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.

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.

Comparison of echocardiographic and clinical characteristics in embolic stroke and migraine patients with patent foramen ovale.

BACKGROUND: This single-center observational study aimed to compare the echocardiographic and clinical features in patients diagnosed with migraine and embolic stroke of undetermined source (ESUS) who presented with a known patent foramen ovale (PFO). METHODS: Two-dimensional and color Doppler images were obtained using various transthoracic echocardiography views for both migraine and ESUS patients. Suspected PFO cases underwent further assessment through contrast echocardiography and transesophageal echocardiography (TEE). High-risk PFO characteristics were evaluated using TEE, and the Risk of Paradoxical Embolism (RoPe) score was calculated. RESULTS: The study included 310 participants (age range: 18-60, 73.2% female), with 43.5% diagnosed with migraine and 56.5% with ESUS. Common comorbidities included diabetes (26.1%). High-velocity shunting through the interatrial septum was observed in 35.5% of patients. ESUS patients were older, with higher rates of diabetes and hypertension, while active smoking was more prevalent among migraine patients. Basic echocardiographic parameters were mostly similar, except for elevated pulmonary artery systolic pressure in ESUS. ESUS patients exhibited a greater occurrence of large microbubble passage through the interatrial septum and longer PFO lengths compared to migraine patients. However, the RoPe and High-risk PFO scores were similar between the groups. CONCLUSIONS: ESUS patients, characterized by older age and higher rates of diabetes and hypertension, demonstrated increased pulmonary artery pressure, more significant microbubble crossings, and longer PFO lengths. Conversely, migraine patients had a higher prevalence of active smoking. Despite differing clinical profiles, the risk scores for PFO-related embolic events were comparable between the groups. These findings underscore potential distinctions between ESUS and migraine patients with PFO and their implications for management strategies.

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

INTRODUCTION: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Vulnerable plaque of the petrous internal carotid artery in embolic stroke of undetermined source.

BACKGROUND AND PURPOSE: The association between nonstenotic plaque at the petrous internal carotid artery (ICA) and embolic stroke of undetermined source (ESUS) remains unknown. We aimed to test the hypothesis that the presence of a larger build-up of petrous plaque is more prevalent in the ipsilateral versus the contralateral side among ESUS patients without plaque in the intracranial and proximal ICA. METHODS: From a total of 243 patients with ESUS and 160 patients with small-vessel disease (SVD) without proximal ICA plaque, we enrolled 88 ESUS and 103 SVD patients without ipsilateral nonstenotic intracranial and proximal ICA plaque in the present study. Targeting the petrous segment of the ICA on two sides, plaque burden including plaque thickness, lumen area, vessel area, wall area, and percentage of luminal stenosis, and composition features (presence/absence of the ruptured fibrous cap, ulcer plaque, thrombus, discontinuity of plaque surface [DPS], intraplaque hemorrhage and complicated plaque) were assessed by high-resolution magnetic resonance imaging. RESULTS: We found a higher prevalence of petrous plaque thickness ≥3.5 mm ipsilateral versus contralateral to the stroke (25/88 [28.4%] vs. 12/88 [13.6%], odds ratio [OR] 3.60, 95% confidence interval [CI] 1.34-9.70), but this imbalance was not seen in SVD. In patients with plaque thickness ≥3.5 mm, the presence of DPS (OR 4.05, 95% CI 1.11-14.78) and complicated plaque (OR 5.00, 95% CI 1.10-22.82) was more closely related to an index ESUS, a finding that was not evident in the subgroup with petrous plaque <3.5 mm (p for interaction = 0.027). CONCLUSIONS: The present study provided the first evidence supporting a potential etiological role of vulnerable petrous plaque in ESUS.

Potential Embolic Sources in Embolic Stroke of Undetermined Source Patients with Patent Foramen Ovale.

INTRODUCTION: A patent foramen ovale (PFO) may coexist with other potential embolic sources (PESs) in patients with embolic stroke of undetermined source (ESUS), leading to difficulty in attributing the stroke to either the PFO or other PESs. We aimed to investigate the prevalence and predictors of concomitant PESs in ESUS patients with PFOs. METHODS: A retrospective cohort study was conducted in a tertiary stroke centre. Consecutive patients with ESUS and a concomitant PFO admitted between 2012 and 2021 were included in the study. Baseline characteristics and investigations as a part of stroke workup including echocardiographic and neuroimaging data were collected. PESs were adjudicated by 2 independent neurologists after reviewing the relevant workup. RESULTS: Out of 1,487 ESUS patients, a total of 309 patients who had a concomitant PFO with mean age of 48.8 ± 13.2 years were identified during the study period. The median Risk of Paradoxical Embolism (RoPE) score for the study cohort was 6 (IQR 5-7.5). Of the 309 patients, 154 (49.8%) only had PFO, 105 (34.0%) patients had 1 other PES, 34 (11.0%) had 2 PES, and 16 (5.2%) had 3 or more PES. The most common PESs were atrial cardiopathy (23.9%), left ventricular dysfunction (22.0%), and cardiac valve disease (12.9%). The presence of additional PESs was associated with age ≥60 years (p < 0.001), RoPE score ≤6 (p ≤0.001), and the presence of comorbidities including diabetes mellitus (p = 0.004), hypertension (p≤ 0.001), and ischaemic heart disease (p = 0.011). CONCLUSION: A large proportion of ESUS patients with PFOs had concomitant PESs. The presence of concomitant PESs was associated with older age and a lower RoPE score. Further, large cohort studies are warranted to investigate the significance of the PES and their overlap with PFOs in ESUS.

Embolic Stroke of Undetermined Source: Role of Implantable Loop Recorder in Secondary Prevention.

BACKGROUND AND AIMS: Atrial fibrillation (AF) is the most important cause of embolic stroke of undetermined source (ESUS). Implantable loop recorder (ILR) demonstrated the highest sensitivity for detecting it. This register was created to confirm the high prevalence of AF in patients after ESUS and to verify possible benefits on clinical outcomes such as TIA (Transient Ischaemic Attack)/stroke recurrence and death using ILR. METHODS: A total of 278 patients admitted to "Molinette" Hospital in Stroke Unit department between 2011 and 2016, diagnosed with ESUS, underwent ILR implantation if they had at least one risk factor for AF. A total of 165 patients admitted to other departments in the same center for the same pathology, without ILR, represent the control group. We used propensity score to select 132 patients from each group (matching age, sex, CHADS-VASC, and HAS-BLEED baseline characteristics). RESULTS: The detection rate of AF episodes was significantly higher in the ILR group (p < 0.001). No significant protective role of ILR for clinical endpoints was found on univariate analysis, although a trend towards significance has been pointed for the composite outcome of death and ischemic events recurrence (OR 0.52, CI 0.26-1.04, p = 0.06). A protective role of ILR was found for deaths (OR 0.4, CI 0.17-0.94, p 0.03) and for the composite outcome (OR 0.41, CI 0.19-0.87, p 0.02) on multivariate analysis in the best subsets. CONCLUSION: With our statistical models, we identified a significant clinical benefit from ILR monitoring, evidenced by a trend of less death and TIA/stroke recurrence and relevant ILR protection for prediction of TIA/stroke recurrence.

Multiparametric identification of subclinical atrial fibrillation after an embolic stroke of undetermined source.

BACKGROUND: Subclinical atrial fibrillation (SCAF) may represent a cause of embolic stroke of undetermined source (ESUS) and its detection has important implications for secondary prevention with anticoagulation. Indications to implantable cardiac monitors (ICM) include SCAF detection. The aims of this study were to (1) evaluate the frequency of ICM-detected SCAF; (2) determine predictors of SCAF; and (3) identify patients who would benefit most from ICM implantation. METHODS: Between February 2017 and November 2020, all consecutive patients referred for ICM implantation after a diagnosis of ESUS and without previous history of atrial fibrillation or atrial flutter were included in this study. SCAF was diagnosed if the ICM electrogram demonstrated an episode of irregularly irregular rhythm without distinct P waves lasting > 2 min. RESULTS: We enrolled 109 patients (age 66, SD = 13 years; 36% females). During a median follow-up of 19.2 (IQR 11.0-27.5) months, SCAF episodes were detected in 36 (33%) patients. Only abnormal P wave terminal force in lead V1, left atrial end-systolic indexed volume > 34 ml/m2, and BMI > 25 kg/m2 were independently associated with an increased risk of SCAF (HR 2.44, 95% CI 1.14-5.21, p = 0.021; HR 2.39, 95% CI 1.11-5.13, p = 0.026; and HR 2.64, 95% CI 1.06-6.49, p = 0.036 respectively). The ROC curve showed that the presence of all three parameters had the best accuracy (74%) to predict SCAF detection (sensitivity 39%, specificity 91%). CONCLUSION: A multiparametric evaluation has the best accuracy to predict SCAF in ESUS patients and may help identifying those who would benefit most from ICM.

Stroke and Noninfective Native Valvular Disease.

PURPOSE OF REVIEW: Embolic stroke of undetermined source is a challenging clinical entity. While less common than atrial fibrillation and endocarditis, many noninfective heart valve lesions have been associated with stroke and may be considered as culprits for cerebral infarcts when other more common causes are excluded. This review discusses the epidemiology, pathophysiology, and management of noninfective valvular diseases that are commonly associated with stroke. RECENT FINDINGS: Calcific debris from degenerating aortic and mitral valves may embolize to the cerebral vasculature causing small- or large-vessel ischemia. Thrombus which may be adherent to calcified valvular structures or left-sided cardiac tumors may also embolize resulting in stroke. Tumors themselves, most commonly myxomas and papillary fibroelastomas, may fragment and travel to the cerebral vasculature. Despite this broad differential, many types of valve diseases are highly comorbid with atrial fibrillation and vascular atheromatous disease. Thus, a high index of suspicion for more common causes of stroke is needed, especially given that treatment for valvular lesions typically involves cardiac surgery whereas secondary prevention of stroke due to occult atrial fibrillation is readily accomplished with anticoagulation.

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: The combination of cTTE and TEE is helpful to the diagnosis of ESUS patients caused by PFO and to judge the degree of RLS.

High-risk patent foramen ovale and elderly in cryptogenic stroke.

BACKGROUND: High-risk patent foramen ovale (PFO) could be pathological in cryptogenic stroke (CS), but its clinical characteristics have not been fully studied, especially in elderly patients. METHODS: Patients with CS were enrolled in the CHALLENGE ESUS/CS registry, a multicenter registry of CS patients undergoing transesophageal echocardiography. Clinical characteristics were compared among three groups: high-risk PFO group, large shunt PFO (≥25 microbubbles) or PFO with atrial septal aneurysm (ASA); right-to-left shunt (RLS) group, RLS including PFO with <25 microbubbles or without ASA; and no-RLS group. RESULTS: In total, 654 patients were analyzed: 91, 221, and 342 in the high-risk PFO, RLS, and no-RLS groups, respectively. In multinomial logistic regression analysis, the male sex (odds ratio [OR] 1.825 [1.067-3.122]) was independently associated with high-risk PFO, but hypertension (OR, 0.562 [0.327-0.967]), multiple infarctions (OR, 0.601 [0.435-0.830]), and other cardioaortic embologenic risks (OR, 0.514 [0.294-0.897]) were inversely associated with high-risk PFO compared with non-RLS. In 517 patients aged ≥60 years, multiple infarctions (OR, 0.549 [0.382-0.788]) and other cardioaortic embologenic risks (OR, 0.523 [0.286-0.959]) were inversely associated with high-risk PFO. CONCLUSIONS: High-risk PFO had specific clinical characteristics and possible mechanistic associations, and this trend was consistent among CS patients aged ≥60 years. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp/ctr/ (UMIN000032957).

Stroke Recurrence in Embolic Stroke of Undetermined Source Without Atrial Fibrillation on Invasive Cardiac Monitoring.

BACKGROUND: More than half of patients with embolic stroke of undetermined source (ESUS) suffer from recurrent ischaemic stroke, despite the absence of atrial fibrillation (AF) on invasive cardiac monitoring (ICM). This study investigated the predictors and prognosis of recurrent stroke in ESUS without AF on ICM. METHOD: This prospective study included patients with ESUS at two tertiary hospitals from 2015 to 2021 who underwent comprehensive neurological imaging, transthoracic echocardiography, and inpatient continuous electrographic monitoring for ≥48 hours prior to ICM for definitive exclusion of AF. Recurrent ischaemic stroke, all-cause mortality, and functional outcome by the modified Rankin scale (mRS) at 3 months were evaluated in patients without AF. RESULTS: Of 185 consecutive patients with ESUS, AF was not detected in 163 (88%) patients (age 62±12 years, 76% men, 25% prior stroke, median time to ICM insertion 26 [7, 123] days), and stroke recurred in 24 (15%) patients. Stroke recurrences were predominantly ESUS (88%), within the first 2 years (75%), and involved a different vascular territory from qualifying ESUS (58%). Pre-existing cancer was the only independent predictor of recurrent stroke (adjusted hazard ratio [AHR] 5.43, 95% CI 1.43-20.64), recurrent ESUS (AHR 5.67, 95% CI 1.15-21.21), and higher mRS score at 3 months (ß 1.27, 95% CI 0.23-2.42). All-cause mortality occurred in 17 (10%) patients. Adjusting for age, cancer, and mRS category (≥3 vs <3), recurrent ESUS was independently associated with more than four times greater hazard of death (AHR 4.66, 95% CI 1.76-12.34). CONCLUSIONS: Patients with recurrent ESUS are a high-risk subgroup. Studies elucidating optimal diagnostic and treatment strategies in non-AF-related ESUS are urgently required.

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.

The characteristics of intracranial plaques of unilateral, anterior circulation embolic stroke of undetermined source: An analysis of different subtypes based on high-resolution imaging.

BACKGROUND AND PURPOSE: The aim was to investigate the characteristics of non-stenotic intracranial plaque (NSIP) in embolic stroke of undetermined source (ESUS) subtypes by high-resolution magnetic resonance imaging. METHODS: Consecutive patients with ESUS who were mandatory for high-resolution magnetic resonance imaging were retrospectively enrolled. Based on the location and arterial supply of the infarct, the ESUS were categorized into three types: cortical ESUS, subcortical ESUS and mixed ESUS. The NSIP parameters including plaque location, morphology (plaque distribution, remodeling index and plaque burden) and composition (thick fibrous cap, discontinuity of plaque surface, intraplaque hemorrhage and complicated plaque) were evaluated amongst the subtypes. RESULTS: Of 243 patients, there were 87 (35.8%) cortical ESUS, 127 (52.3%) subcortical ESUS and 29 (11.9%) mixed ESUS. Significant differences were found in plaque location (p < 0.001), plaque quadrant (p < 0.001), remodeling index (p < 0.001), plaque burden (p < 0.001), discontinuity of plaque surface (p < 0.001), intraplaque hemorrhage (p = 0.001) and complicated plaque (p < 0.001) of ipsilateral NISP amongst the different ESUS subtypes, except for fibrous cap (p = 0.135). However, no differences were found amongst contralateral NISP. In addition, the clinical characteristics of the differences between ESUS subtypes were striking, including age (p = 0.004), initial National Institutes of Health Stroke Scale (p < 0.001), coronary artery disease (p = 0.039), serum urea (p = 0.011) and creatinine (p = 0.002). CONCLUSION: This is the first report of significantly heterogeneous characteristics of ipsilateral NSIP and clinical findings amongst ESUS subtypes, which may suggest their different underlying mechanisms.

Impact of D-dimer for pathologic differentiation on transesophageal echocardiography in embolic stroke of undetermined source: a single-center experience.

BACKGROUND: Embolic stroke of undetermined source (ESUS) encompasses diverse embologenic mechanisms, which transesophageal echocardiography (TEE) is critical to detect. Specific markers related to each embolic source in ESUS is not fully studied. We focused on D-dimer levels, and explored the association of D-dimer with potential embolic sources (PES) identified on TEE in ESUS. METHODS: Consecutive patients with ESUS were included in this study. Clinical characteristics including D-dimer levels were compared between ESUS patients with and without TEE, and among none of, one, and at least two PES in ESUS patients undergoing TEE. Factors related to elevation of D-dimer were analyzed. RESULTS: A total of 211 patients (age, 69.3 ± 13.2 years; 149 males) with ESUS were enrolled. Of these, 115 received TEE, displaying significantly younger age and lower D-dimer levels than patients without TEE (P < 0.05), and 20 (17%), 61 (53%), and 34 (30%) patients were classified into none of, one, and ≥ two PES, respectively. On multiple logistic regression analysis, D-dimer levels were related to one PES (odds ratio [OR]: 9.01; 95% confidence interval [CI]: 1.00-81.51; P = 0.050) and PES ≥ two (OR: 9.76; 95% CI: 1.07-88.97; P = 0.043). Right-to-left shunt (RLS) with deep venous thrombosis (DVT)(OR: 13.94; 95% CI: 1.77-109.99; P = 0.012) and without DVT (OR: 3.90; 95% CI: 1.20-12.70; P = 0.024) were associated with elevation of D-dimer. CONCLUSIONS: D-dimer levels were higher in patients with PES. Among PES, RLS, with and without DVT, were associated with increase of D-dimer in ESUS.

Characteristics of non-stenotic carotid plaque in embolic stroke of undetermined source compared with cardiogenic embolism: a retrospective cross-sectional observational study.

BACKGROUND: Non-stenotic carotid plaque is considered an important etiology of embolic stroke of undetermined source (ESUS). However, only a few previous studies included a negative control group, and the characteristics of non-stenotic carotid plaque in ESUS have yet to be investigated. The objective of this study is to explore the clinical characteristics of ESUS and the correlation between non-stenotic carotid plaque and ESUS. METHODS: This is a single-center, retrospective cross-sectional observational study conducted to compare differences in clinical information among ESUS, CE, and large-artery atherosclerosis (LAA), as well as the prevalence of non-stenotic carotid plaque and non-stenotic carotid plaque with low echo between patients with ESUS and CE in Changzhou No.2 People's Hospital from January 2020 to January 2022. Ultrasound was used to evaluate the characteristics of non-stenotic carotid plaque and vulnerable carotid plaque was defined as plaque with low echo. The binary logistic regression model was used to analyze the relationship between the characteristics of non-stenotic carotid plaque and ESUS. The receiver-operating characteristic curve was used to evaluate the diagnostic efficiency of the characteristics of non-stenotic carotid plaque for ESUS. RESULTS: We had a final studying population of 280 patients including 81 with ESUS, 37 with CE, and 162 with LAA. There were no differences in clinical features between ESUS and LAA, but in the comparison of CE and ESUS, there were differences in age, smoking, hypertension, levels of triglyceride, total cholesterol, and low density lipoprotein cholesterol. In ESUS, the prevalence of non-stenotic carotid plaque was more common on the ipsilateral side of stroke than in CE [55 (67.90%) vs. 18 (48.65%), p = 0.046], so was the prevalence of non-stenotic carotid plaque with low echo [38 (46.91%) vs. 5 (13.51%), p < 0.001]. Logistic regression analysis showed that the prevalence of non-stenotic carotid plaque (OR: 4.19; 95% CI: 1.45-12.11; p = 0.008) and the prevalence of non-stenotic carotid plaque with low echo (OR: 5.12; 95% CI: 1.55-16.93; p = 0.007) were, respectively, the independent predictors of ESUS. The results receiver-operating characteristic (ROC) curve showed that the combination of age, hypertension, and ipsilateral non-stenotic carotid plaque with low echo had the best diagnostic efficiency for ESUS (0.811; 95%CI: 0.727-0.896; p < 0.001). CONCLUSION: Our results suggest that ipsilateral vulnerable non-stenotic carotid plaque is associated with ESUS in anterior circulation infarction.

A score of non-contrast transthoracic echocardiography to screen patent foramen ovale in patients with embolic stroke of undetermined source.

BACKGROUND: The aim of this study was to develop a screening score system of non-contrast transthoracic echocardiography (TTE) for patent foramen ovale (PFO) in patients with embolic stroke of undetermined source (ESUS). METHODS: We performed a retrospective analysis of 218 consecutive patients with a recent ESUS from 2015 to 2018, who received TTE and transcranial Doppler (TCD) as routine examinations. PFO was diagnosed by the bubble test of TCD. Significant differences of the non-contrast TTE findings and patient characteristics between PFO group and non-PFO group were selected into a score. RESULTS: PFO was diagnosed in 35.8% (78/218) of the patients. Compared with non-PFO group, a larger median aortic root diameter (ARd) (34 mm vs. 32 mm, p = 0.005), a lower median peak E wave velocity (Em) (61.5 cm/s vs. 68 cm/s, p = 0.005) and a lower incidence rate of mitral regurgitation (34.6% vs. 50.7%, p = 0.022) were seen in PFO group. ARd>33 mm and Em < 72 cm/s were the best thresholds to predict PFO in ROC analysis. A four-point score system (MEAD) including TTE criteria (including ARd>33 mm, Em < 72 cm/s and without mitral regurgitation) and no history of diabetes predicted PFO with an area under curve of 0.67 (95%CI 0.57-0.72, p < 0.001). MEAD score ≥ 3 was the best threshold to predict PFO with an accuracy of 0.64 (95% CI 0.57-0.7), a sensitivity of 0.65 (95% CI 0.53-0.75) and a specificity of 0.63 (95% CI 0.55-0.71). CONCLUSION: The MEAD score measured with non-contrast TTE can be used to select patients for bubble test of TCD to increase the diagnostic yield of PFO after ESUS.

Prediction of occult atrial fibrillation in patients after cryptogenic stroke and transient ischaemic attack: PROACTIA.

AIMS: Studies with implantable cardiac monitors (ICMs) show that one-third of patients with cryptogenic stroke/transient ischaemic attack (TIA) have episodes of subclinical atrial fibrillation (SCAF) and benefit switching from antiplatelet- to anticoagulant therapy. However, ICMs are costly and resource demanding. We aimed to build a score based on participant's baseline characteristics that could assess individual risk of SCAF. METHODS AND RESULTS: In a prospective study, 236 eligible patients with a final diagnosis of cryptogenic stroke/TIA had an ICM implantated during the index hospitalization. Pre-specified evaluated variables were: CHA2DS2-VASc, P-wave duration, P-wave morphology, premature atrial beats (PAC)/24 h, supraventricular tachycardia/24 h, left atrial end-systolic volume index (LAVI), Troponin-T, NT-proBNP, and D-dimer. SCAF was detected in 84 patients (36%). All pre-specified variables were significantly associated with SCAF detection in univariate analysis. P-wave duration, followed by PAC/24 h, NT-proBNP, and LAVI, had the largest ratio of SCAF prevalence between its upper and lower quartiles (3.3, vs. 3.2, vs. 3.1 vs. 2.8, respectively). However, in a multivariate analysis, only PAC/24t, P-wave duration, P-wave morphology, and LAVIs remained significant predictors and were included in the PROACTIA score. Subclinical atrial fibrillation prevalence was 75% in the highest vs. 10% in the lowest quartile of the PROACTIA score with a 10-fold higher number of patients with an atrial fibrillation burden >6 h in the highest vs. the lowest quartile. CONCLUSION: The PROACTIA score can identify patients with cryptogenic stroke/TIA at risk of subsequent SCAF detection. The large difference in SCAF prevalence between groups may provide a basis for future tailored therapy. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: ClinicalTrials.gov; NCT02725944.

Atrial cardiopathy predicts detection of atrial fibrillation in embolic stroke of undetermined source: real-life data.

OBJECTIVES: Atrial cardiopathy (AC) is more frequent in patients with embolic stroke of undetermined source (ESUS) than in patients with non-cardioembolic stroke. The aim of this work was to describe AC in patients with ESUS and to study its impact on detection of atrial fibrillation (AF) during follow-up. METHODS: This is an observational study of 123 consecutive ESUS patients and 55 ESUS patients from a previous cohort. AC was defined according to the presence of one or more of the following criteria: severe left atrial enlargement, p-wave terminal force in lead V1 > 5000 µVxms, and excessive premature atrial complexes. Unadjusted and adjusted survival analyses for the occurrence of AF and stroke or transient ischemic attack (TIA) were performed. Diagnostic performance of AC for the detection of AF was analyzed. RESULTS: Among 178 patients with ESUS, those with AC (42.7%) were older (p < 0.001), and more frequently had hypertension (p = 0.001) and lower total cholesterol levels (p = 0.001) than patients without AC. The detection of AF during follow-up (median 34 months, interquartile range = 12.8-64) was higher in patients with AC (hazard ratio = 7.00, 95% confidence interval = 2.01-24.39, p = 0.002). This association persisted after adjusting for age, arterial hypertension, and other vascular risk factors. The c-statistic for detection of AF during follow-up for AC was 0.719. There were no differences in stroke or TIA recurrence between groups with and without AC. DISCUSSION: ESUS patients with AC have different baseline clinical characteristics than patients without AC and have a higher detection of AF during follow-up.

Supracardiac atherosclerosis in embolic stroke of undetermined source: the underestimated source.

The term 'embolic stroke of undetermined source' (ESUS) is used to describe patients with a non-lacunar ischaemic stroke without any identified embolic source from the heart or the arteries supplying the ischaemic territory, or any other apparent cause. When the ESUS concept was introduced, covert atrial fibrillation was conceived to be the main underlying cause in the majority of ESUS patients. Another important embolic source in ESUS is the atherosclerotic plaque in the carotid, vertebrobasilar, and intracranial arteries, or the aortic arch-collectively described as supracardiac atherosclerosis. There is emerging evidence showing that the role of supracardiac atherosclerosis is larger than it was initially perceived. Advanced imaging methods are available to identify plaques which high embolic risk. The role of novel antithrombotic strategies in these patients needs to be assessed in randomized controlled trials. This review presents the evidence which points towards a major aetiological association between atherosclerotic plaques and ESUS, summarizes the imaging features which may aid to identify plaques more likely to be associated with ESUS, discusses strategies to reduce the associated stroke risk, and highlights the rationale for future research in this field.