Monocyte-to-Lymphocyte Ratio in Clot Analysis as a Marker of Cardioembolic Stroke Etiology

Background: Risk factors for stroke may alter hemodynamics or invoke ischemic preconditioning, yet the impact of such factors on response to acute stroke treatment and the potential relationship with collateral circulation remains unknown. Methods: Consecutive cases enrolled in the International Multicenter Registry for Mechanical Recanalization Procedures in Acute Stroke (ENDOSTROKE) were analyzed with respect to collateral status on baseline angiography before endovascular therapy. ASITN/SIR collateral grade (0-1/2/3-4) was scored by the core lab, blind to all other data. Collateral grade was analyzed with respect to numerous baseline risk factors, demographics and outcomes after endovascular intervention. Results: 109 patients (median age 69 years (25 th , 75 th percentiles: 56, 77); 51% women; median baseline NIHSS 15 (13, 18)) with complete (TICI 0) anterior circulation occlusions (M1, n=71; ICA, n=28; M2, n=10) at baseline were evaluated based on collateral grade (0-1, n=12; 2, n=41; 3-4, n=56). Worse collaterals were noted in patients with atrial fibrillation (ASITN grades 0-1/2/3-4: 21%/30%/49%) as compared to patients without atrial fibrillation (5%/42%/53%, p=0.024), yet cardioembolic stroke etiology was unrelated. Other baseline features such as age, gender, time to presentation, other co-morbidities and labs were unrelated to collateral grade. Post-procedure reperfusion (TICI 2b-3) was significantly associated with better collaterals (OR 2.58 (1.343-4.957, p=0.004). Similarly, final infarct size was significantly smaller in those with better collaterals. Good clinical outcomes (mRS 0-2 at day 90) were less frequent in those with poorer collaterals (OR 0.403 (0.199-0.813, p=0.011). Conclusions: Atrial fibrillation, but not cardioembolic stroke etiology, is associated with worse collaterals. Hemodynamic implications, such as diminished cardiac output due to atrial fibrillation, may result in less favorable outcomes after endovascular therapy for acute stroke.

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No Association Between Thrombus Perviousness and Cardioembolic Stroke Etiology in Basilar Artery Occlusion Stroke

Frontiers in Neurology ◽

10.3389/fneur.2021.712449 ◽

2021 ◽

Vol 12 ◽

Author(s):

Anna Kufner ◽

Matthias Endres ◽

Michael Scheel ◽

Christoph Leithner ◽

Christian H. Nolte ◽

...

Keyword(s):

Basilar Artery ◽

Binary Logistic Regression ◽

Artery Occlusion ◽

Cardioembolic Stroke ◽

Basilar Artery Occlusion ◽

Large Artery ◽

Anterior Circulation ◽

Stroke Etiology ◽

Proximal Middle Cerebral Artery

Background: Thrombus perviousness (TP) quantified by thrombus attenuation increase (TAI) assessed on acute non-contrast computed tomography (NCCT) and CT angiography (CTA) may be associated with stroke etiology in anterior circulation ischemic stroke. We investigated whether TP is associated with stroke etiology and recanalization after mechanical thrombectomy in patients with acute basilar artery occlusion (BAO).Methods: Eighty patients with complete BAO and in-house acute imaging from a prospectively maintained database were included. Two raters independently segmented the complete thrombus on co-registered NCCT and CTA to determine TAI in Hounsfield units (HUCTA–HUNCCT); averaged values of the raters were used for analysis. Recanalization to modified treatment in cerebral ischemia (mTICI) score 2b/3 was considered successful, and 90-day modified Rankin Scale score 0–2 was considered favorable.Results: TAI did not differ between patients with different stroke etiologies; median TAI in patients with cardioembolic stroke (n = 36) was −0.47 (interquartile range −4.08 to 7.72), 1.94 (−8.14 to 10.75) in patients with large artery atherosclerosis (LAA; n = 25), and −0.99 (−6.49 to 5.40) in patients with stroke of undetermined origin (n = 17; p = 0.955). Binary logistic regression analyses did not identify TAI as an independent indicator of cardioembolic stroke (adjusted odds ratio [OR] vs. LAA stroke: 1.0 [95% CI: 0.95–1.0], p = 0.751). There was no association with successful recanalization (adjusted OR 1.4 [0.70–2.7], p = 0.345) or favorable outcome (adjusted OR 1.1 [95% CI: 0.94–1.2], p = 0.304).Conclusion: In contrast to proximal middle cerebral artery occlusions, TP in BAO patients is not associated with cardioembolic stroke etiology. Larger confirmatory studies to establish the potential role of TP for clinical applications should focus on patients with anterior circulation stroke.

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Midregional proatrial natriuretic peptide improves risk stratification after ischemic stroke

Neurology ◽

10.1212/wnl.0000000000004922 ◽

2018 ◽

Vol 90 (6) ◽

pp. e455-e465 ◽

Cited By ~ 6

Author(s):

Gian Marco De Marchis ◽

Juliane Schneider ◽

Anja Weck ◽

Felix Fluri ◽

Joachim Fladt ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Functional Outcome ◽

Natriuretic Peptide ◽

Mortality Prediction ◽

Cardioembolic Stroke ◽

Prognostic Information ◽

Multicenter Cohort Study ◽

Stroke Etiology ◽

Discriminatory Accuracy

ObjectiveTo validate midregional proatrial natriuretic peptide (MR-proANP) for outcome prediction and diagnosis of cardioembolic stroke etiology compared to established clinical variables.MethodsIn this prospective multicenter cohort study, we quantified MR-proANP levels in ischemic stroke patients within 24 hours of onset. Primary outcome measures were 90-day mortality, unfavorable functional outcome (modified Rankin Scale score >2), and cardioembolic stroke etiology diagnosed during hospitalization.ResultsOf 788 included patients, 783 completed their 90-day follow-up, and 118 patients (15%) died. After full adjustment, MR-proANP levels were associated with 90-day mortality (adjusted hazard ratio 6.12, 95% confidence interval [CI] 2.36–15.84, p = 0.01) and functional outcome (adjusted odds ratio [aOR] 2.46, 95% CI 1.05–5.74, p = 0.038). For mortality prediction, adding MR-proANP to the regression model increased its discriminatory accuracy, and the continuous net reclassification index (cNRI) was 49% (95% CI 26%–78%, p < 0.001). For functional outcome, there was no significant improvement in discrimination or reclassification. Cardioembolic stroke etiology and the diagnosis of atrial fibrillation at hospital discharge were associated with MR-proANP with an aOR of 2.10 (95% CI 1.11–3.97, p = 0.02) and 18.35 (95% CI 7.94–42.45, p < 0.001), respectively. The cNRI of MR-proANP for cardioembolic stroke etiology was not significant, as opposed to atrial fibrillation (78%, 95% CI 60%–89%, p < 0.001). MR-proANP levels ≥289 pmol/L had a specificity of 86% and sensitivity of 48% for the diagnosis of atrial fibrillation.ConclusionMR-proANP is a newly validated blood biomarker providing additional prognostic information for mortality after stroke. Higher MR-proANP levels were associated with cardioembolic stroke etiology and, even more strongly, atrial fibrillation.

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Promising Biomarker Candidates for Cardioembolic Stroke Etiology. A Brief Narrative Review and Current Opinion

Frontiers in Neurology ◽

10.3389/fneur.2021.624930 ◽

2021 ◽

Vol 12 ◽

Author(s):

Arnold Markus ◽

Schütz Valerie ◽

Katan Mira

Keyword(s):

Randomized Clinical Trials ◽

Thrombus Formation ◽

Preventive Treatment ◽

Cardioembolic Stroke ◽

Prevention Strategies ◽

Vessel Occlusion ◽

Cerebral Vessel ◽

Stroke Etiology ◽

Underlying Mechanisms ◽

Made In

Determining the cause of stroke is considered one of the main objectives in evaluating a stroke patient in clinical practice. However, ischemic stroke is a heterogeneous disorder and numerous underlying disorders are implicated in its pathogenesis. Although progress has been made in identifying individual stroke etiology, in many cases underlying mechanisms still remain elusive. Since secondary prevention strategies are tailored toward individual stroke mechanisms, patients whose stroke etiology is unknown may not receive optimal preventive treatment. Cardioembolic stroke is commonly defined as cerebral vessel occlusion by distant embolization arising from thrombus formation in the heart. It accounts for the main proportion of ischemic strokes, and its share to stroke etiology is likely to rise even further in future decades. However, it can be challenging to distinguish cardioembolism from other possible etiologies. As personalized medicine advances, stroke researchers' focus is increasingly drawn to etiology-associated biomarkers. They can provide deeper insight regarding specific stroke mechanisms and can help to unravel previously undetected pathologies. Furthermore, etiology-associated biomarkers could play an important role in guiding future stroke prevention strategies. To achieve this, broad validation of promising candidate biomarkers as well as their implementation in well-designed randomized clinical trials is necessary. This review focuses on the most-promising candidates for diagnosis of cardioembolic stroke. It discusses existing evidence for possible clinical applications of these biomarkers, addresses current challenges, and outlines future perspectives.

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Abstract 50: RNA Expression for Diagnosis of Stroke Etiology Differentiating Large Artery and Cardioembolic Stroke: Analytical Validation of Testing From the BASE Clinical Trial

Stroke ◽

10.1161/str.51.suppl_1.50 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Edward C Jauch ◽

Keyword(s):

Acute Stroke ◽

Symptom Onset ◽

Training Data ◽

Cardioembolic Stroke ◽

Blood Collection ◽

Rna Expression ◽

Large Artery ◽

Hospital Data ◽

Stroke Patients ◽

Stroke Etiology

Background: An accurate test to differentiate large artery stroke (LAS) patients from those with cardioembolic stroke (CES) would be of significant clinical utility. Using the Biomarkers of Acute Stroke Etiology (BASE) trial (NCT02014896) dataset, our purpose was to utilize blood gene expression signatures for accurately differentiating LAS from CES acute stroke etiologies. Methods: The BASE trial enrolled suspected stroke patients presenting to 20 hospitals within 24 hrs of symptom onset. Final gold standard diagnosis and stroke etiology were determined by an adjudication committee using all hospital data but blinded to RNA test results. Whole blood, obtained in PAX tubes, was frozen at -20C within 72 hrs and analyzed at a core lab (Ischemia Care, Dayton, OH) using Affymetrix HTA microarrays. Genes on the HTA microarray were filtered to eliminate genes with low expression or high CV (> 10%) when run on replicate samples leaving 9,513 potential signature genes. A two-way random forest classifier was built through cross validation of the training data resulting in a 45 gene diagnostic signature. Results: This is a planned interim cohort study of the 1700 patients enrolled in the BASE trial that does not include lacunar strokes, TIA, or stroke mimics. Overall, 222 patients were enrolled with NIHSS>5, 70 (32%) with LAS and 152 (68%) with CES; 59% were male, and median (IQR) age was 70.7 yrs (62.0, 80.2). Median (IQR) time from symptom onset to blood collection was 1200 (448, 1568) minutes. Coexistent pathology at presentation included atrial fibrillation 90 (48%), hypertension 153 (82%), hyperlipidemia 87 (47%), diabetes 60 (32%), and coronary artery disease 70 (37%). Patients were randomly divided into training (148), early symptom onset (<18hrs) validation (39) and a late symptom onset (>18 hrs) validation (35). The diagnostic gene signature results in the early validation cohort distinguished LAS from CES; C-statistic 0.78 (0.50-1.0, 95% CI), sensitivity 0.90 (0.55-1.0, 95% CI) and specificity of 0.70 (0.43-1.0, 95% CI). Conclusion: Early RNA expression differentiates large artery stroke patients from those with cardioembolic stroke, and may have therapeutic and secondary prevention implications.

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High Serum Levels of Pro-Brain Natriuretic Peptide (pro BNP) Identify Cardioembolic Origin in Undetermined Stroke

Disease Markers ◽

10.1155/2009/351591 ◽

2009 ◽

Vol 26 (4) ◽

pp. 189-195 ◽

Cited By ~ 18

Author(s):

Manuel Rodríguez-Yáñez ◽

Tomás Sobrino ◽

Miguel Blanco ◽

Natalia Pérez de la Ossa ◽

David Brea ◽

...

Keyword(s):

Molecular Markers ◽

Myocardial Damage ◽

Serum Levels ◽

High Serum ◽

Cardioembolic Stroke ◽

Unknown Etiology ◽

Stroke Subtype ◽

Stroke Etiology ◽

Undetermined Etiology ◽

Toast Criteria

Background: Stroke subtype diagnosis leads to specific therapies to reduce recurrences. Because nearly one third of patients remain with unknown etiology after a complete screening workup, we aim to investigate whether molecular markers of myocardial damage were associated with cardioembolic stroke and if they were useful to reclassify strokes of undetermined etiology.Methods: We included 262 patients with first ischemic stroke within the first 12 hours. Stroke subtype was evaluated by TOAST criteria. Stroke of undetermined origin were reclassified into likely atherothrombotic or likely cardioembolic according to a predefined non-validated algorithm. Blood samples were obtained on admission to determine serum levels of molecular markers (pro-BNP, pro-ANP and CK-MB) of myocardial damage.Results: Patients with cardioembolic infarct showed higher levels of pro-BNP, pro-ANP and CK-MB. Pro-BNP > 360 pg/mL was independently associated with cardioembolic stroke (OR: 28.51, CI95%: 5.90–136.75,p< 0.0001). Stroke etiology was undetermined in 82 patients (31%); 34 were reclassified as likely cardioembolic, 22 as likely atherothrombotic, and 26 remained as undetermined. Pro-BNP > 360 pg/mL was the only factor independently associated with likely cardioembolic stroke.Conclusions: Pro-BNP levels higher than 360 pg/mL are associated with cardioembolic stroke and may be useful to reclassify undetermined strokes as of cardioembolic origin.

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Abstract TP210: Histopathological Evaluation of Thrombus in Acute Stroke and Correlation with Stroke Etiology

Stroke ◽

10.1161/str.48.suppl_1.tp210 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Amre Nouh ◽

Tapan Mehta ◽

Mohammed Hussain ◽

Xianyuan Song ◽

Martin Ollenschleger

Keyword(s):

Acute Stroke ◽

National Institutes Of Health ◽

Cardioembolic Stroke ◽

Platelet Glycoprotein ◽

Carotid Dissection ◽

Stroke Etiology ◽

Glycoprotein Iiia ◽

The Mean ◽

Undetermined Etiology ◽

Clot Material

Background: While more endovascular treatments for acute stroke are being performed, few studies evaluate clot composition with variable results. We sought to evaluate the feasibility of collecting and analyzing the RBC to platelet ratios in clots, and correlated our findings with stroke etiology. Methods: This is an ongoing prospective study analyzing clots retrieved by mechanical thrombectomy in acute stroke patients at our institution. Retrieved clot material was fixed and cut at 4-m thickness. All clots were stained with hematoxylin-eosin to identify red blood cells (RBC’s), and antibodies for platelet glycoprotein IIIa with CD61 (LifeSpan Biosciences, Seattle, Washington) for platelets. Stained slides were scanned at 200x magnification by using a Scanscope XT digital scanner (Apergio, Vista, California). Image-J software (National Institutes of Health, Bethesda, Maryland) was used for semiquantitative analysis of percentage RBC’s and platelets. Correlation of RBC to Platelet ratios with stroke etiology was performed. Results: A total of 18 clots from 18 patients were analyzed. Stroke etiology was cardioembolic in 8, Large vessel atherosclerosis (LVA) in 5, undetermined in 3 and carotid dissection in 2. The mean RBC to platelet ratio was 0.51:1 in cardioembolic and 0.64:1 in LVA strokes. Patients with undetermined etiology had similar clot composition (0.53:1) to cardioembolic stroke. The highest RBC content was found in carotid dissection thrombus with a ratio of 1.73:1 as compared to other etiologies (p=0.01 cardioembolic, p=0.04 undetermined, p=0.02 LVA). Conclusion: In our study’s first phase, clot processing and analysis was found to be feasible. Although a high mean RBC content was found in carotid dissections and strokes of undetermined etiology had similar clot composition to cardioembolic stroke, ongoing collection and analysis will help support these findings.

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Abstract P779: Monocyte to Lymphocyte Ratio in Clot Analysis is a Marker of Cardioembolic Stroke Etiology

Stroke ◽

10.1161/str.52.suppl_1.p779 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Jesus Juega ◽

Jorge Pagola ◽

Carlos Palacio ◽

matias deck ◽

maria teresa Rodriguez ◽

...

Keyword(s):

High Risk ◽

Operating Characteristic ◽

Characteristic Curve ◽

Stroke Treatment ◽

Lymphocyte Ratio ◽

Multiparametric Flow Cytometry ◽

Stroke Etiology ◽

Stroke Population ◽

Number Of Passes ◽

Control Study

Methods: We analyzed data from 190 patients in a prospective unicentric study. Thrombi obtained in emergent endovascular treatment ( EVT) were analyzed by MFC order to calculate the percentage of granulocytes , monocytes and lymphocytes, over total leukocyte population as well as monocyte-to-lymphocyte ratio ( MLR) Clinical and interventional parameters were recorded for each patient. Stroke subtypes were defined by the Trial of ORG 10172 in Acute Stroke Treatment classification. We tested MFC predictors of high risk cardioembolic strokes (HR CE) in patients with undetermined stroke etiology . MFC predictor was obtained by comparison of clots due to Large Arterial Atherosclerosis compared with clots due to HR CE. Results: Among 190 clots retrieved, 163 cases were properly analized. 91 cases with known stroke etiology after EVT and 72 cases of Undetermined stroke. In a demographic (age, gender) and EVT matched (time, tpa, number of passes) case -control study of 56 patients: HR CE strokes (28 cases) and LAA strokes (28 cases), the proportion of monocytes ( OR 1.06 , 95% CI 1.01- 1.11) and MLR ( OR 1.83 , 95% CI 1.12- 2.98) independently predicted HR CE detection. A cut-off point of 1.77% in a receiver operating characteristic curve predicted cardiomebolic etiology with sensitivity of 71% and specificity of 82%. Among Undetermined Strokes (n=72) the percentage of HR CE detection was higher in patients with high MLR (n=40 ; 74%) compared with low MLR (n=6; 33%) ( p< 0.001). Patients with high MLR were older than low MLR cases, although MLR > 1.77 independently predicted HR CE detection among Undetermined strokes (OR, 4.50 ,95% CI 1.35-15.04) in a multivariate model adjusted for age. Conclusion: Measurement of monocyte to lymphocyte ratio in clots by multiparametric flow cytometry detected patients at high risk of hidden cardioembolic origin among undetermined stroke population.

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