Embolic Stroke Of Undetermined Source Patients Research Articles

Machine Learning Modeling to Predict Atrial Fibrillation Detection in Embolic Stroke of Undetermined Source Patients.

In patients with embolic stroke of undetermined source (ESUS), occult atrial fibrillation (AF) has been implicated as a key source of cardioembolism. However, only a minority acquire implantable cardiac loop recorders (ILRs) to detect occult paroxysmal AF, partly due to financial cost and procedural inconvenience. Without the initiation of appropriate anticoagulation, these patients are at risk of increased ischemic stroke recurrence. Hence, cost-effective and accurate methods of predicting AF in ESUS patients are highly sought after. We aimed to incorporate clinical and echocardiography data into machine learning (ML) algorithms for AF prediction on ILRs in ESUS. This was a single-center cohort study that included 157 consecutive patients diagnosed with ESUS from October 2014 to October 2017 who had ILR evaluation. We developed four ML models, with hyperparameters tuned, to predict AF detection on an ILR. The median age of the cohort was 67 (IQR 59-74) years old and the median monitoring duration was 1051 (IQR 478-1287) days. Of the 157 patients, 32 (20.4%) had occult AF detected on the ILR. Support vector machine predicted for AF with a 95% confidence interval area under the receiver operating characteristic curve (AUC) of 0.736-0.737, multilayer perceptron with an AUC of 0.697-0.708, XGBoost with an AUC of 0.697-0.697, and random forest with an AUC of 0.663-0.674. ML feature importance found that age, HDL-C, and admitting heart rate were important non-echocardiography variables, while peak mitral A-wave velocity and left atrial volume were important echocardiography parameters aiding this prediction. Machine learning modeling incorporating clinical and echocardiographic variables predicted AF in ESUS patients with moderate accuracy.

Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC.

One in six ischaemic stroke patients has an embolic stroke of undetermined source (ESUS), defined as a stroke with unclear aetiology despite recommended diagnostic evaluation. The overall cardiovascular risk of ESUS is high and it is important to optimize strategies to prevent recurrent stroke and other cardiovascular events. The aim of clinicians when confronted with a patient not only with ESUS but also with any other medical condition of unclear aetiology is to identify the actual cause amongst a list of potential differential diagnoses, in order to optimize secondary prevention. However, specifically in ESUS, this may be challenging as multiple potential thromboembolic sources frequently coexist. Also, it can be delusively reassuring because despite the implementation of specific treatments for the individual pathology presumed to be the actual thromboembolic source, patients can still be vulnerable to stroke and other cardiovascular events caused by other pathologies already identified during the index diagnostic evaluation but whose thromboembolic potential was underestimated. Therefore, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is important to assess the overall thromboembolic risk of the patient through synthesis of the individual risks linked to all pathologies present, regardless if presumed causally associated or not. In this paper, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in ESUS patients through the composition of individual risks associated with all prevalent pathologies.

Predictors of atrial fibrillation after embolic stroke of undetermined source in patients with implantable loop recorders.

In patients with embolic stroke of undetermined source (ESUS), underlying subclinical atrial fibrillation (AF) is often suspected. Previous studies identifying predictors of AF have been limited in their ability to diagnose episodes of AF. Implantable loop recorders enable prolonged, continuous, and therefore more reliable detection of AF. The aim of this study was to identify clinical and ECG parameters as predictors of AF in ESUS patients with implantable loop recorders. 101 ESUS patients who received an implantable loop recorder between 2012 and 2020 were included in this study. Patients were followed up regularly on a three-monthly outpatient interval. During a mean follow-up of 647 ± 385days, AF was detected in 26 patients (26%). Independent risk factors of AF were age ≥ 60years (HR 2.753, CI 1.129-6.713, p = 0.026), P-wave amplitude in lead II ≤ 0.075mV (HR 3.751, CI 1.606-8.761, p = 0.002), and P-wave duration ≥ 125ms (HR 4.299, CI 1.844-10.021, p < 0.001). In patients without risk factors, the risk of developing AF was 16%. In the presence of one risk factor, the probability increased only slightly to 18%. With two or three risk factors, the risk of AF increased to 70%. AF was detected in about one in four patients after ESUS in this study. A comprehensive evaluation involving multiple parameters and the existence of multiple risk factors yields the highest predictive accuracy for detecting AF in patients with ESUS.

Complex left appendage morphology is associated with Embolic Stroke of Undetermined Source.

Variations in the left atrial appendage (LAA) morphology are associated with different embolic risk in patients with atrial fibrillation (AF). Data are scarce regarding the association between LAA morphology and Embolic stroke of undetermined source (ESUS). Using cardiac computed tomography (CCT) scans, LAA morphology was categorized as either chicken wing (CW), cactus, windsock, or cauliflower. Furthermore, we examined the presence of large secondary lobes arising from the main lobe, considering their existence as indicative of a complex LAA morphology. LAA morphologies were compared between ESUS (n = 134) and AF patients (n = 120); and between ESUS patients with (n = 24) and without (n = 110) subsequent AF diagnosis during long-term follow-up. ESUS patients had a significantly higher prevalence of cauliflower morphology compared to AF group (52% vs 34%, respectively, p = 0.01); however, no significant difference was found between the groups when categorizing LAA morphology to either CW or non-CW. ESUS patients had significantly higher prevalence of large secondary lobes compared with AF patients (50% vs 29%, respectively, p = 0.001). When comparing ESUS patients with and without AF diagnosis during follow-up (20-48 months of follow-up, median 31 months), there were no significant differences in the prevalence of the "classical" morphologies, but large secondary lobes were significantly more prevalent among those without subsequent AF diagnosis. ESUS patients have a high prevalence of complex LAA morphology, which might be associated with an increased risk for thrombus formation even in the absence of AF.

Subclinical atrial fibrillation in embolic stroke of undetermined source: Management and stroke recurrence

Subclinical atrial fibrillation (SAF) represents the most prevalent underlying etiology detected after an embolic stroke of undetermined source (ESUS). Investigating SAF is strongly recommended during the diagnostic work-up. The efficacy of oral anticoagulant (OAC) therapy in reducing the risk of stroke recurrence post-SAF detection remains a conundrum. Thus, our study aimed to analyze the management of secondary antithrombotic prophylaxis and the rate of 12-month stroke recurrence in real-life ESUS patients. We retrospectively analyzed clinical, radiographic, and echocardiographic findings of patients with ESUS who underwent non-implantable 2-week electrocardiogram (ECG) monitoring after discharge. Episodes of SAF of any duration were considered diagnostic. Antithrombotic treatment at hospital discharge and after ECG monitoring, as well as 12-month recurrence, were registered. We compared the rate of stroke recurrence between patients with and without detection of SAF. One hundred and fifty-nine patients (75 females) with a median age of 73.5 (interquartile range [IQR] = 66.75 &amp;ndash; 79) years represented the study population. At hospital discharge, 96.9% of patients received antiplatelet therapy as secondary antithrombotic prophylaxis. SAF was detected in 82 patients (51.5%), and OAC was prescribed in 98.6% of them. The median time from stroke onset to OAC prescription was 143 (IQR = 94 &amp;ndash; 178) days. Overall, 12-month stroke recurrence occurred in eight patients (5%). The stroke recurrence rate was lower in patients prescribed OAC compared with those not prescribed it, although the difference was not significant (3.7% vs. 6.25%; P = 0.7202). In our study, OACs prescribed post-SAF detection in patients with ESUS reduced, but not significantly, the risk of stroke recurrence. Future research and prospective multicenter studies are warranted.

Left atrial shape as a marker of atrial myopathy in embolic stroke of undetermined source.

Embolic Stroke of Undetermined Source (ESUS) results in significant morbidity. A left atrial (LA) myopathy is implicated in a proportion of these patients. We hypothesized that LA shape varies by cause of stroke (cardioembolic versus ESUS). 236 ischemic stroke, atrial fibrillation (AF) patients and controls were recruited prospectively. AF was classified as paroxysmal (PAF) or persistent AF (PersAF). Stroke patients comprised cardioembolic stroke (CE) secondary to AF and ESUS. There were 81 AF (47 PAF, 34 PersAF), 50 ESUS, 57 CE patients (subdivided into CE with PAF (CEpaf) and CE with PersAF (CEpers) and 48 controls. Echocardiographic parameters including LA volume, function, and shape/sphericity (3D LA-sphericity and 2D-derived LA-circularity, ellipticity, sphericity and eccentricity indices) were evaluated. Increased LA volume and sphericity with LA dysfunction was present in CE, AF and ESUS groups compared to controls. K-means cluster analysis demonstrated a spectrum of LA myopathy with controls at the lowest and CEpers and PersAF at the upper extremes, with ESUS, PAF and CEpaf being similar and falling between these extremes. After adjusting for age, sex and left ventricular (LV) and LA parameters, LA sphericity markers differentiated ESUS from controls (p < 0.01). Alterations in LA shape are present in ESUS, AF and CE patients, particularly increased spherical remodelling. The novel markers of LA sphericity proposed may identify LA myopathy in ESUS patients and potentially guide management for secondary prevention.

Predictors of atrial fibrillation detection in embolic stroke of undetermined source patients with implantable loop recorder.

Covert atrial fibrillation (AF) is a predominant aetiology of embolic stroke of undetermined source (ESUS). Evidence suggested that AF is more frequently detected by implantable loop recorder (ILR) than by conventional monitoring. However, the predictive factors associated with occult AF detected using ILRs are not well established yet. In this study we aim to investigate the predictors of AF detection in patients with ESUS undergoing an ILR. This observational multi-centre study included consecutive ESUS patients who underwent ILR implantation. The infarcts were divided in deep, cortical infarcts or both. The infarction sites were categorized as anterior and middle cerebral artery, posterior cerebral artery with and without brainstem/cerebellum involvement. Multivariable logistic regression analysis was performed to investigate variables associated with AF detection. Overall, 3,000 patients were initially identified. However, in total, 127 patients who consecutively underwent ILR implantation were included in our analysis. AF was detected in 33 (26%) out of 127 patients. The median follow-up was 411 days. There were no significant differences in clinical characteristics and comorbidities between patients with and without AF detected. AF was detected more often after posterior cerebral artery infarct with brainstem/cerebellum involvement (p < 0.001) whereas less often after infarction in the anterior and middle cerebral artery (p = 0.021). Multivariable regression analysis demonstrated that posterior cerebral artery infarct with brainstem/cerebellum involvement was an independent predictor of AF detection. Our study showed that posterior circulation infarcts with brainstem/cerebellum involvement are associated with AF detection in ESUS patients undergoing ILR. Larger prospective studies are needed to validate our findings.

Artificial intelligence predicts undiagnosed atrial fibrillation in patients with embolic stroke of undetermined source using sinus rhythm electrocardiograms

BackgroundArtificial intelligence (AI)–enabled sinus rhythm (SR) electrocardiogram (ECG) interpretation can aid in identifying undiagnosed paroxysmal atrial fibrillation (AF) in patients with embolic stroke of undetermined source (ESUS). ObjectiveThe purpose of this study was to assess the efficacy of an AI model in identifying AF based on SR ECGs in patients with ESUS. MethodsA transformer-based vision AI model was developed using 737,815 SR ECGs from patients with and without AF to detect current paroxysmal AF or predict the future development of AF within a 2-year period. Probability of AF was calculated from baseline SR ECGs using this algorithm. Its diagnostic performance was further tested in a cohort of 352 ESUS patients from 4 tertiary hospitals, all of whom were monitored using an insertable cardiac monitor (ICM) for AF surveillance. ResultsOver 25.1-month follow-up, AF episodes lasting ≥1 hour were identified in 58 patients (14.4%) using ICMs. In the receiver operating curve (ROC) analysis, the area under the curve for the AI algorithm to identify AF ≥1 hour was 0.806, which improved to 0.880 after integrating the clinical parameters into the model. The AI algorithm exhibited greater accuracy in identifying longer AF episodes (ROC for AF ≥12 hours: 0.837, for AF ≥24 hours: 0.879) and a temporal trend indicating that the AI-based AF risk score increased as the ECG recording approached the AF onset (P for trend <.0001). ConclusionsOur AI model demonstrated excellent diagnostic performance in predicting AF in patients with ESUS, potentially enhancing patient prognosis through timely intervention and secondary prevention of ischemic stroke in ESUS cohorts.

Abstract WP128: Using Clinical Data to Reclassify ESUS Patients to Either Large Artery Atherosclerotic or Cardioembolic Stroke Mechanisms

Introduction: Defining the specific underlying pathophysiology of ischemic stroke is critical for minimizing the risk of recurrent events with personalized secondary prevention treatments. A notable portion of ischemic strokes are classified as embolic stroke of undetermined source (ESUS), leaving these patients without optimal treatment tailored to their pathophysiology. Hypothesis: Standard clinically collected data can reliably reclassify a substantial portion of ESUS patients into either a large artery atherosclerotic (LAA) or cardioembolic (CE) cause. Methods: A statistical model was developed to discriminate LAA from CE using a retrospective cohort of ischemic stroke patients treated at the University of Washington. A total of 189 patients were included (79 CE and 61 LAA to train the model, 49 ESUS patients to assess reclassification). Sixteen candidate predictors were collected across several sources: clinical risk factors, blood tests, echocardiography, ECG, and neurovascular imaging (Table 1). The LASSO (least absolute shrinkage and selection operator) was used to select important predictors in a penalized logistic regression model with stroke etiology (LAA vs. CE) as the outcome. ESUS patients were considered reclassified if the model-based probability of CE or LAA was at least 75%. Results: Of 189 patients, the mean (SD) age was 68 (14) years and 40% were women. The LASSO selected 12 predictors to discriminate CE vs. LAA (Table 1), with a corresponding cross-validated C-statistic = 0.87 (95% CI: 0.82-0.94). When the model was applied to the 49 ESUS patients, 23 (47%) were reclassified to LAA and 6 (12%) to CE. Conclusions: A multivariate model based on standard clinical data can separate LAA from CE with a high degree of discrimination. Applying this model led to reclassification to either LAA or CE in 59% of ESUS patients. Such approaches may enable more personalized secondary prevention strategies, but need to be tested in future trials.

Abstract TP259: Slower Early Mitral Inflow Velocity and Lesion in Anterior Circulation is Associated With Right-to-Left Shunt in Embolic Stroke of Undetermined Source Right-to-Left Shunt in Embolic Stroke of Undetermined Source

Background and Purpose: Right-to-left shunt (RLS) is one of the potential embolic sources in embolic stroke of undetermined source (ESUS), but the eligibility of conducting shunt study to detect RLS in ESUS is still unknown. To reveal clinical features associated with RLS in ESUS, we aimed to compare clinical features including transthoracic echocardiography findings and imaging findings with and without RLS in ESUS. Methods: Consecutive ischemic stroke patients in a comprehensive stroke center were screened between April 2013 and April 2023. Inclusion criteria were: 1) who fulfilled the ESUS criteria based on NAVIGATE-ESUS trial, 2) who underwent transesophageal echocardiogram, and 3) admitted 7 days from the onset. We compared clinical features, including transthoracic echocardiography findings and imaging findings such as lesion characteristics (size, cortical or subcortical, and anterior or posterior), between ESUS patients with RLS (RLS-ESUS) and without RLS (non RLS-ESUS). Results: We screened 2,304 consecutive ischemic stroke patients, including 225 ESUS patients (166 [74%] male, median age 64 years old). Of all, 76 patients had RLS (59 [78%] male, median age 62 years old, Figure A). RLS-ESUS showed higher frequency of anterior circulation lesion (RLS-ESUS vs. non RLS-ESUS; 84% vs. 71%, p = 0.035), slower early mitral inflow velocity (E) (51.6 vs. 54.9 cm/s, p = 0.021). In multivariable analysis, E (OR 0.83, 95%CI0.70-0.99, p = 0.037) and anterior circulation lesion (OR 2.23, 95%CI 1.08-4.62, p = 0.036) were independently associated with RLS-ESUS (Figure B). Conclusions: In ESUS patients, slower early mitral inflow velocity and lesion in anterior circulation was associated with RLS, suggesting shunt study should be conducted to reveal RLS in such patients.

Embolic stroke of undetermined source: Focusing on atrial cardiopathy and patent foramen ovale

BackgroundAtrial cardiopathy(AC) and patent foramen ovale (PFO) are two etiologies of embolic strokes of undetermined source (ESUS). We aimed to explore the relationship between them in ESUS. MethodsA total of 1146 participants were included from January 2019 to June 2022, which included the ESUS group and non-embolic stroke which includes LAA(large arterial atherosclerosis) + SAO(small artery occlusion) group. AC was defined as the presence of at least one of the following: PTFV1(P-wave terminal force in lead V1) > 4000 μV*ms in the electrocardiograms, NT-proBNP(N-terminal probrain natriuretic peptide) > 250 pg/mL in laboratory tests or LAD(left atrial diameter) > 3.8 cm for women and > 4.0 cm for men in cardiac ultrasound. The presence of PFO was assessed by transthoracic echocardiography, transcranial Doppler ultrasound, transesophageal echocardiography or cardiac MRI. PFO was considered pathogenic if the RoPE score was 7 to 10. ResultsThe prevalence of AC and PFO was higher in the ESUS group than the LAA + SAO group. The prevalence of AC was lower in ESUS patients with pathogenic PFO (37.9%) than those without PFO (68.4%) and with incidental PFO (64.0%) (p = 0.006). The prevalence of pathogenic PFO was lower in ESUS patients with AC than those without AC (6.0% vs. 17.8%, p = 0.006). The AUC(area under the curve) of PTFV1 for predicting ESUS was 0.724 [95%CI (0.686–0.762), p < 0.05)], indicating that PTFV1 the most valuable AC biomarker. ConclusionsThe prevalence of AC is inversely related to the prevalence of pathogenic PFO in ESUS patients. PTFV1 was the most valuable index to predict ESUS among the AC biomarkers.

Left atrial strain, embolic stroke of undetermined source, and atrial fibrillation detection.

Atrial cardiopathy is a proposed mechanism of embolic stroke of undetermined source (ESUS). Left atrial (LA) strain may identify early atrial cardiopathy prior to structural changes. We aim to study the associations between LA strain, ESUS, and atrial fibrillation (AF) detection in ESUS. The study population included patients with ESUS and noncardioembolic (NCE) stroke presenting to the Rhode Island Hospital Stroke Center between January 2016 and June 2017 who underwent transthoracic echocardiography. Speckle tracking echocardiography (STE) was used to measure the three phases of LA strain (reservoir, conduit, and contractile). Binary logistic regression analysis was performed to determine the associations between LA strain and stroke subtype (ESUS vs. NCE) as well as follow-up detection of AF in ESUS patients. We identified 656 patients, 307 with ESUS and 349 with NCE. In binary logistic regression, the lowest tertiles of LA reservoir (adjusted OR 1.944, 95% CI 1.266-2.986, p=.002), contractile (aOR 1.568, 95% CI 1.035-2.374, p=.034), and conduit strain (aOR 2.288, 95% CI 1.448-3.613, p=.001) were more likely to be significantly associated with ESUS compared to NCE stroke. Among all ESUS patients, the lowest tertiles of LA reservoir strain (OR 2.534, 95% CI 1.029-6.236, p=.043), contractile strain (OR 2.828, 95% CI 1.158-6.903, p=.022), and conduit strain (OR 2.614, 95% CI 1.003-6.815, p=.049) were significantly associated with subsequent detection of AF. Reduced LA strain is associated with ESUS occurrence and AF detection in ESUS patients. Therefore, quantification of LA strain in ESUS patients may improve risk stratification and guide secondary prevention strategies.

Clinical practice of continuous rhythm monitoring after embolic stroke of undetermined source.

Embolic stroke of undetermined source (ESUS) accounts for up to 20% of ischemic strokes annually. Undetected atrial fibrillation (AF) is one important potential underlying cause. For AF, oral anticoagulation has evolved as the most preferable means of secondary stroke prevention. To detect unrecognized paroxysmal AF, long-term ECG monitoring is required, and implantable cardiac monitors (ICM) appear most suitable. Yet, ICMs are particularly costly, implantation is invasive, and remote monitoring places a personnel burden on health care providers. Here, we use data from a large cohort of ESUS patients to systematically analyze the effort of ICM remote monitoring for AF diagnosis and the strain on health care providers. From a prospective, single-center, observational ESUS registry, we analyzed all ICM-equipped patients post-ESUS (n = 172) between January 1st, 2018, and December 31st, 2019. Through January 2nd, 2023, 48 patients (27.9%) were diagnosed with AF by ICM remote monitoring. During follow-up, a total of 29,180 remote monitoring episodes were transmitted, of which 17,742 were alarms for AF. A systematic estimation of workload revealed that on average, 20.3 trained physician workhours are required to diagnose one patient with AF. ICM remote monitoring is useful to diagnose AF in cohort of post-ESUS patients. However, the number of ICM alarms is high, even in a cohort at known high risk of AF and in whom AF detection is therapeutically consequential. Improved automated event classification, clear recommendations for ICM interrogation after AF diagnosis, and a careful patient selection for ICM monitoring are warranted.

Symptomatic Non-stenotic Carotid Disease in Embolic Stroke of Undetermined Source : Analysis of the ESCAPE-NA1 Trial.

Non-stenotic (< 50%) carotid disease may play an important etiological role in ischemic stroke classified as embolic stroke of undetermined source (ESUS). We aimed to assess the prevalence of non-stenotic carotid disease and its association with ipsilateral ischemic stroke. Data are from ESCAPE-NA1, arandomized controlled trial investigating the neuroprotectant nerinetide in patients with acute ischemic stroke and large vessel occlusion (LVO). The degree of stenosis of the extracranial internal carotid artery (ICA) and high-risk plaque features were assessed on baseline computed tomography (CT) angiography. We evaluated the association of non-stenotic carotid disease and ipsilateral stroke by age-adjusted and sex-adjusted logistic regression and calculated the attributable risk of ipsilateral stroke caused by non-stenotic carotid disease. After excluding patients with non-assessable imaging, symptomatic > 50% carotid stenosis and extracranial dissection, 799/1105 (72.1%) patients enrolled in ESCAPE-NA1 remained for this analysis. Of these, 127 (15.9%) were classified as ESUS. Non-stenotic carotid disease occurred in 34/127 ESUS patients (26.8%) and was associated with the presence of ipsilateral ischemic stroke (odds ratio, OR1.6, 95% confidence interval, CI 1.0-2.6, p = 0.049). The risk of ipsilateral ischemic stroke attributable to non-stenotic carotid disease in ESUS was estimated to be 19.7% (95% CI -5.7% to 39%), the population attributable risk was calculated as 4.3%. Imaging features such as plaque thickness, plaque irregularity or plaque ulceration were not different between non-stenotic carotids with vs. without ipsilateral stroke. Non-stenotic carotid disease frequently occurs in patients classified as ESUS and is associated with ipsilateral ischemic stroke. Our findings support the role of non-stenotic carotid disease as stroke etiology in ESUS, but further prospective research is needed to prove acausal relationship.

Age-dependent sex differences in non-stenotic intracranial plaque of embolic stroke of undetermined source

Age and sex have effect on atherosclerosis. This study aimed to investigate their effect on non-stenotic intracranial atherosclerotic plaque (NIAP) in embolic stroke of undetermined source (ESUS) using high-resolution magnetic resonance imaging (HR-MRI). We retrospectively recruited consecutive ESUS patients who underwent intracranial HR-MRI to assess the plaque characteristics (remodeling index [RI], plaque burden [PB], fibrous cap [FC], discontinuity of plaque surface [DPS], intraplaque hemorrhage [IPH] and complicated plaque [CP]). We divided patients into three groups (< 60 years, 60–74 years, ≥ 75 years). 155 patients with ipsilateral NIAP were found from 243 ESUS patients, with 106 men (68.39%) and 49 women (31.61%). In total population or age group under 60 years, there were no significant differences in plaque characteristics between men and women (all p > 0.05). In age group of 60–74 years, men were associated with higher PB (66.27 ± 9.17% vs 60.91 ± 8.86%, p = 0.017) and RI (1.174 vs 1.156, p = 0.019), higher prevalence of DPS (82.50% vs 60.00%, p = 0.036) and complicated plaque (85.00% vs 63.33%, p = 0.036). For subjects ≥ 75 years old, PB were significantly higher in twomen vs men (68.85 ± 6.14% vs 62.62 ± 7.36%, p = 0.040). In addition, the probability for PBupper (≥ median PB), RIupper (≥ median RI) and vulnerable plaque increased as age increased, and its predictive power for index ESUS was higher in men than women. This study identified age-dependent sex differences in NIAP characteristics of ESUS patients, which will help us clarify their etiology.

P-wave indices and left atrial mechanics as predictors of atrial cardiopathy in embolic stroke of undetermined source

Recent research has shed light on the culpability of LA (left atrial) abnormality, in the form of atrial cardiopathy, as an independent risk factor for the development of atrial fibrillation, LA thrombus and subsequent stroke. The aim of this study was to measure LA electromechanical dissociation (EMD), LA volumes, P-wave dispersion (PWD) and P-wave terminal force in V1 (PTFV1) as markers of atrial cardiopathy in patients with ESUS (embolic stroke of undetermined source), to determine whether atrial cardiopathy is an integral part in the causal pathway of ESUS. 28 patients presenting with ischemic stroke and fulfilling the criteria for ESUS were enrolled into this cross-sectional, observational study along with a control group of 28 age- and gender-matched apparently healthy individuals. On ECG, PWD and PTFV1 were measured. On echocardiography, LA EMD and LA volumes were recorded. Increased PWD (34.14 ± 9.89 ms vs. 27.32 ± 8.95 ms; p = 0.01), atrial EMD (73.32 ± 16.31 ms vs. 63.63 ± 13.59 ms; p = 0.02) and LA volumes were observed in patients with ESUS as compared to controls. A significant correlation was also found between these parameters (p < 0.01). According to the results of our study, PWD, atrial EMD and LA volumes may be novel predictors for ESUS. Our results support the notion that atrial cardiopathy is a distinct mechanism of thrombosis in ESUS patients. Further research is required to clarify its function in the causation of stroke, ESUS in particular.

Apixaban for TreatmenT of embolIC stroke of Undetermined Source - ATTICUS randomized trial - explorative analysis of AF burden in the ATTICUS cohort

Abstract Background Secondary prevention after embolic stroke of undetermined source (ESUS) has not yet been established. It is likely that a relevant number of ESUS patients have significant episodes of atrial fibrillation (AF) that is not detected by conventional Holter ECGs. Despite high prevalence of occult atrial fibrillation , secondary prevention with acetylsalicylic acid (ASA) is the current standard therapy in ESUS patients. The ATTICUS cohort has been selected for prevalence of at least one suggestive risk factor for cardiac embolism (RF) creating an enriched ESUS population. Purpose This work aims to evaluate overall AF burden in the ATTICUS cohort; to determine the correlation between AF detection and new ischemic lesions; and to explore predictors for atrial fibrillation within the enriched ESUS population. Methods The study enrolled ESUS patients with a risk profile for cardiac thromboembolism. Patients were randomized 1:1 into the ASA or apixaban arm, respectively. Study drug was initiated within 3–28 days after minor/moderate stroke and 14–28 days after major stroke. Cardiac monitoring by either implantable or mobile ECG devices was required during the follow up period. MRI (Flair/DWI) was conducted within 7 days of AF detection and 12 months after randomization. Results Enrollment was stopped after interim analysis including 200 patients, due to futility. Overall, 373 patients were screened with 352 being enrolled in the ITT population (178 and 174 in apixaban and ASA arms, respectively). Mean age of the ATTICUS population was 68.4 years with 51.4% males. 86.1% of the subjects suffered from hypertension. 63.4% of the population showed only one RF, all others showed two or more RFs, whereof most common were CHA2DS2-VASc ≥ 4 (93.8%), PFO (20.5%) and atrial high-rate episodes (AHRE, 13.1%). Analysis of the correlation of AF with each suggestive RF revealed an increased AF detection rate with increased amount of RF (Figure 1) and the most predictive RF to be atrial high-rate episodes. Prevalence of AF increased the risk for new embolic ischemic lesions (OR 2.05 (95% 1.01–4.15)). Newly detected AF was reported in 89 patients (25.3%), 49 occurring in the ASA arm, leading to an immediate switch (from ASA to) apixaban, as required by protocol. Conclusions In contrast to the recently published NAVIGATE and RESPECT ESUS trials, patients enrolled in ATTICUS had to exhibit additional predicting factors for (but no previously diagnosed) AF. These were significantly associated with the incidence of clinical AF with AHRE as the strongest predictor. Continuous cardiac remote monitoring will help to elucidate the AF burden and risk for stroke recurrence in this cohort and the effects of early oral anticoagulation with apixaban compared to antiplatelet therapy with ASA on the incidence of stroke recurrence.

The association of intracranial atherosclerosis with cerebral small vessel disease imaging markers: a high-resolution magnetic resonance imaging study

To evaluate the association of intracranial non-stenotic atherosclerotic plaque with cerebral small vessel disease (CSVD) imaging markers in a CSVD population using 3.0 T high-resolution magnetic resonance imaging (HRMRI), which was validated in embolic stroke of undetermined source (ESUS) cohort. We retrospectively recruited consecutive patients who were diagnosed with CSVD or ESUS from January 2015 to December 2019. All patients underwent intracranial HRMRI to assess intracranial non-stenotic atherosclerotic plaques. Baseline and imaging data were collected and were measured among all patients. Among 153 patients with CSVD, there were 59 with intracranial atherosclerotic plaque (IAP) and 94 with non-IAP, including 36 with intracranial atherosclerotic complicated plaque (IACP). Among 227 ESUS patients, there were 155 with IAP and 72 with non-IAP, including 127 with IACP. In the CSVD population, we found that: (1) CSVD burden was associated with IAP (p = 0.036) and IACP (p = 0.008); (2) IAP was associated with white matter hyperintensity (51% vs. 34%; P = 0.039), and IACP was associated with lacunes (69% vs. 35%; P = 0.009) and enlarge perivascular space (69% vs. 39%; P = 0.022). A similar association of CSVD imaging markers with IAP or IACP was found in the ESUS population. Furthermore, the association of unilateral IAP or IACP with CSVD imaging markers of ipsilateral hemisphere was identified in the two cohorts. This is the first report that intracranial non-stenotic atherosclerotic plaque, especially complicated plaque, is closely associated with CSVD imaging markers, which provide further evidence for the association of large artery atherosclerosis with CSVD.

Prevalence of high-risk aortic arch atherosclerosis features on computed tomography angiography in embolic stroke of undetermined source

IntroductionEmbolic stroke of undetermined source (ESUS) comprises a heterogenous group. There is a need to further identify etiologies within this group to guide management strategies. We examined the prevalence of aortic arch atherosclerosis (AAA) on CT angiography (CTA) in patients with embolic stroke of undetermined source (ESUS) to characterize high-risk plaque features. MethodsAll patients from two prospective multicenter acute ischemic stroke studies (INTERRSeCT and PRove-IT) were included if the CTA adequately imaged the proximal aortic arch and the stroke etiology was recorded. Three readers blinded to stroke etiology analyzed the following AAA plaque features on baseline CTA at the time of stroke: 1) thickness in millimetres (mm); 2) morphology (none, smooth, ulcerated, or protruding); 3) location within the aortic arch (proximal, transverse, or distal); and 4) calcification (none, single small, multiple small, single large, or diffuse extensive). ResultsWe included 1063 patients, of which 293 (27.6%) had ESUS (mean age 67.5 years; 46.4% men; median NIHSS 12; 80.6% large vessel occlusion). Mean AAA thickness was significantly larger in ESUS patients (3.8 mm) compared to non-ESUS patients (3.0 mm; p<0.0001) and to a subgroup of patients with large artery atherosclerosis (2.9 mm; p=0.003). ESUS patients had a significantly higher proportion of ulcerated or protruding plaques (17.4% vs 10.3%; risk ratio 1.7, 95% C.I. 1.2-2.4, p=0.002). The location of AAA in the ESUS group was the ascending aorta in 37.9%, transverse arch in 42.3%, and descending aorta in 84.6%. Although AAA was mostly located in the distal aortic arch, ulcerated or protruding plaques were least common in the distal arch (p=0.002). There was no difference between ESUS and non-ESUS patients in plaque location (p=0.23) or calcification grade (p=0.092). ConclusionESUS patients in our study had thicker AAA and a higher prevalence of ulcerated or protruding plaques located more proximally within the aortic arch. High-risk plaque features may suggest a causal role of AAA in the ESUS population with visible intracranial occlusions.

Predictive value of transesophageal echocardiography combined with contrast transthoracic echocardiography for embolic stroke of undetermined source.

In this study, we aimed to assess the predictive value of transesophageal echocardiography (TEE) combined with contrast transthoracic echocardiography (cTTE) for embolic stroke of undetermined source (ESUS). A total of 52 patients with ESUS were examined by TEE and cTTE. The detection rate of patent foramen ovale (PFO) and right-to-left shunt (RLS) grade were compared in patients with ESUS between cTTE alone and cTTE combined with TEE. The Risk of Paradoxical Embolism (RoPE) score, PFO diameter, and PFO length of patients with PFO-associated ESUS and non-PFO-associated ESUS were compared by cTTE alone and cTTE combined with TEE. The receiver operating characteristic (ROC) curve was utilized to determine the effect of RoPE score and PFO diameter on patients with PFO-associated ESUS. The positive rate of PFO detected by cTTE alone (46.15%) was lower than that detected by cTTE combined with TEE (69.23%). The proportion of patients with RLS grade I + II + III detected by cTTE combined with TEE (69.23%) was higher than that detected by cTTE alone (46.15%). Both the RoPE score and PFO diameter were significantly greater in the patients with PFO-associated ESUS than in the patients with non-PFO-associated ESUS (p < .05). The combination of RoPE score and PFO diameter had the largest area under the ROC curve (AUC = 0.875), which was larger than the AUC alone of RoPE score (AUC = 0.819) and PFO diameter (AUC = 0.783) (p < .05). The combination of cTTE and TEE is helpful to the diagnosis of ESUS patients caused by PFO and to judge the degree of RLS.