Diagnostic Yield of TEE in Patients with Cryptogenic Stroke and TIA with Normal TTE: A Systematic Review and Meta-Analysis

Introduction: The role of transesophageal echocardiography (TEE) in cryptogenic stroke and transient ischemic attack (TIA) with normal transthoracic echocardiography (TTE) remains controversial in the absence of definite guidelines. We aimed to perform a systematic review and meta-analysis to estimate an additional diagnostic yield and clinical impact of TEE in patients with cryptogenic stroke and TIA with normal TTE. Methods: We performed a systematic review of cohort studies on PubMed using the keywords ‘cryptogenic stroke’, cryptogenic TIA’, ‘TEE’, and ‘TTE’ with matching MeSH terms. We included studies with patients who had cryptogenic stroke or TIA and had normal TTE findings, where the study intended to obtain TEE on all patients and reported all TEE abnormalities. The studies containing patients with atrial fibrillation were excluded. All studies were evaluated for internal and external validity. Inverse variance random effects models were used to calculate the effect size, the number needed to diagnose, and the 95% confidence interval. Results: We included 15 studies with 2054 patients and found LA/LAA/aortic thrombus, valvular vegetation, PFO-ASA, valvular abnormalities, and complex aortic plaques on TEE. Of these, 37.5% (29.7%–45.1%) of patients had additional cardiac findings on TEE. Management of 13.6% (8.1%–19.1%) of patients had changed after TEE evaluation. Based on current guidelines, it should change management in 4.1% (2.1%–6.2%) of patients and could potentially change management in 30.4% (21.9%–38.9%) of patients. Sensitivity analysis was also performed with only class II studies to increase internal validity, which showed additional cardiac findings in 38.4% (28.5%–48.3%), changed management in 20.2% (8.7%–31.8%), should change management in 4.7% (1.5%–7.9%), and could potentially change management in 30.4% (17.8%–43.0%) of patients. Conclusions: The diagnostic yield of TEE to find any additional cardiac findings in patients with cryptogenic stroke or TIA is not only high, but it can also change management for certain cardiac abnormalities. TTE in cryptogenic stroke or TIA may mitigate future risks by tailoring the management of these patients.

Cilengitide Inhibits Neovascularization in a Rabbit Abdominal Aortic Plaque Model by Impairing the VEGF Signaling

Background. Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. We sought to investigate the effect of cilengitide on the neovascularization of abdominal aortic plaques in rabbits and explore its underlying antiangiogenic mechanism on human umbilical vein endothelial cells (HUVECs). Materials and Methods. For the in vivo experiment, the abdominal aortic plaque model of rabbits was established and injected with different doses of cilengitide or saline for 14 consecutive days. Conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) were applied to measure the vascular structure and blood flow parameters. CD31 immunofluorescence staining was performed for examining neovascularization. Relative expressions of vascular endothelial growth factor (VEGF) and integrin of the plaque were determined. For in vitro experiments, HUVECs were tested for proliferation, migration, apoptosis, and tube formation in the presence of different doses of cilengitide. Relative expressions of VEGF, integrin, and Ras/ERK/AKT signaling pathways were determined for the exploration of underlying mechanism. Results. CEUS showed modestly increased size and eccentricity index (EI) of plaques in the control group. Different degrees of reduced size and EI of plaques were observed in two cilengitide treatment groups. The expressions of VEGF and integrin in the plaque were inhibited after 14 days of cilengitide treatment. The neovascularization and apoptosis of the abdominal aorta were also significantly alleviated by cilengitide treatment. For in vitro experiments, cilengitide treatment was found to inhibit the proliferation, migration, and tube formation of HUVECs. However, cilengitide did not induce the apoptosis of HUVECs. A higher dose of cilengitide inhibited the mRNA expression of VEGF-A, β3, and β5, but not αV. Lastly, cilengitide treatment significantly inhibited the Ras/ERK/AKT pathway in the HUVECs. Conclusions. This study showed that cilengitide effectively inhibited the growth of plaque size by inhibiting the angiogenesis of the abdominal aortic plaques and blocking the VEGF-mediated angiogenic effect on HUVECs.

Aortic plaques in patients with atrial fibrillation: an often-forgotten risk factor for thromboembolism

Background CHA2DS2-VASc risk score is the main determinant for maintaining anticoagulation after atrial fibrillation (AF) ablation, irrespective of the procedure outcome. The presence of aortic plaques is included in the score, but isn't regularly assessed previously to AF ablation. This way, risk factors for coronary artery disease (CAD) other than arterial hypertension and diabetes mellitus may influence stroke risk in patients with AF, albeit not being included in the CHA2DS2-VASc score. Purpose We sought to evaluate the prevalence of aortic plaques diagnosed during transesophageal echocardiography (TOE) in patients submitted to AF ablation and to assess its determinants and clinical impact on the CHA2DS2-VASc score. Methods Retrospective study of patients submitted to AF ablation that performed TOE prior to the procedure, with assessment of aortic plaques. CHA2DS2-VASc risk score was evaluated in the pre-ablation patient evaluation and reassessed after TOE. Demographic, clinical and echocardiographic data, including cardiovascular risk factors, were analyzed. We assessed AF recurrence rate, cerebrovascular events and death during follow-up. Results 120 patients were submitted to TOE prior to AF ablation from November 2015 to December 2020, mean age 66.6 (±9.55) years, 48% male. In 30 (25%) patients aortic plaques were identified in TOE. Mean CHA2DS2-VASc was 2.2 (±1.47) in pre-ablation evaluation and 2.5 (±1.69) post-TOE, increasing in all patients with aortic plaques and prompting beginning of oral anticoagulation in 5 patients. AF was paroxysmal in 74% and persistent in 26% of patients, mean duration of 6.28 (±3.76) years. Arterial hypertension was present in 79 (66%) of patients, type 2 diabetes mellitus in 24 (20%) and dyslipidemia in 67 (56%). 17 (14%) patients had a prior stroke. During a mean follow-up of 30 (±18.3) months, 32 (27%) patients had AF recurrence and 10 (8%) were submitted to redo procedures. 107 (89%) patients remained under oral anticoagulation, stroke occurred in 1 patient and 2 patients died. In univariate analysis, age, type 2 diabetes mellitus and dyslipidemia predicted an increase in CHA2DS2-VASc score after TOE (respectively, OR 1.113, 95% CI 1.041–1.190, p-value 0.002; OR 2.907, 95% CI 1.145–7.379, p-value 0.025; and OR 2.442, 95% CI 1.016–5.868, p-value 0.046). In multivariate analysis, age is the only independent predictor of increased CHA2DS2-VASc score after TOE (OR 1.095, 95% CI 1.013–1.185, p-value 0.023). No risk factor for CAD was independently associated with the presence of aortic plaques (Table 1). Conclusion In this population, single CAD risk factors were not independent predictors of aortic plaques. If TOE had not been performed prior to AF ablation, 25% of patients would have had an underestimated CHA2DS2-VASc score and would be off anticoagulation after the procedure, unprotected from thromboembolic events. FUNDunding Acknowledgement Type of funding sources: None. Table 1

Atrial fibrillation in patients with embolic stroke of undetermined source during 3 years of prolonged monitoring with an implantable loop recorder

Background: Undocumented atrial fibrillation (AF) is suspected as a main stroke cause in patients with ESUS, but its prevalence is largely unknown. This prospective study therefore aimed at delineating the prevalence of AF in patients with ESUS using continuous cardiac monitoring by implantable loop recorder (ILR) with daily remote interrogation over a period of 3 years and its clinical consequences, including recurrent stroke. Methods: In consecutive patients with an ESUS diagnosis after complete work-up, an ILR was implanted and followed by daily remote monitoring until AF was detected or a follow-up of at least 3 years was completed. Additionally the ILR was interrogated in-hospital in 6-month intervals. Results: A total of 123 patients (74 male, mean age 65±9 years) were enrolledand completed the 3 years study period. AF was detected in 51 patients (41.4%). In 42 of the 51 AF positive patients (82%) oral anticoagulation was established. Recurrent strokes occurred in 28 patients (23%) of this ESUS population, 11 of these patients (21%) being AF positive, 17 (23%) AF negative. Patients with AF were slightly older than patients without AF (63.1±8.8 versus 67.5±9.6 years, p=0.12). Other parameters such as CHA2DS2-VASc score, infarct localization, micro- and macroangiopathy, carotid- or aortic plaques or stroke recurrence were not significantly different between groups. Conclusions: In ESUS patients, early implantation of an ILR with cardiac monitoring and remote transmission over a 3-year period detects AF in 41.4 % and results in oral anticoagulation in 82% of these patients

The effect of TEE on treatment change in patients with acute ischemic stroke

Background and purpose Ischemic stroke is a widespread disease carrying high morbidity and mortality. Transesophageal echocardiography (TEE) is considered an important tool in the work-up of patients with acute ischemic stroke (AIS) and transient ischemic attack (TIA) patients; its utility is limited by a semi-invasive nature. The purpose of this study was to evaluate the probability of treatment change due to TEE findings (yield) in the work-up of AIS and TIA patients. Methods Retrospective data on patients with AIS or TIA who underwent TEE examination between 2000–2013 were collected from the institutional registry. Results The average age of 1284 patients who were included in the study was 57±10.4, 66% of patients were male. The most frequent TEE findings included aortic plaques in 54% and patent foramen ovale (PFO) in 15%. TEE findings led to treatment change in 135 (10.5%) patients; anticoagulant treatment was initiated in 110 of them (81%). Most common etiology for switch to anticoagulation was aortic plaques (71 patients); PFO was second most common reason (26 patients). Significant TEE findings (thrombus, endocarditis, tumor) were found in 1.9% of patients, they were more common in young patients (<55; 56% of the patients). Conclusions The beginning of anticoagulation treatment in patients with thick and complicated plaques was found frequently in our study. Significant TEE findings, were infrequent, constituted an absolute indication for treatment change and were more common in younger patients.

miRNA 146b-5p protects against atherosclerosis by inhibiting vascular smooth muscle cell proliferation and migration

Aim: To explore the potentially important role of miRNA 146b-5p (miR-146b) during the development of atherosclerosis. Materials & methods: Proliferation, migration and luciferase assays and mouse models were used to determine the functions of miR-146b. Results: miR-146b was identified as substantially upregulated in the aortic plaques of ApoE-/- mice as well as in response to inflammatory cytokines. Overexpression of miR-146b repressed proliferation and migration of vascular smooth muscle cells by downregulating Bag1 and Mmp16, respectively. Adeno-associated virus-mediated miR-146b overexpression inhibited neointima formation after carotid injury and suppressed atherosclerotic plaque formation in western diet-induced ApoE-/- mice. Conclusion: miR-146b is a novel regulator of vascular smooth muscle cell function induced by inflammatory response, specifically in neointima formation, and offers a novel therapeutic strategy for treating atherosclerosis.

Abstract WP265: Association Between Brachial-Ankle Pulse Wave Velocity and Aortic Atheroma in Acute Ischemic Stroke

Background and Purpose: Aortic plaques are associated with both larger artery and small artery atherosclerosis. However, association between aortic plaque and aortic stiffness in ischemic stroke is unknown. Brachial-ankle pulse wave velocity (baPWV) is a noninvasive technique to measure aortic stiffness. In the present study, we hypothesized that presence of aortic plaques is associated with increased baPWV. Methods: We reviewed 1099 patients diagnosed with acute ischemic stroke, who had both transesophageal echocardiography (TEE) and brachial-ankle pulse wave velocity (baPWV) measurements. Aortic plaques were classified as complex aortic plaques (CAP) or simple aortic plaques (SAP). CAP were defined as plaques protruding into the lumen ≥4 mm and of mobile lesions located in the proximal aorta. SAP represented plaques <4 mm in the proximal aorta and plaques located in the descending aorta of any sizes. Patients were classified into 4 groups; patients who have CAP only, those who have SAP only, those who have both CAP and SAP, and those without aortic plaques. Results: Among the 1099 patients, aortic atheroma was found in 689 (62.7%) patients. Twenty one (1.9%) patients had only CAP, 142 (12.9%) patients had both SAP and CAP, while 526 (47.9%) patients had SAP without CAP. Mean value of baPWV was 1982±580 cm/sec. baPWV was significantly increased in patients with any aortic atheromas than those without atheromas (2095±577 cm/sec vs. 1793±535 cm/sec, p <0.001). Analysis of variance showed that baPWV was significantly increased in patients with SAP only (p<0.001) and SAP and CAP (p<0.001) compared to those without any aortic atheroma, whereas CAP only patients were not associated with baPWV (p = 0.131). Conclusion: We found that baPWV was associated with SAP but not CAP in acute ischemic stroke patients. These feature suggests that SAP represent generalized atherosclerosis and aortic stiffness, whereas CAP represent the sole mechanism of stroke.