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Metabolome of Cerebral Thrombi Reveals an Association Between High Glycemia at Stroke Onset and Good Clinical Outcome

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Metabolome of Cerebral Thrombi Reveals an Association Between High Glycemia at Stroke Onset and Good Clinical Outcome H OH metabolites OH Article Metabolome of Cerebral Thrombi Reveals an Association between High Glycemia at Stroke Onset and Good Clinical Outcome Laurent Suissa 1,2 , Jean-Marie Guigonis 1, Fanny Graslin 1, Emilie Doche 2, Ophélie Osman 2, Yves Chau 3, Jacques Sedat 3, Sabine Lindenthal 1 and Thierry Pourcher 1,* 1 Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fréderic Joliot, Commissariat à l0Energie Atomique et aux Énergies Alternatives (CEA), University Côte d’Azur, F-06107 Nice, France; [email protected] (L.S.); [email protected] (J.-M.G.); [email protected] (F.G.); [email protected] (S.L.) 2 Stroke Unit, University Hospital, F-13385 Marseille, France; [email protected] (E.D.); [email protected] (O.O.) 3 Interventional Radiology Unit, University Hospital, F-06001 Nice, France; [email protected] (Y.C.); [email protected] (J.S.) * Correspondence: [email protected]; Tel.: +33-4-93-37-77-10 Received: 1 November 2020; Accepted: 23 November 2020; Published: 25 November 2020 Abstract: Despite the fact that glucose is the main fuel of the brain, hyperglycemia at hospital admission is generally associated with a poor functional outcome in stroke patients. This paradox may be explained by the lack of information about the blood glucose level at stroke onset. Here, we analyzed the metabolome of blood cells entrapped in cerebral thrombi to gain insight into their metabolism at stroke onset. Fourty-one consecutive stroke patients completely recanalized by mechanical thrombectomy within 6 h were included. The metabolome of retrieved thrombi was analyzed by liquid chromatography tandem with mass spectrometry. Discriminant Analysis (sparse Partial Least Squares Discriminant Analysis (sPLS-DA)) was performed to identify classification models and significant associated features of favorable clinical outcome at 3 months (modified Rankin Scale (mRS) < 2). sPLS-DA of the metabolomes of cerebral thrombi discriminated between stroke patients with a favorable or poor clinical outcome (Area Under the Curve (AUC) = 0.992 (0.931–1)). In addition, our results revealed that high sorbitol and glucose levels in the thrombi positively correlated with favorable clinical outcomes. Sorbitol, a short-term glycemic index reflecting a high blood glucose level at stroke onset, was found to be an independent predictor of good outcome (AUC = 0.908 (0.807–0.995)). This study demonstrates that a high blood glucose level at stroke onset is beneficial to the clinical outcome of the patient. Keywords: stroke; thrombectomy; thrombosis; metabolomics; glucose; sorbitol 1. Introduction In the last decade, remarkable progress into reperfusion treatment of patients with acute stroke with large artery occlusion has led to improved clinical outcomes [1]. Endovascular thrombectomy after large vessel ischemic stroke within 6 h of symptom onset is proposed in addition to intravenous thrombolysis by alteplase, if eligible [2]. Despite the unquestionable value of this major advance, only less than half of the treated patients show clinical benefit from recanalization leading to the common assumption that recanalization is considered as necessary but not sufficient [1,3]. Metabolites 2020, 10, 483; doi:10.3390/metabo10120483 www.mdpi.com/journal/metabolites Metabolites 2020, 10, 483 2 of 15 Admission hyperglycemia has been strongly associated with a poor functional outcome in patients treated with intravenous recombinant tissue Plasminogen Activator (rt-PA) and more recently, in stroke patients with large vessel occlusion treated with mechanical thrombectomy [4,5]. However, the molecular mechanisms underlying the robust association between admission hyperglycemia and poor clinical outcome are still uncertain. The blood glucose level is certainly a major parameter for the prediction of clinical stroke outcome but measurement of blood glucose at admission, before reperfusion, is affected by a stress response to acute neurologic injury [6,7] and does not automatically reveal the glycemia at stroke onset, which remains unknown in clinical practice. According to the review of Robbins and Swanson [6], glucose has dual opposing effects on stroke and on the reperfusion setting. While the deleterious role of glucose on reperfusion is supported by experimental and clinical data, the beneficial effect of glucose could theoretically be supported by its capacity to produce energy (ATP) even in the absence of oxygen (anaerobic glycolysis) in the ischemic setting [6]. Indeed, some observations reviewed by Robbins and Swanson argue for a beneficial effect of glucose on stroke, which has not been demonstrated in clinical practice until now because glycemia at stroke onset remains unknown [6]. New insight into this area is needed for target neuroprotection strategies for recanalized stroke patients. Metabolomic analyses using a mass spectrometer allow the study of many substrates, intermediates and products of cell metabolism. However, to our knowledge, the metabolome of cerebral thrombi has not yet been studied. Here, we hypothesized that the analysis of the cells entrapped in the cerebral thrombi retrieved during the acute phase of stroke patients could provide information about glucose metabolism of blood cells at stroke onset. 2. Results 2.1. Patient Characteristics Among the 59 stroke patients included in the ThrombiOMIC database, 41 patients met the inclusion criteria for our study. The baseline characteristics of these 41 stroke patients are shown in Table1. All patients (age: 74.8 13.2 years, men: 17/41 (41.5%), baseline National Institutes of Health Stroke ± Scale (NIHSS): 17 (15–22)) were successfully recanalized (mTICI 2b/3) by mechanical thrombectomy for a middle cerebral artery occlusion within 6 h from stroke onset (time elapsed from stroke onset to recanalization: 252.4 62.2 min) according to American Heart Association/American Stroke Association ± (AHA/ASA) guidelines [2]. Of these, 34/41 (82.9%) stroke patients were documented by Magnetic Resonance Imaging (MRI) in the acute phase (Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS): 7 (7–8), stroke volume on Diffusion-Weighted Imaging (DWI): 9.8 (5.2–20.6) cm3). Further, 21/41 (51.2%) patients received intravenous alteplase prior to the endovascular procedure. At 24 h after the reperfusion treatment, asymptomatic hemorrhagic infarcts were observed on systematic brain imaging for 13/41 (31.7%) patients. At 3 months, 18/41 (43.9%) patients had a favorable clinical outcome defined by a mRS of 0 to 1 and 3/41 (7.3%) patients died by 3 months. The subtype etiology of stroke defined according to the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification were distributed as follows: 32/41 (78.1%) cardioembolism, 2/41 (4.9%) large-artery atherosclerosis, 2/41 (4.9%) stroke other determined etiology and 5/41 (12.2%) stroke of undetermined etiology. As expected from the literature, age (p = 0.0247), baseline clinical gravity assessed by the NIHSS score (p = 0.0480) and admission glycemia (p = 0.0378) were significantly associated with clinical outcome (according the modified Rankin Scale (mRS)) in the univariate analysis presented in Table1. In contrast, the medical history, radiological variables, thrombolytic use, timing of recanalization, hemorrhagic complications or even stroke etiological subgroups were not statistically associated with clinical prognosis (Table1). Metabolites 2020, 10, 483 3 of 15 Table 1. Baseline characteristics of stroke patients. * p < 0.05. Patient Characteristics All Patients (n = 41) mRS < 2 (n = 18) mRS 2 (n = 23) p ≥ Demographic characteristics Age, years * 74.8 13.2 70.2 16.7 78.3 12.7 0.0247 ± ± ± Gender, male 17 (41.5%) 5 (27.8%) 12 (52.2%) 0.2010 Medical history Hypertension 17 (41.5%) 6 (33.3%) 11 (47.8%) 0.5240 Diabetes mellitus 4 (9.8%) 1 (5.6%) 3 (13.0%) 0.6180 Coronary artery disease 4 (9.8%) 3 (16.7%) 1 (4.4%) 0.3030 Smoking 6 (14.6%) 4 (22.2%) 2 (8.7%) 0.3770 Atrial fibrillation 29 (70.7%) 12 (66.7%) 17 (73.9%) 0.7340 Clinical characteristics Baseline NIHSS score * 17 (15–22) 15 (13–21) 20 (16–22) 0.0480 Baseline blood * 134 32 125 21 142 38 0.0378 glucose, mg/dL ± ± ± Imaging characteristics Tandem ICA/MCA 5 (12.2%) 1 (5.6%) 4 (17.4%) 0.3630 occlusion MRI brain imaging 34 (82.9%) 15 (83.3%) 19 (82.6%) 1.0000 DWI-ASPECTS 7 (7–8) 8 (7–8) 7 (6–7) 0.1180 DWI-Volume, cm3 9.8 (5.2–20.6) 8.8 (4.9–16.6) 12.6 (5.8–27.5) 0.2746 Treatment characteristics Intravenous 21 (51.2%) 10 (55.6%) 11 (47.8%) 0.7560 thrombolysis Time to 252.4 62.3 245.8 49.4 257.5 71.4 0.2689 recanalization, min ± ± ± 2.2. Composition of Cerebral Thrombi Assessed by Proteomic Analyses We performed proteomic analyses to compare the composition of cerebral thrombi from stroke patients according to their clinical outcome. The cerebral thrombi were assessed by proteomic analysis for cell-type specific biomarkers [8]. Based on previously published immunohistochemical (IHC) data of cerebral thrombi, the following protein biomarkers were used in our study: red blood cells (RBC) (glycophorin-A), platelets (platelet glycoprotein Ib alpha chain, integrin beta-3, platelet endothelial cell adhesion molecule), leukocytes (receptor-type tyrosine-protein phosphatase C), fibrin (fibrinogens α, β and γ) and the von Willebrand factor. We did not detect any significant difference in the levels of these proteins in the cerebral
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