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This topical review assesses the growing role of cardiac biomarkers beyond cardiovascular health and focuses on their importance in stroke and dementia. The first part describes blood-based cardiac biomarkers in patients with stroke and highlights applications in the setting of early diagnosis, poststroke complications, outcome prediction as well as secondary prevention. Among other applications, natriuretic peptides can be helpful in differentiating stroke subtypes. They are also currently being investigated to guide prolonged ECG monitoring and secondary prevention in patients with stroke. Elevated cardiac troponin after ischemic stroke can provide information about various poststroke complications recently termed the stroke-heart syndrome. The second part focuses on the role of cardiac biomarkers in vascular cognitive impairment and dementia, emphasizing their association with structural brain lesions. These lesions such as silent brain infarcts and white matter hyperintensities often co-occur with cardiac disease and may be important mediators between cardiovascular disease and subsequent cognitive decline. ECG and echocardiogram measurements, in addition to blood-based biomarkers, show consistent associations with vascular brain changes and incident dementia, suggesting a role in indicating risk for cognitive decline. Together, the current evidence suggests that cardiac blood-based, electrophysiological, and imaging biomarkers can be used to better understand the heart and brain connection in the setting of not only stroke but also dementia.
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BACKGROUND: Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. METHODS: Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. RESULTS: Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. CONCLUSIONS: There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Feminino , Ativador de Plasminogênio Tecidual , Fibrinolíticos , Terapia Trombolítica/efeitos adversos , Resultado do Tratamento , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/induzido quimicamente , AVC Isquêmico/tratamento farmacológico , Hemorragias Intracranianas/etiologia , Isquemia Encefálica/tratamento farmacológicoRESUMO
BACKGROUND: Recent evidence suggests a beneficial effect of endovascular thrombectomy in acute ischaemic stroke with large infarct; however, previous trials have relied on multimodal brain imaging, whereas non-contrast CT is mostly used in clinical practice. METHODS: In a prospective multicentre, open-label, randomised trial, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and a large established infarct indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3-5 were randomly assigned using a central, web-based system (using a 1:1 ratio) to receive either endovascular thrombectomy with medical treatment or medical treatment (ie, standard of care) alone up to 12 h from stroke onset. The study was conducted in 40 hospitals in Europe and one site in Canada. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days, assessed by investigators masked to treatment assignment. The primary analysis was done in the intention-to-treat population. Safety endpoints included mortality and rates of symptomatic intracranial haemorrhage and were analysed in the safety population, which included all patients based on the treatment they received. This trial is registered with ClinicalTrials.gov, NCT03094715. FINDINGS: From July 17, 2018, to Feb 21, 2023, 253 patients were randomly assigned, with 125 patients assigned to endovascular thrombectomy and 128 to medical treatment alone. The trial was stopped early for efficacy after the first pre-planned interim analysis. At 90 days, endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better outcome (adjusted common OR 2·58 [95% CI 1·60-4·15]; p=0·0001) and with lower mortality (hazard ratio 0·67 [95% CI 0·46-0·98]; p=0·038). Symptomatic intracranial haemorrhage occurred in seven (6%) patients with thrombectomy and in six (5%) with medical treatment alone. INTERPRETATION: Endovascular thrombectomy was associated with improved functional outcome and lower mortality in patients with acute ischaemic stroke from large vessel occlusion with established large infarct in a setting using non-contrast CT as the predominant imaging modality for patient selection. FUNDING: EU Horizon 2020.
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Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/cirurgia , Estudos Prospectivos , Trombectomia/métodos , Hemorragias Intracranianas/etiologia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/cirurgia , Procedimentos Endovasculares/métodos , Infarto/complicações , Alberta , Resultado do TratamentoRESUMO
INTRODUCTION: Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. Understanding the cognitive sequelae and brain structural changes associated with AF is vital for addressing ensuing health care needs. METHODS AND RESULTS: We examined 1335 stroke-free individuals with AF and 2683 matched controls using neuropsychological assessments and multimodal neuroimaging. The analysis revealed that individuals with AF exhibited deficits in executive function, processing speed, and reasoning, accompanied by reduced cortical thickness, elevated extracellular free-water content, and widespread white matter abnormalities, indicative of small vessel pathology. Notably, brain structural differences statistically mediated the relationship between AF and cognitive performance. DISCUSSION: Integrating a comprehensive analysis approach with extensive clinical and magnetic resonance imaging data, our study highlights small vessel pathology as a possible unifying link among AF, cognitive decline, and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies. Highlights We investigated neuropsychological and multimodal neuroimaging data of 1335 individuals with atrial fibrillation (AF) and 2683 matched controls. Our analysis revealed AF-associated deficits in cognitive domains of attention, executive function, processing speed, and reasoning. Cognitive deficits in the AF group were accompanied by structural brain alterations including reduced cortical thickness and gray matter volume, alongside increased extracellular free-water content as well as widespread differences of white matter integrity. Structural brain changes statistically mediated the link between AF and cognitive performance, emphasizing the potential of structural imaging markers as a diagnostic tool in AF-related cognitive decline.
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Fibrilação Atrial , Encéfalo , Disfunção Cognitiva , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Humanos , Fibrilação Atrial/complicações , Masculino , Feminino , Disfunção Cognitiva/patologia , Idoso , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Testes Neuropsicológicos/estatística & dados numéricos , Neuroimagem , Pessoa de Meia-Idade , Função Executiva/fisiologia , Substância Branca/patologia , Substância Branca/diagnóstico por imagemRESUMO
INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.
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Isquemia Encefálica , Acidente Vascular Cerebral , Humanos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Trombectomia , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual , Resultado do TratamentoRESUMO
Diseases of the heart and brain are strongly linked to each other, and cardiac dysfunction is associated with cognitive decline and dementia. This link between cardiovascular disease and dementia offers opportunities for dementia prevention through prevention and treatment of cardiovascular risk factors and heart disease. Increasing evidence suggests the clinical utility of cardiac biomarkers as risk markers for structural brain changes and cognitive impairment. We propose the hypothesis that structural brain changes are the link between impaired cardiac function, as captured by blood-based cardiac biomarkers, and cognitive impairment. This review provides an overview of the literature and illustrates emerging insights into the association of markers of hemodynamic stress (natriuretic peptides) and markers of myocardial injury (cardiac troponins) with imaging findings of brain damage and cognitive impairment or dementia. Based on these findings, we discuss potential pathophysiological mechanisms underlying the association of cardiac biomarkers with structural brain changes and dementia. We suggest testable hypotheses and a research plan to close the gaps in understanding the mechanisms linking vascular damage and neurodegeneration, and to pave the way for targeted effective interventions for dementia prevention. From a clinical perspective, cardiac biomarkers open the window for early identification of patients at risk of dementia, who represent a target population for preventive interventions targeting modifiable cardiovascular risk factors to avert cognitive decline and dementia.
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Disfunção Cognitiva , Demência , Cardiopatias , Humanos , Encéfalo/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Demência/epidemiologia , BiomarcadoresRESUMO
BACKGROUND AND PURPOSE: Cardiac ultrasound to identify sources of cardioembolism is part of the diagnostic workup of acute ischemic stroke. Recommendations on whether transesophageal echocardiography (TEE) should be performed in addition to transthoracic echocardiography (TTE) are controversial. We aimed to determine the incremental diagnostic yield of TEE in addition to TTE in patients with acute ischemic stroke with undetermined cause. METHODS: In a prospective, observational, pragmatic multicenter cohort study, patients with acute ischemic stroke or transient ischemic attack with undetermined cause before cardiac ultrasound were studied by TTE and TEE. The primary outcome was the rate of treatment-relevant findings in TTE and TEE as defined by a panel of experts based on current evidence. Further outcomes included the rate of changes in the assessment of stroke cause after TEE. RESULTS: Between July 1, 2017, and June 30, 2019, we enrolled 494 patients, of whom 492 (99.6%) received TTE and 454 (91.9%) received TEE. Mean age was 64.7 years, and 204 (41.3%) were women. TEE showed a higher rate of treatment-relevant findings than TTE (86 [18.9%] versus 64 [14.1%], P<0.001). TEE in addition to TTE resulted in 29 (6.4%) additional patients with treatment-relevant findings. Among 191 patients ≤60 years additional treatment-relevant findings by TEE were observed in 27 (14.1%) patients. Classification of stroke cause changed after TEE in 52 of 453 patients (11.5%), resulting in a significant difference in the distribution of stroke cause before and after TEE (P<0.001). CONCLUSIONS: In patients with undetermined cause of stroke, TEE yielded a higher number of treatment-relevant findings than TTE. TEE appears especially useful in younger patients with stroke, with treatment-relevant findings in one out of seven patients ≤60 years. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03411642.
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Ecocardiografia Transesofagiana/normas , Ecocardiografia/normas , Cardiopatias/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia , Idoso , Estudos de Coortes , Ecocardiografia/tendências , Ecocardiografia Transesofagiana/tendências , Feminino , Cardiopatias/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND: Although chronic kidney disease (CKD) is associated with worse stroke outcomes, data regarding the influence of CKD on intravenous thrombolysis outcomes are scarce. We sought to assess the efficacy and safety of intravenous thrombolysis for acute ischemic stroke with unknown onset time in patients with CKD. METHODS: Patients with an acute stroke of unknown onset time from the EOS trials (Evaluation of Unknown Onset Stroke Thrombolysis) collaboration were evaluated using an individual patient-level database of randomized controlled trials comparing intravenous thrombolysis with placebo/standard treatment. CKD was defined as baseline estimated glomerular filtration rate of <60 ml/min/1.73m2 Mixed-effect logistic-regression analysis was performed to evaluate treatment effects. A favorable outcome was defined as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes were symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. RESULTS: Baseline data on renal function were available for 688 of 843 patients. Of these, CKD was present in 146 (21%), including 69 of 351 patients receiving alteplase and 77 of 337 patients receiving placebo/standard treatment. Overall, treatment with alteplase was associated with higher odds of favorable outcome, and CKD did not modify the treatment effect (Pinteraction=0.834). A favorable outcome was observed in 31 of 69 (46%) patients with CKD in the alteplase group and in 28 of 77 (36%) patients with CKD in the control group (adjusted odds ratio, 1.19 [95% CI, 0.55-2.58]). Among patients with CKD, symptomatic intracranial hemorrhage occurred in 2 patients (3%) in the alteplase group but in none of the controls (P=0.133). At 90 days, death was reported in 3 patients (4%) in the alteplase group compared with 2 patients (3%) in the controls (P=0.539). CONCLUSIONS: The present analysis indicates that the benefit of alteplase does not differ between stroke patients with unknown onset time with and without CKD, although the statistical power was lacking to confirm the efficacy in subgroups. This study only applies to mild-to-moderate or predialysis CKD.
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Isquemia Encefálica , AVC Isquêmico , Insuficiência Renal Crônica , Acidente Vascular Cerebral , Humanos , Ativador de Plasminogênio Tecidual/uso terapêutico , Fibrinolíticos/uso terapêutico , Resultado do Tratamento , Acidente Vascular Cerebral/tratamento farmacológico , Hemorragias Intracranianas/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Terapia TrombolíticaRESUMO
The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE-UP trial, comparing 127 imaging-selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio-topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network-informed imaging biomarkers and improved prognostication in ischemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Ativador de Plasminogênio Tecidual/uso terapêutico , Ativador de Plasminogênio Tecidual/efeitos adversos , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Fibrinolíticos/uso terapêutico , Fibrinolíticos/efeitos adversos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Resultado do TratamentoRESUMO
OBJECTIVE: The aim was to analyse whether the association between carotid atherosclerosis (CA) and atrial fibrillation (AF), heart function, and renal function is mediated by traditional risk factors. METHODS: In the prospective, single centre, long term, population based Hamburg City Health Study citizens, between 45 and 74 years of age were studied by cross sectional analysis of the first cohort. Laboratory values, blood pressure, heart rhythm, and body mass index (BMI) were examined. Carotid intima media thickness (CIMT) and plaques were assessed by carotid ultrasound, and CA was defined as either CIMT ≥ 1 mm or presence of plaques or both. N-terminal pro-brain natriuretic peptide (NT-proBNP), and glomerular filtration rate (eGFR) were quantified as measures of heart and renal function. Association between CA and AF, NT-proBNP, and eGFR was analysed by multivariable linear and logistic regression. RESULTS: Of the first 10 000 participants, carotid ultrasound was available for 9 466 (95%). Of these, 2 937 (31%) had carotid plaques, 643 (7%) had CIMT ≥ 1 mm, and 412 (4%) presented with both, so that 3 168 (34%) had CA. Participants with CA had AF more frequently (9.6% vs. 4.3%; p < .001), higher levels of NT-proBNP (median 100 vs. 73 pg/mL; p < .001), and lower eGFR (82.8 vs. 87.1 mL/min; p < .001) than those without CA. Adjusted for age and sex, CA was associated with AF (p = .01; OR 1.29) and higher NT-proBNP levels (p < .001; ß = 0.12), but not with eGFR. After further adjustment for vascular risk factors and history of cardiovascular diseases, CA remained associated with NT-proBNP (p < .001; ß = 0.10), but additionally adjusted for NT-proBNP (p < .001; OR 2.80) not with AF. CONCLUSION: CA is independently associated with higher levels of NT-proBNP, through common risk factors and NT-proBNP with AF, and not with renal function. CA's association with a marker of cardiac dysfunction beyond known common risk factors supports the value of carotid ultrasound in defining patients' cardiovascular risk profile. The measures of CA, i.e., CIMT and carotid plaque, had an equally directed and additive influence.
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Fibrilação Atrial , Doenças das Artérias Carótidas , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Biomarcadores , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/epidemiologia , Espessura Intima-Media Carotídea , Estudos Transversais , Humanos , Rim/fisiologia , Estudos ProspectivosRESUMO
BACKGROUND AND PURPOSE: During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke). METHODS: We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE. RESULTS: Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21-0.61], P<0.001). Higher age (P=0.04) and male sex (P=0.01) were predictors for the occurrence of SAE. CONCLUSIONS: SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.
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Fibrinolíticos/efeitos adversos , AVC Isquêmico/tratamento farmacológico , Recuperação de Função Fisiológica , Ativador de Plasminogênio Tecidual/efeitos adversos , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT-/-) mice and AGAT-/- mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT-/- and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism (Ivd, Lcmt2), creatine metabolism (Slc6a8), cerebral myelination (Bcas1) and neuronal excitability (Kcnip3). While Ivd and Kcnip3 showed regulation by hArg supplementation, Bcas1 and Slc6a8 were creatine dependent. Additional regulated genes such as Pla2g4e and Exd1 need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of Bcas1 and Slc6a8. Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.
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Amidinotransferases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Arginina/metabolismo , Creatina/metabolismo , Regulação da Expressão Gênica/fisiologia , Glicina/metabolismo , Homoarginina/metabolismo , Deficiência Intelectual/metabolismo , Distúrbios da Fala/metabolismo , Amidinotransferases/metabolismo , Animais , Encéfalo/metabolismo , Deficiências do Desenvolvimento/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/metabolismoRESUMO
BACKGROUND: Germ cell formation has been investigated in sessile forms of tunicates. This process involves the release of a subset of maternal transcripts from the centrosome-attracting body (CAB) in the progenitor cells of the germ line. When germ-soma segregation is completed, CAB structures are missing from the newly formed primordial germ cells (PGCs). In free-swimming tunicates, knowledge about germ cell formation is lacking. In this investigation, comparative gene expression and electron microscopy studies were used to address germ cell formation in Oikopleura dioica (O. dioica). RESULTS: We found that the RNA localization pattern of pumilio (pum1) is similar to the pattern described for a subset of maternal transcripts marking the posterior end of ascidian embryos. Transcripts marking the posterior end are called postplasmic or posterior-end mark (PEM) transcripts. We found no localization of vasa (vas) transcripts to any sub-region within the germ-line precursor cells. Expression of vas4 was detected in the newly formed PGCs. Electron microscopy studies confirmed the presence of structures with similar morphology to CAB. In the same cytoplasmic compartment, we also identified pum1 transcripts and an epitope recognized by an antibody to histone H3 phosphorylated on serine 28. CONCLUSIONS: Our findings support that a CAB-like structure participates in the segregation of maternal pum1 transcripts during germ-soma separation in O. dioica.
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Centrossomo/metabolismo , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário , Células Germinativas/metabolismo , Urocordados/embriologia , Animais , Centrossomo/ultraestrutura , Gastrulação/genética , Regulação da Expressão Gênica no Desenvolvimento , Células Germinativas/citologia , Células Germinativas/ultraestrutura , Mitose/genética , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica , Urocordados/citologia , Zigoto/metabolismoRESUMO
Selective pressure to maintain small genome size implies control of transposable elements, and most old classes of retrotransposons are indeed absent from the very compact genome of the tunicate Oikopleura dioica. Nonetheless, two families of retrotransposons are present, including the Tor elements. The gene organization within Tor elements is similar to that of LTR retrotransposons and retroviruses. In addition to gag and pol, many Tor elements carry a third gene encoding viral envelope-like proteins (Env) that may mediate infection. We show that the Tor family contains distinct classes of elements. In some classes, env mRNA is transcribed from the 5'LTR as in retroviruses. In others, env is transcribed from an additional promoter located downstream of the 5'LTR. Tor Env proteins are membrane-associated glycoproteins which exhibit some features of viral membrane fusion proteins. Whereas some elements are expressed in the adult testis, many others are specifically expressed in embryonic somatic cells adjacent to primordial germ cells. Such embryonic expression depends on determinants present in the Tor elements and not on their surrounding genomic environment. Our study shows that unusual modes of transcription and expression close to the germline may contribute to the proliferation of Tor elements.
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Retrovirus Endógenos/genética , Regulação da Expressão Gênica no Desenvolvimento , Células Germinativas , RNA/genética , Urocordados/genética , Sequência de Aminoácidos , Animais , Células HEK293 , Humanos , Dados de Sequência Molecular , Polimorfismo Genético , Regiões Promotoras Genéticas , Homologia de Sequência de Aminoácidos , Proteínas do Envelope Viral/químicaRESUMO
INTRODUCTION: Lacunar stroke represents around a quarter of all ischemic strokes; however, their identification with computed tomography in the hyperacute setting is challenging. We aimed to validate a clinical score to identify lacunar stroke in the acute setting, independently, with data from the WAKE-UP trial using magnetic resonance imaging. METHODS: We analyzed data from the WAKE-UP trial and extracted Oxfordshire Community Stroke Project (OCSP) classification. Lacunar score was defined by National Institutes of Health Stroke Scale (NIHSS) < 7 and OCSP lacunar syndrome. Assessment of lacunar infarct by two independent investigators was blinded to clinical data. We calculated sensitivity, specificity, negative and positive predictive value (NPV and PPV, respectively) of lacunar score. RESULTS: We included 503 patients in the analysis, mean (±SD) age 65.2 (±11.6) years, 325 (65%) males, median (IQR) NIHSS = 6 (4-9); 108 (22%) lacunar infarcts were identified on magnetic resonance (MR), patients fulfilling lacunar score criteria were 120 (24%), of which 47 (44%) had a lacunar infarct. Lacunar score was negative in 322 (82%) of patients without lacunar infarct. Patients with lacunar score had lower NIHSS (4 vs 7, p < 0.001), higher systolic (157 vs 151 mmHg, p = 0.001) and diastolic (86 vs 83 mmHg, p = 0.013) blood pressure and smaller infarct volume (2.4 vs 9.5 mL, p < 0.001). Performance of lacunar score was as follows: sensitivity 0.44; specificity 0.82; PPV 0.39; NPV 0.84; and accuracy 0.73. Assuming a prevalence of lacunar stroke of 13%, PPV lowered to 0.30 but NPV was 0.90. Lacunar score performed better for supratentorial lacunar infarcts. CONCLUSION: Lacunar score had a very good specificity and NPV for screening of lacunar stroke. Implementation of this simple tool into clinical practice may help hyperacute management and guide patient selection in clinical trials. DATA ACCESS STATEMENT: Data supporting the results of this paper are available upon reasonable request to the corresponding author.
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BACKGROUND: Long-term data showing the benefits of endovascular thrombectomy for stroke with large infarct are scarce. The TENSION trial showed the safety and efficacy of endovascular thrombectomy in patients with ischaemic stroke and large infarct at 90 days. We aimed to investigate the safety and efficacy at 12 months of endovascular thrombectomy in patients who were enrolled in the TENSION trial. METHODS: TENSION was an open-label, blinded endpoint, randomised trial done at 40 hospitals across Europe and one hospital in Canada. We included patients (aged ≥18 years) with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and who had a large infarct, as indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3-5 on standard-of-care stroke imaging. We randomly assigned patients (1:1) to receive either endovascular thrombectomy with medical treatment or medical treatment only up to 12 h from stroke onset. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days. Here, we report the prespecified 12-month follow-up analyses for functional outcome (using the simplified modified Rankin Scale questionnaire), quality of life (using the Patient-Reported Outcomes Measurement Information System 10-item [PROMIS-10] and EQ-5D questionnaires), post-stroke anxiety and depression (using the Patient Health Questionnaire-4 [PHQ-4]), and overall survival. Outcomes (except survival) were assessed in the intention-to-treat population; the survival analysis was based on treatment received. This trial is registered with ClinicalTrials.gov, NCT03094715, and is completed. FINDINGS: We enrolled patients between July 17, 2018, and Feb 21, 2023, when the trial was stopped early for efficacy. 253 patients were randomly assigned, 125 (49%) to endovascular thrombectomy and 128 (51%) to medical treatment only. Median follow-up was 8·36 months (IQR 0·02-12·00). Endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better functional outcome at 12 months (adjusted common odds ratio 2·39 [95% CI 1·47-3·90]). Endovascular thrombectomy was also associated with a better quality of life compared with medical treatment only, as reflected by median scores on the EQ-5D questionnaire index (0·7 [IQR 0·4-0·9] vs 0·4 [0·2-0·7]), median scores for health status on the EQ-5D questionnaire visual analogue scale (50 [IQR 35-70] vs 30 [5-60]), and median global physical health scores on the PROMIS-10 questionnaire (T-score 39·8 [IQR 37·4-50·8] vs 37·4 [32·4-44·9]); although there was not enough evidence to suggest a difference between groups in global mental health scores on PROMIS-10 (41·1 [IQR 36·3-48·3] vs 38·8 [31·3-44·7]) or the numbers of patients reporting anxiety (13 [22%] of 58 vs 15 [42%] of 36) and depression (18 [31%] vs 18 [50%]) on PHQ-4. Overall survival was slightly better in the endovascular thrombectomy group compared with medical treatment only (adjusted hazard ratio 0·70 [95% CI 0·50-0·99]). INTERPRETATION: In patients with acute ischaemic stroke from large vessel occlusion with established large infarct, compared with medical treatment only, endovascular thrombectomy was associated at 12 months after stroke with better functional outcome, quality of life, and overall survival. These findings suggest that the benefits of endovascular thrombectomy in patients with an ischaemic stroke and a large infarct are sustained in the long term and support the use of endovascular thrombectomy in these patients. FUNDING: European Union Horizon 2020 Research and Innovation Programme.
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PURPOSE: Comorbidities and polypharmacy are risk factors for worse outcome in stroke. However, comorbidities and polypharmacy are mostly studied separately with various approaches to assess them. We aimed to analyze the impact of comorbidity burden and polypharmacy on functional outcome in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT). METHODS: Acute ischemic stroke patients with large vessel occlusion (LVO) treated with MT from a prospective observational study were analyzed. Relevant comorbidity burden was defined as a Charlson Comorbidity Index (CCI) scoreâ¯≥ 2, polypharmacy as the intake of ≥â¯5 medications at time of stroke onset. Favorable outcome was a score of 0-2 on the modified Rankin scale at 90 days after stroke. The effect of comorbidity burden and polypharmacy on favorable outcome was studied via multivariable regression analysis. RESULTS: Of 903 patients enrolled, 703 AIS patients (mean age 73.4 years, 54.9% female) with anterior circulation LVO were included. A CCIâ¯≥ 2 was present in 226 (32.1%) patients, polypharmacy in 315 (44.8%) patients. Favorable outcome was less frequently achieved in patients with a CCIâ¯≥ 2 (47, 20.8% vs. 172, 36.1%, pâ¯< 0.001), and in patients with polypharmacy (69, 21.9% vs. 150, 38.7%, pâ¯< 0.001). In multivariable regression analysis including clinical covariates, a CCIâ¯≥ 2 was associated with lower odds of favorable outcome (odds ratio, OR 0.52, 95% confidence interval, 95% CI 0.33-0.82, pâ¯= 0.005), while polypharmacy was not (OR 0.81, 95% CI 0.52-1.27, pâ¯= 0.362). CONCLUSION: Relevant comorbidity burden and polypharmacy are common in AIS patients with LVO, with comorbidity burden being a risk factor for poor outcome.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Feminino , Idoso , Masculino , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/epidemiologia , AVC Isquêmico/complicações , Resultado do Tratamento , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Comorbidade , Trombectomia/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: Subjective cognitive decline (SCD) is considered to be a preliminary stage of dementia, and its prevalence is increasing with age. OBJECTIVE: We aimed to study the association of SCD with health-related quality of life (HRQoL) in a large population-based sample. METHODS: We analyzed data of the first 10,000 participants from the Hamburg City Health Study in Germany, a single center prospective cohort study, aged between 45 and 74 years that scored higher than 25 points in the Mini-Mental State Examination and had no known pre-existing dementia. HRQoL was assessed by the EQ-5D-5âL index, as well as the mental (MCS) and physical component summary (PCS) score of the Short Form-8. We computed linear regression analyses with 99% bias-corrected and accelerated (BCa) confidence intervals (CI) from 10,000 bootstrap samples to investigate the association between SCD and different indicators of HRQoL, while controlling for depression (PHQ-9), age, sex, and education as potential confounders. RESULTS: Of 7,799 eligible participants (mean (SD) age 62.01 (8.41) years, 51.1% female), 3,708 (47.5%) reported SCD. Participants with SCD were older (62.7 versus 61.4 years) and more frequently female (54.2% versus 48.2%). SCD was independently associated with a lower EQ-5D-5âL index (ß=-0.01, 99% BCa CIâ=â[-0.020, -0.003], pâ<â0.001) and PCS (ß=-1.00, 99% BCa CIâ=â[-1.48, -0.51], pâ<â0.001) but not with MCS score. CONCLUSION: In a population of middle-aged to elderly participants, there is a significant negative association between SCD and HRQoL across different instruments of HRQoL measurement independent of depression, demographics, and education.
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Disfunção Cognitiva , Demência , Humanos , Idoso , Feminino , Pessoa de Meia-Idade , Masculino , Qualidade de Vida/psicologia , Estudos Prospectivos , Disfunção Cognitiva/epidemiologia , Análise de RegressãoRESUMO
BACKGROUND: Patients with atrial fibrillation and a history of stroke are at high risk of recurrent stroke and cardiovascular complications. In the EAST-AFNET 4 trial we showed that a systematic strategy of early rhythm control was associated with a lower risk of cardiovascular outcomes than usual care in patients with atrial fibrillation diagnosed in the past 12 months. In this pre-specified subgroup analysis we aimed to assess whether a strategy of early rhythm control is safe and can prevent adverse cardiovascular outcomes compared with usual care in such patients. METHODS: EAST-AFNET 4 was a randomised, open-label trial with blinded-outcome assessment done at 135 hospitals and secondary care practices in 11 European countries. Adults with early atrial fibrillation (ie, diagnosed ≤12 months before enrolment) were randomly assigned (1:1) to either early rhythm control or usual care, with stratification according to site and variable block lengths used for concealment. The first primary outcome was time to first occurrence of the composite of cardiovascular death, ischaemic or haemorrhagic stroke, or hospital admission with worsening of heart failure or acute coronary syndrome. The second primary outcome was the number of nights spent in hospital in 1 year. The primary safety outcome was the composite of any death, stroke, or serious adverse events related to rhythm-control therapy. Here we present the results of these outcomes in patients with a history of stroke. Analyses were done in the intention-to-treat population. EAST-AFNET 4 is registered with ClinicalTrials.gov (NCT01288352), EudraCT (2010-021258-20), and ISRCTN (ISRCTN04708680). FINDINGS: Between July 28, 2011, and Dec 30, 2016, 2789 patients were randomly assigned in the EAST-AFNET 4 trial to either early rhythm control (n=1395) or usual care (n=1394). Of these patients, five had no information on history of stroke and were excluded from this subgroup analysis. 217 (8%) patients had a history of stroke, of whom 110 were assigned to early rhythm control and 107 to usual care. The median age of participants with a history of stroke was 72·0 years (IQR 66·0-76·0). 95 (44%) participants were female and 122 (56%) were male. During a median follow-up of 4·7 years (3·5-6·4) for patients with a history of stroke, a first primary outcome event occurred in 18 (16%) of 110 patients in the early rhythm-control group (3·7 per 100 person-years) and 33 (31%) of 107 in the usual care group (7·4 per 100 person-years; hazard ratio [HR] 0·52, 95% CI 0·29-0·93). The mean number of nights spent in hospital per year was 5·1 (SD 13·2) for patients with a history of stroke assigned to early rhythm control and 6·6 (10·1) for those assigned to usual care (incidence rate ratio 0·87, 95% CI 0·55-1·38). Among patients with a history of stroke, primary safety events occurred in 17 (15%) patients in the early rhythm-control group versus 30 (28%) in the usual care group. INTERPRETATION: In this prespecified subgroup analysis in patients with recently diagnosed atrial fibrillation and a history of stroke, the effects of early rhythm control were consistent with the findings of the primary analysis. As the evidence from this subgroup analysis is considered supportive and exploratory, further research is needed to confirm the safety and efficacy of this approach in patients with a history of stroke. FUNDING: German Ministry of Education and Research, German Center for Cardiovascular Research (DZHK), Atrial Fibrillation Network (AFNET), European Heart Rhythm Association, St Jude Medical-Abbott, Sanofi, and the German Heart Foundation.
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Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Masculino , Feminino , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/terapia , Fibrilação Atrial/diagnóstico , Resultado do Tratamento , Acidente Vascular Cerebral/complicações , Prevenção Secundária , IncidênciaRESUMO
Homoarginine is associated with cardio- and cerebrovascular morbidity and mortality. However, the underlying pathomechanisms remain elusive. Here, we evaluated the association of homoarginine with adverse events (i.e., death, stroke, and myocardial infarction) and carotid intima-media thickness (cIMT) in stroke patients. In the prospective bioMARKers in STROKE (MARK-STROKE) cohort, patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled. Plasma homoarginine concentrations were analyzed and associated with clinical phenotypes in cross-sectional (374 patients) and prospective (273 patients) analyses. Adjustments for possible confounders were evaluated. A two-fold increase in homoarginine was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score at admission, cIMT, and prevalent atrial fibrillation (mean factor -0.68 [95% confidence interval (CI): -1.30, -0.07], -0.14 [95% CI: -0.22, -0.05]; and odds ratio 0.57 [95% CI: 0.33, 0.96], respectively). During the follow-up (median 284 [25th, 75th percentile: 198, 431] days), individuals with homoarginine levels in the highest tertile had fewer incident events compared with patients in the lowest homoarginine tertile independent of traditional risk factors (hazard ratio 0.22 [95% CI: 0.08, 0.63]). A lower prevalence of atrial fibrillation and a reduced cIMT pinpointed potential underlying pathomechanisms.