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.

Dual Antiplatelet Therapy After Embolic Stroke of Undetermined Source: A Subgroup Analysis of the CHANCE-2 Trial.

BACKGROUND: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS. METHODS: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors. RESULTS: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P=0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P<0.01). The P value was 0.56 for the treatment × ESUS status interaction effect. CONCLUSIONS: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Cardiac stasis imaging, stroke, and silent brain infarcts in patients with nonischemic dilated cardiomyopathy.

Cardioembolic stroke is one of the most devastating complications of nonischemic dilated cardiomyopathy (NIDCM). However, in clinical trials of primary prevention, the benefits of anticoagulation are hampered by the risk of bleeding. Indices of cardiac blood stasis may account for the risk of stroke and be useful to individualize primary prevention treatments. We performed a cross-sectional study in patients with NIDCM and no history of atrial fibrillation (AF) from two sources: 1) a prospective enrollment of unselected patients with left ventricular (LV) ejection fraction <45% and 2) a retrospective identification of patients with a history of previous cardioembolic neurological event. The primary end point integrated a history of ischemic stroke or the presence intraventricular thrombus, or a silent brain infarction (SBI) by imaging. From echocardiography, we calculated blood flow inside the LV, its residence time (TR) maps, and its derived stasis indices. Of the 89 recruited patients, 18 showed a positive end point, 9 had a history of stroke or transient ischemic attack (TIA) and 9 were diagnosed with SBIs in the brain imaging. Averaged TR, [Formula: see text] performed well to identify the primary end point [AUC (95% CI) = 0.75 (0.61-0.89), P = 0.001]. When accounting only for identifying a history of stroke or TIA, AUC for [Formula: see text] was 0.92 (0.85-1.00) with odds ratio = 7.2 (2.3-22.3) per cycle, P < 0.001. These results suggest that in patients with NIDCM in sinus rhythm, stasis imaging derived from echocardiography may account for the burden of stroke.NEW & NOTEWORTHY Patients with nonischemic dilated cardiomyopathy (NIDCM) are at higher risk of stroke than their age-matched population. However, the risk of bleeding neutralizes the benefit of preventive oral anticoagulation. In this work, we show that in patients in sinus rhythm, the burden of stroke is related to intraventricular stasis metrics derived from echocardiography. Therefore, stasis metrics may be useful to personalize primary prevention anticoagulation in these patients.

MRI in the Evaluation of Cryptogenic Stroke and Embolic Stroke of Undetermined Source.

Cryptogenic stroke refers to a stroke of undetermined etiology. It accounts for approximately one-fifth of ischemic strokes and has a higher prevalence in younger patients. Embolic stroke of undetermined source (ESUS) refers to a subgroup of patients with nonlacunar cryptogenic strokes in whom embolism is the suspected stroke mechanism. Under the classifications of cryptogenic stroke or ESUS, there is wide heterogeneity in possible stroke mechanisms. In the absence of a confirmed stroke etiology, there is no established treatment for secondary prevention of stroke in patients experiencing cryptogenic stroke or ESUS, despite several clinical trials, leaving physicians with a clinical dilemma. Both conventional and advanced MRI techniques are available in clinical practice to identify differentiating features and stroke patterns and to determine or infer the underlying etiologic cause, such as atherosclerotic plaques and cardiogenic or paradoxical embolism due to occult pelvic venous thrombi. The aim of this review is to highlight the diagnostic utility of various MRI techniques in patients with cryptogenic stroke or ESUS. Future trends in technological advancement for promoting the adoption of MRI in such a special clinical application are also discussed.

Altered left atrial metrics in patients with cryptogenic stroke: A systematic review and meta-analysis.

BACKGROUND: There is no defined cause for cryptogenic stroke/embolic stroke of undetermined source (CS-ESUS). As atrial fibrillation (AF) develops in a significant proportion of these patients, it has been suggested that left atrial (LA) myopathy may predispose to CS-ESUS. We investigated alterations in echocardiographic measures of LA size and function in patients with CS-ESUS. METHODS: A systematic literature review and meta-analysis was performed. PubMed, EMBASE, Cochrane Library, Web of Science and SCOPUS were searched for articles published between 1 January 1990 and 10 February 2023. All observational studies of adult CS-ESUS patients with LA volume or function measurements performed by transthoracic echocardiogram were included. Individual random effects meta-analyses were performed on LA measurements in the CS-ESUS patients using subgroup analysis of comparator groups. RESULTS: We included 29 articles with 3927 CS-ESUS patients. Analysis of weighted mean differences showed CS-ESUS patients had altered LA structure and function parameters, with a larger maximum indexed LA volume, reduced LA emptying fraction and/or LA reservoir strain, compared to healthy controls and noncardioembolic stroke patients. Conversely, CS-ESUS patients had a smaller left atrium with better function, compared to cardioembolic stroke patients and CS-ESUS patients who subsequently developed atrial fibrillation. CONCLUSIONS: LA volume and function are altered in CS-ESUS patients compared to healthy controls and other stroke aetiologies. An underlying atrial myopathy in a subset of CS-ESUS patients may be involved in both thrombogenesis and dysrhythmia (specifically AF). While LA functional assessment is not currently recommended following stroke, it may offer an opportunity for recurrent stroke risk stratification.

Left atrial appendage occlusion and patent foramen ovale closure using a steerable sheath and intracardiac echocardiography.

A patient presenting with acute ischemic stroke associated with patent foramen ovale (PFO) had concurrent deep vein thrombosis, pulmonary embolism, and new-onset atrial fibrillation. Upon initiation of anticoagulation therapy, the patient developed hemorrhagic transformation of the stroke. The patient's multiple potential sources of embolic stroke were treated with concomitant left atrial appendage occlusion and PFO closure through the PFO, made possible by using the Steerable Amulet Sheath under 3D-intracardiac echocardiography guidance.

Paradoxical Embolic Stroke Following Percutaneous Transluminal Angioplasty in a Hemodialysis Patient.

Paradoxical embolism is a medical condition characterized by the migration of an embolus from a venous source into the systemic circulation. This occurs through a specific cardiac abnormality known as a right-to-left shunt, ultimately resulting in the possibility of arterial embolism. Patent foramen ovale (PFO) is the most common cause of intracardiac shunting. We reported a rare case of a 56-year-old man on hemodialysis with PFO and arteriovenous fistula dysfunction who suffered a paradoxical embolic ischemic stroke after percutaneous transluminal angioplasty. This case emphasized the potential risk of paradoxical embolism in hemodialysis patients with vascular access problems. We aimed to highlight the importance of searching for PFO, as it may serve as a possible source of embolism in these patients.

Direct oral anticoagulants in embolic stroke of undetermined source: an updated meta-analysis.

The efficacy and safety of direct oral anticoagulants (DOAC) in patients with embolic stroke of undetermined source (ESUS) remains unclear. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCT) comparing DOACs versus aspirin in patients with ESUS. Risk ratios (RR) and 95% confidence intervals (CI) were computed for binary endpoints. Four RCTs comprising 13,970 patients were included. Compared with aspirin, DOACs showed no significant reduction of recurrent stroke (RR 0.95; 95% CI 0.84-1.09; p = 0.50; I2 = 0%), ischemic stroke or systemic embolism (RR 0.97; 95% CI 0.80-1.17; p = 0.72; I2 = 0%), ischemic stroke (RR 0.92; 95% CI 0.79-1.06; p = 0.23; I2 = 0%), and all-cause mortality (RR 1.11; 95% CI 0.87-1.42; p = 0.39; I2 = 0%). DOACs increased the risk of clinically relevant non-major bleeding (CRNB) (RR 1.52; 95% CI 1.20-1.93; p < 0.01; I2 = 7%) compared with aspirin, while no significant difference was observed in major bleeding between groups (RR 1.57; 95% CI 0.87-2.83; p = 0.14; I2 = 63%). In a subanalysis of patients with non-major risk factors for cardioembolism, there is no difference in recurrent stroke (RR 0.98; 95% CI 0.67-1.42; p = 0.90; I2 = 0%), all-cause mortality (RR 1.24; 95% CI 0.58-2.66; p = 0.57; I2 = 0%), and major bleeding (RR 1.00, 95% CI 0.32-3.08; p = 1.00; I2 = 0%) between groups. In patients with ESUS, DOACs did not reduce the risk of recurrent stroke, ischemic stroke or systemic embolism, or all-cause mortality. Although there was a significant increase in clinically relevant non-major bleeding, major bleeding was similar between DOACs and aspirin.

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

BACKGROUND: 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. METHODS: 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. RESULTS: During 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%. CONCLUSION: 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.

Cardioembolic Stroke: Past Advancements, Current Challenges, and Future Directions.

Cardioembolic stroke accounts for over 20% of ischemic strokes and is associated with worse outcomes than other types of strokes. Atrial fibrillation (AF) is the most common risk factor for cardioembolic stroke. In this narrative review, we present an update about cardioembolic stroke mainly related to AF and atrial cardiopathy. Direct oral anticoagulants (DOACs) have revolutionized stroke prevention in patients with AF; however, their efficacy in preventing recurrent embolic stroke of unknown source remains uncertain. Various cardiac monitoring methods are used to detect AF, which is crucial for preventing stroke recurrence. DOACs are preferred over warfarin for AF-related stroke prevention; however, the timing of initiation after acute ischemic stroke is debated. Resuming anticoagulation after intracerebral hemorrhage in AF patients requires careful assessment of the risks. While catheter ablation may reduce the incidence of cardiovascular events, its effect on stroke prevention is unclear, especially in heart failure patients. Atrial cardiopathy is the emerging cause of embolic stroke of unknown source, which indicates atrial structural and functional disorders that can precede AF. Future research should focus on refining stroke risk prediction models, optimizing AF detection, understanding the roles of ablation and anticoagulation in stroke prevention, and establishing atrial cardiopathy as a therapeutic target, which could significantly reduce the burden of stroke.

Thrombectomy in young adults with embolic stroke of undetermined source: Analysis of the Young ESUS study.

OBJECTIVES: Embolic Stroke of Undetermined Source (ESUS) is a distinct stroke entity that disproportionately affects young adults. We sought to describe characteristics, workup and outcomes of young adult ESUS patients who underwent thrombectomy, and compare outcomes to those reported in different age groups. MATERIALS AND METHODS: Young-ESUS is a multicenter longitudinal cohort study that enrolled consecutive patients aged 21-50 years at 41 stroke centers in 13 countries between 2017- 2019. Between-group comparisons were performed using Wilcoxon rank sum test for continuous variables or Fisher's exact test for binary variables. Distribution of functional outcomes after thrombectomy for our young adult cohort versus pediatric and older adult cohorts reported in the literature were described using the Kruskal-Wallis test. RESULTS: Of 535 patients enrolled in Young-ESUS, 65 (12.1%) were treated with endovascular thrombectomy. Patients who underwent thrombectomy were more likely to undergo in-depth cardiac testing than those who did not, but cardiac abnormalities were not detected more often in this group. Among thrombectomy patients, 35/63 (55.6%) had minimal to no functional disability at follow up. When adjusted for age, stroke severity and IV alteplase, the odds of achieving favorable outcome did not differ between treated versus untreated patients. CONCLUSIONS: Thrombectomy is not rare in young adults with ESUS. Despite extensive workup, cardiac abnormalities were not more prevalent in the thrombectomy group. More research to determine optimal workup, etiologic factors and favorable outcome of stroke across the lifespan is needed.

Ischemic stroke subtypes: risk factors, treatments, and 1-month prognosis - The Lille, France Stroke Registry.

OBJECTIVES: First, this registry-based study aimed to comprehensively analyze patients' medical histories and treatments based on ischemic strokes' etiology. We focused on the management of atrial fibrillation among patients diagnosed with cardioembolic stroke. Then, our objective was to identify prognostic factors associated with 28-day mortality. MATERIALS AND METHODS: All ischemic strokes occurring in adults between 2014 and 2021 in Lille, France, were categorized using the TOAST classification. Comparative analyses of patients' medical characteristics were conducted across subtypes. Survival rates within 28 days post-stroke were assessed, and factors influencing mortality were identified using a multivariate Cox model. RESULTS: 1912 ischemic strokes were recorded, due to cardioembolism (36%), large-artery atherosclerosis (9%), small-artery occlusion (9%), other determined causes (6%), or undetermined causes (39%). The median NIHSS score after cardioembolic stroke (6, IQR: 3-13) was twice that after small-artery occlusion (3, IQR: 2-5). Among patients with cardioembolic stroke, 26% were diagnosed post-admission with atrial fibrillation. For the 42% diagnosed pre-admission, only 54% had prior prescriptions for oral anticoagulants. Reperfusion therapies were administered in 21% of cases, with significant variations across subtypes. Mortality rates were higher after cardioembolic strokes (17%) than after small-artery occlusions (3%). Prognostic factors included etiology, high NIHSS score, atrial fibrillation, and previous heparin prescription. CONCLUSIONS: While atrial fibrillation was underdiagnosed and undertreated, patients with cardioembolic stroke exhibited high severity and elevated mortality rates. Etiology emerged as an independent predictor of early mortality, regardless of NIHSS score upon admission. These findings underscore the importance of targeted prevention to improve patient outcomes after ischemic stroke.

Hypothyroidism's effect on stroke limited to specific subtypes: A Mendelian randomization study.

BACKGROUND: The association between hypothyroidism and stroke remains controversial and the association between hypothyroidism and stroke subtypes has not been satisfactorily researched. This study aimed to explore the causal effect of hypothyroidism on the risk of stroke and its subtypes by Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms (SNPs) were selected from published genome-wide association studies (GWAS) meta-analysis as instrumental variables (IVs) for hypothyroidism. As outcomes, summary GWAS data for stroke and its subtypes were obtained from two other large GWAS meta-analyses, including any stroke (AS), any ischemic stroke (AIS), large vessel stroke (LAS), cardiogenic embolic stroke (CES), small vessel stroke (SVS), and intracranial hemorrhage (ICH). Univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR) were used to assess the causal effect of hypothyroidism on stroke and its subtypes. RESULTS: In UVMR, genetically predicted hypothyroidism was significantly associated with LAS (OR = 1.14, 95CI = 1.02-1.27) and SVS (OR = 1.14, 95CI = 1.04-1.25), but not with AS, AIS, CES, and ICH. The results of the MVMR showed that after adjusting for smoking, alcohol consumption, hypertension, diabetes, low-density lipoprotein cholesterol (LDL-c), and body mass index (BMI), the causal association between hypothyroidism and SVS remained significant, while the association between hypothyroidism and LAS became nonsignificant. CONCLUSION: Hypothyroidism is causally associated with risk for LAS and SVS, but not for other stroke subtypes. Hypothyroidism may be an independent risk factor for SVS, and vascular risk factors play an important role in hypothyroidism causing LAS.

Exploring vertebral artery stump syndrome: An overlooked cause of posterior ischemic strokes. A narrative review of current management options.

INTRODUCTION: Stump syndrome is defined as a clinical syndrome resulting from a distal intracranial vessel embolic stroke due to an extracranial vessel occlusion. Similar to the anterior circulation, the recurrence of ischemic strokes in territories supplied by the posterior circulation in the presence of vertebral artery occlusion is termed Vertebral Artery Stump Syndrome (VASS). MATERIAL AND METHODS: We conducted a literature review, identifying 72 patients with transient ischemic attacks (TIAs) or ischemic strokes attributed to VASS, according to Kawano criteria. We categorized all patients in two groups focusing on the therapeutic management those who underwent primary medical treatment and those who received endovascular or surgical treatment either in acute or chronic phase. RESULTS: In the anticoagulant therapy group, only 1 patient had a stroke recurrence. Among the 4 on antiplatelets, all had recurrences, but 3 benefited from switching to anticoagulants or endovascular therapy. In the endovascular therapy group, worse outcomes were linked to acute large vessel occlusion. Endovascular treatment of the vertebral artery, in a chronic phase, was explored in literature for recurrent TIAs or minor strokes suggesting that this could be a viable therapeutic alternative when medical treatment failed in preventing recurrence of ischemic stroke. CONCLUSIONS: Some studies suggest that anticoagulant medical therapy may be beneficial for VASS and endovascular therapy has also been reported for selected patients. However, data on treatment outcomes and prognosis are still underreported, making treatment decisions challenging. Randomized Controlled Trials are needed to establish the optimal treatment approach.

Research progress on genetics in cardioembolic stroke.

Cardioembolic stroke, characterized by severe illness, poor prognosis, and high recurrence rate, is one of the important causes of ischemic stroke. In the field of genetic research, numerous genes associated with cardioembolic stroke have been identified, and their potential in predicting disease risk and evaluating risk factors has been progressively explored. Here, we provide an overview of the latest advancements in genetics for cardioembolic stroke, including genome-wide association studies, copy number variation studies, whole-genome sequencing studies. Furthermore, we also summarize the application of genetic datasets in polygenic risk score and Mendelian randomization. The aim of this overview is to provide insights and references from multiple perspectives for future investigations on the genetic information for cardioembolic stroke.

Enlarged left atrium may be associated with laterality of anterior circulation cardioembolic stroke.

BACKGROUND: Propensity for lesion lateralization in atrial fibrillation-related cardiac embolic stroke (AF-stroke) remains controversial. In this study, we compared the hemispheric differences among patients with AF-stroke and identified factors associated with lesion laterality. METHODS: We retrospectively reviewed patients with acute AF-stroke admitted from January, 2017 to March, 2022. Patients were grouped based on whether lesions were right or left hemispheric in the anterior circulation territory, based on diffusion-weighted imaging. Factors associated with right-side propensity were analyzed. RESULTS: Among 385 patients, the mean age was 74±11 years and 52.5 % were male. Right and left hemispheric lesions were observed in 189 (49.1 %) and 196 (50.9%) patients, respectively. In the multivariate analysis, enlarged left atrium (LA) (adjusted odds ratio [aOR]=1.03, 95% confidential interval [CI], 1.007-1.061; p=0.013) and single confluent lesion pattern (aOR= 1.55, 95% CI, 1.012-2.381; p=0.044) were associated with right hemispheric lesions. CONCLUSIONS: Enlarged LA and single confluent lesion pattern were strongly related to right-sided propensity in patients with AF-stroke.

Predictors of Atrial Fibrillation Development in Patients With Embolic Stroke of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial.

BACKGROUND: A proportion of patients with embolic stroke of undetermined source have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of the risk for development of AF is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke attributable to underlying AF. The RE-SPECT ESUS trial (Randomized, Double-Blind Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) provides an opportunity to assess predictors for developing AF and associated recurrent stroke. METHODS: RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) were found to develop AF reported as an adverse event or using cardiac monitoring per standard clinical care. Univariable and multivariable regression analyses were performed to define predictors of AF. RESULTS: In the multivariable model, older age (odds ratio for 10-year increase, 1.99 [95% CI, 1.78-2.23]; P<0.001), hypertension (odds ratio, 1.36 [95% CI, 1.03-1.79]; P=0.0304), diabetes (odds ratio, 0.74 [95% CI, 0.56-0.96]; P=0.022), and body mass index (odds ratio for 5-U increase, 1.29 [95% CI, 1.16-1.43]; P<0.001) were independent predictors of AF during the study. In a sensitivity analysis restricted to 1117 patients with baseline NT-proBNP (N-terminal prohormone of brain natriuretic peptide) measurements, only older age and higher NT-proBNP were significant independent predictors of AF. Performance of several published predictive models was assessed, including HAVOC (AF risk score based on hypertension, age ≥75 years, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, and coronary artery disease) and CHA2DS2-VASc (stroke risk score based on congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, previous stroke, transient ischemic attack or thromboembolism [doubled], vascular disease, age 65 to 74 years, and sex category [female]) scores, and higher scores were associated with higher rates of developing AF. CONCLUSIONS: Besides age, the most important variable, several other factors, including hypertension, higher body mass index, and lack of diabetes, are independent predictors of AF after embolic stroke of undetermined source. When baseline NT-proBNP was available, only older age and elevation of this biomarker were predictive of subsequent AF. Understanding who is at higher risk of developing AF will assist in identifying patients who may benefit from more intense, long-term cardiac monitoring. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

Atrial cardiopathy and non-stenotic intracranial complicated atherosclerotic plaque in patients with embolic stroke of undetermined source.

OBJECTIVE: To assess (1) the association between atrial cardiopathy (AC) and non-stenotic intracranial complicated atherosclerotic plaque (NICAP) in patients with embolic stroke of undetermined source (ESUS) or small-vessel disease (SVD), and (2) the performance of previously proposed biomarkers to identify AC as the underlying aetiology in ESUS. METHODS: Based on our high-resolution MRI (HR-MRI) cohort, 403 subjects (243 ESUS and 160 SVD) were enrolled in the final analysis. All patients underwent intracranial HR-MRI to assess the presence of ipsilateral NICAP. Biomarkers of AC (ie, P-wave terminal force in lead V1 (PTFV1) on ECG, N-terminal probrain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T and left atrial diameter) were collected within 24 hours after admission. RESULTS: Among patients without ipsilateral NICAP, we found an association between the presence of AC (adjusted OR (aOR): 4.76, 95% CI 2.48 to 9.14), increased PTFV1 (aOR: 5.70, 95% CI: 2.43 to 13.39) and NT-proBNP (aOR: 1.65, 95% CI: 1.16 to 2.35) with ESUS. This association was not evident among patients with ipsilateral NICAP. The discrimination between ESUS versus SVD by AC/AC-related biomarkers was significantly improved after excluding ipsilateral NICAP. Similarly, the discrimination between ESUS and SVD by ipsilateral NICAP was notably augmented after excluding AC, PTFV1 and NT-proBNP. INTERPRETATION: AC is more prevalent in patients who had ESUS without ipsilateral NICAP compared with patients with, implying that AC and ipsilateral NICAP are two distinct, competing aetiologies of ESUS. Among the AC biomarkers studied in this analysis, PTFV1 seems to be the most informative.

Classification of patients with embolic stroke of undetermined source into cardioembolic and non-cardioembolic profile subgroups.

BACKGROUND AND PURPOSE: It is currently thought that embolic stroke of undetermined source (ESUS) has diverse underlying hidden etiologies, of which cardioembolism is one of the most important. The subgroup of patients with this etiology could theoretically benefit from oral anticoagulation, but it remains unclear if these patients can be correctly identified from other ESUS subgroups and which markers should be used. We aimed to determine whether a machine-learning (ML) model could discriminate between ESUS patients with cardioembolic and those with non-cardioembolic profiles using baseline demographic and laboratory variables. METHODS: Based on a prospective registry of consecutive ischemic stroke patients submitted to acute revascularization therapies, an ML model was trained using the age, sex and 11 selected baseline laboratory parameters of patients with known stroke etiology, with the aim of correctly identifying patients with cardioembolic and non-cardioembolic etiologies. The resulting model was used to classify ESUS patients into those with cardioembolic and those with non-cardioembolic profiles. RESULTS: The ML model was able to distinguish patients with known stroke etiology into cardioembolic or non-cardioembolic profile groups with excellent accuracy (area under the curve = 0.82). When applied to ESUS patients, the model classified 40.3% as having cardioembolic profiles. ESUS patients with cardioembolic profiles were older, more frequently female, more frequently had hypertension, less frequently were active smokers, had higher CHA2 DS2 -VASc (Congestive heart failure or left ventricular systolic dysfunction, Hypertension, Age ≥ 75 [doubled], Diabetes, Stroke/transient ischemic attack [doubled], Vascular disease, Age 65-74, and Sex category) scores, and had more premature atrial complexes per hour. CONCLUSIONS: An ML model based on baseline demographic and laboratory variables was able to classify ESUS patients into cardioembolic or non-cardioembolic profile groups and predicted that 40% of the ESUS patients had a cardioembolic profile.

Association Between Oral Anticoagulants and Stroke Severity at Onset in Elderly Patients with Cardioembolic Stroke Due to Non-Valvular Atrial Fibrillation.

OBJECTIVES: This study aimed to determine whether oral anticoagulant therapy affects the severity of cerebral infarction at onset in elderly patients with non-valvular atrial fibrillation. MATERIALS AND METHODS: This retrospective study included 330 elderly patients (aged ≥75 years) who were hospitalized for cardioembolic stroke due to non-valvular atrial fibrillation. Patients' medical history, stroke severity at onset (National Institutes of Health Stroke Scale score), and the prevalence of large vessel occlusion were compared between patients who received oral anticoagulant therapy (n = 109) and those who did not receive oral anticoagulant therapy (n = 221). RESULTS: Stroke severity was significantly lower in patients who received anticoagulants than in those who did not receive anticoagulants (6 versus 12; P = 0.021). Patients who did not receive anticoagulants had a significantly higher prevalence of large vessel occlusion (52% versus 37%; P = 0.010). After resampling based on propensity score matching, both median stroke severity (7 versus 12; P = 0.046) and large vessel occlusion prevalence (36% versus 57%; P = 0.019) were significantly lower in patients who received anticoagulant therapy. CONCLUSIONS: The results of this study suggest that elderly patients with non-valvular atrial fibrillation who are administered oral anticoagulant therapy before the onset of cerebral infarction develop less severe stroke than those who are not receiving oral anticoagulant therapy. Thus, oral anticoagulant therapy should be actively considered in patients with non-valvular atrial fibrillation as it does not only prevents cerebral embolism, but also reduces the risk of severe sequelae.