Myocardial transcriptomic analysis of diabetic patients with aortic stenosis: key role for mitochondrial calcium signaling.

BACKGROUND: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism. OBJECTIVES: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease. METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy. RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D. CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique Identifier: NCT01862237.

Interrater reliability in neurology objective structured clinical examination across specialties.

PURPOSE: To assess interrater reliability and examiners' characteristics, especially specialty, associated with scoring of neurology objective structured clinical examination (OSCE). MATERIAL AND METHODS: During a neurology mock OSCE, five randomly chosen students volunteers were filmed while performing 1 of the 5 stations. Video recordings were scored by physicians from the Lyon and Clermont-Ferrand university teaching hospitals to assess students performance using both a checklist scoring and a global rating scale. Interrater reliability between examiners were assessed using intraclass coefficient correlation. Multivariable linear regression models including video recording as random effect dependent variable were performed to detect factors associated with scoring. RESULTS: Thirty examiners including 15 (50%) neurologists participated. The intraclass correlation coefficient of checklist scores and global ratings between examiners were 0.71 (CI95% [0.45-0.95]) and 0.54 (CI95% [0.28-0.91]), respectively. In multivariable analyses, no factor was associated with checklist scores, while male gender of examiner was associated with lower global rating (ß coefficient = -0.37; CI 95% [-0.62-0.11]). CONCLUSIONS: Our study demonstrated through a video-based scoring method that agreement among examiners was good using checklist scoring while moderate using global rating scale in neurology OSCE. Examiner's specialty did not affect scoring whereas gender was associated with global rating scale.

Impact of Age on Systemic Inflammatory Profile of Patients With ST-Segment-Elevation Myocardial Infarction and Acute Ischemic Stroke.

BACKGROUND: Aging is associated with a chronic low-grade inflammatory state. This condition may affect the acute inflammatory response involved in ST-segment-elevation myocardial infarction (STEMI) or acute ischemic stroke (AIS). We sought to compare the profile of a set of circulating inflammatory markers between young and older patients admitted for STEMI or AIS. METHODS: HIBISCUS-STEMI (Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in ST Elevation Myocardial Infarction) and HIBISCUS-STROKE (Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in Stroke) are 2 cohort studies that enrolled patients with STEMI treated with primary percutaneous coronary intervention in the cardiac intensive care unit of Lyon and patients with AIS treated with mechanical thrombectomy in the Lyon Stroke Center, respectively from 2016 to 2019. Patients were classified as older if they were ≥65 years and as young if they were <65 years. In both cohorts, CRP (C-reactive protein), IL (interleukin)-6, IL-8, IL-10, MCP (monocyte chemoattractant protein), sTNF-RI (soluble tumor necrosis factor receptor I), sST2 (soluble form suppression of tumorigenicity 2), and VCAM-1 (vascular cellular adhesion molecule-1) were measured on serum collected at 5 time points using enzyme-linked immunosorbent assay. A multiple logistic regression model was performed to detect an association between area under the curve of circulating inflammatory markers within the first 48 hours and older age. RESULTS: A total of 260 patients with STEMI and 164 patients with AIS were included. Of them, there were 76 (29%) and 105 (64%) older patients with STEMI and AIS, respectively. Following multivariable analysis, a high area under the curve of IL-6 and sTNF-RI, a low lymphocyte count, and a high neutrophil-lymphocyte ratio at 24 hours were associated with older age in patients with STEMI and AIS. CONCLUSIONS: Older patients had higher IL-6 and sTFN-RI levels within the first 48 hours associated with a lower lymphocyte count and a higher neutrophil-lymphocyte ratio at 24 hours in both cohorts.

Large vessel cardioembolic stroke and embolic stroke of undetermined source share a common profile of matrix metalloproteinase-9 level and susceptibility vessel sign length.

BACKGROUND: Embolic stroke of undetermined source (ESUS) accounts for up to 25% of ischemic strokes. Identification of biomarkers that could improve the prediction of stroke subtype and subsequently of stroke prevention still remains a major issue. METHODS: The HIBISCUS-STROKE cohort includes ischemic stroke patients with large vessel occlusion treated with mechanical thrombectomy following admission magnetic resonance imaging. Presence and length of susceptibility vessel sign (SVS) were assessed by gradient-recalled echo T2*-weighted imaging. Matrix metalloproteinase-9 (MMP-9) was measured on sera collected at admission. A multiple logistic regression model was performed to detect independent markers distinguishing cardioembolic (CE) from large-artery atherosclerosis (LAA) subtype. RESULTS: A total of 147 patients were included, of them the etiology was distributed as follows: 86 (58.5%) CE, 26 (17.7%) LAA, and 35 (23.8%) ESUS. The optimal cutoff for differentiating CE from LAA subtype was 14.5 mm for SVS length (sensitivity, 79.7%; specificity, 72.7%) and 1110 ng/ml for admission MMP-9 level (sensitivity, 85.3%; specificity, 52.2%). Multivariate analysis revealed that current smoking (odds ratio [OR] 0.07, 95% confidence interval [CI] 0.01-0.93), tandem occlusion (OR 0.01, 95% CI 0.01-0.21), SVS length (OR 0.78, 95% CI 0.63-0.97), and admission MMP-9 level (OR 0.99, 95% CI 0.99-1.00) were inversely associated with CE subtype. SVS length and MMP-9 level did not differ between ESUS and CE subtypes. CONCLUSION: SVS length and admission MMP-9 level may improve the prediction of CE subtype whose profile is close to ESUS, thus suggesting a common cardiac embolic source.

Longitudinal assessment of IFN-I activity and immune profile in critically ill COVID-19 patients with acute respiratory distress syndrome.

BACKGROUND: Since the onset of the pandemic, only few studies focused on longitudinal immune monitoring in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) whereas their hospital stay may last for several weeks. Consequently, the question of whether immune parameters may drive or associate with delayed unfavorable outcome in these critically ill patients remains unsolved. METHODS: We present a dynamic description of immuno-inflammatory derangements in 64 critically ill COVID-19 patients including plasma IFNα2 levels and IFN-stimulated genes (ISG) score measurements. RESULTS: ARDS patients presented with persistently decreased lymphocyte count and mHLA-DR expression and increased cytokine levels. Type-I IFN response was initially induced with elevation of IFNα2 levels and ISG score followed by a rapid decrease over time. Survivors and non-survivors presented with apparent common immune responses over the first 3 weeks after ICU admission mixing gradual return to normal values of cellular markers and progressive decrease of cytokines levels including IFNα2. Only plasma TNF-α presented with a slow increase over time and higher values in non-survivors compared with survivors. This paralleled with an extremely high occurrence of secondary infections in COVID-19 patients with ARDS. CONCLUSIONS: Occurrence of ARDS in response to SARS-CoV2 infection appears to be strongly associated with the intensity of immune alterations upon ICU admission of COVID-19 patients. In these critically ill patients, immune profile presents with similarities with the delayed step of immunosuppression described in bacterial sepsis.

Matrix Metalloproteinase-9 and Monocyte Chemoattractant Protein-1 Are Associated With Collateral Status in Acute Ischemic Stroke With Large Vessel Occlusion.

BACKGROUND AND PURPOSE: In ischemic stroke, inflammatory status may condition the development of collateral circulation. Here we assessed the relationship between systemic inflammatory biomarkers and collateral status in large vessel occlusion before mechanical thrombectomy. METHODS: HIBISCUS-STROKE is a cohort study including acute ischemic stroke patients with large vessel occlusion treated with mechanical thrombectomy following admission magnetic resonance imaging. MMP-9 (matrix metalloproteinase-9) and MCP-1 (monocyte chemoattractant protein-1) were measured on blood sampling collected at admission. Collateral status was assessed on pretreatment Digital subtraction angiography and categorized into poor (Higashida score, 0-2) and good (Higashida score, 3-4). A multiple logistic regression model was performed to detect independent markers of good collateral status. RESULTS: One hundred and twenty-two patients were included, of them 71 patients (58.2%) had a good collateral status. In univariate analysis, low MMP-9 levels (P=0.01), high MCP-1 levels (P<0.01), a low National Institute of Health Stroke Score (P=0.046), a high diastolic blood pressure (P=0.049), the absence of tandem occlusion (P=0.046), a high Alberta Stroke Program Early CT Score (P<0.01) and a low volume on the diffusion-weighted imaging (P<0.01) were associated with good collateral status. Following multivariate analysis, low MMP-9 levels (P=0.02) and high MCP-1 levels (P<0.01) remained associated with good collateral status. CONCLUSIONS: Low MMP-9 and high MCP-1 levels were associated with good pretreatment collateral status in patients with acute ischemic stroke with large vessel occlusion. These results might suggest a relationship between collateral status and inflammation.

The apparent mechanical effect of isolated amyloid-ß and α-synuclein aggregates revealed by multi-frequency MRE.

Several biological processes are involved in dementia, and fibrillar aggregation of misshaped endogenous proteins appears to be an early hallmark of neurodegenerative disease. A recently developed means of studying neurodegenerative diseases is magnetic resonance elastography (MRE), an imaging technique investigating the mechanical properties of tissues. Although mechanical changes associated with these diseases have been detected, the specific signal of fibrils has not yet been isolated in clinical or preclinical studies. The current study aims to exploit the fractal-like properties of fibrils to separate them from nonaggregated proteins using a multi-frequency MRE power law exponent in a phantom study. Two types of fibril, α-synuclein (α-Syn) and amyloid-ß (Aß), and a nonaggregated protein, bovine serum albumin, used as control, were incorporated in a dedicated nondispersive agarose phantom. Elastography was performed at multiple frequencies between 400 and 1200 Hz. After 3D-direct inversion, storage modulus (G'), phase angle (ϕ), wave speed and the power law exponent (y) were computed. No significant changes in G' and ϕ were detected. Both α-Syn and Aß inclusions showed significantly higher y values than control inclusions (P = 0.005) but did not differ between each other. The current phantom study highlighted a specific biomechanical effect of α-Syn and Aß aggregates, which was better captured with the power law exponent derived from multi-frequency MRE than with single frequency-derived parameters.

Importance of infarct size versus other variables for clinical outcomes after PPCI in STEMI patients.

Despite promising experimental studies and encouraging proof-of-concept clinical trials, interventions aimed at limiting infarct size have failed to improve clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Our objective was to examine whether variables (cardiovascular risk factors, comorbidities, post-procedural variables, cotreatments) might be associated with clinical outcomes in STEMI patients independently from infarct size reduction. The present study was based on a post hoc analysis of the CIRCUS trial database (Clinicaltrials.gov NCT01502774) that assessed the clinical benefit of a single intravenous bolus of cyclosporine in 969 patients with anterior STEMI. Since cyclosporine had no detectable effect on clinical outcomes as well as on any measured variable, we here considered the whole study population as one group. Multivariate analysis was performed to address the respective weight of infarct size and variables in clinical outcomes. Multivariate analysis revealed that several variables (including gender, hypertension, renal dysfunction, TIMI flow grade post-PCI < 3, and treatment administered after PCI with betablockers and angiotensin-converting enzyme inhibitors) had per se a significant influence on the occurrence of [death or hospitalization for heart failure] at 1 year. The relative weight of infarct size and variables on the composite endpoint of [death or hospitalization for heart failure] at 1 year was 18% and 82%, respectively. Several variables contribute strongly to the clinical outcomes of STEMI patients suggesting that cardioprotective strategy might not only focus on infarct size reduction.

Hospitalisation costs of metastatic melanoma in France; the MELISSA study (MELanoma In hoSpital coSts Assessment).

BACKGROUND: Management of metastatic melanoma is changing rapidly following the introduction of innovative effective therapies, with consequences for the allocation of healthcare resources. The objective of this study was to assess hospitalisation costs of metastatic melanoma in France from 2011 to 2013 from the perspective of the government payer. METHODS: The population studied corresponded to all adults with metastatic melanoma hospitalised in France between 1st January 2011 and 31st December 2013 who required chemotherapy, immunotherapy or radiotherapy due to tumour progression and unresectable Stage III or Stage IV melanoma. Metastatic melanoma was identified by ICD-10 codes documented in the hospital patient discharge records. For each patient, hospital stays were stratified into a pre- or post- progression health state using proxy variables for the RECIST criteria. All healthcare expenditure documented in the French national hospital claims system database and incurred between the index hospitalisation (or change of progression state) and the end of follow-up were analysed. For the principal analysis, valuation of healthcare resource consumption was performed using official national hospitalisation tariffs. Any expensive therapy administered during the stay was documented from a linked database of expensive drugs (FICHCOMP). RESULTS: Seventy-eight thousand seven hundred fifty hospital stays by 10,337 patients with metastatic melanoma were identified over the three-year study period. Annual per capita costs of hospitalisation were € 5046 in the pre-progression stage and € 19,006 in the post-progression stage. Hospitalisations attributed to adverse drug reactions to chemotherapy or immunotherapy were observed in 27% of patients. Annual per capita costs of these hospitalisations related to adverse drug reactions were € 3762 in the pre-progression stage and € 5523 in the post-progression stage. CONCLUSIONS: Hospitalisation costs related to metastatic melanoma rise substantially as the disease progresses. Treatment strategies which slow down disease progression would be expected to reduce costs of hospitalisation for metastatic melanoma, although they may also entail significant acquisition costs. This will entail organisational changes of resource allocation for the treatment of metastatic melanoma in hospitals.

Celsior® vs. St Thomas® cardioplegia: analysis of myocardial protection and clinical safety in neonates.

Objective: To compare the effectiveness and safety of Celsior® crystalloid solution to St Thomas® solution as cardioplegia in pediatric arterial switch surgery. Methods: A retrospective study was conducted on 180 patients who underwent arterial switch operation (ASO) between 2005 and 2019. The patients were divided into two groups: the St Thomas group receiving St Thomas solution and the Celsior® group receiving Celsior® solution. The study aimed to assess myocardial protection while evaluating clinical outcomes of patients between groups. Results: Baseline characteristics not different between groups. The postoperative troponin release trends and blood lactate levels were not different between groups. However, the Celsior® group had a significant lower incidence of delayed sternal closure (9.7% vs. 19.5%; p = 0.09) and mechanical circulatory support (ECMO) (4.9% vs. 24.7%; p < 0.001) compared to the St Thomas group. The length of stay in the intensive care unit (ICU) was significantly shorter in the Celsior® group (4.6 ± 3.36 days vs. 8.72 ± 5.08 days, respectively; p < 0.001). There was no significant difference in 30-day mortality between the two groups (2.9% vs. 2.6%; p = 0.147). Conclusion: The study suggests that Celsior® solution is effective and safe for myocardial protection in pediatric arterial switch surgery. It may offer potential benefits such as reduced need for delayed sternal closure and ECMO support, as well as shorter ICU stay. However, the study has limitations including its retrospective design and the use of different cardioplegic solutions during different time periods. Further prospective randomized trials are needed for confirmation. Clinical Registration Number: ClinicalTrials.gov, ID: NCT04616222.

Colchicine in acute myocardial infarction: cardiovascular events at 1-year follow up.

OBJECTIVE: In the COVERT-MI randomised placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days in acute ST-elevated myocardial infarction did not reduce infarct size but was associated with a significant increase in left ventricular thrombus (LVT) in comparison to placebo. We aimed to assess the 1-year clinical outcomes of the study population. METHODS: This study is a follow-up analysis of the COVERT-MI study on prespecified secondary clinical endpoints at 1 year. The primary endpoint of this study was a composite of major adverse cardiovascular events (MACEs), including all-cause death, acute coronary syndromes, heart failure events, ischaemic strokes, sustained ventricular arrhythmias and acute kidney injury at 1-year follow-up. The quality of life (QOL) and the drug therapy prescription were also assessed. RESULTS: At 1 year, 192 patients (101 patients in the colchicine group, 91 in the placebo group) were followed up. Seventy-six (39.6%) MACEs were reported in the study population. There was no significant difference regarding the number of MACEs between groups: 36 (35.6%) in the colchicine group and 40 (44.1%) in the placebo group (p=0.3). There were no differences in the occurrence of ischaemic strokes between the colchicine group and the control group (3 (3%) vs 2 (2.2%), respectively, p=0.99). There was a trend towards fewer heart failure events in the colchicine group compared with the placebo group (12 (11.9%) vs 18 (19.8%), p=0.20). There was no significant difference in QOL scores at 1 year (75.8±15.7 vs 72.7±16.2 respectively, p=0.18). CONCLUSIONS: There was no significant difference between the colchicine and placebo groups at 1 year regarding MACEs, especially concerning deaths or ischaemic strokes. No excess of ischaemic adverse events was observed despite the initial increase in LVT in the colchicine group. TRIAL REGISTRATION NUMBER: NCT0315681.

Deleterious Anti-Inflammatory Macrophage Recruitment in Early Post-Infarction Phase: Unraveling the IL-6/MCP-1/STAT3 Axis.

Using a translational approach with an ST-segment myocardial infarction (STEMI) cohort and mouse model of myocardial infarction, we highlighted the role of the secreted IL-6 and MCP-1 cytokines and the STAT3 pathway in heart macrophage recruitment and activation. Cardiac myocytes secrete IL-6 and MCP-1 in response to hypoxic stress, leading to a recruitment and/or polarization of anti-inflammatory macrophages via the STAT3 pathway. In our preclinical model of myocardial infarction, neutralization of IL-6 and MCP-1 or STAT3 pathway reduced infarct size. Together, our data demonstrate that anti-inflammatory macrophages can be deleterious in the acute phase of STEMI.

Specific inflammatory profile of acute ischemic stroke patients with left atrial enlargement.

Background: The inflammatory process underlying atrial myopathy may affect the inflammatory response activated in acute ischemic stroke (AIS). Objectives: We aimed to assess whether left atrial enlargement (LAE) as a marker of atrial myopathy is associated with a different profile of circulating inflammatory markers in AIS patients. Methods: HIBISCUS-STROKE is a cohort study including anterior circulation AIS patients treated with mechanical thrombectomy following MRI. Ten circulating inflammatory markers were measured at admission and 6, 24, and 48 h after admission. LAE was defined as a left atrial volume index (LAVi) ≥34 ml/m2. A multiple logistic regression model was performed to detect an independent association between the area under the curve (AUC) of these markers and LAE. Results: We included 143 patients. Of them, 85 (59.4%) had LAE. On univariable analysis, we found that patients with LAE had higher soluble form suppression of tumorigenicity 2 (sST2), soluble tumor necrosis factor receptor I (sTNFR1), and vascular cellular adhesion molecule-1 (VCAM-1) AUC, were older, mostly female, had a higher National Institutes of Health Stroke Scale (NIHSS) score and blood glucose level at admission, had more often hypertension, and a cardioembolic source of AIS, such as atrial fibrillation, while they were less frequently current smokers and had a lower rate of tandem occlusion than patients without LAE. On multivariable analysis, we found that among circulating inflammatory markers, only high VCAM-1 (OR: 9.13, 95% CI: 3.21-25.9) and sST2 (OR: 3.40, 95% CI: 1.68-6.86) AUC remained associated with LAE. Conclusions: High VCAM-1 and sST2 levels within the first 48 h are associated with LAE in AIS patients.

What underlies sex differences in heart failure onset within the first year after a first myocardial infarction?

Background: Women are more likely to develop heart failure (HF) after myocardial infarction. However, diagnosis and reperfusion are often delayed. Objectives: To compare the prevalence of HF after primary percutaneous coronary intervention (PPCI)-treated ST segment myocardial infarction (STEMI) between sexes and to study its associations with comorbidities, infarct size, and left ventricular (LV) systolic and diastolic dysfunctions (DD). Methods: The patients with PPCI-treated anterior STEMI, from the CIRCUS study cohort, were followed up for 1 year and HF events were recorded. Evaluation of ejection fraction (LVEF) and DD were performed at baseline and at 1 year. The elevated LV filling pressure (LVFP) included Grades 2 and 3 DD. Results: Of the 791 patients from the CIRCUS study, 135 were women. At 1 year, the proportion of patients who developed HF was 21% among men and 34% among women (p = 0.001). In the subset of 407 patients with available diastolic parameters, the rate of HF was also higher in women. HF during the initial hospitalization was comparable between the sexes. However, women had a higher incidence of rehospitalization for HF within the first year after STEMI (14.1% vs. 4.1%, p = 0.005). Women were older with a higher prevalence of hypertension. The infarct size and LVEF were similar between the sexes. Elevated LVFP was observed more frequently in women than in men during the initial hospitalization and at 1 year (26% vs. 12%, p = 0.04, and 22% vs. 12%, p = 0.006, respectively). Interestingly, only initial elevated LVFP (HR 5.9, 95% CI: 2.4-14.5, p < 0.001), age, and hypertension were independently associated with rehospitalization for HF. Conclusions: After PPCI-treated anterior STEMI, despite comparable infarct size and LVEF, women presented a higher proportion of rehospitalization for HF than men. That was likely due to a greater DD associated with older age and hypertension.

Remote ischemic conditioning in septic shock: the RECO-Sepsis randomized clinical trial.

PURPOSE: To determine whether remote ischemic conditioning (RECO), compared to standard care, limits the severity and the consequences of multiple organ failure in patients with septic shock. METHODS: The RECO-Sepsis trial, a prospective, multicenter, randomized, open-label, parallel group trial with blinded assessment of the outcome, was conducted at six intensive care units in France in adult patients with septic shock. Within 12 h after the onset of septic shock, patients were randomized (1:1 ratio) to receive either RECO applied by inflating/deflating (200/0 mmHg for 5/5 min) 4 times a cuff around an arm or a sham procedure every 12 h for 24 h. The primary endpoint was the severity of multiple organ failure assessed by the mean daily Sequential Organ Failure Assessment (SOFA) score from inclusion to the fourth day after inclusion (day 4). Patients were followed for 90 days. RESULTS: Among 180 randomized patients, 178 completed the trial (RECO group: 87; control group: 91) and were included in the intention-to-treat analysis (108 men [60.7%], median age 68 [59-75] years). There was no significant difference in the mean daily SOFA score between the intervention group and the control group (7.2 points [5.2-10.7] versus 7.6 points [4.9-10.7], respectively; p = 0.919). Cumulative mortality within 90 days was 27.6% in the RECO group and 39.6% control group (Log-rank test, p = 0.10; adjusted hazard ratio 0.59, 95% CI, 0.35 to 0.99; p = 0.049). CONCLUSIONS: In patients with septic shock, RECO failed to reduce the severity of organ failures assessed by mean daily SOFA score from inclusion to day 4. Adequately powered trials are needed to assess potential delayed benefits of RECO.

Does the Brush-Sign Reflect Collateral Status and DWI-ASPECTS in Large Vessel Occlusion?

Introduction: The relevance of the brush-sign remained poorly documented in large vessel occlusion (LVO). We aimed to assess the relationship between the brush-sign and collateral status and its potential impact on baseline diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) in acute ischemic stroke (AIS) patients eligible to mechanical thrombectomy (MT). Methods: Consecutive patients admitted in the Lyon Stroke Center with anterior circulation AIS due to intracranial internal carotid artery (ICA) and/or M1 or M2 segment of the middle cerebral artery (MCA) occlusion eligible for MT were included. The brush-sign was assessed on T2-gradient-echo MRI. Collateral status was assessed on digital subtraction angiography according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) score. Results: In this study, 504 patients were included, among which 171 (33.9%) patients had a brush-sign. Patients with a brush-sign more frequently had a poor collateral status [72 (42.1%) vs. 103 (30.9%); p = 0.017]. In univariable analysis, a DWI-ASPECTS < 7 was associated with a brush sign. Following multivariable analysis, the brush-sign no longer affected DWI-ASPECTS < 7 while the latter remained associated with younger age [odds ratio (OR) 0.97, 95% CI.96-0.99], male sex (OR 1.79, 95% CI 1.08-2.99), a higher National Institutes of Health Stroke Scale (NIHSS) score (OR 1.16, 95% CI 1.1-1.21), a poor collateral status (OR 9.35, 95% CI 5.59-16.02), MCA segment (OR 2.54, 95% CI 1.25-5.38), and intracranial ICA (OR 3.01, 95% CI 1.16-8) occlusion. Conclusions and Relevance: The brush-sign may be a marker of poor collateral status but did not independently predict a lower DWI-ASPECTS. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04620642.

Inflammatory profile and white matter hyperintensity burden in acute ischemic stroke patients.

Inflammation is involved in small vessel disease (SVD). We aim to clarify whether inflammation related to white matter hyperintensities (WMH), a key component of SVD, may affect the inflammatory response in acute ischemic stroke (AIS) patients. For this, we sequentially measured 10 circulating inflammatory markers and assessed WMH burden on admission MRI in AIS patients treated with thrombectomy. Of 149 patients, 57 (38.3%) had a high WMH burden (Fazekas≥3). A high WMH burden was associated with 4 markers levels but this association did not remain following multivariable analyses. WMH burden is not associated with a specific inflammatory profile in AIS.

Neurofunctional and neuroimaging readouts for designing a preclinical stem-cell therapy trial in experimental stroke.

With the aim of designing a preclinical study evaluating an intracerebral cell-based therapy for stroke, an observational study was performed in the rat suture model of ischemic stroke. Objectives were threefold: (i) to characterize neurofunctional and imaging readouts in the first weeks following transient ischemic stroke, according to lesion subtype (hypothalamic, striatal, corticostriatal); (ii) to confirm that intracerebral administration does not negatively impact these readouts; and (iii) to calculate sample sizes for a future therapeutic trial using these readouts as endpoints. Our results suggested that the most relevant endpoints were side bias (staircase test) and axial diffusivity (AD) (diffusion tensor imaging). Hypothalamic-only lesions did not affect those parameters, which were close to normal. Side bias in striatal lesions reached near-normal levels within 2 weeks, while rats with corticostriatal lesions remained impaired until week 14. AD values were decreased at 4 days and increased at 5 weeks post-surgery, with a subtype gradient: hypothalamic < striatal < corticostriatal. Intracerebral administration did not impact these readouts. After sample size calculation (18-147 rats per group according to the endpoint considered), we conclude that a therapeutic trial based on both readouts would be feasible only in the framework of a multicenter trial.

Prognosis value of serum soluble ST2 level in acute ischemic stroke and STEMI patients in the era of mechanical reperfusion therapy.

BACKGROUND: Soluble form suppression of tumorigenicity 2 (sST2) is known to have prognostic value in ST-elevation myocardial infarction (STEMI) and could impact mortality after acute ischemic stroke (AIS). However, before considering sST2 as a therapeutic target, the kinetics of release and its association with adverse clinical events in both STEMI and AIS patients have to be determined. METHODS: We prospectively enrolled 251 STEMI patients, treated with primary percutaneous coronary intervention, and 152 AIS patients treated with mechanical thrombectomy. We evaluated the level of sST2 in patient sera at five time point (admission, 4, 24, 48 h and 1 month from admission for STEMI patients and admission, 6, 24, 48 h and 3 months from admission for AIS patients). Major adverse clinical events (MACE) (all-cause death, acute myocardial infarction, stroke or hospitalization for heart failure) in STEMI patients and all-cause death in AIS patients were recorded during a 12-month follow-up. RESULTS: Mean age of the study population was 59 ± 12 and 69 ± 15 years in STEMI and AIS patients, respectively. In STEMI patients, sST2 peaked 24 h after admission (25.5 ng/mL interquartile range (IQR) [14.9-29.1]) whereas an earlier and lower peak was observed in AIS patients (16.8 ng/mL IQR [15.2-18.3] at 6 h). Twenty-five (10.0%) STEMI patients experienced a MACE and 12 (7.9%) AIS patients had all-cause death within the first 12 months. A high level of sST2 at 24 h was associated with MACE in STEMI patients (hazard ratio (HR) = 2.5; 95% confidence interval (CI) [1.1-5.6], p = 0.03) and all-cause death in AIS patients (HR = 11.7; 95% CI [3.8-36.2], p < 0.01) within the first 12 months. CONCLUSIONS: The study highlights that sST2 levels at 24 h are associated with an increased risk to adverse clinical events in both diseases.