DNA Content in Ischemic Stroke Thrombi Can Help Identify Cardioembolic Strokes Among Strokes of Undetermined Cause

Background and Purpose: Identification of acute ischemic stroke (AIS) cause is crucial for guidance of secondary prevention. Previous studies have yielded inconsistent results regarding possible correlations between AIS cause and thrombus composition, as assessed by semiquantitative histological analysis. Here, we performed a correlation analysis between AIS cause and AIS thrombus cellular composition and content, as assessed using quantitative biochemical assays. Methods: Homogenates of 250 patients with AIS thrombi were prepared by mechanical grinding. Platelet, red blood cell, and leukocyte content of AIS thrombi were estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. AIS cause was defined as cardioembolic, noncardioembolic, or embolic stroke of undetermined source, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment). Results: Cardioembolic thrombi were richer in DNA (35.8 versus 13.8 ng/mg, P <0.001) and poorer in GPVI (0.104 versus 0.117 ng/mg, P =0.045) than noncardioembolic ones. The area under the receiver operating characteristic curve of DNA content to discriminate cardioembolic thrombi from noncardioembolic was 0.72 (95% CI, 0.63–0.81). With a threshold of 44.7 ng DNA/mg thrombus, 47% of thrombi from undetermined cause would be classified as cardioembolic with a specificity of 90%. Conclusions: Thrombus DNA content may provide an accurate biomarker for identification of cardioembolic thrombi in patients with AIS with embolic stroke of undetermined source. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03268668.

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Rivaroxaban versus aspirin for prevention of covert brain infarcts in patients with embolic stroke of undetermined source: NAVIGATE ESUS MRI substudy

International Journal of Stroke ◽

10.1177/17474930211058012 ◽

2021 ◽

pp. 174749302110580

Author(s):

Mukul Sharma ◽

Eric E Smith ◽

Lesly A Pearce ◽

Kanjana S Perera ◽

Scott E Kasner ◽

...

Keyword(s):

Ischemic Stroke ◽

Treatment Effects ◽

Brain Mri ◽

Embolic Stroke ◽

Brain Infarct ◽

Unique Identifier ◽

Stroke Treatment ◽

Brain Infarcts ◽

Neurological Morbidity ◽

To Receive

Background Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. Aims To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. Methods At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. Results Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52–1.7). Conclusions Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide. Registration: https://www.clinicaltrials.gov . Unique identifier: NCT 02313909

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

Disease Markers ◽

10.1155/2019/3090364 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Yanyan Cao ◽

Congxian Cui ◽

Hongqin Zhao ◽

Xudong Pan ◽

Wenjian Li ◽

...

Keyword(s):

Ischemic Stroke ◽

Operating Characteristic ◽

Characteristic Curve ◽

National Institutes Of Health ◽

Atherosclerotic Plaques ◽

Stroke Severity ◽

Large Artery ◽

Unstable Plaque ◽

Cutoff Value ◽

Operating Characteristic Curve

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.

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Retinal Microvascular Changes in Subtypes of Ischemic Stroke

Frontiers in Neurology ◽

10.3389/fneur.2020.619554 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ying Zhao ◽

Bing Yang ◽

An-Ding Xu ◽

Yi-Wen Ruan ◽

Ying Xu ◽

...

Keyword(s):

Ischemic Stroke ◽

Large Scale ◽

Causal Explanation ◽

Characteristic Curve ◽

Underlying Mechanism ◽

Stroke Subtype ◽

Stroke Treatment ◽

Disk Diameter ◽

Retinal Microvasculature ◽

Fundus Photographs

Aims: Retinal microvasculature shares prominent similarities with the brain vasculature. We aimed to assess the association between retinal microvasculature and subtypes of ischemic stroke.Method: We consecutively enrolled ischemic stroke patients within 7 days of onset, who met the criteria of subtype of atherothrombosis (AT), small artery disease (SAD), or cardioembolism (CE) according to a modified version of the Trial of Org 10172 in Acute Stroke Treatment (NEW-TOAST). Digital fundus photographs were taken within 72 h of hospital admission using a digital camera (Topcon TRC-50DX), and fundus photographs were semi-automatically measured by software (Canvus 14 and NeuroLucida) for retinal vasculature parameters.Results: A total of 141 patients were enrolled, including 72 with AT, 54 with SAD, and 15 with CE. AT subtype patients had the widest mean venular diameter within 0.5–1.0 disk diameter (MVD0.5−1.0DD) followed by SAD and CE subtypes (86.37 ± 13.49 vs. 83.55 ± 11.54 vs. 77.90 ± 8.50, respectively, P = 0.047); CE subtype patients had the highest mean arteriovenous ratio within 0.5–1.0 disk diameter (MAVR0.5−1.0DD) followed by the AT and SAD subtype groups (0.97 ± 0.03 vs. 0.89 ± 0.99 vs. 0.89 ± 0.11, respectively, P = 0.010); SAD subtype patients were found with the highest mean venular tortuosity within 0.0–2.0 disk diameter (MVT0.0−2.0DD) followed by the AT and CE subtypes (1.0294 ± 0.0081 vs. 1.0259 ± 0.0084 vs. 1.0243 ± 0.0066, respectively, P = 0.024). After adjusting for clinic characteristics, MVD0.5−1.0DD was significantly different among AT, SAD, and CE subtypes (P = 0.033). By receiver operating characteristic curve analysis, MVD0.5−1.0DD predicted the AT subtype (area 0.690, 95% confidence interval, 0.566–0.815), with a cutoff value of 82.23 μm (sensitivity 61.1%, specificity 73.3%).Conclusion: Retinal MVD0.5−1.0DD (>82.23 μm) might be associated with the AT stroke subtype; however, we need large-scale prospective studies in future to explore the underlying mechanism and causal explanation for this finding.

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Elevated Pulse Pressure and Recurrent Hemorrhagic Stroke Risk in Stroke With Cerebral Microbleeds or Intracerebral Hemorrhage

Journal of the American Heart Association ◽

10.1161/jaha.121.022317 ◽

2021 ◽

Author(s):

Jong‐Ho Park ◽

Juneyoung Lee ◽

Sun U. Kwon ◽

Hyuk Sung Kwon ◽

Min Hwan Lee ◽

...

Keyword(s):

Blood Pressure ◽

Ischemic Stroke ◽

Intracerebral Hemorrhage ◽

Cardiovascular Events ◽

Operating Characteristic ◽

Hemorrhagic Stroke ◽

Stroke Risk ◽

Characteristic Curve ◽

Cerebral Microbleeds ◽

Major Adverse Cardiovascular Events

Background Which type of recurrent stroke is associated with pulse pressure (PP) remains uncertain in ischemic stroke with cerebral microbleeds or intracerebral hemorrhage. Methods and Results The (PICASSO) Prevention of Cardiovascular Events in Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage database involving 1454 subjects was analyzed. Subjects were stratified into quartiles according to the distribution of mean PP (mm Hg) during follow‐up (mean, 1.9 years): <47 (first quartile), 48 to 53 (second quartile), 54 to 59 (third quartile), and ≥60 mm Hg (fourth quartile). The primary end point was hemorrhagic stroke, and the secondary end points were ischemic stroke, stroke of any type, and major adverse cardiovascular events. Adjusted time‐dependent area under the receiver operating characteristic curve analysis was performed to assess the prediction accuracy of mean PP. The mean frequency of visit for blood pressure checkup was 9.4±5.5 times. The stroke incidence rate per 100 person‐years was 3.14, 2.24, 5.52, and 6.22, respectively in increasing quartile of mean PP, and the rate of major adverse cardiovascular events was 3.82, 2.84, 6.37, and 7.14, respectively. In the presence of mean arterial pressure, hemorrhagic stroke risk was higher in the highest quartile (adjusted hazard ratio, 6.03; 95% CI, 1.04–34.99) versus the lowest quartile, which was evident at higher mean systolic blood pressure. Higher mean PP as a continuous variable was also a predictor of hemorrhagic stroke (1.09, 1.03−1.15). The time‐dependent area under the receiver operating characteristic curve for hemorrhagic stroke was 0.79. Conclusions Long‐term elevated PP with higher systolic blood pressure confers a greater risk of subsequent hemorrhagic stroke among stroke patients with cerebral microbleeds or intracerebral hemorrhage. Registration URL: https://www.clinicaltrials.gov ; Unique identifier, NCT01013532.

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Application of the genetic risk model for the analysis of predisposition to nonlacunar ischemic stroke

Personalized Medicine ◽

10.2217/pme-2018-0104 ◽

2019 ◽

Vol 16 (5) ◽

pp. 369-378

Author(s):

Vitaly Korchagin ◽

Konstantin Mironov ◽

Alexander Platonov ◽

Olga Dribnokhodova ◽

Elina Akselrod ◽

...

Keyword(s):

Ischemic Stroke ◽

Genetic Risk ◽

Operating Characteristic ◽

Risk Model ◽

Characteristic Curve ◽

Predictive Ability ◽

Classification Model ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Satisfactory Performance

Aim: The purpose of our study was to analyze the predictive ability of the multiplicative model of genetic risk of nonlacunar ischemic stroke (IS) for independent samples from Russia. Patients & methods: A total of 181 patients and 360 healthy controls were included in this study. The discriminative accuracy of model was evaluated by the area under the receiver operating characteristic curve (AUC). Results: Classification model based on 15 single-nucleotide polymorphisms (SNPs), which are associated with a cardioembolic subtype of IS, had an AUC of 0.62 in patients with corresponding subtypes and an AUC of 0.58 for all patients. Conclusion: Risk calculation approach based on IS-associated SNPs had satisfactory performance in predicting the predisposition to the disease.

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SAA (Serum Amyloid A)

Stroke ◽

10.1161/strokeaha.120.030064 ◽

2020 ◽

Vol 51 (12) ◽

pp. 3523-3530

Author(s):

Juliane Schweizer ◽

Alejandro Bustamante ◽

Vanessa Lapierre-Fétaud ◽

Júlia Faura ◽

Natalie Scherrer ◽

...

Keyword(s):

Ischemic Stroke ◽

Receiver Operating Characteristic Curve ◽

Odds Ratio ◽

Adjusted Odds Ratio ◽

Serum Amyloid A ◽

Operating Characteristic ◽

Independent Predictor ◽

Characteristic Curve ◽

Amyloid A ◽

Operating Characteristic Curve

Background and Purpose: The aim of this study was to evaluate and independently validate SAA (serum amyloid A)—a recently discovered blood biomarker—to predict poststroke infections. Methods: The derivation cohort (A) was composed of 283 acute ischemic stroke patients and the independent validation cohort (B), of 367 patients. The primary outcome measure was any stroke-associated infection, defined by the criteria of the US Centers for Disease Control and Prevention, occurring during hospitalization. To determine the association of SAA levels on admission with the development of infections, logistic regression models were calculated. The discriminatory ability of SAA was assessed, by calculating the area under the receiver operating characteristic curve. Results: After adjusting for all predictors that were significantly associated with any infection in the univariate analysis, SAA remained an independent predictor in study A (adjusted odds ratio, 1.44 [95% CI, 1.16–1.79]; P =0.001) and in study B (adjusted odds ratio, 1.52 [1.05–2.22]; P =0.028). Adding SAA to the best regression model without the biomarker, the discriminatory accuracy improved from 0.76 (0.69–0.83) to 0.79 (0.72–0.86; P <0.001; likelihood ratio test) in study A. These results were externally validated in study B with an improvement in the area under the receiver operating characteristic curve, from 0.75 (0.70–0.81) to 0.76 (0.71–0.82; P <0.038). Conclusions: Among patients with ischemic stroke, blood SAA measured on admission is a novel independent predictor of infection after stroke. SAA improved the discrimination between patients who developed an infection compared with those who did not in both derivation and validation cohorts. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00390962.

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Abstract 2597: Centralized and Study-specific Phenotyping in a Large-scale Stroke Genetics Study: An Analysis from the NINDS Stroke Genetics Network (SiGN)

Stroke ◽

10.1161/str.43.suppl_1.a2597 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Bradford B Worrall ◽

Alejandro Rabinstein ◽

Dale M Gamble ◽

Kevin M Barrett ◽

Shaneela Malik ◽

...

Keyword(s):

Ischemic Stroke ◽

Large Scale ◽

Association Studies ◽

Web Based ◽

Stroke Treatment ◽

Automated Algorithm ◽

Genome Association ◽

Whole Genome Association ◽

Toast Classification ◽

User Friendly

Background: The Stroke Genetics Network (SiGN) funded by the NINDS aims to identify genetic risk factors in ischemic stroke using whole-genome association studies (GWAS). High quality phenotyping is crucial to successful application of GWAS. As a heterogenous disorder, stroke poses specific challenges. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification is a broadly used, but its validity is challenged especially when performed by multiple investigators with differing interpretations of the system. The Causative Classification System for Ischemic Stroke (CCS) system is a new, web-based, and computerized algorithm that integrates clinical, diagnostic, and etiologic stroke characteristics in an evidence-based manner ( ccs.mgh.harvard.edu ) to generate subtypes. Methods: In planning the SiGN proposal, a sample of 20 coded charts were collected from a subset of participating studies to assess feasibility of central adjudication and comparability to study-specific TOAST. Two central adjudicators reviewed all records and generated TOAST and CCS subtypes. These were compared to study-specific TOAST subtype and the CCS phenotype generated for SiGN by local trained adjudicators. CCS data is now available for 7134 included cases using both a 5 and a 7 category system as defined in the table . Results: All 4 phenotypes were available for 115 ischemic stroke cases from 6 studies in SiGN. Basic demographics were 54% women, 63% white, and median age between 65-74. Table 1 provides the agreement between the various subtypes. Table 2 describes the types of disagreement. Conclusions: Central adjudication with only two adjudicators and curated medical records yielded more consistent subtyping independent of phenotyping system. The agreement for TOAST was higher than published rates by independent groups (∼0.50). In contrast, the agreement for CCS was lower than previously published (0.85-0.95). Site adjudicators' familiarity with TOAST and inexperience with CCS may contribute. Although CCS is an automated algorithm and has a number of user friendly features, our findings suggest that formal training and certification process before starting to use CCS may be worthwhile to achieve optimal benefit from the system.

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Abstract TP375: Using Characteristics of Secondary Ischemic Stroke Events to Improve Stroke Education Initiatives

Stroke ◽

10.1161/str.51.suppl_1.tp375 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Amanda Dirickson ◽

Suzanne Stone

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Stroke Prevention ◽

Small Vessel Disease ◽

Secondary Stroke Prevention ◽

Stroke Treatment ◽

Vessel Disease ◽

Acute Stroke Treatment ◽

Stroke Education ◽

Toast Classification

Purpose: While it is common practice for nursing to perform the duty of stroke education,it is not common to use secondary stroke event data to determine what aspect of stroke education should be emphasized for the greatest impact on secondary stroke prevention. The purpose of this descriptive study is to exam the characteristics of secondary stroke events using the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria so future educational initiatives can be customized to the needs of the local high risk population. Methods: The team collected data characteristics on all ischemic stroke admissions with previous admitting diagnosis of acute ischemic stroke. The strokes were further characterized using the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification to determine any emerging patterns of both risk factors and etiological types. Conclusions: A total of n=51 admissions were previous adult stroke survivors, (M=30, F=21). Pre-morbid risk factors were as follows: hypertension=78%, type 2 diabetes=39%, hyperlipidemia =54%, smoking=8%, atrial fibrillation=24%. TOAST classification results: Large Vessel Atherosclerosis=14%, Cardioembolic =17%, Small Vessel Disease=3%, Other Known Cause=2%, Cryptogenic=15%. Summary: The results reveal a striking pattern of the presence of premorbid hypertension. While the TOAST classification did not have a single dominant type, but nearly equal distribution of large vessel atherosclerosis, cardioembolic, and small vessel disease etiologies. Not surprising, the decline in stroke mortality is felt to be due to improved blood pressure control, but in discharge stroke education, hypertension is not necessarily emphasized over other perhaps less impactful risk factors. Yet, the most recent acute ischemic stroke clinical guidelines gave providers a first-time recommendation to start or restart antihypertensive therapy in stable patients with BP > 140/90. Nursing has enough encouragement to take the lead on hypertension prevention education in appropriate stable patients ready for discharge. The next goal will be to develop a multimedia educational effort in patient stroke education on hypertension as a risk factor for secondary stroke prevention in this Comprehensive Stroke Center.

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Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial

Stroke ◽

10.1161/strokeaha.119.028669 ◽

2020 ◽

Vol 51 (6) ◽

pp. 1797-1804 ◽

Cited By ~ 1

Author(s):

George Ntaios ◽

Lesly A. Pearce ◽

Roland Veltkamp ◽

Mukul Sharma ◽

Scott E. Kasner ◽

...

Keyword(s):

Ischemic Stroke ◽

Recurrent Stroke ◽

Factor Xa ◽

Left Ventricular ◽

Embolic Stroke ◽

Stroke Recurrence ◽

Recurrence Rates ◽

Unique Identifier ◽

Treatment Groups ◽

All Cause Mortality

Background and Purpose— Emboli in embolic stroke of undetermined source (ESUS) may originate from various potential embolic sources (PES), some of which may respond better to anticoagulation, whereas others to antiplatelets. We analyzed whether rivaroxaban is associated with reduction of recurrent stroke compared with aspirin in patients with ESUS across different PES and by number of PES. Methods— We assessed the presence/absence of each PES (atrial cardiopathy, atrial fibrillation, arterial atherosclerosis, left ventricular dysfunction, cardiac valvulopathy, patent foramen ovale, cancer) in NAVIGATE-ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) participants. Prevalence of each PES, as well as treatment effect and risk of event for each PES were determined. Results by number of PES were also determined. The outcomes were ischemic stroke, all-cause mortality, cardiovascular mortality, and myocardial infarction. Results— In 7213 patients (38% women, mean age 67years) followed for a median of 11 months, the 3 most prevalent PES were atrial cardiopathy (37%), left ventricular disease (36%), and arterial atherosclerosis (29%). Forty-one percent of all patients had multiple PES, with 15% having ≥3 PES. None or a single PES was present in 23% and 36%, respectively. Recurrent ischemic stroke risk was similar for rivaroxaban- and aspirin-assigned patients for each PES, except for those with cardiac valvular disease which was marginally higher in rivaroxaban-assigned patients (hazard ratio, 1.8 [95% CI, 1.0–3.0]). All-cause mortality risks were similar across treatment groups for each PES while too few myocardial infarctions and cardiovascular deaths occurred for meaningful assessment. Increasing number of PES was not associated with increased stroke recurrence nor all-cause mortality, and outcomes did not vary between rivaroxaban- and aspirin-assigned patients by number of PES. Conclusions— A large proportion of patients with ESUS had multiple PES which could explain the neutral results of NAVIGATE-ESUS. Recurrence rates between rivaroxaban- and aspirin-assigned patients were similar across the spectrum of PES. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

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