Embolic Stroke Of Undetermined Source Patients Research Articles

Abstract TMP102: Title: Prediction of Post-Stroke AF in ESUS Patients is Enhanced by Combining Expert-Derived Predictors and Embedding of Full Diagnostic Codes using Pre-Trained Hypergraph Neural Networks

Background: Atrial Fibrillation (AF) occurs in about one-fourth of patients with Embolic Stroke of Undetermined Source (ESUS). Accurate prediction of post-stroke AF upon discharge from an index stroke admission informs a personalized post-stroke monitoring strategy of AF and interventions. While clinical risk scores predict AF, machine learning (ML) models have shown superior performance. However, traditional ML approaches only use expert-derived predictors available in an electronic health record (EHR) and thus may miss variables that would potentially increase the accuracy of prediction. Aims: This study aims to enhance AF prediction by augmenting expert-derived predictors with an unbiased selection of full diagnostic codes and medication histories up to index strokes. Through embedding learning with hypergraph neural networks, we generate compact representations of high-dimensional data to improve prediction accuracy by capturing complex feature interactions. Methods: We analyzed data from 510 ESUS patients (55.3% female, mean age 61.4 years) from 2015 to 2023 at Emory Healthcare. We focus on experiments using a logistic regression (LR) model to predict AF from different sets of features. At baseline, we use 58 clinically motivated predictors, including comorbidities characterized by 17 ICD codes manually extracted based on literature, and 41 other features extracted from lab results, echocardiographic and ECG. To directly model the full history of comorbidities and medications, another baseline uses the full 1530 ICD codes plus the 41 other features (1571 in total). In contrast, the embedding method uses the full 1530 ICD codes to generate condensed, informative embedding vectors (32-dimensional), eventually getting 32+41=73 features. To generate the embedding, a hypergraph neural network was trained on a larger stroke cohort (n=7956) to model the interactions between the 1530 ICD codes. A nested cross-validation approach was employed within 5-fold splits, and ROC-AUC scores were recorded. Result: Among 510 ESUS patients, 107 (21.0%) developed AF (mean age 67.9 years, 57% female). We compared the performance of LR model with different features from ICD codes (Table 1). The results show that the learned 32-dim embedding vectors improves the prediction of post-ESUS AF. Conclusion: The embedding technique can significantly enhance predictive performance by integrating comprehensive medical information, maximizing the use of available data for improved outcomes.

Factors associated with the detection of atrial fibrillation in patients with embolic stroke of undetermined source

BackgroundDetection of atrial fibrillation (AF) in patients with embolic stroke of undetermined source (ESUS) is important for the secondary prevention of stroke. We investigated the factors associated with the detection of newly diagnosed AF in ESUS patients during follow-up.MethodsPatients with acute ischemic stroke classified as ESUS were included. All patients underwent transthoracic echocardiography and Holter to detect the source of embolism. Structural, electrophysiological markers of left atrial cardiopathy (i.e., left atrial enlargement [LAE], non-sustained tachycardia [NSAT]) as well as lesion patterns of ischemic stroke were examined. Implantable loop recorder (ILR) was implanted in selective patients. Sensitivity and positive predictive value analysis was used to assess the predictive value for AF detection.ResultsAmong 312 patients with ESUS, AF was detected in 24 (7.7%) patients during follow-up. Patients with AF had a higher prevalence of LAE, NSAT, and the imaging pattern of confluent plus additional lesions in a single vascular territory. Multivariable analysis showed that ILR implantation (hazards ratio 11.497 [95% confidence interval 3.795–34.818]), LAE (3.204 [1.096–9.370]), NSAT (4.070 [1.378–12.018]), and confluent plus additional lesions (4.977 [1.649–15.019]) were independent predictors of AF detection. The sensitivity of detecting AF in those with LAE, NSAT, or confluent plus additional lesions pattern was 91.7%. The positive predictive value of detecting AF in those with LAE, NSAT and confluent plus additional lesions pattern was 40.0%.ConclusionIn conclusion, patients with LAE, NSAT, or confluent plus additional lesions may benefit from ILR monitoring detecting new AF.

Left ventricular disease as a risk factor for adverse outcomes and stroke recurrence in patients with embolic stroke of undetermined source.

Severe left ventricular (LV) systolic dysfunction (ejection fraction [EF] < 30%) is a known cardiovascular risk factor and a major cause of cardioembolism. However, less severe forms of LV disease (LVD), such as mild-to-moderate LV dysfunction and LV wall motion abnormalities (LVWMAs), are considered potential minor cardiac sources in Embolic Stroke of Undetermined Source (ESUS), but their role is underexplored. This study aims to evaluate the prevalence of LVD in ESUS and its association with adverse vascular events and mortality. Retrospective, single-center study including consecutive ESUS patients admitted from January 2016 to May 2024. LVD was defined as either global systolic dysfunction (LV ejection fraction 30%-49%) or regional LVWMAs, unrelated to acute or recent (within 4 weeks) myocardial infarction. Univariate and multivariate Cox regression analyses evaluated the association of LVD with a primary composite outcome (including ischemic stroke recurrence, acute coronary events, and all-cause mortality), and its components separately. Among the 556 ESUS patients (median age 71 years [IQR 60-80], 44.6% female), 95 (17.1%) had LVD, including 51 (53.7%) with reduced LVEF (30%-49%), and 81 (85.3%) presenting LVWMAs. During follow-up (median 30 months), LVD(+) patients had significantly higher rates of the composite outcome (41.0% vs 21.3%, p < 0.001), ischemic stroke recurrence (13.7% vs 5.9%, p = 0.007), acute coronary events (7.4% vs 2.4%, p = 0.012), and all-cause mortality (28.4% vs 15.2%, p = 0.002), compared to LVD(-) patients. Multivariate Cox regression analysis showed that LVD independently increased the risk of ischemic stroke recurrence (adjusted HR 2.13, 95%CI 1.08-4.24, p = 0.032) and the composite outcome (aHR 1.92, 95%CI 1.27-2.90, p = 0.002), but not acute coronary events (aHR 1.65; 95%CI 0.54-5.01, p = 0.374), or all-cause mortality (aHR 1.62; 95%CI 0.98-2.70, p = 0.062). LVD is significantly associated with an increased risk of ischemic stroke recurrence and adverse outcomes in ESUS patients. These findings highlight the clinical importance of identifying and optimizing LVD management among ESUS to improve long-term outcomes in this population.

Predicting the Propensity of Atrial Cardiopathy and Paroxysmal Atrial Fibrillation in Patients with Embolic Stroke of Undetermined Source (ESUS).

There is still a significant population of patients with embolic stroke of Undetermined Source (ESUS) whose specific attributable cause of the stroke remains unknown. Our research aimed to assess clinical, electrocardiogram, laboratory, and echocardiographic parameters that may predict the propensity of paroxysmal atrial fibrillation (PAF). We enrolled seventy-five ESUS patients who were in sinus rhythm at the time of stroke diagnosis to undergo in-hospital 7-day Holter monitoring, testing for Pro-BNP, and a standard echocardiographic examination. For statistical analysis, a P-value < 0.05 was considered significant. The average age of the 75 ESUS patients was 58 years old. 60% of the patients were male, and the most prevalent concomitant condition was hypertension (53.3%). Forty patients had atrial cardiopathy, and 15 patients had PAF episodes. Hypertension and the E/e- > 12 were independent predictors of atrial cardiopathy, with p-values of 0.001 and 0.02, respectively. In patients with atrial cardiopathy, multivariable regression analysis was performed; PTFV > 5000 Mv.ms, LA volume index > 34 ml/m2, and ejection fraction < 45% were significant independent predictors of AF with significant p values of 0.001, < 0.001, and 0.001 respectively. In ESUS patients, atrial cardiopathy was prevalent. Hypertension and an E/e- ratio greater than 12 were independent predictors for it. Multivariable regression analysis identified PTFV1 > 5000 mV.ms, LA volume index > 34 ml/m2, and ejection fraction < 45% as independent predictors for new-onset atrial fibrillation.

Predição da Propensão à Cardiopatia Atrial e Fibrilação Atrial Paroxística em Pacientes com Acidente Vascular Cerebral Embólico de Origem Indeterminada (ESUS)

Abstract Background There is still a significant population of patients with embolic stroke of Undetermined Source (ESUS) whose specific attributable cause of the stroke remains unknown. Objectives Our research aimed to assess clinical, electrocardiogram, laboratory, and echocardiographic parameters that may predict the propensity of paroxysmal atrial fibrillation (PAF). Methods We enrolled seventy-five ESUS patients who were in sinus rhythm at the time of stroke diagnosis to undergo in-hospital 7-day Holter monitoring, testing for Pro-BNP, and a standard echocardiographic examination. For statistical analysis, a P-value &lt; 0.05 was considered significant. Results The average age of the 75 ESUS patients was 58 years old. 60% of the patients were male, and the most prevalent concomitant condition was hypertension (53.3%). Forty patients had atrial cardiopathy, and 15 patients had PAF episodes. Hypertension and the E/e- &gt; 12 were independent predictors of atrial cardiopathy, with p-values of 0.001 and 0.02, respectively. In patients with atrial cardiopathy, multivariable regression analysis was performed; PTFV &gt; 5000 Mv.ms, LA volume index &gt; 34 ml/m2, and ejection fraction &lt; 45% were significant independent predictors of AF with significant p values of 0.001, &lt; 0.001, and 0.001 respectively. Conclusions In ESUS patients, atrial cardiopathy was prevalent. Hypertension and an E/e- ratio greater than 12 were independent predictors for it. Multivariable regression analysis identified PTFV1 &gt; 5000 mV.ms, LA volume index &gt; 34 ml/m2, and ejection fraction &lt; 45% as independent predictors for new-onset atrial fibrillation.

Prevalence of ipsilateral “vulnerable carotid plaques with

Carotid plaques may be an important etiology in ischemic stroke. We aimed to assess carotid plaque characteristics ipsilateral and contralateral to the ischemic stroke and assessed the prevalence of "vulnerable carotid plaques with <50% stenosis" based on different imaging-based definitions in patients with large vessel occlusion and source of embolic stroke of undetermined source (ESUS) on CT Angiography (CTA). Data are from the ESCAPE-NA1 trial (Efficacy and safety of nerinetide for the treatment of acute ischemic stroke), a multicenter, randomized study that included anterior circulation large vessel occlusion patients undergoing thrombectomy. Various CTA features of plaque vulnerability were combined to define "vulnerable carotid plaques" in different ways. Within ESUS patients, prevalence of vulnerable plaques ipsilateral vs. contralateral to the intracranial occlusion was compared. We analyzed 132 patients whose ischemic stroke mechanism was determined to be ESUS. Plaques causing 30-50% stenosis (as compared to no stenosis) and plaque surface irregularity were significantly more common in ipsilateral carotid arteries (37[28.0%] vs. 18[13.6%]; p<0.001 and 102[77.3%] vs. 78[59.1%]; p=0.002). The prevalence of ipsilateral "vulnerable carotid plaques" varied depending on imaging definition used for such plaques between 55 and 74%, but irrespective of the definition used, the prevalence of "vulnerable carotid plaques" was consistently higher in ipsilateral carotid arteries compared to contralateral carotid arteries. In ESUS patients undergoing thrombectomy for anterior circulation large vessel occlusion, vulnerable carotid plaques are more prevalent ipsilateral to the intracranial occlusion. Irregular plaque surface, and a higher degree of stenosis were the most common vulnerable plaque features.

Oral anticoagulants or antiplatelets for cryptogenic stroke: a systematic review and meta-analysis

Abstract Background Cryptogenic strokes comprise 20 to 30% of ischemic strokes and include a substantial proportion classified as embolic stroke of undetermined source (ESUS). However, the optimal antithrombotic strategy for cryptogenic stroke remains contentious. Purpose We conducted a systematic review and meta-analysis to compare the efficacy and safety of oral anticoagulants (OAC) versus antiplatelets in patients with cryptogenic stroke. Methods Six electronic databases of PubMed, Embase, Web of Science, the Cochrane Library, Google Scholar and ClinicalTrials.gov were searched from inception to Feb 15, 2024 to identify relevant randomized controlled trials (RCTs) comparing stroke recurrence and major bleeding rates between OAC and antiplatelets in cryptogenic stroke patients. We included trials adhering to a stringent diagnostic work-up for cryptogenic stroke, defined as cerebral infarction not attributed to definite sources of cardioembolism, large artery atherosclerosis, or small artery disease despite undergoing comprehensive investigations. The primary outcome was recurrent ischemic stroke, and the secondary outcome was major bleeding based on International Society of Thrombosis and Hemostasis criteria. Subgroup analysis was conducted for ESUS patients with an increased risk of cardiac emboli, such as patent foramen ovale (PFO) and atrial cardiopathy, defined as lead V1 terminal P-wave &amp;gt; 5000 μV × ms in electrocardiogram, serum N-terminal pro-B-type natriuretic peptide level &amp;gt; 250 pg/mL, and left atrial diameter (LAE) &amp;gt; 4 cm, or LAE index ≥ 3 cm/m2 on echocardiogram. Hazard ratio (HR) with 95% confidence (CI) was used as a measure of the effect estimates for aforementioned outcomes. Random-effects meta-analysis was performed using a restricted maximum likelihood model given between-study variance is inevitable. Results Our meta-analysis included 9 RCTs with a total of 15,139 patients (OAC = 7,343; antiplatelets = 7,796). ARCADIA, RE-SPECT ESUS, and NAVIGATE ESUS Trial investigated apixaban, dabigatran, and rivaroxaban, respectively, while warfarin was primarily used as OAC in the remaining six trials. Aspirin was predominantly utilized for antiplatelet therapy. There was no significant difference in recurrent ischemic stroke between OAC and antiplatelets (HR, 0.90; 95% CI, 0.78 to 1.04; I2 = 0%). However, OAC use was associated with a significantly higher risk of major bleeding (HR, 1.66; 95% CI, 1.07 to 2.56; I2 = 36%). Subgroup analysis in ESUS patients revealed comparable rates of recurrent ischemic stroke in those with atrial cardiopathy (HR, 0.91; 95% CI, 0.65 to 1.29; I2 = 0%) and PFO (HR, 0.72; 95% CI, 0.49 to 1.07; I2 = 0%). Conclusions Our meta-analysis suggests that OAC use does not decrease the risk of recurrent ischemic stroke compared with antiplatelet use but is associated with a significantly higher risk of major bleeding in patients with cryptogenic stroke.Primary (A) and secondary (B) outcomesSubgroup analysis for recurrent stroke

Atrial fibrillation detection on implantable loop recorders in embolic stroke of undetermined source

Abstract Introduction Embolic stroke of undetermined source (ESUS) represents 17% of all ischaemic strokes, and has a 5% annual stroke recurrence risk. Recent large randomised control trials failed to demonstrate a benefit of empirical anticoagulation for all ESUS patients, with sub-analyses supporting the need for a tailored approach to those patients at greatest risk of atrial fibrillation (AF) development. Understanding how the increased incidence of ILR-detected AF in the ESUS cohort, compares with ILR-detected AF in other cohorts is an essential step in understanding the significance of this finding. Purpose To compare the incidence of ILR-detected AF following ESUS against patients undergoing ILR implantation for non-stroke indications for example syncope and palpitations. Methods We retrospectively studied all patients without known AF who were referred to our institution for ILR implantation following ESUS, syncope or palpitations from 2009 to 2019. The primary endpoint was any detection of AF or atrial flutter (AFL) by ILR. Kaplan-Meier and multivariable Cox-regression analyses were utilised to account for time-to-event. Results A total of 750 patients were included and followed up for a mean of 731 days (SD 443). An ILR was implanted following ESUS in 323 patients and for another reason in 427 patients (figure 1). The incidence of AF was significantly higher among patients with ESUS compared to the non-ESUS group; 48.6% versus 13.8% (for any duration of AF) and 32.2% versus 12.4% (for AF lasting &amp;gt; 30 seconds) both p &amp;lt;0.001. Kaplan-Meier analysis (figure 2), showed significantly higher incidence of AF for ESUS for any duration of AF. This was driven predominantly by AF duration &amp;lt;6 minutes and between 5.5 hours and 24 hours. Importantly, in a multivariable Cox regression analysis, ESUS independently conferred an almost 5-fold increase in the hazard for any duration of AF (Hazard Ratio 4.948, 95% confidence interval 3.587 – 6.825, p&amp;lt;0.001). Conclusion The incidence of AF is significantly higher amongst ESUS versus non-ESUS patients monitored constantly by an ILR. A high number of ESUS survivors have short duration AF episodes. Further work is needed to determine the optimal treatment strategy of these AF episodes in ESUS considering AF duration and overall burden.

Left Ventricular Diastolic Dysfunction with Elevated Filling Pressures Is Associated with Embolic Stroke of Undetermined Source and Atrial Fibrillation.

Background/Objectives: Left ventricular diastolic dysfunction (LVDD) and elevated left ventricular filling pressure (LVFP) are strong predictors of clinical outcomes across various populations. However, their diagnostic utility in embolic stroke of undetermined source (ESUS) remains unclear. We hypothesized that LVDD with elevated LVFP (based on echocardiography) was more likely to be prevalent in ESUS compared to non-cardioembolic stroke (NCE) and to be associated with atrial fibrillation (AF) on follow-up monitoring. Methods: This is a single-center retrospective study that included adult patients with a diagnosis of acute ischemic stroke between January 2016 and June 2017. LV function was assessed by inpatient transthoracic echocardiogram (TTE), and stroke etiology was adjudicated by the neurologist per the consensus criteria. Patients with cardioembolic stroke and those with indeterminate diastolic function on TTE were excluded. Baseline patient characteristics and clinical variables were compared among patients with and without LVDD and elevated LVFP. Multivariable regression models were used to assess the associations between diastolic dysfunction, ESUS, and AF detection in ESUS patients. Results: We identified 509 patients with ESUS and NCE stroke who had reported diastolic function. The mean age was 64.19 years, 45.19% were female, and 146 had LVDD with available LVFP data. LVDD was not associated with ESUS (adjusted OR: 1.43, 95% CI: 0.90-2.27, p = 0.130) or atrial fibrillation (AF) detection on cardiac monitoring (adjusted OR: 1.88, 95% CI: 0.75-4.72, p = 0.179). However, LVDD with elevated LVFP was borderline associated with ESUS (adjusted OR: 2.17, 95% CI: 0.99-4.77, p = 0.054) and significantly associated with AF detection (adjusted OR: 3.59, 95% CI: 1.07-12.06, p = 0.038). Conclusions: Our data suggest that LVDD with elevated LVFP is borderline associated with ESUS and significantly associated with AF detection on follow-up cardiac monitoring. Therefore, the presence of LVDD with an increased probability of elevated LVFP may help identify a subset of stroke patients more likely to have ESUS, potentially due to atrial cardiopathy with underlying occult AF. Further studies are needed to confirm our findings and to evaluate the safety and efficacy of anticoagulation in patients with ESUS and LVDD with elevated LVFP.

SERPINE1 and MTHFR genetic variants in patients with embolic stroke of undetermined source: links with fibrin clot properties.

The SERPINE1 c.-820G (4_5), MTHFR gene variants, and unfavourably altered fibrin clot features, have been suspected to be associated with embolic stroke of undetermined source (ESUS). We investigated the SERPINE1 c.-820G (4_5) gene variants alone and coexisting with MTHFR c.665C > T and c.1286A > C gene variants in relation to thrombophilic factors and plasma fibrin clot properties in Polish patients with ESUS. Unrelated consecutive patients with ESUS (n = 206) were genotyped by TaqMan assay. Thrombophilia screening was performed four weeks or more after a thrombotic event while off oral anticoagulation. Factor VIII (FVIII) activity was determined by a coagulometric assay, while lipoprotein(a) was determined using immunoturbidimetry. We determined fibrin clot permeability (Ks) and clot lysis time (CLT). Apparently healthy individuals without a family history of stroke or venous thromboembolism (n = 30), and patients with a history of atrial fibrillation (n = 25) or carotid artery disease-related stroke (n = 21), served as controls. Among ESUS patients, the SERPINE1 c.-820G (4_5) minor allele frequency was 0.57. There were no differences in common factors associated with thrombophilia among ESUS patients regarding SERPINE1 variants. The overall prevalence of FVIII > 150IU/dL was 26% (n = 53) and elevated FVIII predominated in SERPINE1 variants carriers (n = 45; 84.9%), including 36 (68%) carriers of MTHFR variant. Moreover, 4.3-fold higher Lp(a) levels along with 50% reduced Ks and 46% prolonged CLT were found in patients with mutant SERPINE1 combined with mutant homozygotes in the MTHFR c.665C > T variant compared to the wild type SERPINE1 combined with mutant homozygotes in the MTHFR c.665C >T (P < 0.001). The SERPINE1 c.-820G (4_5) variants carriers have increased FVIII levels, while the SERPINE1 c.-820G (4_5) mutant homozygotes coexisting with MTHFR c.665C > T have more prothrombotic fibrin clot features and elevated Lp(a). Our study underlines the cumulative effect of genetic risk factors in patients with ESUS that might require specific antithrombotic therapy.

The Usefulness of Outpatient Cardiac Telemetry in Patients with Cryptogenic Stroke.

Introduction: Atrial fibrillation (AF), apart from non-stenotic supracardiac atherosclerosis and neoplastic disease, is the leading cause of cryptogenic stroke, including embolic stroke of un-determined source (ESUS). The aim of our study was to determine the prevalence of AF in ESUS patients based on 30-day telemetric heart rate monitoring initiated within three months after stroke onset. Another aim was to identify factors that increase the likelihood of detecting subsequent AF among ESUS patients. Material and Methods: patients with first-ever stroke classified as per the ESUS definition were eligible for this study. All patients underwent outpatient 30-day telemetric heart rate monitoring. Results: In the period between 2020 and 2022, 145 patients were included. The mean age of all qualified patients was 54; 40% of eligible patients were female. Six patients (4.14%), mostly male patients (4 vs. 2), were diagnosed with AF within the study period. In each case, the diagnosis related to a patient whose stroke occurred in the course of large vessel occlusion. Episodes of AF were detected between day 1 and 25 after starting ECG monitoring. Out of the analyzed parameters that increase the probability of, A.F.; only supraventricular extrasystoles proved to be an independent factor regarding an increased risk of AF [OR 1.046, CI 95% 1.016-1.071, p-value < 0.01]. Conclusions: The use of telemetry heart rhythm monitoring in an outpatient setting can detect AF in 4% of ESUS patients who have undergone prior diagnostic procedures for cardiogenic embolism. Supraventricular extrasystoles significantly increases the likelihood of AF detection in patients with ESUS within three months following stroke. Comorbid coronary artery disease, diabetes and hypertension, rather than a single-factor clinical burden, increase the likelihood of AF detection in older ESUS patients. ESUS in the course of large vessel occlusion is probably associated with an increased likelihood of cardiogenic embolism.

The Role of Galectin-3 Levels for Predicting Paroxysmal Atrial Fibrillation in Patients with Embolic Stroke of Undetermined Source.

Background/Objectives: Paroxysmal atrial fibrillation (PAF) is an important cause that is thought main potential factor in Embolic stroke of undetermined source (ESUS). Extended Holter ECG is an expensive and time-consuming examination. It needs another tools for predicting PAF in ESUS patients. In this study, serum galectin-3 levels, ECG parameters (PR interval, P wave time and P wave peak time) LA volume index, LA global peak strain and atrial electromechanical conduction time values were investigated for predicting PAF. Methods: 150 patients with ESUS and 30 volunteers for the control group were recruited to study. 48-72 h Holter ECG monitoring was used for detecting PAF. Patients were divided into two groups (ESUS + PAF and ESUS-PAF) according to the development of PAF in Holter ECG monitoring. Results: 30 patients with ESUS whose Holter ECG monitoring showed PAF, were recruited to the ESUS + PAF group. Other 120 patients with ESUS were recruited to the ESUS-PAF group. PA lateral, PA septum, and PA tricuspid were higher in the ESUS + PAF group (p < 0.001 for all). Serum galectin-3 levels were significantly higher in ESUS + PAF than in ESUS-PAF and control groups (479.0 pg/mL ± 435.8 pg/mL, 297.8 pg/mL ± 280.3 pg/mL, and 125.4 ± 87.0 pg/mL, p < 0.001, respectively). Serum galectin-3 levels were significantly correlated with LAVI, PA lateral, and global peak LA strain (r = 0.246, p = 0.001, p = 0.158, p = 0.035, r = -0.176, p = 0.018, respectively). Conclusion: Serum galectin-3 levels is found higher in ESUS patients which developed PAF and Serum galectin-3 levels are associated LA adverse remodeling in patients with ESUS.

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

BackgroundIn 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.Methods101 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.ResultsDuring a mean follow-up of 647 ± 385 days, AF was detected in 26 patients (26%). Independent risk factors of AF were age ≥ 60 years (HR 2.753, CI 1.129–6.713, p = 0.026), P-wave amplitude in lead II ≤ 0.075 mV (HR 3.751, CI 1.606–8.761, p = 0.002), and P-wave duration ≥ 125 ms (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%.ConclusionAF 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 [CE (cardioembolic) vs. ESUS]. A total of 236 ischaemic stroke and atrial fibrillation (AF) patients and controls were recruited prospectively. AF was classified as paroxysmal AF (PAF) or persistent AF (PersAF). Stroke patients comprised CE stroke 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 were present in CE, AF, and ESUS groups compared with 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.

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

Artificial 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). The purpose of this study was to assess the efficacy of an AI model in identifying AF based on SR ECGs in patients with ESUS. A 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. Over 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). Our 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.

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.