Causative Classification System Research Articles

Non-O blood types are associated with a greater risk of large artery atherosclerosis stroke and dysregulation of cholesterol metabolism: an observational study

BackgroundPrevious research on ABO blood types and stroke has been controversial, predominantly suggesting heightened risk of stroke in non-O blood types. Nonetheless, investigations into the correlation and underlying mechanisms between ABO blood groups and stroke subtypes, especially within Chinese cohorts, remain limited.MethodsThe ABO blood types of 9,542 ischaemic stroke (IS) patients were inferred using two ABO gene loci (c.261G > del; c.802G > A). The healthy population was derived from the 1000 Genomes Project. Patients were classified by the causative classification system (CCS). Volcano plot and gene ontology (GO) analysis were employed to explore protein differential expression among blood types. Additionally, HT29 and SW480 cell lines with downregulated ABO expression were generated to evaluate its impact on cholesterol uptake and efflux.ResultsA greater proportion of stroke patients had non-O blood types (70.46%) than did healthy individuals (61.54%). Notable differences in blood type distributions were observed among stroke subtypes, with non-O blood type patients mainly classified as having large artery atherosclerosis (LAA). Clinical baseline characteristics, such as the low-density lipoprotein cholesterol level, activated partial thromboplastin time and thrombin time, varied significantly among blood types. A volcano plot revealed 17 upregulated and 42 downregulated proteins in the O blood type. GO term analysis indicated that downregulated proteins were primarily associated with lipid metabolism pathways. In vitro experiments revealed that reducing ABO gene expression decreased cholesterol uptake and increased cholesterol efflux.ConclusionsThis study revealed that the non-O blood type increased the risk of LAA stroke through cholesterol metabolism.

Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke

Although increasing evidence suggests that trimethylamine N-oxide (TMAO) is associated with atherosclerosis, little is known about whether TMAO and its related metabolites (ie, choline, betaine, and carnitine) are associated with small vessel disease. To evaluate the association between TMAO and its related metabolites with features of cerebral small vessel disease, including white matter hyperintensity volume (WMHV) and acute lacunar infarction. This cross-sectional study included patients enrolled in the Specialized Programs of Translational Research in Acute Stroke biorepository. The registry included 522 patients with acute ischemic stroke who were 18 years or older who presented at the Massachusetts General Hospital or Brigham and Women's Hospital within 9 hours after onset between January 2007 and April 2010. The analyses in this study were conducted between November 2022 and April 2023. Plasma TMAO, choline, betaine, and carnitine were measured by liquid chromatography-tandem mass spectrometry. WMHV was quantified by a semiautomated approach using signal intensity threshold with subsequent manual editing. Ischemic stroke subtype was classified using the Causative Classification System. Among 351 patients included in this study, the mean (SD) age was 69 (15) years; 209 patients (59.5%) were male and had a median (IQR) admission National Institute of Health Stroke Scale of 6 (3-13). The magnetic resonance imaging subgroup consisted of 291 patients with a mean (SD) age of 67 (15) years. Among these, the median (IQR) WMHV was 3.2 (1.31-8.4) cm3. TMAO was associated with WMHV after adjustment for age and sex (β, 0.15; 95% CI, 0.01-0.29; P < .001). TMAO remained significant in a multivariate analysis adjusted for age, sex, hypertension, diabetes, and smoking (β, 0.14; 95% CI, 0-0.29; P = .05). TMAO was associated with lacunar stroke but not other ischemic stroke subtypes in a model adjusted for age, sex, hypertension, diabetes, and smoking (OR, 1.67; 95% CI, 1.05-2.66; P = .03). In this observational study, TMAO was associated with cerebral small vessel disease determined by WMHV and acute lacunar infarction. The association was independent of traditional vascular risk factors.

Demographics, Risk Factors, and Etiology of Posterior Cerebral Artery Stroke Causing Homonymous Hemianopia.

Posterior cerebral artery (PCA) strokes account for up to 10% of all ischemic strokes, often presenting with homonymous hemianopia. The proportion of these strokes attributed to various etiologies varies widely in previously published studies, owing largely to differing patient populations, definitions of stroke pathogenesis, and vascular territories involved. The Causative Classification System (CCS), an automated version of the Stop Stroke Study (SSS) Trial of Org 10,172 in Acute Stroke Treatment (TOAST) system, allows for a more rigorous assignment of stroke etiology. We excerpted clinical and imaging data on 85 patients who had PCA stroke with homonymous hemianopia examined at the University of Michigan. We compared the stroke risk factor profile of our PCA cohort with that of 135 patients with stroke in the distribution of the internal carotid artery (ICA) and middle cerebral artery (MCA) in an unpublished University of Michigan registry. We applied the CCS web-based calculator to our PCA cohort to determine stroke etiology. In our PCA cohort, 80.0% had at least 2 conventional stroke risk factors and 30.6% had 4 risk factors, most commonly systemic hypertension. The risk factor profile of our PCA cohort resembled that of our ICA/MCA cohort except that the mean age of our PCA cohort was more than a decade younger and had a significantly lower frequency of atrial fibrillation (AF) than our ICA/MCA cohort. In nearly half of the patients with AF in our PCA cohort, AF was diagnosed after the stroke. Among stroke etiologies in our PCA cohort, 40.0% were of undetermined cause, 30.6% were from cardioaortic embolism, 17.6% were from other determined causes, and only 11.8% were from supra-aortic large artery atherosclerosis. Strokes after endovascular or surgical interventions were prominent among other determined causes. Most patients in our PCA cohort had multiple conventional stroke risk factors, a finding not previously documented. Mean age at stroke onset and AF frequency were lower than in our ICA/MCA cohort, in agreement with previous studies. As some other studies have found, nearly 1/3 of strokes were attributed to cardioaortic embolism. Within that group, AF was often a poststroke diagnosis, a finding not previously highlighted. Compared with earlier studies, a relatively high portion of strokes were of undetermined etiology and of other determined etiologies, including stroke after endovascular or surgical interventions. Supra-aortic large artery atherosclerosis was a relatively uncommon explanation for stroke.

Heterogeneity in diagnosis and prognosis of ischaemic stroke subtypes: 9-year follow-up of 22000 cases in Chinese adults.

Reliable classification of ischaemic stroke (IS) aetiological subtypes is required in research and clinical practice, but the predictive properties of these subtypes in population studies with incomplete investigations are poorly understood. To compare the prognosis of aetiologically-classified IS subtypes and use machine learning (ML) to classify incompletely investigated IS cases. In a 9-year follow-up of a prospective study of 512,726 Chinese adults, 22,216 incident IS cases, confirmed by clinical adjudication of medical records, were assigned subtypes using a modified Causative Classification System for Ischemic Stroke (CCS) (LAA: large artery atherosclerosis; SAO: small artery occlusion, CE: cardioaortic embolism; or undetermined aetiology) and classified by CCS as "evident", "probable", or "possible" IS cases. For incompletely investigated IS cases where CCS yielded an undetermined aetiology, a ML model was developed to predict IS subtypes from baseline risk factors and screening for cardioaortic sources of embolism. The 5-year risks of subsequent stroke and all-cause mortality (measured using cumulative incidence functions and 1 minus Kaplan-Meier estimates, respectively) for the ML-predicted IS subtypes were compared with aetiologically-classified IS subtypes. Among 7,443 IS subtypes with evident or probable aetiology, 66% had SAO, 32% had LAA and 2% had CE, but proportions of SAO-to-LAA cases varied by regions in China. CE had the highest rates of subsequent stroke and mortality (43.5%, 40.7%), followed by LAA (43.2%, 17.4%) and SAO (38.1%, 11.1%), respectively. ML provided classifications for cases with undetermined aetiology and incomplete clinical data (24% of all IS cases; n=5,276), with area under the curves (AUC) of 0.99 (0.99-1.00) for CE, 0.67 (0.64-0.70) for LAA, and 0.70 (0.67-0.73) for SAO for unseen cases. ML-predicted IS subtypes yielded comparable subsequent stroke and all-cause mortality rates to the aetiologically-classified IS subtypes. This study highlighted substantial heterogeneity in prognosis of IS subtypes and utility of ML approaches for classification of IS cases with incomplete clinical investigations.

Transseptal puncture for left atrial ablation: risk factors for cardiac tamponade and a proposed causative classification system

Abstract Background Cardiac tamponade is a high morbidity complication of transseptal puncture (TSP). Purpose We examined the associations of TSP-related cardiac tamponade (TRCT) for all patients undergoing left atrial ablation at our centre from 2016–2020. Methods Patient and procedural variables were extracted retrospectively. Cases of cardiac tamponade were scrutinised to adjudicate TSP culpability. Adjusted multivariate analysis examined predictors of TRCT. Results 3,239 consecutive TSPs were performed; cardiac tamponade occurred in 51 patients (incidence: 1.6%) and was adjudicated as TSP-related in 35 (incidence: 1.1%; 68.6% of all tamponades). Patients of above-median age (OR 2.4 (1.19–4.2), p=0.006) and those undergoing re-do procedures (OR 1.95 (1.29–3.43, p=0.042) were at higher risk of TRCT. Of the operator-dependent variables, choice of transseptal needle (Endrys vs Brockenbrough, p&amp;gt;0.1) or puncture sheath (Swartz vs Mullins vs Agilis vs Vizigo vs Cryosheath, all p&amp;gt;0.1) did not predict TRCT. Adjusting for operator, equipment and demographics, failure to cross the septum first pass increased TRCT risk (OR 4.42 (2.45–8.2), p=0.001), whilst top quartile operator experience (OR 0.4 (0.17–0.85, p=0.002), transoesophageal echocardiogram (TOE prevalence: 26%, OR 0.51 (0.11–0.94), p=0.023), and use of the SafeSept guidewire (OR 0.22 (0.08–0.62), p=0.001) reduced TRCT risk. An increase in SafeSept wire use over time (2016: 15.6%, 2020: 60.2%) correlated with an annual reduction in TRCT (R2=0.72, p&amp;lt;0.001) and was associated with a relative risk reduction of 70%. Conclusions During left atrial ablation, the independent predictors of TRCT were patient age, re-do procedure, operator experience, unsuccessful first pass, TOE-guidance, and use of the SafeSept wire. A novel classification system for the causes of cardiac tamponade is proposed (table 1); this may be of interest to clinical trialists or auditors evaluating patient safety. Funding Acknowledgement Type of funding sources: None.

Transseptal puncture for left atrial ablation: Risk factors for cardiac tamponade and a proposed causative classification system.

AimsCardiac tamponade is a high morbidity complication of transseptal puncture (TSP). We examined the associations of TSP‐related cardiac tamponade (TRCT) for all patients undergoing left atrial ablation at our center from 2016 to 2020.Methods and ResultsPatient and procedural variables were extracted retrospectively. Cases of cardiac tamponade were scrutinized to adjudicate TSP culpability. Adjusted multivariate analysis examined predictors of TRCT. A total of 3239 consecutive TSPs were performed; cardiac tamponade occurred in 51 patients (incidence: 1.6%) and was adjudicated as TSP‐related in 35 (incidence: 1.1%; 68.6% of all tamponades). Patients of above‐median age [odds ratio (OR): 2.4 (1.19–4.2), p = .006] and those undergoing re‐do procedures [OR: 1.95 (1.29–3.43, p = .042] were at higher risk of TRCT. Of the operator‐dependent variables, choice of transseptal needle (Endrys vs. Brockenbrough, p > .1) or puncture sheath (Swartz vs. Mullins vs. Agilis vs. Vizigo vs. Cryosheath, all p > .1) did not predict TRCT. Adjusting for operator, equipment and demographics, failure to cross the septum first pass increased TRCT risk [OR: 4.42 (2.45–8.2), p = .001], whilst top quartile operator experience [OR: 0.4 (0.17–0.85), p = .002], transoesophageal echocardiogram [TOE prevalence: 26%, OR: 0.51 (0.11–0.94), p = .023], and use of the SafeSept transseptal guidewire [OR: 0.22 (0.08–0.62), p = .001] reduced TRCT risk. An increase in transseptal guidewire use over time (2016: 15.6%, 2020: 60.2%) correlated with an annual reduction in TRCT (R 2 = 0.72, p < .001) and was associated with a relative risk reduction of 70%.ConclusionsDuring left atrial ablation, the risk of TRCT was reduced by operator experience, TOE‐guidance, and use of a transseptal guidewire, and was increased by patient age, re‐do procedures, and failure to cross the septum first pass.

Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke

Ischemic stroke (IS), caused by obstruction of cerebral blood flow, is one of the leading causes of death. While neurologists agree on delineation of IS into three subtypes (cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS)), several subtyping systems exist. The most commonly used systems are TOAST (Trial of Org 10172 in Acute Stroke Treatment) and CCS (Causative Classification System for Stroke), but agreement is only moderate. We have compared two approaches to combining the existing subtyping systems for a phenotype suited for a genome-wide association study (GWAS). We used the NINDS Stroke Genetics Network dataset (SiGN, 11,477 cases with CCS and TOAST subtypes and 28,026 controls). We defined two new phenotypes: the intersect, for which an individual must be assigned the same subtype by CCS and TOAST; and the union, for which an individual must be assigned a subtype by either CCS or TOAST. The union yields the largest sample size while the intersect yields a phenotype with less potential misclassification. We performed GWAS for all subtypes, using the original subtyping systems, the intersect, and the union as phenotypes. In each subtype, heritability was higher for the intersect compared with the other phenotypes. We observed stronger effects at known IS variants with the intersect compared with the other phenotypes. With the intersect, we identify rs10029218:G>A as an associated variant with SVS. We conclude that this approach increases the likelihood to detect genetic associations in ischemic stroke.

Left atrial cross-sectional area is a novel measure of atrial shape associated with cardioembolic strokes

ObjectiveCardioembolic (CE) stroke carries significant morbidity and mortality. Left atrial (LA) size has been associated with CE risk. We hypothesised that differential LA remodelling impacts on pathophysiological mechanism of major...

Long-Term Stroke Recurrence after Transient Ischemic Attack: Implications of Etiology.

Background and PurposeTo analyze long-term stroke recurrence (SR) characteristics after transient ischemic attack (TIA) according to initial etiological classification. MethodsA prospective cohort of 706 TIA patients was followed up in a single tertiary stroke center. Endpoint was SR. Etiologic subgroup was determined according to the evidence-based causative classification system. Location of TIA and SR was recorded as right, left, or posterior territory. Disability stroke recurrence (DSR) was defined as modified Rankin Scale (mRS) score >1 or a onepoint increase in those with previous mRS >1 at 3-month follow-up. ResultsDuring a follow-up of 3,493 patient-years (mean follow-up of 58.9±35.9 months), total SR was 125 (17.7%), corresponding to 3.6 recurrences per 100 patient-years. The etiology subgroups with a higher risk of SR were the unclassified (more than one cause) and large-artery atherosclerosis (LAA) categories. Of the SR cases, 88 (70.4%) had the same etiology as the index TIA; again, LAA etiology was the most frequent (83.9%). Notably, cardioaortic embolism was the most frequent cause (62.5%) of SR in the subgroup of 24 patients with undetermined TIA. Overall, SR occurred in the same territory in 74 of 125 patients (59.2%), with significant differences between etiological TIA subgroups (P=0.015). Eighty-two of 125 (65.6%) with SR had DSR, without differences between etiologies (P=0.453). ConclusionsSR occurred mainly with the same etiology and location as initial TIA, although undetermined TIA was associated with a high proportion of cardioaortic embolism SR. More than half of the recurrences caused some disability, regardless of etiology.

Abstract 191: Socioeconomic Disparity Independently Predicts Initial Ischemic Stroke Severity

Introduction: Lower socioeconomic status (SES) associates independently with poorer outcomes after stroke. We have previously demonstrated that the relationship between low SES and worse stroke outcomes is mediated by larger infarct size on presentation. Here, we tested the hypothesis that the relationship between SES and initial stroke severity varies across stroke subtypes. Methods: Consecutive patients (N=1168) presenting to Massachusetts General Hospital with acute ischemic stroke (mean age= 68, 55.1% male) underwent brain MRI within 24 hrs of admission. Infarct volume on DWI and admission NIH stroke scale (NIHSS) score were recorded. Stroke etiology was classified using the causative classification system. SES was assessed using local median household income as a proxy (by home zip code, using U.S. Census Bureau Fact Finder). Results: Both infarct volume and admission NIHSS score increased with decreasing SES tertiles: [NIHSS median (IQR): 5.0 (2.0, 12.0) vs. 4.0 (2.0, 11.0), vs. 3.0 (1.0, 9.0), p = 0.002], [Infarct volume median (IQR): 7.2 (1.5, 28.2) vs. 5.9 (1.5, 30.2) vs. 4.6 (1.0, 19.9), p = 0.02]. This relationship was mainly driven by LAA and CE categories (Figure). Lower SES predicted infarct volume and NIHSS score in combined group of LAA and CE after adjusting for traditional stroke risk factors and history of previous stroke (standardized β [95% CI]) NIHSS: -0.15 [-1.6, - 0.5] p &lt; 0.001, infarct size: - 0.10 [-10.6, -1.8], p = 0.006). Conclusions: While disparities in post stroke care may play an important role in the relationship between lower SES and worse outcomes, we show that this association is also significantly driven by a tendency towards developing larger, more severe strokes on presentation, mainly caused by LAA and CE.

Correction to: Polygenic Risk for Depression Increases Risk of Ischemic Stroke From the Stroke Genetics Network Study.

Correction to: Polygenic Risk for Depression Increases Risk of Ischemic Stroke From the Stroke Genetics Network Study.

Which Ischemic Stroke Subtype Is Associated with Hyperhomocysteinemia?

Stroke is still a major global health problem in both developed and developing countries. Defining stroke subtype and underlying etiologies is a major step to choose the best method for prophylaxis. Homocysteine is an endothelial toxin and elevated levels have been associated with stroke risk. In this study, we hypothesized that serum total homocysteine level may be related with specific atherothrombotic ischemic stroke subtypes and aimed to find if high serum homocysteine levels are correlated with any specific ischemic stroke subtype. Patients with ischemic stroke and aged between 18 and 65 are included. Ischemic stroke subtype is defined according to Causative Classification System. Hospital records are examined retrospectively to define patient demographics, ischemic stroke subtype, vascular risk factors, serum homocysteine, B12, and folic acid levels. A total of 262 patients were included. Serum homocysteine level was elevated (≥16 µmol/L) in 99 patients (37.79%). The rate of patients with hyperhomocysteinemia was significantly more common in strokes due to intracranial stenosis (72.41%) (odds ratio 8.138; 95% confidence interval 2.366-27.989; P < .01) than extracranial large artery stenosis (52.00%), craniocervical arterial dissections (35.71%), cardioembolic strokes (27.87%), and lacunar infarctions (25.00%) after adjustment for other risk factors. High homocysteine levels were significantly more common in men and smokers (P < .05). Elevated levels of serum homocysteine are correlated with ischemic strokes due to intracranial large artery stenosis in young and middle-aged patients. This association may have an implication in stroke prophylaxis for intracranial atherosclerosis by using homocysteine-lowering therapies.

Abstract WMP51: Towards a Simplified Method for Ischemic Stroke Subtyping Suitable for Electronic Medical Record Systems

Background: Current ischemic stroke (IS) subtyping systems are very labor-intensive and costly to implement in large samples. There is a need to develop phenotyping approaches for genetic and other studies that can be implemented using generally available items captured in electronic medical records. Objective: In this report, we seek to validate a simplified approach using results from a genetic association study. Specifically, the strength of association for known genetic signals in the NINDS Stroke Genetics Network study (SiGN) is compared between the established IS subtyping systems (TOAST and Causative Classification System (CCS) subtypes) and phenotyping based on a single item within the CCS. Methods: Non-mutually exclusive “Simple” IS subtypes were defined from single CCS items as follows: 1) Small vessel stroke- lacunar infarct on imaging (with no other imaging or other requirements); 2) large artery stroke - vascular imaging showing &gt; 50% stenosis or &lt;50% stenosis with plaque rupture or thrombosis judged to be due to atherosclerosis in clinically relevant artery; and 3) cardioembolic stroke - persistent or paroxysmal atrial fibrillation. We compared the GWAS signals using these definitions to the published SiGN GWAS results for TOAST and CCS, among those of European ancestry only. Results: The Table shows that, for loci significant in SiGN GWAS study, the “Simple” IS subtypes had similar strengths of association and p-values compared to results from TOAST and the causative and phenotypic CCS subtypes. Conclusions: “Simple” IS subtypes perform as well in GWAS analyses as more complex phenotyping systems and could potentially be derived through automated or semi-automated methods applied to electronic medical record systems. Since the ‘Simple” phenotypes were based on high quality CCS data, the current findings reflect optimal performance. Additional validation studies will be required for implementation in other settings.

Joinville stroke biobank: study protocol and first year's results.

Blood samples were collected from patients included in the Joinville Stroke Registry and four Brazilian cities. Demographic socio-economic data, cardiovascular risk factors, Causative Classification System for Ischemic Stroke, Trial of Org 10172 in Acute Stroke Treatment and National Institutes of Health scores, functional stroke status (modified Rankin) and brain images were recorded. Additionally, controls from both geographic regions were recruited. High-molecular-weight genomic DNA was obtained from all participants. A total of 2,688 patients and 3,282 controls were included. Among the patients, 76% had ischemic stroke, 12% transient ischemic attacks, 9% hemorrhagic stroke and 3% subarachnoid hemorrhage. Patients with undetermined ischemic stroke were most common according the Trial of Org 10172 in Acute Stroke Treatment (40%) and Causative Classification System for Ischemic Stroke (47%) criteria. A quarter of the patients were under 55 years of age at the first-ever episode. We established the Joinville Stroke Biobank and discuss its potential for contributing to the understanding of the risk factors leading to stroke.

Etiological Classification of Stroke in Patients with Chagas Disease Using TOAST, Causative Classification System TOAST, and ASCOD Phenotyping

Cardioembolism is considered a major pathophysiological mechanism in patients with ischemic stroke (IS) and Chagas disease (CD). However, a previous study reported that other stroke subtypes are present in more than 40% of CD patients according to the TOAST classification. Therefore, the aim of our study was to evaluate the etiologic classification of stroke in patients with CD using the Causative Classification System (CCS), the ASCOD, and the TOAST classifications in a prospective cohort of patients. Patients evaluated in our outpatient clinic from 2012 to 2015 with IS and CD were included and underwent full investigation for stroke etiology. TOAST, CCS TOAST, and the ASCOD classifications were compared. We Included 32 patients (18 men; mean age 62.7 +/-10.1 years). A total of 93.8% had at least 1 vascular risk factor; the most frequent was hypertension (87.5%). According to TOAST, we defined 87.5% as having cardioembolic stroke, being 9.4% as large-artery atherosclerotic (LAA) and 3.1% as undetermined cause. Using the CCS TOAST, 62.5% were classified as cardioaortic embolism evident and 15.6% as possible, 6.3% as small artery occlusion evident and 3.1% as probable, and 12.5% as LAA evident. When ASCOD phenotyping was applied, atherosclerosis was present in 50.1% of patients (A1 = 6.3%, A3 = 43.8%), cardiac pathology in 84.4% (C1 = 62.5%, C2 = 15.6%, C3 = 6.3%), and small-vessel disease in 66% (S1 = 9.4%, S2 = 3.1%, S3 = 3.1%). In conclusion, the use of the CCS and the ASCOD phenotyping in patients with CD confirmed a high frequency of cardioembolic IS but also showed that other etiologies are prevalent, such as large-artery atherosclerosis and small-vessel occlusion.

Cardiac magnetic resonance imaging has limited additional yield in cryptogenic stroke evaluation after transesophageal echocardiography.

Background The use of cardiac magnetic resonance imaging is increasing, but its role in the diagnostic work-up following ischemic stroke has received limited study. We aimed to explore the added yield of cardiac magnetic resonance imaging to identify cardio-aortic sources not detected by transesophageal echocardiography among patients with cryptogenic stroke. Methods A retrospective single-center cohort study was performed from 01 January 2009 to 01 March 2013. Consecutive patients who had both a stroke protocol cardiac magnetic resonance imaging and a transesophageal echocardiography preformed during a single hospitalization were included. All cardiac magnetic resonance imaging studies underwent independent, blinded review by two investigators. We applied the causative classification system for ischemic stroke to all patients, first blinded to cardiac magnetic resonance imaging results; we then reapplied the causative classification system using cardiac magnetic resonance imaging. Standard statistical tests to evaluate stroke subtype reclassification rates were used. Results Ninety-three patients were included in the final analysis; 68.8% were classified as cryptogenic stroke after initial diagnostic evaluation. Among patients with cryptogenic stroke, five (7.8%) were reclassified due to cardiac magnetic resonance imaging findings: one was reclassified as "cardio-aortic embolism evident" due to the presence of a patent foramen ovale and focal cardiac infarct and four were reclassified as "cardio-aortic embolism possible" due to mitral valve thickening (n = 1) or hypertensive cardiomyopathy (n = 3). Overall, findings on cardiac magnetic resonance imaging reduced the percentage of patients with cryptogenic stroke by slightly more than 1%. Conclusion Our stroke subtype reclassification rate after the addition of cardiac magnetic resonance imaging results to a diagnostic work-up which includes transesophageal echocardiography was very low. Prospective studies evaluating the role of cardiac magnetic resonance imaging and transesophageal echocardiography among patients with cryptogenic stroke should be considered.

Abstract WP234: Metabolite Profiling Identifies a Specific Profile for Cardioembolic Stroke

Introduction: Accurate determination of stroke etiology is important in order to implement appropriate secondary stroke prevention. Approximately 25% are embolic strokes of undetermined source, a subset of which are eventually attributed to cardioembolism after prolonged outpatient electrocardiogram monitoring. We applied metabolite profiling to determine whether a metabolomic profile could identify a cardioembolic signature that could inform stroke of undetermined source. Hypothesis: We hypothesized that a specific metabolomic profile reflected by circulating metabolites could be derived from patients with stroke due to cardioembolism. Methods: Using liquid chromatography-tandem mass spectrometry, we analyzed 153 metabolites measured in plasma samples collected within 9 hours of stroke onset. Three hundred twenty six patients from an acute stroke cohort collected at two institutions were analyzed. Stroke subtypes were assigned using the Causative Classification System. Association with cardioembolic subtype was assessed and metabolites exceeding the Bonferroni corrected p value threshold were identified. Logistic regression was used to identify independent metabolite predictors of cardioembolic stroke. Results and Conclusion: The following metabolites were significant in univariate analysis: 2-hydroxyglutaric acid, glutathione, glyceric acid, hippuric acid, threonine, ornithine, histidine, cotinine, pseudouridine, C18:2-carnitine, tricarboxylic acid metabolites, and tryptophan pathway metabolites (all p&lt;6.5x10-3). Regression analysis identified the following multivariate predictors of cardioembolic stroke: hippuric acid (p=0.045), ornithine (p=6x10-5), histidine (p=4x10-6), and a composite sum of tricarboxylic acid metabolites (p=0.004). Metabolite profiling may augment traditional approaches to diagnosing cardioembolic stroke and may have implications for the diagnosis of embolic stroke of undetermined source.

Abstract TMP116: White Matter Hyperintensity Lesion Patterns in Patients With Cardioembolic Strokes

Background: Among patients with a cardioembolic stroke, atrial fibrillation (AF) is a common comorbidity that is associated with a worse outcome. Mounting data indicates that AF may relate to stroke pathogenesis through mechanisms other than cerebral thromboembolic complications. We sought to identify different WMH patterns between patients with AF vs. non-AF related embolic ischemic strokes. Methods: We retrospectively analyzed consecutive patients with acute anterior circulation embolic ischemic stroke included in an academic medical center’s stroke registry. The stroke etiology was determined using the Causative Classification System of ischemic stroke. WMH lesion burden was assessed according to the Fazekas scale. An independent blinded examiner classified the different WMH-patterns, which included 5 categories: periventricular, subcortical spots, posterior subcortical patches, anterior subcortical patches, and severe confluent subcortical patches. Their association with AF was investigated using multivariable logistic regression (with backward elimination). Results: Overall, 174 patients (94 with and 80 without AF) were included. In unadjusted analyses, patients with AF had a significantly higher rate of anterior subcortical patches (p=0.018) and a lower rate of a periventricular pattern (p=0.022). After adjusting for WMH lesion burden, presence of multiple infarcts, infarct volume, the CHA2DS2-VASc score as well as pertinent two-way and three-way interactions the presence of anterior subcortical patches (OR 2.41, 95%-CI 1.02-5.72, p=0.045) and a higher CHA2DS2-VASc score (per point, OR 1.28, 95%-CI 1.08-1.52, p=0.005) were independently associated with AF. Conclusions: We found that AF is associated with specific WMH lesion patterns on MRI. The clinical significance of this observation remains to be clarified; yet it suggests that the well-established link between stroke and AF extends beyond thromboembolism and may reflect an underlying cardiovasculopathy that can be characterized by WMH. If confirmed in future studies further investigation into the underlying pathophysiological mechanisms may provide novel avenues to AF detection and treatment.

Atrial Fibrillation Is Associated With a Worse 90-Day Outcome Than Other Cardioembolic Stroke Subtypes.

Patients with a cardioembolic stroke (CES) have worse outcomes than stroke patients with other causes of stroke. Among patients with CES, atrial fibrillation (AF) is a common comorbidity. Mounting data indicate that AF may be related to stroke pathogenesis beyond acute cerebral thromboembolism. We sought to determine whether AF represents an independent risk factor for stroke severity and outcome among patients with CES. We retrospectively analyzed patients with acute hemispheric CES included in an academic medical center's stroke registry. CES was determined using the Causative Classification System of ischemic stroke. Multivariable logistic regression was used to determine whether AF was associated with 90-day outcome functional status. Our cohort included 140 patients. Of these, 52 had prevalent AF and 28 had incident AF diagnosed during their index hospitalization or within 90 days of hospital discharge. After adjustment for potential confounders or mediators, any AF (odds ratio, 2.51; 95% confidence interval, 1.03-6.33; P=0.049), infarct volume (odds ratio, 1.03; 95% confidence interval, 1.01-1.06; P=0.005), preadmission modified Rankin Scale score (odds ratio, 2.58; 95% confidence interval, 1.66-4.01; P<0.001), and admission National Institutes of Health Stroke Scale score (odds ratio, 1.17; 95% confidence interval, 1.08-1.28; P<0.001) remained associated with an unfavorable 90-day outcome (modified Rankin Scale score, 2-6). AF is associated with an unfavorable 90-day outcome among patients with a CES independent of established risk factors and initial stroke severity. This suggests that AF-specific mechanisms affect CES severity and functional status after CES. If confirmed in future studies, further investigation into the underlying pathophysiological mechanisms may provide novel avenues to AF detection and treatment.

Abstract 17308: Leukoaraiosis is Associated With Atrial Fibrillation and Greater Disability at 90-days in Patients Hospitalized With a Cardioembolic Stroke

Introduction: Atrial fibrillation (AF) has been associated with a poor post-stroke prognosis. AF has been linked to increased leukoaraiosis (LA) burden, which is associated with greater functional impairment after stroke. Hypothesis: We hypothesized that AF is associated with the severity of LA burden and thus impacts 90-day outcomes in patients hospitalized with acute cardioembolic ischemic stroke. Methods: We retrospectively analyzed 317 consecutive patients with acute cardioembolic ischemic stroke enrolled in the University of Massachusetts Medical Center’s Stroke Registry between 2010 and 2014. Stroke mechanism was determined according to the Causative Classification System. LA burden was graded on MRI using the Fazekas scale. Infarct volume was quantified on diffusion weighted images. Neurological deficit severity was assessed at admission according to the National Institutes of Health Stroke Scale (NIHSS). We evaluated the degree of disability using the modified Rankin score (mRS) at 90 days. Participants were categorized as having excellent (mRS 0-1), or poor (mRS 2-6) status. Results: A total of 132 patients were classified as having a definite (n=81) or probable (n=51) cardioembolic stroke. Of these, 54 (41%) had AF (previously known or newly documented). Compared to patients without AF, patients with AF were older (p=0.001), more likely to be receiving antihypertensives(p=0.008) and anticoagulants (p&lt;0.05 each), were associated with a poor outcome at 90 days. Conclusions: We observed that AF was related to severity of LA and that LA burden was an independent predictor of significant disability 90-days post-discharge. Further study is needed to investigate the links between AF, LA, and outcomes after cardioembolic stroke.