Basilar artery occlusion (BAO) remains one of the most devastating subtypes of stroke with high mortality and poor outcome. Early recanalisation is the most powerful predictor of favourable outcome ...in patients with stroke, and may be improved with mechanical thrombectomy using stent retriever devices. However, the benefit in functional outcome and safety of stent retrievers are not yet well known. The aim of this study was to assess efficacy and safety profiles of stent retriever thrombectomy in BAO patients with stroke.
We analysed data retrospectively from our consecutive clinical series and conducted a systematic review and meta-analysis of all previous studies of stent retriever thrombectomy in BAO patients with stroke between November 2010 and April 2014.
From March 2010 to March 2013, 22 patients with acute BAO were treated with a Solitaire stent retriever in our series. Favourable outcome was significantly associated with younger age and distal BAO. The literature search identified 15 previous studies involving a total of 312 subjects. In the meta-analysis, including our series data, the recanalisation rate (Thrombolysis In Cerebral Infarction (TICI) score ≥ 2b) reached 81% (95% CI 73% to 87%). The rate of symptomatic intracranial haemorrhage was 4% (95% CI 2% to 8%), favourable outcome (modified Rankin Scale (mRS) ≤ 2 at 3 months) was found in 42% (95% CI 36% to 48%) and mortality rate was 30% (95% CI 25% to 36%).
Stent retriever thrombectomy is a safe treatment modality for patients with stroke presenting with BAO. Although the stent retrievers showed a good recanalisation rate, there are currently no randomised clinical trials to assess its clinical efficacy in comparison with the reference treatment.
Objectives
To assess spatiotemporal brain infarction evolution by sequential multimodal magnetic resonance (MR) imaging in an endovascular model of acute stroke in rats.
Materials and methods
A ...microwire was selectively placed in the middle cerebral artery (MCA) in 16 consecutives rats during 90 minutes occlusion. Longitudinal 7-T MR imaging, including angiography, diffusion, and perfusion was performed during ischemia, immediately after reperfusion, 3 h and 24 h after subsequent reperfusion.
Results
MCA occlusion was complete in 75 % and partial in 18.7 %. Hypoperfusion (mean ± SD) was observed in all animals during ischemia (-59 ± 18 % of contralateral hemisphere, area 31 ± 5 mm
2
). Infarction volume (mean ± SD) was 90 ± 64 mm
3
during ischemia and 57 ± 67 mm
3
at 24 h. Brain infarction was fronto-parietal cortical in five animals (31 %), striatal in four animals (25 %), and cortico-striatal in seven animals (44 %) at 24 h. All rats survived at 24 h.
Conclusion
This model is suitable to neuroprotection studies because of possible acute and close characterization of spatiotemporal evolution of brain infarction by MR imaging techniques, and evidence of ischemic penumbra, the target of neuroprotection agents. However, optimization of the brain infarct reproducibility needs further technical and neurointerventional tools improvements.
Key points
•
Nitinol microwire is MRI compatible allowing spatiotemporal characterization of brain infarction in rats
.
•
Microwire selective placement in middle cerebral artery allows complete artery occlusion in 75
%.
•
A diffusion
/
perfusion mismatch during arterial occlusion is observed in 77
%
of rats
.
The molecular basis of endothelial cell (EC)-specific gene expression is poorly understood. Roundabout 4 (Robo4) is expressed exclusively in ECs. We previously reported that the 3-kb 5'-flanking ...region of the human Robo4 gene contains information for lineage-specific expression in the ECs. Our studies implicated a critical role for GA-binding protein and specificity protein 1 (SP1) in mediating overall expression levels. However, these transcription factors are also expressed in non-ECs. In this study, we tested the hypothesis that epigenetic mechanisms contribute to EC-specific Robo4 gene expression.
Bisulfite sequencing analysis indicated that the proximal promoter of Robo4 is methylated in non-ECs but not in ECs. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine increased Robo4 gene expression in non-ECs but not in ECs. Proximal promoter methylation significantly decreased the promoter activity in ECs. Electrophoretic mobility shift assays showed that DNA methylation of the proximal promoter inhibited SP1 binding to the -42 SP1 site. In DNase hypersensitivity assays, chromatin condensation of the Robo4 promoter was observed in some but not all nonexpressing cell types. In Hprt (hypoxanthine phosphoribosyltransferase)-targeted mice, a 0.3-kb proximal promoter directed cell-type-specific expression in the endothelium. Bisulfite sequencing analysis using embryonic stem cell-derived mesodermal cells and ECs indicated that the EC-specific methylation pattern of the promoter is determined by demethylation during differentiation and that binding of GA-binding protein and SP1 to the proximal promoter is not essential for demethylation.
The EC-specific DNA methylation pattern of the Robo4 proximal promoter is determined during cell differentiation and contributes to regulation of EC-specific Robo4 gene expression.
BACKGROUND AND PURPOSEThe modified TICI Infarction grading system is a metric currently used to evaluate angiographic results of thrombectomy for large-vessel occlusion in ischemic stroke. Originally ...designed for evaluating MCA territories, it is currently used for other vessel occlusions, including the posterior circulation. We postulate that the modified TICI use for the posterior circulation is not accurate due to the different vascular territories supplied by vertebrobasilar vasculature, making grading more complex. MATERIALS AND METHODSWe collected angiographic results from 30 patients who presented with acute posterior circulation occlusions between 2015 and 2018 and underwent thrombectomy in our institution. Eight observers were asked to evaluate the TICI scores before and after thrombectomy. The multirater statistics were computed using Fleiss κ analysis. Further data were collected regarding the potential brain territories at risk and the existence of atherosclerotic disease in the basilar artery. RESULTSThe overall agreement κ reached 0.277 (SD, 0.013), which suggests a "fair" agreement among the raters. On average, 45% of observers achieved a high accuracy in predicting brain areas at risk of ischemia. As for the existence of basilar atherosclerotic disease, a high agreement (defined as at least 5 of 6 observers) was seen in 20 of the 30 patients. CONCLUSIONSDespite TICI being ubiquitous in stroke diagnostics, the high variability of posterior circulation TICI scores calls into question its use in these strokes. Other methods should be developed to assess recanalization in the posterior circulation.
Abstract only
Atherosclerosis and its consequences, myocardial infarction and stroke continue to be the leading cause of mortality worldwide. Despite recent progress in our understanding of the ...initiation and progression of atherosclerosis, there is an increasing need to identify novel signaling pathways with potential therapeutic targeting. One of the earliest events in atherogenesis is endothelial dysfunction triggered by disturbed flow characteristic of atherosclerosis susceptible regions. This event is followed by monocyte transmigration and differentiation into macrophages. To mechanistically dissect the contribution of atheroprone flow on the endothelial cell phenotype and monocyte transmigration and specification, we have developed a novel in vitro model in which endothelial cells (EC) are seeded on a collagen gel and exposed to athero‐prone and ‐protective shear stress waveforms. Using this model, we have demonstrated that atheroprone but not atheroprotective flow promotes monocyte recruitment via a Krüppel Like Factor‐2‐dependent pathway. Furthermore, we have documented that transmigrated monocytes under atheroprone flow polarize toward a pro‐inflammatory phenotype as measured by gene expression of a set of pro‐inflammatory markers. This work supports the hypothesis that the hemodynamic environment promotes EC‐monocyte interactions, which are a key determinant of macrophage polarization.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Materials Science and Engineering, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages ...121-129).
This thesis describes the development of a novel in vitro model of monocytes transmigration under flow and use in the study of early molecular events of atherogenesis. In this work, we focused on how endothelial dysfunction, specifically mediated by disturbed flow from atherosusceptible regions of the vasculature, is both communicated to recruited monocytes as they reside in the subendothelial matrix, and how reciprocally, monocytes may exacerbate the endothelial dysfunctional state. We built and integrated our in vitro model to a unique flow apparatus that can precisely replicate atheroprone and atheroprotective shear stress waveforms. We carefully characterized the model that relies on a fibronectin-coated collagenous matrix seeded with a confluent monolayer of endothelial cells co-cultured with THP- 1 monocytes under flow. We used the model to draw biological insight from endothelial:monocyte co-cultures under flow. We found that monocytes preferentially accumulate on endothelial monolayers exposed to atheroprone flow. We also observed the upregulation of IL-1beta in endothelial cells exposed to atheroprone flow when co-cultured with monocytes but not in endothelial cells alone, in each of three independent experiments; yet the aggregated results are not statistically relevant due to variability. Flow-driven dysfunctional endothelium recruits and interacts with monocytes that soon after transmigration become dysfunctional foam cells. Our novel in vitro model that congregates endothelial cells, monocytes and flow responds to the pressing need to understand the interplay between these protagonist cells during atherogenesis, and allowed us to define further monocyte- and flow-mediated transition of endothelium from normal to dysfunctional to diseased states. Harnessing the power of a versatile platform of transmigration under flow may foster the discovery of novel targets for atherogenesis and the development of original therapeutic strategies.
by Alexis S. Turjman.
Ph. D.
Background and Purpose- Little is known about the real-life factors that clinicians use in selection of patients that would receive endovascular treatment (EVT) in the real world. We sought to ...determine patient, practitioner, and health system factors associated with therapeutic decisions around endovascular treatment. Methods- We conducted a multinational cross-sectional web-based study comprising of 607 clinicians and interventionalists from 38 countries who are directly involved in acute stroke care. Participants were randomly allocated to 10 from a pool of 22 acute stroke case scenarios. Each case was classified as either Class I, Class II, or unknown evidence according to the current guidelines. We used logistic regression analysis applying weight of evidence approach. Main outcome measures were multilevel factors associated with EVT, adherence to current EVT guidelines, and practice gaps between current and ideal practice settings. Results- Of the 1330 invited participants, 607 (45.6%) participants completed the study (53.7% neurologists, 28.5% neurointerventional radiologists, 17.8% other clinicians). The weighed evidence approach revealed that National Institutes of Health Stroke Scale (34.9%), level of evidence (30.2%), ASPECTS (Alberta Stroke Program Early CT Score) or ischemic core volume (22.4%), patient's age (21.6%), and clinicians' experience in EVT use (19.3%) are the most important factors for EVT decision. Of 2208 responses that met Class I evidence for EVT, 1917 (86.8%) were in favor of EVT. In case scenarios with no available guidelines, 1070 of 1380 (77.5%) responses favored EVT. Comparison between current and ideal practice settings revealed a small practice gap (941 of 6070 responses, 15.5%). Conclusions- In this large multinational survey, stroke severity, guideline-based level of evidence, baseline brain imaging, patients' age and physicians' experience were the most relevant factors for EVT decision-making. The high agreement between responses and Class I guideline recommendations and high EVT use even when guidelines were not available reflect the real-world acceptance of EVT as standard of care in patients with disabling acute ischemic stroke.
Background and Purpose- The American Heart Association and the American Stroke Association guidelines for early management of patients with ischemic stroke offer guidance to physicians involved in ...acute stroke care and clarify endovascular treatment indications. The purpose of this study was to assess concordance of physicians' endovascular treatment decision-making with current American Heart Association and the American Stroke Association stroke treatment guidelines using a survey-approach and to explore how decision-making in the absence of guideline recommendations is approached. Methods- In an international cross-sectional survey (UNMASK-EVT), physicians were randomly assigned 10 of 22 case scenarios (8 constructed with level 1A and 11 with level 2B evidence for endovascular treatment and 3 scenarios without guideline coverage) and asked to declare their treatment approach (1) under their current local resources and (2) assuming there were no external constraints. The proportion of physicians offering endovascular therapy (EVT) was calculated. Subgroup analysis was performed for different specialties, geographic regions, with regard to physicians' age, endovascular, and general stroke treatment experience. Results- When facing level 1A evidence, participants decided in favor of EVT in 86.8% under current local resources and in 90.6% under assumed ideal conditions, that is, 9.4% decided against EVT even under assumed ideal conditions. In case scenarios with level 2B evidence, 66.3% decided to proceed with EVT under current local resources and 69.7% under assumed ideal conditions. Conclusions- There is potential for improving thinking around the decision to offer endovascular treatment, since physicians did not offer EVT even under assumed ideal conditions in 9.4% despite facing level 1A evidence. A majority of physicians would offer EVT even for level 2B evidence cases.
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