Background: Vasoregulatory autoantibodies including autoantibodies targeting G-protein-coupled receptors might play a functional role in vascular diseases. We investigated the impact of... Show moreBackground: Vasoregulatory autoantibodies including autoantibodies targeting G-protein-coupled receptors might play a functional role in vascular diseases. We investigated the impact of vasoregulatory autoantibodies on clinical outcome after ischemic stroke.Methods and results: Data were used from the PROSCIS-B (Prospective Cohort With Incident Stroke-Berlin). Autoantibody-targeting receptors such as angiotensin II type 1 receptor (AT1R), endothelin-1 type A receptor, complement factor-3 and -5 receptors, vascular endothelial growth factor receptor-1 and -2, vascular endothelial growth factor A and factor B were measured. We explored associations of high antibody levels with (1) poor functional outcome defined as modified Rankin Scale >2 or Barthel Index <60 at 1 year after stroke, (2) Barthel Index scores over time using general estimating equations, and (3) secondary vascular events (recurrent stroke, myocardial infarction) or death up to 3 years using Cox proportional hazard models. We included 491 patients with ischemic stroke with data on autoantibody levels and outcome. In models adjusted for demographics and vascular risk factors, high autoantibody concentrations (quartile 4) targeting complement factor C3a receptor, vascular endothelial growth factor receptor-2, and vascular endothelial growth factor B were associated with poor functional outcome at 1 year: (odds ratio, 2.0 [95% CI, 1.1-3.6]; odds ratio, 1.8 [95% CI, 1.1-3.2]; and odds ratio, 2.1 [95% CI, 1.2-3.6], respectively) and with lower Barthel Index scores over 3 years (complement factor C3a receptor: adjusted beta=-3.3 [95% CI, -5.7 to -0.5]; VEGF-B: adjusted beta=-2.4 [95% CI, -4.8 to -0.06]). Patients with high autoantibody levels were not at higher risk for secondary vascular events or death.Conclusions: High levels of autoantibodies against vascular endothelial growth factor receptor-2, vascular endothelial growth factor B, and complement factor C3a receptor measured are associated with poor functional outcome after stroke but not with recurrent vascular events or death. Show less
Chemaly, M.; Marlevi, D.; Iglesias, M.J.; Lengquist, M.; Kronqvist, M.; Bos, D.; ... ; Hedin, U. 2023
Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid... Show moreBackground: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. Methods: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Results: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 & PLUSMN; 693.21 vs. 520.94 & PLUSMN; 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 & PLUSMN; 928.49 vs. 582.07 & PLUSMN; 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 & PLUSMN; 258.73 vs. 1752 & PLUSMN; 366.84 MFI; p = 0.004). Conclusions: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability. Show less
Background:Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according... Show moreBackground:Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according to current classification systems (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] and atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection [ASCOD]). The aim was to identify risk factors and leads for (new) causes of cryptogenic ischemic stroke in young adults, using the pediatric classification system from the IPSS study (International Pediatric Stroke Study).Methods:This is a multicenter prospective cohort study conducted in 17 hospitals in the Netherlands, consisting of 1322 patients aged 18 to 49 years with first-ever, imaging confirmed, ischemic stroke between 2013 and 2021. The main outcome was distribution of risk factors according to IPSS classification in patients with cryptogenic and noncryptogenic stroke according to the TOAST and ASCOD classification.Results:The median age was 44.2 years, and 697 (52.7%) were men. Of these 1322 patients, 333 (25.2%) had a cryptogenic stroke according to the TOAST classification. Additional classification using the ASCOD criteria reduced the number patients with cryptogenic stroke from 333 to 260 (19.7%). When risk factors according to the IPSS were taken into account, the number of patients with no potential cause or risk factor for stroke reduced to 10 (0.8%).Conclusions:Among young adults aged 18 to 49 years with a cryptogenic ischemic stroke according to the TOAST classification, risk factors for stroke are highly prevalent. Using a pediatric classification system provides new leads for the possible causes in cryptogenic stroke, and could potentially lead to more tailored treatment for young individuals with stroke. Show less
Introduction: Low ankle-brachial index (ABI) <= 0. 9 is a marker for generalized atherosclerosis and a risk factor for cognitive decline in the general population. Objective: To evaluate the... Show moreIntroduction: Low ankle-brachial index (ABI) <= 0. 9 is a marker for generalized atherosclerosis and a risk factor for cognitive decline in the general population. Objective: To evaluate the impact of ABI <= 0.9 on cognitive function up to 3 years after first-ever ischemic stroke. Methods: Data was used from the "PROspective Cohort with Incident Stroke-Berlin" (PROSCIS-B; NCT01363856). ABI was measured at baseline and categorized into normal (1.4-0.9) vs. low (<= 0.9). Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental-State-Examination (MMSE) at baseline and with the Telephone Interview for Cognitive Status-modified (TICS-m) at 1-3 years of follow-up. We performed confounder adjusted generalized linear models (GLM) to calculate relative risks (RR) for cognitive impairment at baseline (MMSE <= 26; MoCA <= 25) and linear mixed models (LMM) to estimate the impact of low ABI on TICS-m over time. Results: We included 325 patients [mean age: 66 (SD = 13); 38% female, median NIHSS = 2 (IQR = 1-4), ABI <= 0.9: 59 (18%)). Patients with tow ABI were at increased risk of cognitive impairment at baseline (adjusted RR for MoCA <= 25 = 1.98; 95%-CI:1.24 to 3.16). TICS-m scores were consistently lower over time in patients with low ABI (adjusted beta = -1.96; 95%-CI:-3.55 to -0.37). Independent of ABI, cognitive function did not decline over time (adjusted 95%-CI:-0.06 to 0.64). Conclusion: In patients with mild to moderate first-ever ischemic stroke, low ABI is associated with reduced cognitive function over a 3-year follow-up. Show less
Background: Residual risk of ischemic stroke despite anticoagulation in patients with atrial fibrillation (AF) represents a significant clinical issue that remains unaddressed. We aimed to evaluate... Show moreBackground: Residual risk of ischemic stroke despite anticoagulation in patients with atrial fibrillation (AF) represents a significant clinical issue that remains unaddressed. We aimed to evaluate the incidence and risk factors for residual adverse events in AF. Methods and Results: Using data from phase II/III of the prospective GLORIA-AF (Global Registry on Long-Term Oral Anti-thrombotic Treatment in Patients With Atrial Fibrillation) registry, we studied anticoagulated patients with newly diagnosed AF and an increased risk of stroke (CHA(2)DS(2)-VASc >= 1). The primary outcome of interest was ischemic stroke. Secondary outcomes were all-cause death, cardiovascular death and myocardial infarction. A total of 22 410 patients were included; median age 65 (interquartile range 71-78) and 10 044 (44.8%) were female. During a median follow-up period of 3.0 (interquartile range 2.2-3.1) years, the incidence of ischemic stroke was 0.60 (95% CI, 0.54-0.67) per 100-PYs, all-cause death 3.22 (95% CI, 3.08-3.37) per 100-PYs, cardiovascular death 1.08 (95% CI, 1.00-1.16) per 100-PYs and myocardial infarction 0.59 (95% CI, 0.53-0.66) per 100-PYs. Using multivariable Cox proportional hazards analysis, independent predictors of residual ischemic stroke were age (HR 1.05 [95% CI, 1.03-1.07]), diabetes (HR 1.42 [95% CI, 1.08-1.87]), prior thromboembolism (HR 2.27 [95% CI, 1.73-2.98]) and use of antiarrhythmic drugs (HR 0.66 [95% CI, 0.47-0.92]). The incidence of ischemic stroke was comparable among patients treated with nonvitamin K antagonist oral anticoagulants versus vitamin K antagonist; however, there were differences in the independent predictors between both groups. Conclusions: Patients with AF remain at significant residual risk of developing complications including ischemic stroke despite anticoagulation therapy. Further efforts among these patients should be directed at the management of modifiable risk factors that contribute to this risk. Show less
Background: In patients with large vessel occlusion stroke of the anterior circulation, underlying cause is a determinant of outcome. Whether this is the case for posterior circulation large vessel... Show moreBackground: In patients with large vessel occlusion stroke of the anterior circulation, underlying cause is a determinant of outcome. Whether this is the case for posterior circulation large vessel occlusion stroke has yet to be determined. We aimed to report on cause in patients with posterior circulation stroke treated with endovascular thrombectomy and to analyze the association with functional outcome. Methods: We used data of patients with posterior circulation stroke included in the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) registry, a prospective multicenter observational study, between 2014 and 2018. Stroke cause was categorized into large artery atherosclerosis (LAA), cardioembolism, arterial dissection, embolic stroke of undetermined source (ESUS), other determined cause, or undetermined cause. For primary analysis on the association between cause and outcome, we used multivariable ordinal logistic regression analysis to estimate the adjusted common odds ratio for a shift towards a better functional outcome on the modified Rankin Scale at 90 days with LAA as a reference group. Secondary outcomes included favorable functional outcome (modified Rankin Scale score 0-3), National Institutes of Health Stroke Scale score at 24 to 48 hours, reperfusion on digital subtraction angiography, and stroke progression. Results: Of 264 patients with posterior circulation stroke, 84 (32%) had LAA, 48 (18%) cardioembolism, 31 (12%) dissection, and 14 (5%) ESUS. Patients with a dissection were younger (48 [interquartile range, 43-60] years) and had a lower National Institutes of Health Stroke Scale at baseline (12 [interquartile range, 6-31]) than patients with other cause. Functional outcome was better for patients with cardioembolism and ESUS compared to LAA (modified Rankin Scale adjusted common odds ratio, 2.4 [95% CI, 1.1-5.2], respectively adjusted common odds ratio, 3.1 [95% CI, 1.0-9.3]). Patients with a dissection had a lower chance of successful reperfusion compared with LAA (adjusted odds ratio, 0.20 [95% CI, 0.06-0.70]). Conclusions: Unlike the anterior circulation, most frequent cause in our posterior large vessel occlusion stroke cohort is LAA followed by cardioembolism, dissection, and ESUS. Patients with cardioembolism and ESUS have a better prognosis for functional outcome after endovascular thrombectomy than patients with LAA. Show less
Nave, A.H.; Kaynak, N.; Mai, K.; Siegerink, B.; Laufs, U.; Heuschmann, P.U.; ... ; Endres, M. 2022
Background: Elevated triglyceride and glucose levels are associated with an increased cardiovascular disease risk including ischemic stroke. It is not known whether the response to a combined oral... Show moreBackground: Elevated triglyceride and glucose levels are associated with an increased cardiovascular disease risk including ischemic stroke. It is not known whether the response to a combined oral triglyceride and glucose challenge after ischemic stroke improves identification of patients with increased risk for recurrent vascular events. Methods: The prospective, observational Berlin "Cream&Sugar" study was conducted at 3 different university hospital sites of the Charite-Universitatsmedizin Berlin, Germany, between January 24, 2009 and July 31, 2017. Patients with first-ever ischemic stroke were recruited 3 to 7 days after stroke. An oral triglyceride tolerance test (OTTT) and consecutive blood tests before (t(0)) as well as 3 (t(1)), 4 (t(2)), and 5 hours (t(3)) after OTTT were performed in fasting patients. An oral glucose tolerance test was performed in all nondiabetic patients 3 hours after the start of OTTT. Outcomes of the study were recurrent fatal or nonfatal stroke as well as a composite vascular end point including stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death assessed 1 year after stroke. Cox regression models were used to estimate hazard ratios and corresponding 95% CIs between patients with high versus low levels of triglyceride and glucose levels. Results: Overall 755 patients were included; 523 patients completed OTTT and 1-year follow-up. Patients were largely minor strokes patients with a median National Institutes of Health Stroke Scale score of 1 (0-3). Comparing highest versus lowest quartiles of triglyceride levels, neither fasting (adjusted hazard ratio(t0), 1.24 [95% CI, 0.45-3.42]) nor postprandial triglyceride levels (adjusted hazard ratio(t3), 0.44 [95% CI, 0.16-1.25]) were associated with recurrent stroke. With regard to recurrent vascular events, results were similar for fasting triglycerides (adjusted hazard ratio(t0), 1.09 [95% CI, 0.49-2.43]), however, higher postprandial triglyceride levels were significantly associated with a lower risk for recurrent vascular events (adjusted hazard ratio(t3), 0.42 [95% CI, 0.18-0.95]). No associations were observed between fasting and post-oral glucose tolerance test blood glucose levels and recurrent vascular risk. All findings were irrespective of the diabetic status of patients. Conclusions: In this cohort of patients with first-ever, minor ischemic stroke, fasting triglyceride or glucose levels were not associated with recurrent stroke at one year after stroke. However, higher postprandial triglyceride levels were associated with a lower risk of recurrent vascular events which requires further validation in future studies. Overall, our results do not support the routine use of a combined OTTT/oral glucose tolerance test to improve risk prediction for recurrent stroke. Show less
Lith, T.J. van; Sluis, W.M.; Wijers, N.T.; Meijer, F.J.A.; Kamphuis-van Ulzen, K.; Bresser, J. de; ... ; Leeuw, F.E. de 2022
Background: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of... Show moreBackground: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of silent cerebral ischemia, and the long-term functional outcome in these patients are currently unknown. Patients and methods: CORONavirus and Ischemic Stroke (CORONIS) is a multicentre prospective cohort study investigating the prevalence, risk factors and long-term incidence of (silent) cerebral ischemia, and the long-term functional outcome among patients with COVID-19. We aim to include 200 adult patients hospitalized with COVID-19 without symptomatic ischemic stroke to investigate the prevalence of silent cerebral ischemia compared with 60 (matched) controls with MRI. In addition, we will identify potential risk factors and/or causes of cerebral ischemia in COVID-19 patients with (n = 70) or without symptomatic stroke (n = 200) by means of blood sampling, cardiac workup and brain MRI. We will measure functional outcome and cognitive function after 3 and 12 months with standardized questionnaires in all patients with COVID-19. Finally, the long-term incidence of (new) silent cerebral ischemia in patients with COVID-19 will be assessed with follow up MRI (n = 120). The CORONIS study is designed to add further insight into the prevalence, long-term incidence and risk factors of cerebral ischemia, and the long-term functional outcome in hospitalized adult patients with COVID-19. Show less
BACKGROUND AND PURPOSE: Endovascular treatment for acute ischemic stroke has been proven clinically effective, but evidence of the cost-effectiveness based on real-world data is scarce. The aim of... Show moreBACKGROUND AND PURPOSE: Endovascular treatment for acute ischemic stroke has been proven clinically effective, but evidence of the cost-effectiveness based on real-world data is scarce. The aim of this study was to assess whether endovascular therapy plus usual care is cost-effective in comparison to usual care alone in acute ischemic stroke patients. METHODS: An economic evaluation was performed from a societal perspective with a 2-year time horizon. Empirical data on health outcomes and the use of resources following endovascular treatment were gathered parallel to the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) and its 2-year follow-up study. Incremental cost-effectiveness ratios were calculated as the extra costs per additional patient with functional independence (modified Rankin Scale score 0-2) and the extra cost per quality-adjusted life year gained. RESULTS: The mean costs per patient in the intervention group were $126 494 versus $143 331 in the control group (mean difference, -$16 839 [95% CI, -$38 113 to $5456]). Compared with patients in the control group, more patients in the intervention group achieved functional independence, 37.2% versus 23.9% (absolute difference, 13.3% [95% CI, 4.0%-22.0%]) and they generated more quality-adjusted life years, 0.99 versus 0.83 (mean difference of 0.16 [95% CI, 0.04-0.29]). Endovascular treatment dominated standard treatment with $18 233 saved per extra patient with a good outcome and $105 869 saved per additional quality-adjusted life year. CONCLUSIONS: Endovascular treatment added to usual care is clinically effective, and cost saving in comparison to usual care alone in patients with acute ischemic stroke. Registration: URL: ; Unique identifier: NL695. URL: ; Unique identifier: ISRCTN10888758. Show less
Ali, M.; Os, H.J.A. van; Weerd, N. van der; Schoones, J.W.; Heymans, M.W.; Kruyt, N.D.; ... ; Wermer, M.J.H. 2022
Background and Purpose: Women have worse outcomes than men after stroke. Differences in presentation may lead to misdiagnosis and, in part, explain these disparities. We investigated whether there... Show moreBackground and Purpose: Women have worse outcomes than men after stroke. Differences in presentation may lead to misdiagnosis and, in part, explain these disparities. We investigated whether there are sex differences in clinical presentation of acute stroke or transient ischemic attack. Methods: We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Inclusion criteria were (1) cohort, cross-sectional, case-control, or randomized controlled trial design; (2) admission for (suspicion of) ischemic or hemorrhagic stroke or transient ischemic attack; and (3) comparisons possible between sexes in >= 1 nonfocal or focal acute stroke symptom(s). A random-effects model was used for our analyses. We performed sensitivity and subanalyses to help explain heterogeneity and used the Newcastle-Ottawa Scale to assess bias. Results: We included 60 studies (n=582 844; 50% women). In women, headache (pooled odds ratio [OR], 1.24 [95% CI, 1.11-1.39]; I-2=75.2%; 30 studies) occurred more frequently than in men with any type of stroke, as well as changes in consciousness/mental status (OR, 1.38 [95% CI, 1.19-1.61]; I-2=95.0%; 17 studies) and coma/stupor (OR, 1.39 [95% CI, 1.25-1.55]; I-2=27.0%; 13 studies). Aspecific or other neurological symptoms (nonrotatory dizziness and non-neurological symptoms) occurred less frequently in women (OR, 0.96 [95% CI, 0.94-0.97]; I-2=0.1%; 5 studies). Overall, the presence of focal symptoms was not associated with sex (pooled OR, 1.03) although dysarthria (OR, 1.14 [95% CI, 1.04-1.24]; I-2=48.6%; 11 studies) and vertigo (OR, 1.23 [95% CI, 1.13-1.34]; I-2=44.0%; 8 studies) occurred more frequently, whereas symptoms of paresis/hemiparesis (OR, 0.73 [95% CI, 0.54-0.97]; I-2=72.6%; 7 studies) and focal visual disturbances (OR, 0.83 [95% CI, 0.70-0.99]; I-2=62.8%; 16 studies) occurred less frequently in women compared with men with any type of stroke. Most studies contained possible sources of bias. Conclusions: There may be substantive differences in nonfocal and focal stroke symptoms between men and women presenting with acute stroke or transient ischemic attack, but sufficiently high-quality studies are lacking. More studies are needed to address this because sex differences in presentation may lead to misdiagnosis and undertreatment. Show less
BACKGROUND AND PURPOSE: Blinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased... Show moreBACKGROUND AND PURPOSE: Blinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased treatment effect estimates. An outcome adjudication committee assures blinded outcome assessment, but the added value for trials with prospective randomized open blinded end point design and subjective outcomes is unknown. We aimed to assess the degree of misclassification of modified Rankin Scale (mRS) scores by a central assessor and its impact on treatment effect estimates in a stroke trial with prospective randomized open blinded end point design.METHODS: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was the mRS at 90 days. Standardized, algorithm-based telephone interviews to assess the mRS were conducted from a central location by an experienced research nurse, unaware but not formally blinded to treatment allocation (central assessor). Masked reports of these interviews were adjudicated by a blinded outcome committee. Misclassification was defined as an incorrect classification of the mRS by the central assessor. The effect of endovascular treatment on the mRS was assessed with multivariable ordinal logistic regression.RESULTS: In MR CLEAN, 53/500 (10.6%) of the mRS scores were misclassified. The degree and direction of misclassification did not differ between treatment arms (P=0.59). Benefit of endovascular treatment was shown on the mRS when scored by the central assessor (adjusted common odds ratio, 1.60 [95% CI, 1.16-2.21]) and the outcome adjudication committee (adjusted common odds ratio, 1.67 [95% CI, 1.21-2.20]).CONCLUSIONS: Misclassification by the central assessor was small, randomly distributed over treatment arms, and did not affect treatment effect estimates. This study suggests that the added value of a blinded outcome adjudication committee is limited in a stroke trial with prospective randomized open blinded end point design applying standardized, algorithm-based outcome assessment by a central assessor, who is unaware but not formally blinded to treatment allocation. Show less
Martens, L.G.; Luo, J.; Dijk, K.W. van; Jukema, J.W.; Noordam, R.; Heemst, D. van 2021
Background Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be... Show moreBackground Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization. Methods and Results For each circulating antioxidant (vitamins E and C, lycopene, beta-carotene, and retinol), which were assessed as either absolute blood levels and/or high-throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome-wide association studies (P<5x10(-8)). We used summary statistics for single-nucleotide polymorphisms-stroke associations from 3 European-ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance-weighted analyses and subsequently meta-analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85-1.05) for vitamin C and 1.04 (95% CI, 0.99-1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98-1.03) for retinol and 1.12 (95% CI, 0.88-1.42) for vitamin E. Conclusions This study did not provide evidence for a causal association between dietary-derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke. Show less
Samuels, N.; Graaf, R.A. van de; Berg, C.A.L. van den; Venema, S.M.U.; Bala, K.; Doormaal, P.J. van; ... ; MR CLEAN Registry Investigators 2021
Background and Purpose: Optimal blood pressure (BP) management in the acute phase of ischemic stroke remains an unresolved issue. It is uncertain whether guidelines for BP management during and... Show moreBackground and Purpose: Optimal blood pressure (BP) management in the acute phase of ischemic stroke remains an unresolved issue. It is uncertain whether guidelines for BP management during and after intravenous alteplase can be extrapolated to endovascular treatment (EVT) for stroke due to large artery occlusion in the anterior circulation. We evaluated the associations between systolic BP (SBP) in the first 6 hours following EVT and functional outcome as well as symptomatic intracranial hemorrhage. Methods: Patients of 8 MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry centers, with available data on SBP in the 6 hours following EVT, were analyzed. We evaluated maximum, minimum, and mean SBP. Study outcomes were functional outcome (modified Rankin Scale) at 90 days and symptomatic intracranial hemorrhage. We used multivariable ordinal and binary regression analysis to adjust for important prognostic factors and studied possible effect modification by successful reperfusion. Results: Post-EVT SBP data were available for 1161/1796 patients. Higher maximum SBP (per 10 mm Hg increments) was associated with worse functional outcome (adjusted common odds ratio, 0.93 [95% CI, 0.88-0.98]) and a higher rate of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.17 [95% CI, 1.02-1.36]). The association between minimum SBP and functional outcome was nonlinear with an inflection point at 124 mm Hg. Minimum SBP lower and higher than the inflection point were associated with worse functional outcomes (adjusted common odds ratio, 0.85 per 10 mm Hg decrements [95% CI, 0.76-0.95] and adjusted common odds ratio, 0.81 per 10 mm Hg increments [95% CI, 0.71-0.92]). No association between mean SBP and functional outcome was observed. Successful reperfusion did not modify the relation of SBP with any of the outcomes. Conclusions: Maximum SBP in the first 6 hours following EVT is positively associated with worse functional outcome and an increased risk of symptomatic intracranial hemorrhage. Both lower and higher minimum SBP are associated with worse outcomes. A randomized trial to evaluate whether modifying post-intervention SBP results in better outcomes after EVT for ischemic stroke seems justified. Show less
Background and purpose We investigated whether the annual volume of patients with acute ischemic stroke referred from a primary stroke center (PSC) for endovascular treatment (EVT) is associated... Show moreBackground and purpose We investigated whether the annual volume of patients with acute ischemic stroke referred from a primary stroke center (PSC) for endovascular treatment (EVT) is associated with treatment times and functional outcome. Methods We used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) registry (2014-2017). We included patients with acute ischemic stroke of the anterior circulation who were transferred from a PSC to a comprehensive stroke center (CSC) for EVT. We examined the association between EVT referral volume of PSCs and treatment times and functional outcome using multivariable regression modeling. The main outcomes were time from arrival at the PSC to groin puncture (PSC-door-to-groin time), adjusted for estimated ambulance travel times, time from arrival at the CSC to groin puncture (CSC-door-to-groin time), and modified Rankin Scale (mRS) score at 90 days after stroke. Results Of the 3637 patients in the registry, 1541 patients (42%) from 65 PSCs were included. Mean age was 71 years (SD +/- 13.3), median National Institutes of Health Stroke Scale score was 16 (interquartile range [IQR]: 12-19), and median time from stroke onset to arrival at the PSC was 53 min (IQR: 38-90). Eighty-three percent had received intravenous thrombolysis. EVT referral volume was not associated with PSC-door-to-groin time (adjusted coefficient: -0.49 min/annual referral, 95% confidence interval [CI]: -1.27 to 0.29), CSC-door-to-groin time (adjusted coefficient: -0.34 min/annual referral, 95% CI: -0.69 to 0.01) or 90-day mRS score (adjusted common odds ratio: 0.99, 95% CI: 0.96-1.01). Conclusions In patients transferred from a PSC for EVT, higher PSC volumes do not seem to translate into better workflow metrics or patient outcome. Show less
Guey, S.; Oberstein, S.A.J.L.; Tournier-Lasserve, E.; Chabriat, H. 2021
Cerebral small vessel diseases represent a frequent cause of stroke and cognitive or motor disability in adults. A small proportion of cerebral small vessel diseases is attributable to monogenic... Show moreCerebral small vessel diseases represent a frequent cause of stroke and cognitive or motor disability in adults. A small proportion of cerebral small vessel diseases is attributable to monogenic conditions. Since the characterization in the late 1990s of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, several other monogenic conditions leading to adult-onset ischemic or hemorrhagic stroke have been described. In this practical guide, we summarize the key features that should elicit the differential diagnosis of a hereditary cerebral small vessel diseases in adult stroke patients, describe the main clinical and imaging characteristics of the major hereditary cerebral small vessel diseases that can manifest as stroke, and provide general recommendations for the clinical management of affected patients and their relatives. Show less
BACKGROUND AND PURPOSE: Benefit of early endovascular treatment (EVT) for ischemic stroke varies considerably among patients. The MR PREDICTS decision tool, derived from MR CLEAN (Multicenter... Show moreBACKGROUND AND PURPOSE: Benefit of early endovascular treatment (EVT) for ischemic stroke varies considerably among patients. The MR PREDICTS decision tool, derived from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), predicts outcome and treatment benefit based on baseline characteristics. Our aim was to externally validate and update MR PREDICTS with data from international trials and daily clinical practice.METHODS: We used individual patient data from 6 randomized controlled trials within the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration to validate the original model. Then, we updated the model and performed a second validation with data from the observational MR CLEAN Registry. Primary outcome was functional independence (defined as modified Rankin Scale score 0-2) 3 months after stroke. Treatment benefit was defined as the difference between the probability of functional independence with and without EVT. Discriminative performance was evaluated using a concordance (C) statistic.RESULTS: We included 1242 patients from HERMES (633 assigned to EVT, 609 assigned to control) and 3156 patients from the MR CLEAN Registry (all of whom underwent EVT within 6.5 hours). The C-statistic for functional independence was 0.74 (95% CI, 0.72-0.77) in HERMES and, after model updating, 0.80 (0.78-0.82) in the Registry. Median predicted treatment benefit of routinely treated patients (Registry) was 10.3% (interquartile range, 5.8%-14.4%). Patients with low (<1%) predicted treatment benefit (n=135/3156 [4.3%]) had low rates of functional independence, irrespective of reperfusion status, suggesting potential absence of treatment benefit. The updated model was made available online for clinicians and researchers at .CONCLUSIONS: Because of the substantial treatment effect and small potential harm of EVT, most patients arriving within 6 hours at an endovascular-capable center should be treated regardless of their clinical characteristics. MR PREDICTS can be used to support clinical judgement when there is uncertainty about the treatment indication, when resources are limited, or before a patient is to be transferred to an endovascular-capable center. Show less
BackgroundRecent evidence suggests cardiac troponin levels to be a marker of increased vascular risk. We aimed to assess whether levels of high-sensitivity cardiac troponin T (hs-cTnT) are... Show moreBackgroundRecent evidence suggests cardiac troponin levels to be a marker of increased vascular risk. We aimed to assess whether levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with recurrent vascular events and death in patients with first-ever, mild to moderate ischemic stroke.Methods and ResultsWe used data from the PROSCIS-B (Prospective Cohort With Incident Stroke Berlin) study. We computed Cox proportional hazards regression analyses to assess the association between hs-cTnT levels upon study entry (Roche Elecsys, upper reference limit, 14 ng/L) and the primary outcome (composite of recurrent stroke, myocardial infarction, and all-cause death). A total of 562 patients were analyzed (mean age, 67 years [SD 13]; 38.6% women; median National Institutes of Health Stroke Scale=2; hs-cTnT above upper reference limit, 39.2%). During a mean follow-up of 3 years, the primary outcome occurred in 89 patients (15.8%), including 40 (7.1%) recurrent strokes, 4 (0.7%) myocardial infarctions, and 51 (9.1%) events of all-cause death. The primary outcome occurred more often in patients with hs-cTnT above the upper reference limit (27.3% versus 10.2%; adjusted hazard ratio, 2.0; 95% CI, 1.3-3.3), with a dose-response relationship when the highest and lowest hs-cTnT quartiles were compared (15.2 versus 1.8 events per 100 person-years; adjusted hazard ratio, 4.8; 95% CI, 1.9-11.8). This association remained consistent in sensitivity analyses, which included age matching and stratification for sex.ConclusionsHs-cTnT is dose-dependently associated with an increased risk of recurrent vascular events and death within 3 years after first-ever, mild to moderate ischemic stroke. These findings support further studies of the utility of hs-cTnT for individualized risk stratification after stroke.RegistrationURL: ; Unique identifier: NCT01363856. Show less
Es, A.C.G.M. van; Hunfeld, M.A.W.; Wijngaard, I. van den; Kraemer, U.; Engelen, M.; Hasselt, B.A.A.M. van; ... ; MR CLEAN Registry Investigators 2021
Background and Purpose:Multiple trials have shown the efficacy and safety of endovascular therapy (EVT) of acute ischemic stroke in adults. Trials in children are lacking and only case reports and... Show moreBackground and Purpose:Multiple trials have shown the efficacy and safety of endovascular therapy (EVT) of acute ischemic stroke in adults. Trials in children are lacking and only case reports and case series exist. However, the long-term outcome of children with acute ischemic stroke can be devastating with significant mortality and morbidity. In this study, we describe the safety and efficacy of EVT in children with anterior circulation acute ischemic stroke who were included in the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands).Methods:Patients under the age of 18 years who were treated with EVT for acute ischemic stroke between March 2014 and July 2017 were retrospectively reviewed up to 6 months after EVT. Nine children, aged 13 months to 16 years (median 14 years, interquartile range, 3-15 years), underwent EVT. Stroke cause was thromboembolism in children with end-stage heart failure on left ventricular assist device (4 of these 9 cases). Median time from onset to imaging was 133 minutes. Four children received intravenous alteplase before EVT, with median onset to needle time of 165 minutes. In all but one patient, EVT was technically successful. No major periprocedural complications occurred.Results:At 24 hours after EVT, 3 children completely recovered and 4 children showed partial recovery (median National Institutes of Health Stroke Scale, 3.5), whereas 2 patients on left ventricular assist device died within the first week due to the occurrence of multiple strokes. One patient on left ventricular assist device developed a fatal massive intracranial hemorrhage and another child died due to left ventricular assist device-related complications. Among the 5 stroke survivors, all had a favorable outcome (modified Rankin Scale score, 0-2) at 6 months follow-up.Conclusions:EVT of children with acute ischemic stroke seems safe and feasible. However, these findings should be interpreted with caution as more and larger studies are needed to clarify the trade-off between risks and benefits of this treatment. Show less
Moerman, A.M.; Visscher, M.; Slijkhuis, N.; Gaalen, K. van; Heijs, B.; Klein, T.; ... ; Soest, G. van 2021
Carotid atherosclerosis is a risk factor for ischemic stroke, one of the main causes of mortality and disability worldwide. The disease is characterized by plaques, heterogeneous deposits of lipids... Show moreCarotid atherosclerosis is a risk factor for ischemic stroke, one of the main causes of mortality and disability worldwide. The disease is characterized by plaques, heterogeneous deposits of lipids, and necrotic debris in the vascular wall, which grow gradually and may remain asymptomatic for decades. However, at some point a plaque can evolve to a high-risk plaque phenotype, which may trigger a cerebrovascular event. Lipids play a key role in the development and progression of atherosclerosis, but the nature of their involvement is not fully understood. Using matrix-assisted laser desorption/ionization mass spectrometry imaging, we visualized the distribution of approximately 200 different lipid signals, originating of >90 uniquely assigned species, in 106 tissue sections of 12 human carotid atherosclerotic plaques. We performed unsupervised classification of the mass spectrometry dataset, as well as a histology-directed multivariate analysis. These data allowed us to extract the spatial lipid patterns associated with morphological plaque features in advanced plaques from a symptomatic population, revealing spatial lipid patterns in atherosclerosis and their relation to histological tissue type. The abundances of sphingomyelin and oxidized cholesteryl ester species were elevated specifically in necrotic intima areas, whereas diacylglycerols and tri-acylglycerols were spatially correlated to areas containing the coagulation protein fibrin. These results demonstrate a clear colocalization between plaque features and specific lipid classes, as well as individual lipid species in high-risk atherosclerotic plaques. Show less
Background and Purpose:Optimal blood pressure (BP) targets before endovascular treatment (EVT) for acute ischemic stroke are unknown. We aimed to assess the relation between admission BP and... Show moreBackground and Purpose:Optimal blood pressure (BP) targets before endovascular treatment (EVT) for acute ischemic stroke are unknown. We aimed to assess the relation between admission BP and clinical outcomes and successful reperfusion after EVT.Methods:We used data from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, an observational, prospective, nationwide cohort study of patients with ischemic stroke treated with EVT in routine clinical practice in the Netherlands. Baseline systolic BP (SBP) and diastolic BP (DBP) were recorded on admission. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included successful reperfusion (extended Thrombolysis in Cerebral Infarction score 2B-3), symptomatic intracranial hemorrhage, and 90-day mortality. Multivariable logistic and linear regression were used to assess the associations of SBP and DBP with outcomes. The relations between BPs and outcomes were tested for nonlinearity. Parameter estimates were calculated per 10 mm Hg increase or decrease in BP.Results:We included 3180 patients treated with EVT between March 2014 and November 2017. The relations between admission SBP and DBP with 90-day modified Rankin Scale scores and mortality were J-shaped, with inflection points around 150 and 81 mm Hg, respectively. An increase in SBP above 150 mm Hg was associated with poor functional outcome (adjusted common odds ratio, 1.09 [95% CI, 1.04-1.15]) and mortality at 90 days (adjusted odds ratio, 1.09 [95% CI, 1.03-1.16]). Following linear relationships, higher SBP was associated with a lower probability of successful reperfusion (adjusted odds ratio, 0.97 [95% CI, 0.94-0.99]) and with the occurrence of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.06 [95% CI, 0.99-1.13]). Results for DBP were largely similar.Conclusions:In patients with acute ischemic stroke treated with EVT, higher admission BP is associated with lower probability of successful reperfusion and with poor clinical outcomes. Further research is needed to investigate whether these patients benefit from BP reduction before EVT. Show less
