Endothelial Progenitor Cells Predict Cardiovascular Events after Atherothrombotic Stroke and Acute Myocardial Infarction. A PROCELL Substudy.

Introduction: The aim of this study was to determine prognostic factors for the risk of new vascular events during the first 6 months after acute myocardial infarction (AMI) or atherothrombotic stroke (AS). We were interested in the prognostic role of endothelial progenitor cells (EPC) and circulating endothelial cells (CEC). Methods: Between February 2009 and July 2012, 100 AMI and 50 AS patients were consecutively studied in three Spanish centres. Patients with previously documented coronary artery disease or ischemic strokes were excluded. Samples were collected within 24h of onset of symptoms. EPC and CEC were studied using flow cytometry and categorized by quartiles. Patients were followed for up to 6 months. NVE was defined as new acute coronary syndrome, transient ischemic attack (TIA), stroke, or any hospitalization or death from cardiovascular causes. The variables included in the analysis included: vascular risk factors, carotid intima-media thickness (IMT), atherosclerotic burden and basal EPC and CEC count. Multivariate survival analysis was performed using Cox regression analysis. Results: During follow-up, 19 patients (12.66%) had a new vascular event (5 strokes; 3 TIAs; 4 AMI; 6 hospitalizations; 1 death). Vascular events were associated with age (P = 0.039), carotid IMT≥0.9 (P = 0.044), and EPC count (P = 0.041) in the univariate analysis. Multivariate Cox regression analysis showed an independent association with EPC in the lowest quartile (HR: 10.33, 95%CI (1.22-87.34), P = 0.032] and IMT≥0.9 [HR: 4.12, 95%CI (1.21-13.95), P = 0.023]. Conclusions: Basal EPC and IMT≥0.9 can predict future vascular events in patients with AMI and AS, but CEC count does not affect cardiovascular risk

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.C.L.R., G.D.S., G.S., J.L.M., K.B., M. Suderman, T.G.R. and T.R.G. are supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/5). C.L.R. receives support from a Cancer Research UK Programme grant (no. C18281/A191169). G.H. is funded by the Wellcome Trust and the Royal Society (208806/Z/17/Z). E.H. and J.M. were supported by MRC project grants (nos. MR/K013807/1 and MR/R005176/1 to J.M.) and an MRC Clinical Infrastructure award (no. MR/M008924/1 to J.M.). B.T.H. is supported by the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-19, CVON2017-20). J.T.B. was supported by the Economic and Social Research Council (grant no. ES/N000404/1). The present study was also supported by JPI HDHL-funded DIMENSION project (administered by the BBSRC UK, grant no. BB/S020845/1 to J.T.B., and by ZonMW the Netherlands, grant no. 529051021 to B.T.H). A.D.B. has been supported by a Wellcome Trust PhD Training Fellowship for Clinicians and the Edinburgh Clinical Academic Track programme (204979/Z/16/Z). J. Klughammer was supported by a DOC fellowship of the Austrian Academy of Sciences. Cohort-specific acknowledgements and funding are presented in the Supplementary Note

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.Molecular Epidemiolog

Detección de ictus intrahospitalario: evaluación de resultados de un programa de formación y entrenamiento a personal médico y de enfermería

Resumen: Introducción: El ictus intrahospitalario (IIH) es frecuente, pero su atención preferente no está bien establecida en muchos centros hospitalarios. En nuestro centro, como medida de calidad asistencial, se intentó reorganizar la atención al IIH mediante un programa de formación teórica y entrenamiento a profesionales sanitarios no implicados habitualmente en el manejo de pacientes con ictus, para optimizar la detección y el tratamiento del IIH. Se evalúan resultados del programa de formación. Métodos: Estudio prospectivo longitudinal de intervención. Se elaboró un programa de formación a personal médico y enfermería. Se registró a los pacientes con IIH pre (PRE) y posformación (POST) (6 meses cada grupo) y se evaluaron los datos de incidencia, datos epidemiológicos, motivo de ingreso y servicio, etiología, severidad, tiempo hasta evaluación por Neurología, tratamiento recanalizador (trombólisis intravenosa/intravascular), criterios de exclusión en no tratados y pronóstico (mortalidad/discapacidad) en ambos grupos. Resultados: Se identificó a 60 pacientes con IIH, con una edad media de 75,3 ± 12,5, 41% hombres; 19 PRE/41 POST. Sin diferencias entre grupos en el tiempo de evaluación, el tratamiento o la morbimortalidad. El 68,3% de ellos fueron evaluados en < 4,5 h, de los cuales solo fue posible administrar tratamiento recanalizador en 6 pacientes (10%), debido fundamentalmente a dependencia previa (26%) y comorbilidad (13%). Conclusiones: El programa de formación realizado permite un mayor número de activaciones de código ictus intrahospitalario. Sin embargo, en el periodo evaluado, esto no se tradujo en mayor porcentaje de pacientes tratados o mejor pronóstico, probablemente debido a la discapacidad previa y comorbilidad elevada en esta serie. Abstract: Introduction: In-hospital stroke (IHS) is a frequent event, but its care priority level is not well established in many hospitals. IHS care at our centre has been redefined by implementing a training programme for medical personnel not usually involved in stroke management, in order to optimise IHS detection and treatment. This study evaluates results from the training programme. Methods: Prospective longitudinal intervention study. Neurologists experienced in vascular diseases developed a training programme for medical personnel. We recorded incidence, epidemiological data, reason for hospitalisation, department, aetiology, severity (NIHSS), time from symptom onset to neurological assessment, use of endovascular thrombolysis, exclusion criteria for untreated patients, and 90-day outcome (mortality/disability) in 2 patient groups: patients experiencing IHS in the 6 months before (PRE) and the 6 months after the training programme (POST). Results: Sixty patients were included (19 PRE, 41 POST) with a mean age of 75.3 ± 12.5; 41% were male. There were no differences between groups regarding assessment time, treatment administered, or morbidity/mortality. Overall, 68.3% of the patients were assessed in < 4.5 hours; however, only 6 patients (10%) were able to undergo endovascular therapy. This situation was mainly due to pre-existing disability (26%) and comorbidity (13%). Conclusions: More IHS code activations were recorded after the training programme. However, that increase was not accompanied by a higher percentage of treated patients or improvements in patient prognosis during the study period, and these findings could probably be explained by the high rates of pre-existing disability and comorbidity in this series. Palabras clave: Ictus intrahospitalario, Programa de formación, Código ictus, Keywords: In-hospital stroke, Training programme, Stroke cod

Aproximación al conocimiento de las bases genéticas del ictus. Consorcio español de genética del ictus

Resumen: El presente artículo revisa la evolución de los estudios en genética del ictus desde la aproximación por gen candidato hasta los recientes estudios de genome wide association. Se destaca la complejidad de esta afección por sus muy variados mecanismos etiopatogénicos, las dificultades que comporta el estudio de su componente genético y las soluciones que se han aportado. Se subraya en especial el valor de las colaboraciones entre distintos centros, ya sea de manera puntual o sobre todo a través de la creación de consorcios estables. Esta estrategia actualmente se hace imprescindible a la hora de realizar estudios de alta calidad científica que permitan seguir avanzando en el conocimiento de las bases genéticas del ictus tanto en etiología, como en tratamiento y prevención. Abstract: This article provides an overview of stroke genetics studies ranging from the candidate gene approach to more recent studies by the genome wide association. It highlights the complexity of stroke owing to its different aetiopathogenic mechanisms, the difficulties in studying its genetic component, and the solutions provided to date. The study emphasises the importance of cooperation between the different centres, whether this takes places occasionally or through the creation of lasting consortiums. This strategy is currently essential to the completion of high-quality scientific studies that allow researchers to gain a better knowledge of the genetic component of stroke as it relates to aetiology, treatment, and prevention. Palabras clave: Ictus, Genética, Asociación, Factores de riesgo genético, Predicción, Consorcio, Keywords: Stroke, Genetics, Association, Genetic risk factors, Prediction, Consortiu

Exploring the genetic basis of stroke. Spanish stroke genetics consortium

This article provides an overview of stroke genetics studies ranging from the candidate gene approach to more recent studies by the genome wide association. It highlights the complexity of stroke owing to its different aetiopathogenic mechanisms, the difficulties in studying its genetic component, and the solutions provided to date. The study emphasises the importance of cooperation between the different centres, whether this takes place occasionally or through the creation of lasting consortiums. This strategy is currently essential to the completion of high-quality scientific studies that allow researchers to gain a better knowledge of the genetic component of stroke as it relates to aetiology, treatment, and prevention. Resumen: El presente artículo revisa la evolución de los estudios en genética del ictus desde la aproximación por gen candidato hasta los recientes estudios de genome wide association. Se destaca la complejidad de esta afección por sus muy variados mecanismos etiopatogénicos, las dificultades que comporta el estudio de su componente genético y las soluciones que se han aportado. Se subraya en especial el valor de las colaboraciones entre distintos centros, ya sea de manera puntual o sobre todo a través de la creación de consorcios estables. Esta estrategia actualmente se hace imprescindible a la hora de realizar estudios de alta calidad científica que permitan seguir avanzando en el conocimiento de las bases genéticas del ictus tanto en etiología, como en tratamiento y prevención. Keywords: Stroke, Genetics, Association, Genetic risk factors, Prediction, Consortium, Palabras clave: Ictus, Genética, Asociación, Factores de riesgo genético, Predicción, Consorci

Description of stroke mimics after complete neurovascular assessment

Introduction: A considerable percentage of events initially diagnosed as ischaemic stroke have non-cerebrovascular causes; these are called stroke mimics (SM). Currently available evidence about these events is heterogeneous and comes from studies with small samples. Objective: The purpose of our study is to identify conditions that may present as SM, define their epidemiological and clinical characteristics, and determine the percentage of cases of SM treated with intravenous fibrinolysis. Methods: Prospective study including all patients admitted to a tertiary university hospital between June 2005 and April 2015 with a diagnosis of acute stroke. We analysed demographic data, cardiovascular risk factors, time from code stroke activation to admission, stroke severity (NIHSS), final destination after discharge, degree of disability (mRS), and treatment. We compared SM and ischaemic strokes. We ruled out patients with intracranial haemorrhage, subarachnoid haemorrhage, or other causes of SM that may be detected on the baseline CT scan. Results: Four hundred four of the 4570 included patients (8.8%) were found to have SM. Patients with SM were younger (70.3% vs 74, P < .0001), less likely to exhibit cardiovascular risk factors and atrial fibrillation (13% vs 34%, P < .0001), scored lower on the NIHSS at baseline (2 vs 4, P < .0001), and included fewer cases of aphasia (9.4% vs 19.6%, P < .02) and dysphagia (1.2% vs 17%, P < .0001) than patients with stroke. SM caused fewer code stroke activations (28% vs 40%, P < .0001). Patients with SM required shorter hospital stays (4.9 vs 7.8 days, P < .0001), were less frequently admitted to the stroke unit (47% vs 60%, P < .0001) and more frequently discharged home (95% vs 62%, P < .0001), and had better outcomes (mRS scores 0-2; 76% vs 54%, P < .0001). Intravenous fibrinolysis was administered to 4.7% of these patients. Epileptic seizures were the most frequent cause of SM (26%). Conclusions: In our sample, 8.8% of all diagnoses of ischaemic stroke were SM. These events have different demographic, clinical, and prognostic characteristics; epilepsy is the most common aetiology. Despite receiving specialised emergency care, 19 patients with SM (4.7%) were treated with intravenous fibrinolysis. Resumen: Introducción: Un porcentaje de casos diagnosticados inicialmente como infartos isquémicos son de causa no cerebrovascular o stroke mimics (SM). Los datos publicados al respecto son heterogéneos y, generalmente, con cohortes pequeñas. Objetivo: Nuestro objetivo es establecer qué enfermedades cursan como SM, definir sus características epidemiológicas y clínicas e identificar el porcentaje de casos tratados con fibrinólisis. Métodos: Registro prospectivo de los eventos considerados cerebrovasculares desde junio del 2005 a abril del 2015, analizando datos demográficos, factores de riesgo cardiovascular, activación de Código Ictus e ingreso, severidad (NIHSS), destino al alta, morbilidad (mRS) y tratamiento recibido. Se han comparado los ictus isquémicos con los SM. Se excluyeron las hemorragias intracraneales, subaracnoideas y las causas de SM detectables en la TC inicial. Resultados: Sobre 4.570 casos, 404 (8,8%) son SM. Los pacientes con SM son más jóvenes (70,3 vs. 74 años, p < 0,0001), tienen menos factores de riesgo cardiovascular y fibrilación auricular (13 vs. 34%, p < 0,0001), una menor puntuación en NIHSS (2 vs. 4, p < 0,0001) y menos afasia (9,4 vs. 19,6%, p < 0,02) y disfagia (1,2 vs. 17%, p < 0,0001). En los SM se activan menos códigos ictus (28 vs. 40%, p < 0,0001) y requieren menos días de ingreso (4,9 vs. 7,8; p < 0,0001) y menos ingresos en la unidad de ictus (47 vs. 60%, p < 0,0001). Los SM son dados de alta a domicilio con mayor frecuencia (95 vs. 62%, p < 0,0001) y con menor discapacidad (mRS 0-2; 76 vs. 54%, p < 0,0001). Un 4,7% de los SM recibieron fibrinólisis. La primera causa de SM fueron las crisis epilépticas (26%). Conclusiones: Los SM supusieron el 8,8% de los ingresos con diagnóstico inicial de ictus isquémico. Los SM tienen características demográficas, clínicas y pronósticas diferentes, siendo la epilepsia la etiología más frecuente. Pese a recibir atención urgente especializada, 19 pacientes (4,7%) fueron trataron con fibrinólisis. Keywords: Stroke mimics, Acute stroke, Fibrinolysis, Ischaemic stroke, Epileptic seizures, Stroke Code, Palabras clave: Stroke mimic, Ictus agudo, Fibrinólisis, Ictus isquémico, Crisis epiléptica, Código Ictu