Sex-Specific Risk Factors of Nonstenotic Carotid Plaque in Embolic Stroke of Unknown Source: A Case-Control Study.

BACKGROUND: Many ischemic strokes are diagnosed as embolic strokes of undetermined source (ESUS). Recent evidence suggests that nonstenotic carotid plaque (nsCP) may be a substantial contributor to the risk for ESUS. We aimed to investigate the risk factor profile associated with nsCP in ESUS and defined stroke etiologies. METHODS: In this retrospective case-control study, we investigated consecutive patients with acute ischemic stroke due to ESUS, small-vessel disease, or cardioembolism proven by magnetic resonance imaging. The association of vascular risk factors age, arterial hypertension, diabetes, dyslipoproteinemia, body mass index, alcohol consumption, tobacco use, kidney failure, and history of stroke with the presence of nsCP was investigated using binary logistic regression analysis and further stratified by stroke etiology and sex. RESULTS: In total, 609 patients (median age, 76 years; 46% women) who were treated from 2018 to 2020 were considered. In patients with ESUS, sex played a more important role for the prevalence of nsCP than in defined etiologies. Female patients with ESUS had lower odds of exhibiting nsCP compared with male patients with ESUS (adjusted odds ratio, 0.36 [95% CI, 0.15-0.86]). In male patients with ESUS, we observed that age (adjusted odds ratio per 10-year increase, 2.55 [95% CI, 1.26-5.17]) and hypertension (adjusted odds ratio, 2.49 [95% CI, 0.56-11.1]) were the main risk factors for nsCP, whereas in female patients with ESUS also tobacco use was particularly relevant (adjusted odds ratio, 3.71 [95% CI, 0.61-22.5]). These results were in line with a sensitivity analysis in nsCP located ipsilateral to the infarct. CONCLUSIONS: Sex differences play an important role in nsCP prevalence in patients with ESUS. These findings may have important implications for the management in targeted secondary prevention following ESUS.

Impact of high-power short-duration atrial fibrillation ablation technique on the incidence of silent cerebral embolism: a prospective randomized controlled study.

BACKGROUND: High-power short-duration (HPSD) ablation strategy has emerged as a popular approach for treating atrial fibrillation (AF), with shorter ablation time. The utilized Smart Touch Surround Flow (STSF) catheter, with 56 holes around the electrode, lowers electrode-tissue temperature and thrombus risk. Thus, we conducted this prospective, randomized study to investigate if the HPSD strategy with STSF catheter in AF ablation procedures reduces the silent cerebral embolism (SCE) risk compared to the conventional approach with the Smart Touch (ST) catheter. METHODS: From June 2020 to September 2021, 100 AF patients were randomized 1:1 to the HPSD group using the STSF catheter (power set at 50 W) or the conventional group using the ST catheter (power set at 30 to 35 W). Pulmonary vein isolation was performed in all patients, with additional lesions at operator's discretion. High-resolution cerebral diffusion-weighted magnetic resonance imaging (hDWI) with slice thickness of 1 mm was performed before and 24-72 h after ablation. The incidence of new periprocedural SCE was defined as the primary outcome. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) test. RESULTS: All enrolled AF patients (median age 63, 60% male, 59% paroxysmal AF) underwent successful ablation. Post-procedural hDWI identified 106 lesions in 42 enrolled patients (42%), with 55 lesions in 22 patients (44%) in the HPSD group and 51 lesions in 20 patients (40%) in the conventional group (p = 0.685). No significant differences were observed between two groups regarding the average number of lesions (p = 0.751), maximum lesion diameter (p = 0.405), and total lesion volume per patient (p = 0.669). Persistent AF and CHA2DS2-VASc score were identified as SCE determinants during AF ablation procedure by multivariable regression analysis. No significant differences in MoCA scores were observed between patients with SCE and those without, both immediately post-procedure (p = 0.572) and at the 3-month follow-up (p = 0.743). CONCLUSIONS: Involving a small sample size of 100 AF patients, this study reveals a similar incidence of SCE in AF ablation procedures, comparing the HPSD strategy using the STSF catheter to the conventional approach with the ST catheter. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04408716. AF = Atrial fibrillation, DWI = Diffusion-weighted magnetic resonance imaging, HPSD = High-power short-duration, ST = Smart Touch, STSF = Smart Touch Surround Flow.

Incidence and predictors of stroke and silent cerebral embolism following very high-power short-duration atrial fibrillation ablation.

AIMS: Cerebral thrombo-embolism is a dreaded complication of pulmonary vein isolation (PVI) for atrial fibrillation; its surrogate, silent cerebral embolism (SCE) can be detected by diffusion-weighted brain magnetic resonance imaging (bMRI). Initial investigations have raised a concern that very high-power, short-duration (vHPSD; 90 W/4 s) temperature-controlled PVI with the QDOT Micro catheter may be associated with a higher incidence of SCE compared with low-power long-duration ablation. We aimed to assess the incidence of procedural complications of vHPSD PVI with an emphasis on cerebral safety. METHODS AND RESULTS: We enrolled 328 consecutive patients undergoing their PVI procedure using vHPSD. A subgroup of 61 consecutive patients underwent diffusion-weighted bMRI within 24 h of the procedure, and incidence and predictors of SCE were studied. The mean procedure time and left atrial dwell time for the overall cohort were 69.6 ± 24.1 and 46.5 ± 21.5 min, respectively. First-pass isolation was achieved in 82%. No stroke or transient ischaemic attack occurred. Silent cerebral embolism was identified in 5 of 61 patients (8.2%). Silent cerebral embolism following procedures was significantly associated with lower baseline generator impedance (105.8 vs. 112.6 Ω, P < 0.0001) and with intermittent loss of catheter-tissue contact during ablation (14.1% vs. 6.1%, P < 0.0001). CONCLUSION: Very high-power, short-duration PVI is a safe technique with an excellent acute success rate. Silent cerebral embolism incidence in our cohort was below the previously reported range, with no clinically overt cerebral complications. Lower baseline generator impedance and loss of contact during ablation may contribute to a higher risk of SCEs.

Non-stenosing carotid artery plaques in embolic stroke of undetermined source: a retrospective analysis.

BACKGROUND: We aim to identify the association between high-risk carotid plaques and their laterality to stroke in ESUS patient population. We also discuss recurrent stroke events and their laterality to the index stroke. METHODS: This was a retrospective study. We reviewed data for patients with ESUS between June 20, 2016, and June 20, 2021. Using computed tomography angiography, we analyzed plaque features that are associated with ESUS, and then, we identified the recurrent stroke events and characterized lateralization to the index stroke. RESULTS: Out of 1779 patients with cryptogenic ischemic stroke, we included 152 patients who met the criteria for ESUS. High-risk plaque features were found more often ipsilateral to the stroke side when compared contralaterally: plaque ulceration (19.08% vs 5.26%, p < .0001), plaque thickness > 3 mm (19.08% vs 7.24%, p = 0.001), and plaque length > 1 cm (13.16% vs 5.92%, p = 0.0218). There was also a significant difference in plaque component in which both components (soft and calcified) and only soft plaques were more prevalent ipsilaterally (42.76% vs 23.68% and 17.76% vs 9.21%, respectively, p < .0001). Of the 152 patients, 17 patients were found to have a recurrent stroke event, and 47% (n = 8) had an ipsilateral stroke to the index event. Moreover, stroke was bilateral in 41% of the patients (n = 7), and contralateral in 12% (n = 2). CONCLUSION: High-risk plaque features studied here were more prevalent ipsilaterally to the stroke side in ESUS than contralaterally. Multicenter studies are needed to form precise prediction models and scoring systems to help guide treatment, i.e., choice of medical therapy and/or revascularization.

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

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

Age Alters Prevalence of Left Atrial Enlargement and Nonstenotic Carotid Plaque in Embolic Stroke of Undetermined Source.

BACKGROUND: Nonstenotic carotid plaque and undetected atrial fibrillation are potential mechanisms of embolic stroke of undetermined source (ESUS), but it is unclear which is more likely to be the contributing stroke mechanism. We explored the relationship between left atrial enlargement (LAE) and nonstenotic carotid plaque across age ranges in an ESUS population. METHODS: A retrospective multicenter cohort of consecutive patients with unilateral, anterior circulation ESUS was queried (2015 to 2021). LAE and plaque thickness were determined by transthoracic echocardiography and computed tomography angiography, respectively. Descriptive statistics were used to compare plaque features in relation to age and left atrial dimensions. RESULTS: Among the 4155 patients screened, 273 (7%) met the inclusion criteria. The median age was 65 years (interquartile range [IQR] 54-74), 133 (48.7%) were female, and the median left atrial diameter was 3.5 cm (IQR 3.1-4.1). Patients with any LAE more frequently had hypertension (85.9% versus 67.2%, P<0.01), diabetes (41.0% versus 25.6%, P=0.01), dyslipidemia (56.4% versus 40.0%, P=0.01), and coronary artery disease (22.8% versus 11.3%, P=0.02). Carotid plaque thickness was greater ipsilateral versus contralateral to the stroke hemisphere in the overall cohort (median 1.9 mm [IQR 0-3] versus 1.5 mm [IQR 0-2.6], P<0.01); however, this was largely driven by the subgroup of patients without any LAE (median 1.8 mm [IQR 0-2.9] versus 1.5 mm [IQR 0-2.5], P<0.01). Compared with patients ≥70 years, younger patients had more carotid plaque ipsilateral versus contralateral (mean difference 0.42 mm±1.24 versus 0.08 mm±1.54, P=0.047) and less moderate-to-severe LAE (6.3% versus 15.3%, P=0.02). CONCLUSIONS: Younger patients with ESUS had greater prevalence of ipsilateral nonstenotic plaque, while the elderly had more LAE. The differential effect of age on the probability of specific mechanisms underlying ESUS should be considered in future studies.

Stroke events after transcatheter aortic valve implantation: Temporal relationships and affected brain regions.

BACKGROUND: Despite continuous improvements in transcatheter aortic valve implantation (TAVI), periprocedural strokes remain a devastating complication. Randomized controlled trials failed to demonstrate a reduction in clinically apparent strokes or mortality after TAVI due to cerebral embolic protection (CEP). To identify potential targets of CEP strategies during TAVI, we evaluated affected brain regions, and temporal patterns of stroke onset in a routine clinical sample. METHODS AND RESULTS: A total of 3,164 consecutive patients treated with TAVI from 2008 to 2019 at a single center were screened for cerebrovascular events. Affected cerebral regions were determined according to clinical symptoms and brain imaging. Rates of disabling stroke and non-disabling stroke at 30 days were 2.2% and 1.4%, respectively. The frequency of all strokes decreased from 5.0% to 3.0% over time (P = .012). Patients with impaired left-ventricular function (OR 2.19), increased CHA2DS2-VASc (OR 1.39) and moderate/severe spontaneous echo contrast (OR 3.60) had a higher stroke risk. Acute symptom onset occurred during TAVI (19.4%), within 24 hours (40.3%) or later (25.0%); 98.3% of strokes were of ischemic origin. In intraprocedural strokes, 53.2% of lesions were found in locations considered protected by current CEP devices, and 37.5% of patients with intraprocedural strokes were exclusively affected in these areas. Baseline or procedural parameters were not associated with embolic distribution patterns. CONCLUSIONS: Most strokes occurred early after TAVI - but not necessarily during the procedure - and affected multiple brain regions only partially protected by current CEP devices. Efficient prevention of cerebrovascular events may require strategies beyond the TAVI procedure to minimize stroke risk and additional randomized controlled trials will be required to clarify the role of CEP in efficient stroke prevention during TAVI.

Cerebral embolic protection and severity of stroke following transcatheter aortic valve replacement.

BACKGROUND: The cerebral embolic protection (CEP) device captures embolic debris during transcatheter aortic valve replacement (TAVR). However, the impact of CEP on stroke severity following TAVR remains unclear. Therefore, we aimed to examine whether CEP was associated with reduced severity of stroke following TAVR. METHODS: This was a retrospective cohort study of 2839 consecutive patients (mean age: 79.2 ± 9.5 years, females: 41.5%) who underwent transfemoral TAVR at our institution between 2013 and 2020. We categorized patients into Sentinel CEP users and nonusers. Neuroimaging data were reviewed and the final diagnosis of a cerebrovascular event was adjudicated by a neurologist blinded to the CEP use or nonuse. We compared the incidence and severity (assessed by the National Institutes of Health Stroke Scale [NIHSS]) of stroke through 72 h post-TAVR or discharge between the two groups using stabilized inverse probability of treatment weighting (IPTW) of propensity scores. RESULTS: Of the eligible patients, 1802 (63.5%) received CEP during TAVR and 1037 (36.5%) did not. After adjustment for patient characteristics by stabilized IPTW, the rate of overall stroke was numerically lower in CEP users than in CEP nonusers, but the difference did not reach statistical significance (0.49% vs. 1.18%, p = 0.064). However, CEP users had significantly lower rates of moderate-or-severe stroke (NIHSS ≥ 6: 0.11% vs. 0.69%, p = 0.013) and severe stroke (NIHSS ≥ 15: 0% vs. 0.29%, p = 0.046). Stroke following CEP use (n = 8), compared with stroke following CEP nonuse (n = 15), tended to carry a lower NIHSS (median [IQR], 4.0 [2.0-7.0] vs. 7.0 [4.5-19.0], p = 0.087). Four (26.7%) out of 15 patients with stroke following CEP nonuse died within 30 days, with no death after stroke following CEP use. CONCLUSIONS: CEP use may be associated with attenuated severity of stroke despite no significant difference in overall stroke incidence compared with CEP nonuse. This finding is considered hypothesis-generating and needs to be confirmed in large prospective studies.

Micro-Embolic Signals and Dissection: Association or Causation for Stroke? A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Although the mechanism of stroke in cervical artery dissection (CAD) has been hypothesized to be embolization rather than hemodynamic compromise, there are a limited number of studies supporting this hypothesis. Detection of micro-embolic signals (MESs) using transcranial Doppler (TCD) helps in understanding the mechanism in these patients. A systematic review and meta-analysis were performed to estimate the prevalence of MES and its association with stroke outcomes in patients with acute stroke/TIA secondary to dissection. METHODS: A comprehensive literature search was conducted for studies before January 26, 2021, in PubMed, Embase, Google Scholar, Cochrane Library, and ClinicalTrials.gov. Studies were identified that used TCD to detect MES in stroke/TIA patients secondary to CAD. Pooled prevalence was calculated. Entire statistical analysis was conducted in R version 3.6.2. RESULTS: Eleven studies involving 112 patients (50 MES+, 62 MES-) were included in our meta-analysis. The pooled prevalence of MES among acute stroke/TIA patients secondary to dissection was 46.0% (95% CI 26.0-67.0%). The presence of MES was associated with an increased risk of early ischemic recurrence in patients with CAD. We could not estimate the functional outcome and mortality associated with the presence of MES due to the scarcity of data. CONCLUSIONS: Our meta-analysis showed 46% prevalence of MES in the studies which looked at acute stroke/TIA secondary to CAD using TCD. This finding supports the assumption that embolism may be a major cause of stroke in patients with dissection although this could be determined only in a small population.

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.

Data-driven machine-learning analysis of potential embolic sources in embolic stroke of undetermined source.

BACKGROUND AND PURPOSE: Hierarchical clustering, a common 'unsupervised' machine-learning algorithm, is advantageous for exploring potential underlying aetiology in particularly heterogeneous diseases. We investigated potential embolic sources in embolic stroke of undetermined source (ESUS) using a data-driven machine-learning method, and explored variation in stroke recurrence between clusters. METHODS: We used a hierarchical k-means clustering algorithm on patients' baseline data, which assigned each individual into a unique clustering group, using a minimum-variance method to calculate the similarity between ESUS patients based on all baseline features. Potential embolic sources were categorised into atrial cardiopathy, atrial fibrillation, arterial disease, left ventricular disease, cardiac valvulopathy, patent foramen ovale (PFO) and cancer. RESULTS: Among 800 consecutive ESUS patients (43.3% women, median age 67 years), the optimal number of clusters was four. Left ventricular disease was most prevalent in cluster 1 (present in all patients) and perfectly associated with cluster 1. PFO was most prevalent in cluster 2 (38.9% of patients) and associated significantly with increased likelihood of cluster 2 [adjusted odds ratio: 2.69, 95% confidence interval (CI): 1.64-4.41]. Arterial disease was most prevalent in cluster 3 (57.7%) and associated with increased likelihood of cluster 3 (adjusted odds ratio: 2.21, 95% CI: 1.43-3.13). Atrial cardiopathy was most prevalent in cluster 4 (100%) and perfectly associated with cluster 4. Cluster 3 was the largest cluster involving 53.7% of patients. Atrial fibrillation was not significantly associated with any cluster. CONCLUSIONS: This data-driven machine-learning analysis identified four clusters of ESUS that were strongly associated with arterial disease, atrial cardiopathy, PFO and left ventricular disease, respectively. More than half of the patients were assigned to the cluster associated with arterial disease.

The role of haematological traits in risk of ischaemic stroke and its subtypes.

Thrombosis and platelet activation play a central role in stroke pathogenesis, and antiplatelet and anticoagulant therapies are central to stroke prevention. However, whether haematological traits contribute equally to all ischaemic stroke subtypes is uncertain. Furthermore, identification of associations with new traits may offer novel treatment opportunities. The aim of this research was to ascertain causal relationships between a wide range of haematological traits and ischaemic stroke and its subtypes. We obtained summary statistics from 27 published genome-wide association studies of haematological traits involving over 375 000 individuals, and genetic associations with stroke from the MEGASTROKE Consortium (n = 67 000 stroke cases). Using two-sample Mendelian randomization we analysed the association of genetically elevated levels of 36 blood cell traits (platelets, mature/immature red cells, and myeloid/lymphoid/compound white cells) and 49 haemostasis traits (including clotting cascade factors and markers of platelet function) with risk of developing ischaemic (AIS), cardioembolic (CES), large artery (LAS), and small vessel stroke (SVS). Several factors on the intrinsic clotting pathway were significantly associated (P < 3.85 × 10-4) with CES and LAS, but not with SVS (e.g. reduced factor VIII activity with AIS/CES/LAS; raised factor VIII antigen with AIS/CES; and increased factor XI activity with AIS/CES). On the common pathway, increased gamma (γ') fibrinogen was significantly associated with AIS/CES. Furthermore, elevated plateletcrit was significantly associated with AIS/CES, eosinophil percentage of white cells with LAS, and thrombin-activatable fibrinolysis inhibitor activation peptide antigen with AIS. We also conducted a follow-up analysis in UK Biobank, which showed that amongst individuals with atrial fibrillation, those with genetically lower levels of factor XI are at reduced risk of AIS compared to those with normal levels of factor XI. These results implicate components of the intrinsic and common pathways of the clotting cascade, as well as several other haematological traits, in the pathogenesis of CES and possibly LAS, but not SVS. The lack of associations with SVS suggests thrombosis may be less important for this stroke subtype. Plateletcrit and factor XI are potentially tractable new targets for secondary prevention of ischaemic stroke, while factor VIII and γ' fibrinogen require further population-based studies to ascertain their possible aetiological roles.

Clinical phenotypes of embolic strokes of undetermined source.

BACKGROUND AND PURPOSE: The embolic stroke of undetermined source (ESUS) represents a heterogeneous clinical entity. The aim of this study was to investigate whether distinct clinical phenotypes may be identified in the ESUS population. METHODS: We retrospectively identified consecutive patients hospitalized for acute ischemic stroke who met the ESUS diagnostic criteria. Baseline characteristics and diagnostic workup findings were collected. Hierarchical cluster analysis was carried out to classify clinical features and identify different groups of ESUS patients. RESULTS: One hundred twenty-seven patients with a mean age of 68.6 (12.5) years were included. Three main clusters were identified. The first cluster associated young age, male sex, presence of patent foramen ovale, and posterior circulation infarct. The second phenotype linked hypertension, severe stroke, left atrial cardiopathy, diabetes mellitus, and involvement of multiple vascular territories. The third cluster gathered smoking, dyslipidemia, ipsilateral vulnerable sub-stenotic carotid plaque, and infarct of anterior vascular territory. CONCLUSIONS: Distinct clinical phenotypes have been identified within the ESUS population, which may supply clues to the underlying pathogenic mechanisms.

Prevalence and predictors of atrial fibrillation in patients with embolic stroke of undetermined source: a real-life single-center retrospective study.

INTRODUCTION: Up to one-third of ischemic strokes remained cryptogenic despite extensive investigations. Atrial fibrillation may be detected in a significant proportion of patients with embolic stroke of undetermined source, particularly after the introduction of implantable loop recorder in clinical practice. METHODS: We retrospectively included all the consecutive patients with embolic stroke of undetermined source referred to our units in the period November 2013 to December 2018 and in which an implantable loop recorder was positioned within 6 months from stroke event. Prevalence and predictors of atrial fibrillation were investigated. RESULTS: One hundred thirty-eight patients with embolic stroke of undetermined source fulfilling inclusion criteria were identified. The crude prevalence of atrial fibrillation at the end of observation period was of 45.7%. Incidence rates at 6, 12, 18, 24, and 36 months resulted, respectively, 31.8% (95% CI, 30.4-46.7), 38.0% (95% CI, 30.4-46.9), 42.6% (95% CI, 34.5-51.6), 46.6% (95% CI, 38.2-55.8), and 50.4% (95% CI, 41.6-59.9). On multivariate analysis, only excessive supraventricular electric activity and left atrial enlargement resulted to be significant predictors of atrial fibrillation (p = 0.037 and p < 0.0001, respectively). CONCLUSIONS: Atrial fibrillation may be detected in a relevant proportion (up to 50%) of patients with embolic stroke of undetermined source if a careful and extensive diagnostic work-up is employed. Excessive supraventricular electric activity and left atrial enlargement are significant predictors of the occurrence of atrial fibrillation in these patients.

Cerebral Microembolism in Intracerebral Hemorrhage: A Prospective Case-Control Study.

BACKGROUND: Small and remote acute ischemic lesions may occur in up to one-third of patients with spontaneous intracerebral hemorrhage (ICH). Possible mechanisms include cerebral embolism, small vessel disease, blood pressure variability and others. The embolic mechanism has not been adequately studied. Using transcranial Doppler (TCD), we assessed the incidence of spontaneous microembolic signals (MESs) in patients with acute ICH. METHODS: Twenty acute ICH patients were prospectively evaluated within 48 h of hospital admission. Clinical and imaging data were collected. Continuous TCD monitoring was performed in both middle cerebral arteries for a one-hour period on days 1, 3 and 7 of hospital admission. Monitoring was performed in the emergency room, ICU or ward, according to patient location. We compared the frequency and risk factors for MES in patients with ICH and in 20 age- and gender-matched controls without history of ischemic or hemorrhagic stroke. RESULTS: The mean age was 57.5 ± 14.1 years, and 60% were male. MESs were detected in 7 patients with ICH and in one control patient without ICH (35% vs 5%, p = 0.048). The frequency of MES on day 1 was 15% (3 of 20 patients), on day 3, 26% (5 of 19 patients) and on day 7, 37.5% (3 of 8 patients). Among patients with ICH, those with MES had a tendency to higher frequencies of dyslipidemia (83% vs 33%, p = 0.13) and lobar location of hemorrhages (71% vs 30%, p = 0.15). Two out of 6 patients with ICH who also underwent MRI had remote DWI lesions, of whom one showed MES on TCD. CONCLUSION: Micro-embolic signals occur in over one-third of patients with ICH. Further research is needed to identify the sources of cerebral microembolism and their relationship with small acute infarcts in ICH.

Stroke Etiology Modifies the Effect of Endovascular Treatment in Acute Stroke.

Background and Purpose- Stroke etiology drives thrombus composition. We thus hypothesized that endovascular treatment shows different efficacy in cardioembolic versus noncardioembolic large-vessel occlusions (LVOs). Methods- Procedural characteristics, grade of reperfusion, and functional outcome at discharge and 90 days were compared between patients with cardioembolic versus noncardioembolic LVO from the GSR-ET (German Stroke Registry-Endovascular Treatment; n=2589). To determine associations with functional outcome, adjusted odds ratios and 95% CIs were calculated using ordinal multivariable logistic regression models adjusting for potential baseline confounder variables. Results- Endovascular treatment of cardioembolic LVO had a higher rate of successful reperfusion (85.6% versus 81.0%; P=0.002) and a higher rate of complete reperfusion after a single thrombectomy pass (45.7% versus 38.1%; P<0.001) compared with noncardioembolic LVO. Cardioembolic LVO was associated with better functional outcome at discharge (adjusted odds ratio, 1.61 [95% CI, 1.37-1.88]) and 90 days (adjusted odds ratio, 1.29 [95% CI, 1.09-1.53]). In mediation analysis, reperfusion explained 47% of the effect of etiology on functional outcome at discharge. Conclusions- These results provide evidence for higher efficacy of endovascular treatment in cardioembolic LVO compared with noncardioembolic LVO.

Prevalence of Microembolic Signals in Embolic Stroke of Undetermined Source and Other Subtypes of Ischemic Stroke.

Background and Purpose- Embolic stroke of undetermined source (ESUS) has been proposed to cause thromboembolic infarction from unknown but potential embolic sources. However, an embolus remains undetected in ESUS. The goal of this study was to characterize the prevalence and risk factors of microembolic signals (MESs) in ESUS. Methods- We examined 108 patients with acute ischemic stroke in the internal carotid artery territory or transient ischemic attack within 14 days of symptom onset and who were admitted to our hospital between April 2017 and March 2019. MESs were monitored in the middle cerebral artery on transcranial Doppler for 60 minutes. We examined the prevalence and number of MES in ESUS and other stroke subtypes, such as cardioembolism, large artery atherosclerosis, cerebral small vessel disease, and transient ischemic attack. The present study was registered in University Hospital Medical Information Network Clinical Trials Registry (UMIN000031913). Results- MESs were detected in 33 (31%) of 108 patients. ESUS showed the highest proportion (12/24 [50%]), followed by large artery atherosclerosis (8/20 [40%]), cardioembolism (6/18 [33%]), transient ischemic attack (4/24 [17%]), and cerebral small vessel disease (3/21 [14%]). Univariate analysis showed that higher systolic blood pressure, body mass index, hemoglobin A1c, and ESUS were significantly associated with MES. In multiple logistic regression analysis, ESUS remained significantly associated with MES after adjustment for described covariates from univariate analysis (odds ratio, 2.86 [95% CI, 1.01-8.08]). Conclusions- This study demonstrated significant association of ESUS with MES, supporting the embolic nature of this stroke subtype. Registration- URL: https://upload.umin.ac.jp. Unique identifier: UMIN000031913.

External Performance of the HAVOC Score for the Prediction of New Incident Atrial Fibrillation.

Background and Purpose- The HAVOC score (hypertension, age, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, coronary artery disease) was proposed for the prediction of atrial fibrillation (AF) after cryptogenic stroke. It showed good model discrimination (area under the curve, 0.77). Only 2.5% of patients with a low-risk HAVOC score (ie, 0-4) were diagnosed with new incident AF. We aimed to assess its performance in an external cohort of patients with embolic stroke of undetermined source. Methods- In the AF-embolic stroke of undetermined source dataset, we assessed the discriminatory power, calibration, specificity, negative predictive value, and accuracy of the HAVOC score to predict new incident AF. Patients with a HAVOC score of 0 to 4 were considered as low-risk, as proposed in its original publication. Results- In 658 embolic stroke of undetermined source patients (median age, 67 years; 44% women), the median HAVOC score was 2 (interquartile range, 3). There were 540 (82%) patients with a HAVOC score of 0 to 4 and 118 (18%) with a score of ≥5. New incident AF was diagnosed in 95 (14.4%) patients (28.8% among patients with HAVOC score ≥5 and 11.3% among patients with HAVOC score 0-4 [age- and sex-adjusted odds ratio, 2.29 (95% CI, 1.37-3.82)]). The specificity of low-risk HAVOC score to identify patients without new incident AF was 88.7%. The negative predictive value of low-risk HAVOC score was 85.1%. The accuracy was 78.0%, and the area under the curve was 68.7% (95% CI, 62.1%-73.3%). Conclusions- The previously reported low rate of AF among embolic stroke of undetermined source patients with low-risk HAVOC score was not confirmed in our cohort. Further assessment of the HAVOC score is warranted before it is routinely implemented in clinical practice.

Age-related burden and characteristics of embolic stroke of undetermined source in the real world clinical practice.

Few data are available on age-related burden and characteristics of embolic stroke of undetermined source (ESUS) in the real world clinical practice. The aim of our study was to provide information about it. We retrospectively analyzed data of patients consecutively admitted to our Stroke Unit along 1 year (2017, November 1st-2018, October 31st). The etiology of ischemic stroke was defined at hospital discharge; ESUS was considered as a subset of cryptogenic stroke, and defined according to the 2014 international criteria. In the analyzed period, 306 patients, 52.3% females, mean age ± SD 77.9 ± 11.9 years, were discharged with diagnosis of ischemic stroke. Ischemic strokes of cardioembolic and lacunar origin were the most frequent subtypes: 30.1% and 29.4%, respectively. Cardioembolic strokes were particularly frequent in patients ≥ 75 years, and almost always associated with atrial fibrillation. Overall, in 80 patients (26.1%) the etiology of stroke was undetermined; in 25 (8.2%) it remained undefined because of death or severe comorbidity, making further diagnostic work-up not worthy. Cryptogenic stroke occurred in 55 patients (18%), and ESUS criteria were satisfied in 39 of them (12.7%). According to age, cryptogenic stroke was diagnosed in 21.1% (21.1% ESUS) of patients < 65 years, 24.2% (19.4% ESUS) of patients aged 65-74 years, 15.5% (9.2% ESUS) of patients ≥ 75 years. After diagnostic work-up, patent foramen ovale was most commonly associated with ESUS (17.9%), especially in patients < 65 years (62.5%); covert paroxysmal atrial fibrillation was detected in 10.5% of ESUS patients ≥ 75 years. In the real world clinical practice, the frequency of ischemic strokes of undetermined etiology, and of those satisfying ESUS criteria, is not negligible, especially in younger patients. A thorough diagnostic work-up, with an age-specific approach, is therefore necessary and of the utmost importance for the identification of stroke etiology, in order to optimize secondary stroke prevention strategies.

The ASCOD Phenotyping of Embolic Strokes of Undetermined Source.

BACKGROUND AND PURPOSE: Various pathogenesis are presumed to be involved in the etiology of embolic stroke of undetermined source (ESUS), which has a high recurrence rate, and much remains unknown about the clinical subtype of recurrent stroke. The purpose of this study was to clarify the pathogenesis of ESUS using the ASCOD classification for ESUS patients and to examine the factors involved in the recurrence of ischemic stroke. METHODS: The subjects of this study were 236 of these patients who fulfilled the criteria for ESUS. The rate of stroke recurrent, subtype of recurrent ischemic stroke, and new-onset atrial fibrillation (AF) in these patients were surveyed retrospectively, and each patient was graded for the A, S, and C categories of the ASCOD classification. RESULTS: Ischemic stroke recurred in 32 patients during the follow-up period (7 days to 12.9 years [median 54.3 months]), and new-onset AF was seen in 44 (18.6%) patients. The most subtype of recurrent ischemic stroke was ESUS again (19 patients). Multivariate analysis with a Cox proportional hazards model, the S score (hazard ratio 5.21; 95% confidence interval (CI) 2.38-11.42; P < .001) and the number of A, S, C categories (hazard ratio 1.90; 95% CI 1.14-3.10; P = .013) were factors significantly related to recurrent ischemic stroke. CONCLUSIONS: Assessment of comorbid conditions in ESUS patients based on the ASCOD classification may be useful in predicting the likelihood of recurrence of ischemic stroke.