Artificial intelligence to enhance prehospital stroke diagnosis and triage: a perspective.

As health systems organize to deliver the highest quality stroke care to their patients, there is increasing emphasis being placed on prehospital stroke recognition, accurate diagnosis, and efficient triage to improve outcomes after stroke. Emergency medical services (EMS) personnel currently rely heavily on dispatch accuracy, stroke screening tools, bypass protocols and prehospital notification to care for patients with suspected stroke, but novel tools including mobile stroke units and telemedicine-enabled ambulances are already changing the landscape of prehospital stroke care. Herein, the authors provide our perspective on the current state of prehospital stroke diagnosis and triage including several of these emerging trends. Then, we provide commentary to highlight potential artificial intelligence (AI) applications to improve stroke detection, improve accurate and timely dispatch, enhance EMS training and performance, and develop novel stroke diagnostic tools for prehospital use.

Statin Usage Increases White Matter Hyperintensities: A Post Hoc Analysis of SPRINT-MIND.

BACKGROUND: Progression of white matter hyperintensities (WMHs), a radiographic marker of cerebral small vessel disease, occurs with uncontrolled conventional cerebrovascular risk factors. Less certain, however, is the influence of dyslipidemia and the impact of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) on WMH progression. The goal of this study was to evaluate the influence of statins on the progression of WMH over a 4-year interval. METHODS: We performed a post hoc analysis of the SPRINT-MIND database on those with serial volumetric WMH data. WMH progression was calculated as the difference in WMH volume between the 2 scans and then segmented into tertiles due to rightward skew. We defined statin usage as no therapy (0% of visits), partial therapy (1% to 99% of visits) or full therapy (100% of visits) as logged during study visits. Analysis of variance and χ 2 tests were used for continuous and categorical variables with adjustments made for variables known to influence WMH development. RESULTS: A total of 425 individuals were included in this study: 53% without statins use, 27% partial use, and 20% full use. Demographic characteristics and baseline WMH volumes were similar among the cohort. Those with full statin use were significantly more likely to be in the top tertile of WMH progression (adjusted odds ratio: 2.30, 95% confidence interval: 1.11-4.77, P =0.025), despite improvement in dyslipidemia. CONCLUSIONS: SPRINT-MIND participants prescribed a statin were nearly 2.5 times more likely to be within the top tertile of WMH progression over 4 years, despite adjustment for synergistic risk factors and improvement in low-density lipoprotein.

Mutation of breast cancer susceptibility genes increases cerebral microbleeds: A pilot study.

OBJECTIVES: Growing evidence suggests breast cancer susceptibility gene (BRCA) mutations may augment cerebrovascular risk factors. With this influence in mind, we aimed to identify if BRCA mutations increased the prevalence of cerebral small vessel disease (CSVD). METHODS AND MATERIALS: We performed a retrospective cross-sectional analysis of adults undergoing malignancy evaluation with confirmed BRCA mutations compared to BRCA wildtype individuals. A standard-of-care brain MRI was reviewed. Chi-squared or Fisher's, Wilcoxon rank-sum and the Student's t-test analyses were used when appropriate. Adjusted logistic regression models were fit to calculate odds ratio. Multicollinearity was tested by variance inflation factor calculation and for goodness-of-fit via the Hosmer-Lemeshow test. RESULTS: Of 116 individuals, 44.8% (52/116) carried a BRCA mutation. Demographic and cerebrovascular risk factors did not differ. Cerebral microbleeds were more common in those with BRCA mutation: [32.7% (17/52) vs. 17.2% (11/64), p = 0.05] with an adjusted odds ratio of 2.8 (95%CI 1.08-6.89, p = 0.03). Other markers of CSVD were similar amongst the cohort. CONCLUSIONS: We identified a nearly 3-fold increase in identified cerebral microbleed in those with BRCA mutations compared with BRCA wildtype individuals suggestive of an interaction between the BRCA gene and cerebral microbleed formation. Further studies are needed to confirm our findings and to understand clinical implications.

Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide.

Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment.

Effect of Antihypertensives by Class on Cerebral Small Vessel Disease: A Post Hoc Analysis of SPRINT-MIND.

BACKGROUND: Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, although it is unclear whether this reduction occurs due to blood pressure control or class-specific pleiotropic effects, such as improved beat-to-beat arterial pressure variability with calcium channel blockers. The goal of this study was to investigate the influence of antihypertensive medication class, particularly with calcium channel blocker, on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. METHODS: We completed an observational cohort analysis of the SPRINT-MIND trial (Systolic Blood Pressure Trial Memory and Cognition in Decreased Hypertension), a large randomized controlled trial of participants who completed a baseline and 4-year follow-up brain magnetic resonance image with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the magnetic resonance images. A percentage of follow-up time participants were prescribed each of the 11 classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between 2 scans and, to address skew, dichotomized into a top tertile of the distribution compared with the remaining. RESULTS: Among 448 individuals, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 versus 65.7±7.3 years; P<0.001) and systolic blood pressure (128.3±11.0 versus 126.2±9.4 mm Hg; P=0.039). Seventy-two (48.3%) of the top tertile cohort and 177 (59.2%) of the remaining cohort were in the intensive blood pressure arm. Those within the top tertile of progression had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL (P<0.001). Use of angiotensin-converting enzyme inhibitors (odds ratio, 0.36 [95% CI, 0.16-0.79]; P=0.011) and dihydropyridine calcium channel blockers (odds ratio, 0.39 [95% CI, 0.19-0.80]; P=0.011) was associated with less WMH progression, although dihydropyridine calcium channel blockers lost significance when WMH was treated as a continuous variable. CONCLUSIONS: Among participants of SPRINT-MIND trial, angiotensin-converting enzyme inhibitor was most consistently associated with less WMH progression independent of blood pressure control and age.

Leukemic High Grade B Cell Lymphoma is Associated With MYC Translocation, Double Hit/Triple Hit Status, Transformation, and CNS Disease Risk: The Mayo Clinic Experience.

INTRODUCTION: Leukemic involvement in high grade B cell lymphoma (L-HGBL) is rare and has been sparsely described in the literature. We report our experience in a large single institution multicenter academic setting. MATERIALS AND METHODS: Medical records of patients with HGBL who received care at Mayo Clinic between 2003 and 2020 were reviewed. L-HGBL was confirmed by peripheral blood smear and flow cytometry with corroboration from tissue and bone marrow biopsy findings. RESULTS: Twenty patients met inclusion criteria. All patients had significant bone marrow involvement by HGBL. Leukemic involvement presented in 11 of 20 (55%) in the de novo and 9 of 20 (45%) in the relapsed setting. Seven of 20 patients had DLBCL, NOS, 6 of 20 had transformation (t-DLBCL), 3 of 20 had transformed double/triple hit lymphoma (t-DHL/THL), 2 of 20 had double hit lymphoma (DHL), and 2 of 20 had HGBL with intermediate features between DLBCL and Burkitt lymphoma. Nine of 15 patients had MYC translocation. Based on Hans criteria, 11 of 20 had germinal center B-cell (GCB) cell of origin (COO) and 9/20 had non-GCB COO. Five of 11 de novo patients experienced CNS relapse/progression. All de novo patients received anthracycline-based chemoimmunotherapy. Eighteen of 20 patients died of progressive disease. Median overall survival was significantly better in the de novo compared to relapsed group (8.9 months vs. 2.8 months, P = .01). COO, MYC status, DHL/THL status, HGBL subtype, or treatment group did not demonstrate a significant effect on overall survival. CONCLUSION: L-HGBL carries a poor prognosis and is associated with MYC translocation, DHL/THL status, transformation, and high CNS risk. Novel therapeutic approaches are needed for L-HGBL.

Effect of dihydropyridine calcium channel blockers on blood pressure variability in the SPRINT trial: a treatment effects approach.

OBJECTIVE: Increased visit-to-visit blood pressure variability (vvBPV) has negative effects on multiple organ systems. Prior research has suggested that dihydropyridine calcium channel blockers (CCB) may reduce vvBPV, which we attempted to verify in a high-quality dataset with robust statistical methodology. METHODS: We performed a post hoc analysis of the SPRINT trial and included participants who were on a dihydropyridine CCB either 0 or 100% of follow-up study visits. The primary outcome was vvBPV, defined as residual standard deviation (rSD) of SBP from month 6 until study completion. We estimated the average treatment effect of the treated (ATET) after augmented inverse-probability-weighting (AIPW) matching. RESULTS: Of the 9361 participants enrolled in SPRINT, we included 5020, of whom 1959 were on a dihydropyridine CCB and 3061 were not; mean age was 67.4 ±â€Š9.2 years, 34.5% were men, 65.9% were white, 49.4% were randomized to intensive blood pressure control, and the rSD was 10.1 ±â€Š4.0 mmHg. Amlodipine represented greater than 95% of dihydropyridine CCB use. After AIPW matching of demographics and other antihypertensive medications, the ATET estimation for participants on a dihydropyridine CCB was an rSD that was 2.05 mmHg lower (95% CI -3.19 to -0.91). We did not find that other antihypertensive medications classes decreased vvBPV, and several increased it. CONCLUSION: In the SPRINT trial, consistent use of a dihydropyridine CCB was associated with a 2 mmHg reduction in vvBPV. The implication of this hypothesis-generating finding in a high-quality dataset is that future trials to reduce vvBPV could consider using dihydropyridine CCBs.

Continuous Glibenclamide Prevents Hemorrhagic Transformation in a Rodent Model of Severe Ischemia-Reperfusion.

BACKGROUND: Endovascular thrombectomy (EVT) is highly effective but may also lead to hemorrhagic transformation (HT) and edema, which may be more pronounced in severe ischemia. We sought to determine whether glibenclamide can attenuate HT and edema in a severe ischemia-reperfusion model that reflects EVT. METHODS: Using a transient middle cerebral artery occlusion (tMCAo) rodent model of stroke, we studied two rat cohorts, one without rt-PA and a second cohort treated with rt-PA. Glibenclamide or vehicle control was administered as an intravenous bolus at reperfusion, followed by continuous subcutaneous administration with an osmotic pump. RESULTS: Compared to vehicle control, glibenclamide improved neurological outcome (median 7, interquartile range [IQR 6-8] vs. control median 6 [IQR 0-6], p = 0.025), reduced stroke volume (323 ± 42 vs. 484 ± 60 mm3, p < 0.01), swelling volume (10 ± 4 vs. 28 ± 7%, p < 0.01) and water content (84 ± 1 vs. 85 ± 1%, p < 0.05). Glibenclamide administration also reduced HT based on ECASS criteria, densitometry (0.94 ± 0.1 vs. 1.15 ± 0.2, p < 0.01), and quantitative hemoglobin concentration (2.7 ± 1.5 vs. 6.2 ± 4.6 uL, p = 0.011). In the second cohort with rt-PA coadministration, concordant effects on HT were observed with glibenclamide. CONCLUSIONS: Taken together, these studies demonstrated that glibenclamide reduced the amount of edema and HT after severe ischemia. This study suggests that co-administration of glibenclamide may be worth further study in severe stroke patients treated with EVT with or without IV rt-PA.

Time-dependent, dynamic prediction of fatty acid-binding protein 4, Galectin-3, and soluble ST2 measurement with poor outcome after acute stroke.

BACKGROUND: Time-dependent change in the level of biomarkers after stroke is not well understood. We sought to compare fatty acid-binding protein 4 (FABP4), Galectin-3, and soluble ST2 to ascertain for a change in prediction of outcome at admission and 48 h later. METHODS: Plasma FABP4, Galectin-3, and soluble ST2 were measured in biospecimens from acute stroke patients at the time of admission (n = 383) and 48 h later (n = 244). Functional outcome was assessed at 90 days using the modified Rankin Scale and dichotomized into good (modified Rankin Scale 0-2) and poor outcome (modified Rankin Scale 3-6). RESULTS: On admission, elevated levels of each biomarker predicted poor outcome (FABP4: OR 1.92, 95% CI 1.42-2.59, P < 0.0001; Galectin-3: OR 1.85, 95% CI 1.42-2.40, P < 0.0001; soluble ST2: OR 1.55, 95% CI 1.22-1.97, P < 0.0001) and death (FABP4: OR 2.45; 95% CI 1.51-3.98; P < 0.0001; Galectin-3: OR 2.12; 95% CI 1.50-3.30; P < 0.0001; soluble ST2: OR 2.17; 95% CI 1.58-2.99; P < 0.0001). At 48 h, soluble ST2 predicted poor outcome (OR 2.62, 95% CI 1.77-3.88, P < 0.0001) and mortality (OR 3.36, 95% CI 2.06-5.48, P < 0.0001), and Galectin-3 predicted mortality only (OR 1.81, 95% CI 1.05-3.10, P = 0.033). FABP4 measured at 48 h was not predictive of outcome or death. Associations of Galectin-3 and soluble ST2 with outcome or mortality were independent of age, sex, and NIHSS, whereas those with FABP4 were not. CONCLUSIONS: Galectin-3 performed better when measured on admission, whereas soluble ST2 was predictive at admission and better at 48 h after stroke. The time-dependent differences may reflect the evolving role of these pathways after acute stroke.

Uric Acid and Gluconic Acid as Predictors of Hyperglycemia and Cytotoxic Injury after Stroke.

Hyperglycemia is a feature of worse brain injury after acute ischemic stroke, but the underlying metabolic changes and the link to cytotoxic brain injury are not fully understood. In this observational study, we applied regression and machine learning classification analyses to identify metabolites associated with hyperglycemia and a neuroimaging proxy for cytotoxic brain injury. Metabolomics and lipidomics were carried out using liquid chromatography-tandem mass spectrometry in admission plasma samples from 381 patients presenting with an acute stroke. Glucose was measured by a central clinical laboratory, and a subgroup of patients (n = 201) had apparent diffusion coefficient (ADC) imaging quantified on magnetic resonance imaging (MRI) to estimate cytotoxic injury. Uric acid was the leading metabolite in univariate analysis of both hyperglycemia (OR 19.6, 95% CI 8.6-44.7, P = 1.44 × 10-12) and ADC (OR 5.3, 95% CI 2.2-13.0, P = 2.42 × 10-4). To further prioritize model features and account for non-linear correlation structure, a random forest machine learning algorithm was applied to separately model hyperglycemia and ADC. The statistical techniques used have identified uric acid and gluconic acids as leading candidate markers common to all models (R2 = 68%, P = 2.2 × 10-10 for uric acid; R2 = 15%, P = 8.09 × 10-10 for gluconic acid). Both uric acid and gluconic acid were associated with hyperglycemia and cytotoxic brain injury. Both metabolites are linked to oxidative stress, which highlights two candidate targets for limiting brain injury after stroke.

Elevated miR-9 in Cerebrospinal Fluid Is Associated with Poor Functional Outcome After Subarachnoid Hemorrhage.

This study evaluated microRNA (miRNA) changes in cerebrospinal fluid (CSF) and their association with the occurrence of delayed cerebral ischemia (DCI) and poor functional outcome after SAH. Forty-three selected miRNAs were measured in daily CSF samples from a discovery cohort of SAH patients admitted to Rigshospitalet, Copenhagen, Denmark, and compared with neurologically healthy patients. Findings were validated in CSF from a replication cohort of SAH patients admitted to Massachusetts General Hospital, Boston, Massachusetts. The CSF levels of miRNA over time were compared with the occurrence of DCI, and functional outcome after 3 months. miRNAs were quantified in 427 CSF samples from 63 SAH patients in the discovery cohort, in 104 CSF samples from 63 SAH patients in the replication cohort, and in 11 CSF samples from 11 neurologically healthy patients. The miRNA profile changed remarkably immediately after SAH. Elevated miR-9-3p was associated with a poor functional outcome in the discovery cohort (p < 0.0001) after correction for multiple testing (q < 0.01) and in the replication cohort (p < 0.01). Furthermore, elevated miR-9-5p was associated with a poor functional outcome in the discovery cohort (p < 0.01) after correction for multiple testing (q < 0.05). No miRNA was associated with DCI in both cohorts. miR-9-3p and miR-9-5p are elevated in the CSF following SAH and this elevation is associated with a poor functional outcome. These elevations have potential roles in the progression of cerebral injury and could add to early prognostication.

High-throughput metabolite profiling: identification of plasma taurine as a potential biomarker of functional outcome after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Metabolite profiling (or metabolomics) can identify candidate biomarkers for disease and potentially uncover new pathways for intervention. The goal of this study was to identify potential biomarkers of functional outcome after subarachnoid hemorrhage (SAH). METHODS: The authors performed high-throughput metabolite profiling across a broad spectrum of chemical classes (163 metabolites) on plasma samples taken from 191 patients with SAH who presented to Massachusetts General Hospital between May 2011 and October 2016. Samples were drawn at 3 time points following ictus: 0-5, 6-10, and 11-14 days. Elastic net (EN) and LASSO (least absolute shrinkage and selection operator) machine learning analyses were performed to identify metabolites associated with 90-day functional outcomes as assessed by the modified Rankin Scale (mRS). Additional univariate and multivariate analyses were then conducted to further examine the relationship between metabolites and clinical variables and 90-day functional outcomes. RESULTS: One hundred thirty-seven (71.7%) patients with aneurysmal SAH met the criteria for inclusion. A good functional outcome (mRS score 0-2) at 90 days was found in 79 (57.7%) patients. Patients with good outcomes were younger (p = 0.002), had lower admission Hunt and Hess grades (p < 0.0001) and modified Fisher grades (p < 0.0001), and did not develop hydrocephalus (p < 0.0001) or delayed cerebral ischemia (DCI) (p = 0.049). EN and LASSO machine learning methods identified taurine as the leading metabolite associated with 90-day functional outcome (p < 0.0001). Plasma concentrations of the amino acid taurine from samples collected between days 0 and 5 after aneurysmal SAH were 21.9% (p = 0.002) higher in patients with good versus poor outcomes. Logistic regression demonstrated that taurine remained a significant predictor of functional outcome (p = 0.013; OR 3.41, 95% CI 1.28-11.4), after adjusting for age, Hunt and Hess grade, modified Fisher grade, hydrocephalus, and DCI. CONCLUSIONS: Elevated plasma taurine levels following aneurysmal SAH predict a good 90-day functional outcome. While experimental evidence in animals suggests that this effect may be mediated through downregulation of pro-inflammatory cytokines, additional studies are required to validate this hypothesis in humans.

Soluble ST2 links inflammation to outcome after subarachnoid hemorrhage.

OBJECTIVE: To investigate whether soluble growth stimulation expressed gene 2 (sST2), a prognostic marker in cardiovascular and inflammatory disorders, is associated with neurological injury after aneurysmal subarachnoid hemorrhage (SAH). METHODS: We studied SAH patients from 2 independent cohorts. Outcome assessments included functional status at 90 days using the modified Rankin Scale (mRS), mortality, and delayed cerebral ischemia (DCI). The relationships between sST2 plasma level and outcome measures were assessed in both cross-sectional and longitudinal analysis. Primary blood mononuclear cells from SAH patients and elective aneurysm controls were analyzed by multiparameter flow cytometry. RESULTS: In the discovery cohort, sST2 predicted 90-day mRS 3-6 (C index = 0.724, p < 0.001) and mortality in Kaplan-Meier analysis (p < 0.001). The association with functional status was independent of age, sex, World Federation of Neurosurgical Societies score, modified Fisher score, treatment modality, and cardiac comorbidities (adjusted odds ratio = 2.28, 95% confidence interval = 1.04-5.00, p = 0.039). Higher sST2 concentration was observed in those patients with DCI (90.8 vs 53.7ng/ml, p = 0.003). These associations were confirmed in a replication cohort. In patients with high sST2, flow cytometry identified decreased expression of CD14 (4.27 × 105 ± 2,950 arbitrary unit (AU) vs 5.64 × 105 ± 1,290 AU, p < 0.001), and increased expression of CD16 (39,960 ± 272 AU vs 34,869 ± 183 AU, p < 0.001). INTERPRETATION: Plasma sST2 predicts DCI, functional outcome, and mortality after SAH, independent of clinical and radiographic markers. Elevated sST2 is also associated with changes in CD14+ CD16+ monocytes. ANN NEUROL 2019;86:384-394.

Intermittent CSF drainage and rapid EVD weaning approach after subarachnoid hemorrhage: association with fewer VP shunts and shorter length of stay.

OBJECTIVE: There is variability and uncertainty about the optimal approach to the management and discontinuation of an external ventricular drain (EVD) after subarachnoid hemorrhage (SAH). Evidence from single-center randomized trials suggests that intermittent CSF drainage and rapid EVD weans are safe and associated with shorter ICU length of stay (LOS) and fewer EVD complications. However, a recent survey revealed that most neurocritical care units across the United States employ continuous CSF drainage with a gradual wean strategy. Therefore, the authors sought to determine the optimal EVD management approach at their institution. METHODS: The authors reviewed records of 200 patients admitted to their institution from 2010 to 2016 with aneurysmal SAH requiring an EVD. In 2014, the neurocritical care unit of the authors' institution revised the internal EVD management guidelines from a continuous CSF drainage with gradual wean approach (continuous/gradual) to an intermittent CSF drainage with rapid EVD wean approach (intermittent/rapid). The authors performed a retrospective multivariable analysis to compare outcomes before and after the guideline change. RESULTS: The authors observed a significant reduction in ventriculoperitoneal (VP) shunt rates after changing to an intermittent CSF drainage with rapid EVD wean approach (13% intermittent/rapid vs 35% continuous/gradual, OR 0.21, p = 0.001). There was no increase in delayed VP shunt placement at 3 months (9.3% vs 8.6%, univariate p = 0.41). The intermittent/rapid EVD approach was also associated with a shorter mean EVD duration (10.2 vs 15.6 days, p < 0.001), shorter ICU LOS (14.2 vs 16.9 days, p = 0.001), shorter hospital LOS (18.2 vs 23.7 days, p < 0.0001), and lower incidence of a nonfunctioning EVD (15% vs 30%, OR 0.29, p = 0.006). The authors found no significant differences in the rates of symptomatic vasospasm (24.6% vs 20.2%, p = 0.52) or ventriculostomy-associated infections (1.3% vs 8.8%, OR 0.30, p = 0.315) between the 2 groups. CONCLUSIONS: An intermittent CSF drainage with rapid EVD wean approach is associated with fewer VP shunt placements, fewer complications, and shorter LOS compared to a continuous CSF drainage with gradual EVD wean approach. There is a critical need for prospective multicenter studies to determine if the authors' experience is generalizable to other centers.

Succinate links atrial dysfunction and cardioembolic stroke.

OBJECTIVE: To determine whether altered metabolic profiles represent a link between atrial dysfunction and cardioembolic (CE) stroke, and thus whether underlying dysfunctional atrial substrate may contribute to thromboembolism risk in CE stroke. METHODS: A total of 144 metabolites were measured using liquid chromatography-tandem mass spectrometry in plasma samples collected within 9 hours of stroke onset in 367 acute stroke patients. Stroke subtype was assigned using the Causative Classification of Stroke System, and CE stroke (n = 181) was compared to non-CE stroke (n = 186). Markers of left atrial dysfunction included abnormal atrial function (P-wave terminal force in lead V1, PTFV1 >4,000 µV·ms), left atrial enlargement on echocardiography, and frank atrial fibrillation on ECG. Stroke recurrence risk was assessed using CHADS2 and CHA2DS2-VASc scores. Associations between metabolites and CE stroke, atrial dysfunction, and stroke recurrence risk were evaluated using logistic regression models. RESULTS: Three tricarboxylic acid metabolites-succinate (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.36-2.15, p = 1.37 × 10-6), α-ketoglutarate (OR 1.62, 95% CI 1.29-2.04, p = 1.62 × 10-5), and malate (OR 1.58, 95% CI 1.26-1.97, p = 2.57 × 10-5)-were associated with CE stroke. Succinate (OR 1.36, 95% CI 1.31-1.98, p = 1.22 × 10-6), α-ketoglutarate (OR 2.14, 95% CI 1.60-2.87, p = 2.08 × 10-8), and malate (OR 2.02, 95% CI 1.53-2.66, p = 1.60 × 10-7) were among metabolites also associated with subclinical atrial dysfunction. Of these, succinate was also associated with left atrial enlargement (OR 1.54, 95% CI 1.23-1.94, p = 1.06 × 10-4) and stroke recurrence based on dichotomized CHADS2 (OR 2.63, 95% CI 1.68-4.13, p = 3.00 × 10-6) and CHA2DS2-VASc (OR 2.43, 95% CI 1.60-3.68, p = 4.25 × 10-6) scores. CONCLUSIONS: Metabolite profiling identified changes in succinate associated with CE stroke, atrial dysfunction, and stroke recurrence, revealing a putative underlying link between CE stroke and energy metabolism.

Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke.

OBJECTIVE: ST2 is a member of the toll-like receptor superfamily that can alter inflammatory signaling of helper T-cells. We investigated whether soluble ST2 (sST2) could independently predict outcome and hemorrhagic transformation (HT) in the setting of stroke. METHODS: We measured sST2 in patients enrolled in the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) network biomarker study. 646 patients had plasma samples collected at the time of hospital admission and 210 patients had a second sample collected 48 h after stroke onset. Functional outcome was assessed using the modified Rankin Scale (mRS), with good and poor outcomes defined as mRS 0-2 and 3-6, respectively. HT was classified using ECASS criteria. The relationships between sST2, outcome, and HT were evaluated using multivariable logistic regression, Kaplan-Meier survival analysis and receiver operating characteristic curves. RESULTS: 646 patients were included in the analysis (mean age 69 years; 44% women), with a median NIHSS of 5 [IQR: 2-12]. The median sST2 level on hospital admission was 35.0 ng/mL [IQR: 25.7-49.8 ng/mL] and at 48 h it was 37.4 ng/mL [IQR 27.9-55.6 ng/mL]. sST2 was independently associated with poor outcome (OR: 2.77, 95% CI: 1.54-5.06; P = 0.003) and mortality (OR: 3.56, 95% CI: 1.58-8.38, P = 0.001) after multivariable adjustment. Plasma sST2 was also associated with hemorrhagic transformation after adjustment for traditional risk factors (OR: 5.58, 95% CI: 1.40-37.44, P = 0.039). INTERPRETATION: Soluble ST2 may serve as a prognostic biomarker for outcome and hemorrhagic transformation in patients with acute stroke. ST2 may link neuroinflammation and secondary injury after stroke.