Stroke Of Undetermined Source Research Articles

Differences in Left atrial stain, endothelial glycocalyx, arterial elasticity and myocardial efficiency between ESUS, lacunar and atherosclerotic type of stroke

Abstract Background and aims Patients with stroke are at high risk to develop cardiovascular complications. We assessed endothelial glycocalyx, aortic elastic properties, left atrial and ventricular function in patients with lacunar, atherosclerotic and stroke of undetermined source (ESUS). Patients and methods In 111 patients (age 57,1±10.6) with acute cerebral stroke (37 lacunar, 36 atherosclerotic and 38 ESUS) and 20 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5–25 μm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) Left atrial (LA) strain using speckle-tracking imaging, (4) left ventricular global longitudinal strain and (5) left ventricular myocardial work index (GWI), constructive work (GCW), wasted work (GWW) and work efficiency (GWE). Results Compared with controls, patients with stroke had higher PWV (11.74±3.18 vs 9.61±1.28 m/sec, p=0.003), PBR (2.16±0.28 vs 1.94±0.20, p=0.029) and central SBP (142±25 vs 121±17 mmHg, p=0.025), while ventricular (−18.31±3.21 vs −20.89±2.45%, p=0.001) and atrial deformation (28.59±6.99 vs 37.05±5.08%, p<0.001) were impaired in patients with stroke (p<0.05). GWI and GCW were similar between two groups and GWW and GWE were worse in patients with stroke (106.98±81.52 vs 68.92±36.52 mmHg%, p=0.022, 94.00±4.51 vs 96.46±1.75%, p=0.007, respectively). LA reservoir strain and contraction strain were more impaired in patients with thromboembolic strain compared to other 2 stroke types (ESUS 30.55±6.02%, −15.57±3.57%, Lacunar 28.19±6.92%, −13.76±3,74%, atherosclerotic 24.73±7.86%, −12.65±2,53%, p<0.05). Regarding endothelial glycocalyx, PBR5–25 was similar between all stroke types (ESUS 2.12±0.21 μm, LACUNAR 2.23±0.32 μm, ATHEROSCLEROTIC 2.11±0.30 μm, p>0.05). PWV was significantly higher in patients with atherosclerotic stroke (13.50±3.83 m/sec, p=0.007), while in patients with lacunar (11.31±3.01 m/sec) and in ESUS patients it was mildly elevated (11.66±2.63 m/sec). Despite there was no significant difference in GWI, GCW and GWW between patients with different types of stroke, GWE was higher in patients with ESUS (95.41±2.32%) than in patients with lacunar 92.86±6.13%) and atherothrombotic stoke (92.27±6.21%) (p<0.05). Conclusions Patients with stroke have impaired atrial strain, endothelial glycocalyx and arterial elasticity, compared with controls. Arterial stiffness and LA deformation are more affected in atherosclerotic stroke, while GWE is preserved in ESUS patients. Funding Acknowledgement Type of funding sources: None.

Advances in Stroke: Genetics, Genomics, Precision Medicine.

Advances in Stroke: Genetics, Genomics, Precision Medicine.

Diagnostic and Prognostic Value of Left Atrial Function in Identification of Cardioembolism and Prediction of Outcomes in Patients with Cryptogenic Stroke

Stroke of undetermined source, commonly termed cryptogenic stroke (CS), accounts for a significant proportion of ischemic stroke etiology and have high rates of stroke recurrence. The heterogeneous etiology of CS makes decisions regarding treatment for such patients challenging. The aim of this study was to evaluate the diagnostic and prognostic value of left atrial (LA) function in the identification of cardioembolism and prediction of outcomes in patients with CS. Consecutive patients admitted to a tertiary institution with ischemic stroke or transient ischemic attack (TIA) who underwent transthoracic echocardiography were recruited, with comprehensive evaluation of LA metrics including LA strain. Ischemic strokes and TIAs were classified as noncardioembolic, cryptogenic, or cardioembolic. A total of 709 patients (mean age, 66.0±15.1years; 55% men) were recruited. Two hundred ninety-one patients had CS, 189 had noncardioembolic stroke, and 229 had cardioembolic stroke. Patients with CS were followed for 20.0±13.8months for recurrent ischemic stroke or TIA. Receiver operating characteristic curves showed LA reservoir and contractile strain to be strong discriminators of cardioembolic strokes, and log-rank tests showed both measures to be significantly associated with the distribution of time to recurrent ischemic stroke or TIA in patients with CS. Multivariable hazard models showed LA reservoir and contractile strain to be independent predictors of recurrent ischemic stroke or TIA in patients with CS, in addition to estimated glomerular filtration rate and active smoking. LA reservoir and contractile strain were strong discriminators of cardioembolic stroke and independently predicted recurrent ischemic stroke or TIA in patients with CS. Use of LA strain may improve risk stratification and decision-making in patients with CS, with particular regard to prolonged ambulatory heart rhythm monitoring and/or empiric anticoagulation.

Het nut van implanteerbare looprecorders na een embolische beroerte van ongekende oorsprong

The use of implantable loop recorders after embolic stroke of undetermined source Unknown intermittent atrial fibrillation (AF) is a potential source of embolism in patients with embolic stroke of undetermined source (ESUS). Prolonged heart rhythm monitoring with implantable loop recorders (ILR) could increase the detection of AF. Patients with detected (subclinical) AF may benefit from a therapy with anticoagulants after ESUS. The authors of this article performed a retrospective analysis of patients who received an ILR after suspected ESUS at the University Hospitals of Leuven (Belgium) between April 2008 and March 2019. They describe the proportion of patients in whom AF was detected and studied the predictors of AF detection. With prolonged monitoring, the AF detection rate increased, mainly in the first 2 years after implantation. AF was detected in 28 out of 84 patients (33.3%) after a median follow-up of 8 months. Patients with AF were significantly older and tended to have more arterial hypertension. All patients with detected AF received oral anticoagulation. Although a 24-hour Holter monitoring and a week recorder were negative for AF detection, an ILR established (subclinical) AF in 1 out of 3 patients after ESUS.

Potential Embolic Sources Differ in Patients With Embolic Stroke of Undetermined Source According to Age: A 15-Year Study.

IntroductionUnderstanding the potential embolic source in young patients with ESUS may improve the diagnosis and treatment of such patients.HypothesisPotential embolic sources (PES) differ in young vs. older patients with ESUS, and, therefore, not all patients with ESUS have the same risk profile for stroke recurrence.MethodsYoung patients (age 18-49) with ESUS, who were admitted to our stroke center from 2006 to 2019, were identified retrospectively and matched with next consecutive older patients (age 50–99) with ESUS by admission date. PES were categorized as atrial cardiopathy, AFib diagnosed during follow-up, left ventricular disease (LVD), cardiac valvular disease (CVD), PFO or atrial septal aneurysm (ASA), and arterial disease. Patients, who had cancer or thrombophilia, were excluded. The type and number of PES and stroke recurrence rates were determined and compared between young and older patients.ResultsIn young patients (55.3% women, median age 39 years), the most common PES was PFO/ASA, and the rate of other PES was low (2–7%). Half of the young patients (54.1%) had a single PES, only 10% had multiple PES, and 35.3% of young patients did not have any PES identified. In older patients (41.7% women, median age 74 years), the 3 most common PES were atrial cardiopathy (38.1%), LVD (35.7%), and arterial disease (23.8%). Nearly half of older patients (42.9%) had multiple PES. The rate of stroke recurrence tended to be lower in young patients as compared to older patients (4.9 vs. 11.4%, p = 0.29). During a median follow-up of 3 years, only 3 young patients (4.9%) had a recurrent stroke, and two of them had unclosed PFO. There were no recurrent strokes among young patients with no PES identified.ConclusionsIt was noted that PES differ in patients with ESUS according to age and differences in recurrence. PFO is the only common PES in young patients with ESUS. Future studies prospectively evaluating PES in both age groups are needed.

The Relationship Between Aortic Arch Calcification and Recurrent Stroke in Patients With Embolic Stroke of Undetermined Source-A Case-Control Study.

BackgroundAortic arch calcification (AoAC) is associated with plaque development and cardiovascular events. We aimed to estimate the predictive value of AoAC for stroke recurrence in patients with embolic stroke of undetermined source (ESUS).MethodsConsecutive patients with ESUS who were admitted to our center between October 2019 and October 2020 and who had a 1-year follow-up of stroke recurrence were retrospectively reviewed. According to our AoAC grading scale (AGS), AoAC was classified into four grades based on chest computed tomography (CT) findings: no visible calcification (grade 0), spotty calcification (grade 1), lamellar calcification (grade 2), and circular calcification (grade 3).ResultsOf the 158 patients with ESUS (age, 62.1 ± 14.5 years; 120 men) enrolled, 24 (15.2%) had recurrent stroke within a 1-year follow-up. The Cox regression analysis showed that stroke history [hazard ratio (HR), 4.625; 95% confidence interval (CI), 1.828–11.700, p = 0.001] and AoAC (HR, 2.672; 95% CI, 1.129–6.319; p = 0.025) predicted recurrent stroke. AGS grade 1 was associated with a significantly higher risk of stroke recurrence than AGS grade 0 (HR, 5.033; 95% CI, 1.858–13.635, p = 0.001) and AGS grade 2 plus 3 (HR, 3.388; 95% CI, 1.124–10.206, p = 0.030). In patients with AoAC, receiver operating characteristic (ROC) analysis showed that AGS had a good value in predicting stroke recurrence in patients with ESUS, with an area under curve (AUC) of 0.735 (95% CI = 0.601–0.869, p = 0.005).ConclusionsAortic arch calcification, especially spotty calcification, had a good predictive value for stroke recurrence in patients with ESUS.

Young Adults with Embolic Stroke of Undetermined Source Have Low Rate of Recurrent Stroke

Young Adults with Embolic Stroke of Undetermined Source Have Low Rate of Recurrent Stroke

Transthoracic echocardiography indices as a biomarker in patients with embolic stroke of undetermined source

BackgroundEmbolic stroke of undetermined source (ESUS) refers to a nonlacunar, nonatherosclerotic infarct in the absence of cardioembolic source or other specific causes of stroke. The presence of ESUS strokes indicates that the conventional risk factors cannot fully account for the pathogenesis of stroke. It is very important to detect useful biomarkers of the risk of ESUS for appropriate 2ry prevention.ResultsThe present study showed significant increase in left ventricular hypertrophy (LVH) measured by left ventricular mass index and increased left atrial volume index, measuring left atrial dilatation, among ESUS patients.ConclusionsPatients with ESUS tended to have Echocardiographic features of heart failure with a preserved ejection fraction (HFpEF) as LVH and left atrial dilatation. Therefore, they should be considered as biomarkers for cardioembolic cerebrovascular accidents with the consideration of anticoagulation with new oral anticoagulants as a primary preventive measure.

Genetic Architecture of Stroke of Undetermined Source: Overlap with Known Stroke Etiologies and Associations with Modifiable Risk Factors.

Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large-artery atherosclerotic (LAAS), cardioembolic (CES), and small-vessel stroke (SVS) contribute to its pathogenesis. We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS-PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source. Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis-related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist-to-hip ratio, inflammatory pathways (IL-6 signaling, MCP-1/CCL2 levels), and factor XI levels on stroke of undetermined source. Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022;91:640-651.

Differences in Left atrial stain, endothelial glycocalyx and arterial elasticity between ESUS, lacunar and atherosclerotic type of stroke

Abstract Funding Acknowledgements Type of funding sources: None. Background and Aims Patients with stroke are at high risk to develop cardiovascular complications. We assessed endothelial glycocalyx, aortic elastic properties, left atrial and ventricular function in patients with lacunar, atherosclerotic and stroke of undetermined source (ESUS). Patients and methods In 75 patients (age 55.2 ± 10.6) with acute cerebral stroke (25 lacunar, 20 atherosclerotic and 30 ESUS) and 20 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5–25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) Left atrial (LA) strain using speckle-tracking imaging, and (4) left ventricular global longitudinal strain. Results Compared with controls, patients with stroke had higher PWV (11.38 ± 3.62 vs 9.51 ± 1.57 m/sec, p = 0.045), PBR (2.10 ± 0.27 vs 1.94 ± 0.20, p = 0.039) and central SBP (139.64 ± 26.31 vs 116.36 ± 37.23 mmHg, p = 0.039), while ventricular (-17.902 ± 3.77 vs - 19.87 ± 1.17%, p = 0.025) and atrial deformation (24.8 ± 9.99 vs 39.05 ± 2.08%, p < 0.001) were impaired in patients with stroke (p < 0.05). LA reservoir strain was more reduced in ESUS patients compared to other 2 stroke types (ESUS 21.7 ± 6.6%, Lacunar 25.6 ± 13.2%, atherosclerotic 22.3 ± 7.8%, P < 0.05). Regarding endothelial glycocalyx, PBR5-9 (the smallest vessels with diameter 5-9 μm) was higher in patients with ESUS than in the other two types of stroke (ESUS 1.22 ± 0.12 μm, LACUNAR 1.19 ± 0.12 μm, ATHEROSCLEROTIC 1.15 ± 0.09 μm, p < 0.05), despite the fact that PBR5-25 was similar between all stroke types (ESUS 2.09 ± 0.23 μm, LACUNAR 2.13 ± 0.33 μm, ATHEROSCLEROTIC 2.09 ± 0.24 μm, p = 0.8). PWV was significantly higher in patients with atherosclerotic stroke (15.57 ± 5.50 m/sec, p = 0.007), while in patients with lacunar it was mildly elevated (10.53 ± 3.22 m/sec) and in ESUS patients it was moderately increased (11.7 ± 3 m/sec). Conclusions Patients with stroke have impaired atrial strain, endothelial glycocalyx and arterial elasticity, compared with controls. Arterial stiffness is more affected in atherosclerotic stroke, while LA deformation and glycocalyx of small size micro vessels are more affected in ESUS patients.

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

BackgroundThe 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).MethodsWe 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.ResultsPFO 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).ConclusionThe 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.

Abstract TMP99: Genetics Of Stroke Of Undetermined Source: Overlap With Known Stroke Etiologies And Associations With Modifiable Risk Factors

Introduction: Stroke etiology remains unknown in 30% of cases, hindering secondary prevention efforts. We leveraged human genetic data in order to identify evidence of overlap between stroke of undetermined source and defined stroke etiologies as well as causal relationships with modifiable risk factors. Methods: We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls from the NINDS Stroke Genetics Network with TOAST- and CCS-defined subtypes. Using genetic risk scores for large artery, cardioembolic, and small vessel stroke (LAS, CES, SVS) we assessed the degree of overlap with stroke of undetermined source and used pairwise GWAS to search for shared loci. We then applied Mendelian randomization (MR) to identify causal risk factors for stroke of undetermined source. Results: There was significant overlap between stroke of undetermined source and all defined stroke subtypes at a genome-wide and locus level (19 shared loci with LAS, 2 with CES, 5 with SVS). Shared loci pointed to altered gene expression in arterial tissue and blood and atherosclerosis-related mechanisms. Further, genetically predicted carotid intima media thickness was associated with stroke of undetermined source. While genetic liability to atrial fibrillation also showed a significant association, this was attenuated in analyses excluding cases with incomplete diagnostic workup. MR analyses showed significant associations in blood pressure, diabetes, waist-to-hip ratio, inflammatory pathways (IL-6 signaling, MCP-1 levels), and elevated factor XI levels with stroke of undetermined source (Figure). Conclusion: These analyses suggest that stroke of undetermined source shares genetic and modifiable risk factors with defined stroke subtypes. Together, they raise the hypothesis that refinement of current subtyping approaches can reduce the proportion of cases classified as undetermined and optimize secondary prevention strategies.

Abstract TP202: Nonstenotic Carotid Plaque As An Inverse Predictor Of PFO In Cryptogenic Stroke

Background: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of all strokes. Potential contributors to ESUS include patent foramen ovale (PFO) and non-stenotic plaque (&lt;50%, NSP) of the ipsilateral internal carotid artery (ICA). To better differentiate these as unique mechanisms, we explored the prevalence of each in a multicenter observational cohort. Methods: A retrospective multicenter cohort of consecutive patients with ESUS was queried (2015-2021). Patients with unilateral, anterior circulation ESUS who had a CTA neck scan and a transthoracic echocardiogram (TTE) and/or transesophageal echocardiogram (TEE) with adequate visualization of a PFO were included. Patients with prior carotid stent, endarterectomy or alternative etiologies were excluded from the study. Descriptive statistics were used to characterize patients with and without PFO, with multivariable logistic regression used to predict the presence of a PFO based on clinicoradiographic factors as well as degree of luminal stenosis and ipsilateral plaque thickness &gt;3mm, based on previously published thresholds of clinical relevance. Results: Of the 234 included patients with unilateral anterior ESUS and adequate TTE or TEE, 17 (7.3%) had a PFO and 64 (27.4%) had ≥3mm of ipsilateral ICA plaque. Patients with PFO had significantly less NSP and less ipsilateral cervical ICA stenosis (0% [IQR 0-0%] vs. 0% [IQR 0-50%], p=0.03; Table). After adjustment for all predictors of PFO in multivariable regression (p&lt;0.2: non-White race, Hispanic ethnicity, and ipsilateral plaque thickness), ipsilateral NSP was non-significantly associated with an 86% lower odds of finding a PFO (ORadj per 1cm of plaque 1.86, 95%CI 0.97-3.55, p=0.06). No patients with a PFO had ≥3mm of ipsilateral ICA plaque. Conclusion: Ipsilateral NSP is more common in ESUS patients without a PFO. While this study is limited by the small PFO event rate, it supports the notion that NSP and PFO may be independent contributors to ESUS.

Abstract WMP69: Features Of Calcified Carotid Atherosclerosis Are Associated With Stroke In Patients With Embolic Stroke Of Undetermined Source

Introduction: We examined qualitative features of calcified plaque in patients with embolic stroke of undetermined source (ESUS). Methods: A retrospective cohort of anterior circulation acute ischemic stroke patients with CTA neck and meeting criteria for ESUS was identified. A segmentation software measured carotid bifurcation calcified plaque volumes. A neuroradiologist manually measured maximum carotid wall and calcified wall thickness (WT), maximum craniocaudal calcified plaque length, degree of circumferential involvement (none, punctate, 90°, 180°, 270°, 360°) and assessed for intimal, transmural, and adventitial calcifications. Descriptive statistics included medians and interquartile ranges. Differences between ipsilateral (carotid ipsi ) and contralateral (carotid contra ) carotid arteries to stroke side were tested using Wilcoxon Signed-Rank, McNemar, and marginal homogeneity tests. Results: Ninety-four subjects met criteria for ESUS. Mean age was 65 years and 55% were women. Carotid ipsi had a significantly higher volume of calcified plaque [Vol ipsi =39.1 (12.4, 86.7) vs Vol contra =25.9 (4.9, 71.7), p=0.05] and maximum calcified WT [CalcWT ipsi= 1.4 (0, 2.6) vs CalcWT contra =0 (0, 2.1), p=0.03] than carotid contra . There were no significant differences in the maximum craniocaudal calcified plaque length (p=0.09) or degree of circumferential calcified plaque involvement (p=0.35) between carotid ipsi and carotid contra . Intimal (p=0.03) but not transmural (p=0.14) or adventitial (p=0.12) calcifications were significantly more frequent in carotid ipsi than carotid contra . A subgroup analysis (n=48) including either carotid artery measuring ≥3mm in maximum WT showed intimal calcifications remained significantly associated with stroke side (p=0.02; Figure). Conclusion: Higher calcified plaque volumes, calcified wall thickness and intimal calcifications may be associated with ischemic stroke in patients with ESUS.

Abstract TMP41: Local Epidemiology And Diagnostic Results Of Truly Occult Emboli In Patients With ESUS

Introduction: Ipsilateral nonstenotic (&lt;50%) internal carotid artery (ICA) plaque, cardiac atriopathy, and patent foramen ovale (PFO) may account for a substantial proportion of embolic stroke of undetermined source (ESUS). Methods: Consecutive stroke patients at our center (2019-2021) with unilateral, anterior ESUS were categorized into the following mutually exclusive etiologies: (1) nonstenotic ipsilateral ICA plaque (≥3mm), (2) atriopathy (sex-adjusted mod-to-severe atrial enlargement) &amp; (3) PFO. Clinical and diagnostic results were compared between patients in each group, and against those with “true ESUS” (who failed to meet criteria for these 3 groups). Results: Of 133 included patients, there was minimal overlap between the mutually exclusive ESUS etiologies (2 having nonstenotic plaque + atriopathy, and 1 having atriopathy + PFO). Older patients more frequently had atriopathy, while patients with PFO had fewer vascular risk factors when compared to the other groups (padj≤0.1; Table). Patients with nonstenotic plaque had more frequent tobacco use (p=0.06), more severe white matter disease (p=0.07), and greater ipsilateral v. contralateral plaque (p&lt;0.01). Twice as many patients with atriopathy presented with an ICA/M1/basilar occlusion (54%) when compared to other groups (p=0.03). Atriopathy was independently associated with older age (ORadj 1.09/year, 95%CI 1.02-1.17) and proximal occlusion (ORadj 16.47, 95%CI 2.86-94.65), with tobacco use associated with a non-atriopathic origin (ORadj 5.56/year, 95%CI 1.07-29.01). Five of 8 patients with atriopathy (63%) monitored with outpatient telemetry had atrial fibrillation, while 3/30 (10%) “true ESUS” and 0/12 (0%) nonstenotic plaque patients had atrial fibrillation. Conclusions: Certain clinical and radiographic features may be useful in predicting the proximal source of occult cerebral emboli, and can be used for cost-effective outpatient diagnostic testing.

Abstract WMP108: Prevalence Of High-Risk Aortic Arch Atherosclerosis Features Among Patients With 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) in ESUS patients on CT angiography (CTA) to characterize high-risk plaque features. Methods: All patients from two prospective multicenter studies (INTERRSeCT and PRove-IT) were included if the CTA adequately imaged the proximal aortic arch and the etiology was recorded. Three independent readers analyzed the following AAA plaque features on CTA at the time of acute ischemic stroke: 1) thickness in mm (radial measurement at thickest point); 2) morphology (Figure a-c): none, smooth, ulcerated, or protruding; 3) location within the aortic arch (proximal, transverse, or distal); and 4) calcification (Figure a, d-f): none, single small, multiple small, single large, or diffuse extensive. Reader disagreement was resolved by consensus. Results: We included 1063 patients, of which 293 (27.6%) had ESUS (mean age 67.5 years; 46.4% men). The mean AAA thickness was significantly larger in ESUS versus non-ESUS patients (3.8 vs 3.0 mm, p&lt;0.0001). The ESUS group had a significantly higher proportion of ulcerated or protruding plaques (17.4% vs 10.3%; risk ratio 1.7, CI 95 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). Conclusions: ESUS patients had thicker AAA plaques and a higher prevalence of ulcerated or protruding plaques located more proximally within the aortic arch. High-risk plaque features could be a potential cause of acute ischemic stroke in the ESUS population.

Abstract TP209: Potential Embolic Sources Differ In Patients With Embolic Stroke Of Undetermined Source According To Age

Introduction: Understanding the potential embolic source (PES) in ESUS patients may improve the diagnosis and treatment of such patients. Hypothesis: PES differ in young vs old patients with ESUS. Methods: Young patients (age 18-49) with ESUS who were admitted to our stroke center from 2006 to 2019 were identified retrospectively and matched with next consecutive older patients (age 50-99) with ESUS by admission date. PES were categorized as atrial cardiopathy, AFib diagnosed during follow up, left ventricular disease (LVD), cardiac valvular disease (CVD), PFO or Atrial septal aneurysm (ASA) and arterial disease. Patients who had cancer or a coagulopathy were excluded. Rate of types and number of PES and stroke recurrence were determined and compared between young and older patients. Results: In young patients (55.3% women, median age 39 years), the most common PES was PFO/ASA and rate of other PES was low. Most of young patients had a single PES (54.1%), only 9 of the young patients had multiple PES. In older patients (41.7% women, median age 74 years), the 3 most common PES were atrial cardiopathy, LVD, and arterial disease. More older patients had multiple PES than single PES. More young patients as compared to older patients didn’t have any PES identified. The rate of stroke recurrence was lower in young patients as compared to older patients, the difference approached but did not reach statistical significance. During a median follow up of 3 years, only 3 young patients had recurrent stroke, two of them had unclosed PFO. There were no recurrent strokes among young patients with no PES identified. Among 9 older patients who had recurrent stroke, 6 had atrial cardiopathy, and AFib was detected in 4 patients during follow up. Conclusions: PFO is the only common PES in young patients with ESUS, atrial cardiopathy is the most common PES in old patients with ESUS. Rate of other types of PES and stroke recurrence is low in young patients.

Abstract TP214: Sex Differences In Non-Stenotic Carotid Plaque Burden Among Patients With ESUS

Background: Sex differences in patients with embolic stroke of undetermined source (ESUS) and non-stenotic internal carotid artery (ICA) plaque have not been reported. Non-stenotic ICA plaque has been identified in patients with ESUS, is inversely proportional to cardioembolic stroke risk in our cohort, and could represent a stroke mechanism in these patients. Sex differences have been observed in patients with stroke and stenotic ICA plaque. Thus, we examined whether sex differences were present in a cohort of patients with ESUS and non-stenotic plaque. Methods: A retrospective multicenter cohort of consecutive patients with ESUS was queried (2015-2021). Patients with unilateral, anterior circulation ESUS who had a CTA neck scan and a transthoracic echocardiogram (TTE) were included. Multiple linear regression was used to model independent contributors to thicker ipsilateral plaque. Results: Of the 273 included patients with unilateral anterior ESUS and adequate TTE or TEE, 133 (49%) were women. While vascular profiles were largely similar, women were older but had less significant ipsilateral plaque compared to men (Table). After adjustment for independent predictors of greater ipsilateral plaque, female sex remained strongly and independently protective against plaque thickness (β -0.46, 95%CI -0.83- -0.09), while older age (β 0.03/yr, 95%CI 0.01-0.04), tobacco use (β 0.38, 95%CI 0.002-0.76), and coronary artery disease (β 0.46, 95%CI -0.05 - 0.97) were associated with thicker ICA plaque. Conclusion: Non-stenotic ICA plaque may contribute to ESUS, but it is less common in women than men. Further investigation of factors that might account for this difference, such as hormonal factors, is warranted. Table.

Abstract WP169: The Utility Of Transesophageal Echocardiogram In Embolic Strokes Of Undetermined Source Not Associated With Patent Foramen Ovale

Introduction: Transesophageal echocardiography (TEE) is frequently utilized in the diagnosis of embolic stroke of undetermined significance (ESUS), with a patent foramen ovale (PFO) being the most common finding. Transcranial doppler (TCD) is comparable to TEE in diagnosing a right-to-left shunt, while being less invasive. Our aim is to evaluate the diagnostic yield of TEE excluding the diagnosis of PFO, in patients with ischemic stroke satisfying ESUS criteria. Methods: We retrospectively evaluated patients at our institution with acute ischemic stroke fulfilling ESUS criteria who underwent TEE examination during a 50-month period (May 2017 to July 2021). In these patients, we also evaluated whether TCD bubble study was done. We assessed whether non-PFO TEE findings altered management course. Results: We identified 113 patients with ESUS who underwent investigation with TEE (mean age 65 ± 13.5 years, 62% men, 38% women, median NIH Stroke Scale = 4 points [interquartile range: 2-9]). TEE revealed a PFO in 23.4% (95% CI: 19%-28.8%). TCD was performed in 55.6% of the patients with a PFO found on TEE, and revealed a right-to-left shunt in 80% of them. Excluding the finding of PFO, TEE revealed additional findings in 27 (23.9% [95% CI: 15.9%-31.2%]) patients. This changed management (anticoagulation therapy or surgical evaluation) in 3 (2.7% [95% CI: 0%-5.6%]) patients. The surgical evaluation was due to marantic valve endocarditis. No patients required IV antibiotic therapy due to TEE findings. Conclusions: Abnormal TEE findings only rarely affect the management in ESUS. TCD may be sufficient to screen for PFO in ESUS patients.

Abstract 141: Atrial Cardiopathy And Left Ventricular Dysfunction In Patients With ESUS: Findings From The Arcadia Trial

Background: Recent data suggest biomarkers of atrial cardiopathy (ACP) can potentially identify a subset of patients with cryptogenic stroke who may benefit from anticoagulation. However, the specificity of these markers for atrial disease and their independence from measures of more global cardiac dysfunction remain unclear. We hypothesized that biomarkers of ACP collectively reflect left atrial pathology and are not strongly affected by coexisting left ventricular dysfunction. Methods: ARCADIA is an ongoing multicenter trial comparing standard dose apixaban to aspirin therapy in patients with Embolic Stroke of Undetermined Source (ESUS) with ACP, defined as either N-terminal pro-brain natriuretic peptide [NT-proBNP] &gt; 250 pg/mL; P wave terminal force velocity on ECG lead V1 [PTFV1] &gt; 5000 μV*ms; or echocardiographic left atrial diameter index [LADI] ≥ 3 cm/m 2 . Pearson correlation coefficients and descriptive statistics were used to examine the relationship between left ventricular ejection fraction (LVEF) and ACP biomarkers. Results: Among 2,616 ESUS patients screened, 1,046 met ≥ 1 ACP criterion (665 BNP, 531 PTFV1, 14 LADI). Patients with ACP were older (68 ± 11 vs 64 ± 10 years) and 54.5% were women. The great majority (84%) of subjects with ACP had normal LVEF (≥55%). Among them there was no correlation between LVEF and NT-proBNP (r= -0.01, P= 0.5) or PTFV1 (r=0.002, P=0.9). In patients with abnormal LVEF, there was a strong inverse correlation of LVEF with NT-proBNP (r=-0.4, P&lt;0.001), but no correlation with PTFV1 (r=0.11, P=0.16). The LADI criterion was only met in a few patients, precluding further analyses. Among patients with NT-proBNP &gt;250 pg/mL and measured LVEF (n=435), only 19% had abnormal LVEF. Compared to patients with abnormal NT-proBNP alone, those with both abnormal NT-proBNP and abnormal LVEF were younger (66.4 ± 11.0 vs. 71.6 ± 11.0, P&lt;0.001), more often African American (29.6% vs. 11.5%, P&lt;0.001), and more often male (56% vs. 40%, P=0.01). Conclusion: Left ventricular dysfunction (EF ≤ 55%) is uncommon in patients with ACP as defined in ARCADIA. These findings suggest that, among patients with ESUS, atrial cardiopathy may represent a separate entity from LV dysfunction.