioembolic strokes were significantly associated with higher values of all biomarkers, whereas discrimination was best for MRproANP (AUC = 0.811 for maximum value). CONCLUSIONS: The tested biomarkers are associated with SAP and poor functional outcome. However, these biomarkers only slightly improve prediction of SAP and do not improve long-term outcome prediction over clinical parameters. MRproANP showed the best discrimination for identifying cardioembolic stroke, warranting further studies to confirm our finding. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01264549 and NCT01079728.