L'Ús d'escales clíniques en els ictus isquèmics secundaris a fibril·lació auricular

La FA és l'arítmia cardíaca més freqüent. És conegut el seu elevat potencial de produir esdeveniments tromboembòlics, com els ictus isquèmics. Aquests ictus cardioembòlics no solament són freqüents sinó també s'associen a una elevada morbi-mortalitat. És per aquest motiu que ens proposem estudiar-los en més profunditat. Així mateix, és conegut que no tots els pacients amb una FA tenen el mateix risc tromboembòlic. Diferents factors de risc cardiovasculars com l'edat avançada, la hipertensió arterial, la diabetis mellitus, entre d'altres, contribueixen a atorgar un risc anual de tromboembolisme. S'han creat múltiples escales per tal d'estratificar aquest risc. D'aquestes, la més emprada clàssicament ha estat la CHADS2 per la seva simplicitat. Però en el 2010 es publica l'escala CHA2DS2-VASc. El primer objectiu d'aquesta tesi és avaluar com classifica l'escala CHADS2 a una cohort de pacients en el moment previ al primer ictus isquèmic i comparar-ho amb la classificació si l'escala CHA2DS2-VASc hagués estat utilitzada. Els resultats d'aquest estudi mostren que la nova escala reclassifica a una gran part dels pacients que posteriorment pateixen un ictus, fora de la categoria de risc baix o intermedi, a una categoria on se'ls hauria d'haver indicat un tractament anticoagulant. Arrel de treballs com el nostre han canviat les recomanacions, tant en les guies europees com en les americanes, envers a ĺús de l'escala CHA2DS2-VASc per l'estratificació de risc. El segon objectiu ha estat avaluar l'ús d'aquesta nova escala CHA2DS2-VASc no només per estratificar el risc d'ictus sinó també la seva utilitat com a eina pronòstica en pacients que han patit un ictus isquèmic. Demostrem que per cada increment d'un punt en l'escala, s'incrementa un 36% la possibilitat de tenir un mal pronòstic als 3 mesos de l'ictus. En ambdues investigacions, trobem una baixa indicació de tractament anticoagulant en prevenció primària, en pacients d'alt risc, tot i l'efecte conegut clarament protector dels anticoagulants sobre la severitat de l'ictus, que es replica en el nostre estudi. La nostra línia d́investigació (amb el tercer treball) també s'ha orientat envers a la detecció d'un debut de fibril·lació auricular paroxística (FAp) un cop s'ha produït l'ictus, sobretot per la gran importància d'una correcta prevenció secundària, donat que la no detecció d'aquesta arítmia relega als pacients a un tractament clarament ineficient amb antiagregants plaquetaris. En la nostra cohort d'ictus isquèmics no seleccionats, que ingressen a la unitat d'ictus, diagnostiquem un 11.2% de FAp. Analitzem quins són els factors clínics que s'associen a aquest debut en un anàlisis bivariant i posteriorment multivariant (que són l'edat avançada, el sexe femení, la severitat inicial de l'ictus i la història prèvia d'insuficiència cardíaca congestiva). D'aquest anàlisis obtenim uns riscos de debut de FAp segons cada perfil clínic, que hem representat en unes taules de risc per a la seva fàcil i immediata interpretació a l'arribada del pacientAF is the most common cardiac arrhythmia in clinical practice, and is a well-known risk factor for cardiogenic embolism. These cardioembolic strokes are frequent and associated with a substantial increased risk of morbidity and mortality. However the risk of stroke and thromboembolism in AF patients is not homogeneous. Different risk factors such as advancing age, hypertension and diabetes mellitus, among others, contribute to the annual thromboembolic risk. Various stroke risk-stratification schemes have been developed for people with AF. The CHADS2 was probably the most often used because of its simplicity. But in 2010 a new scale was published: CHA2DS2-VASc. The first purpose of this thesis was to evaluate how CHADS2 classifies a cohort of patients previous to its first ischemic stroke and compare this risk stratification if the CHA2DS2-VASc scale would have been used. The results of this study showed that this new scale reclassifies a lot of patients out of the category of low-intermediate risk, into a category in which anticoagulation would have been indicated. Studies like ours changed recommendations of both European and U.S guidelines towards the use of the CHA2DS2-VASc score as the main scheme to assess patientís stroke risk. The second objective of our thesis was to evaluate the use of this new scale, not only for risk stratification, but also as prognosis tool in patients who suffered a stroke. We found that each point increase in the scale is associated with a 36% increase in the risk for poor 90-day outcome, independently of stroke severity. In both works, we found a low use of anticoagulation in primary prevention for high risk patients, despite its well-established protective effect, that we were able to replicate. Our research is also orientated towards the detection of a new paroxysmal atrial fibrillation (pAF) in stroke patients, since undetected pAF would lead to a suboptimal secondary prevention with antiplatelet agents. Therefore in the third work, in our cohort with unselected patients, who were admitted in the stroke unit, we detected 11.2% of pAF until de three-month visit. We analyzed which are the clinical risk factors associated to this new diagnosis in a bivariate and afterwards a multivariate analysis (which were advancing age, female sex, initial stroke severity and previous history of congestive heart failure). From this analysis we obtained a risk for new pAF detection for each vascular risk profile, that we represented into two risk charts for easy and immediately interpretation at patientís arrival

Increased COVID-19 mortality in people with previous cerebrovascular disease: a population-based cohort study

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Ictus hemorràgic; Ictus isquèmic; Hemorràgia subaracnoideaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Ictus hemorrágico; Ictus isquémico; Hemorragia subaracnoideaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hemorrhagic stroke; Ischemic stroke; Subarachnoid hemorrhageBackground: The aim of the study was to determine the association between previous stroke and mortality after coronavirus disease 2019 (COVID-19) according to sex, age groups, and stroke subtypes. Methods: Prospective population-based cohort study including all COVID-19 positive cases between February 1 and July 31, 2020. Comorbidities and mortality were extracted using linked health administration databases. Previous stroke included transient ischemic attack, ischemic stroke, hemorrhagic stroke, spontaneous subarachnoid hemorrhage, and combined stroke for cases with more than one category. Other comorbidities were obesity, diabetes, hypertension, ischemic heart disease, atrial fibrillation, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, cirrhosis, dementia, individual socioeconomic index, and deprivation index. Cases were followed up until December 31, 2020. Primary outcome was mortality of any cause after COVID-19 positivity. Cox proportional regression analysis adjusted for comorbidities was used. Stratified analyses were performed for sex and age (<60, 60-79, and ≥80 years). Results: There were 91 629 COVID-19 cases. Previous strokes were 5752 (6.27%), of which 3887 (67.57%) were ischemic, 1237 (21.50%) transient ischemic attack, 255 (4.43%) combined, 203 (3.53%) hemorrhagic, and 170 (2.96%) subarachnoid hemorrhage. There were 9512 deaths (10.38%). Mortality was associated with previous stroke (hazard ratio [HR]=1.12 [95% CI, 1.06-1.18]; P<0.001), in both sexes separately (men=1.13 [1.05-1.22]; P=0.001; women=1.09 [1.01-1.18]; P=0.023), in people <60 years (HR=2.97 [1.97-4.48]; P<0.001) and 60 to 79 years (HR=1.32 [1.19-1.48]; P<0.001) but not in people ≥80 years (HR=1.02 [0.96-1.09]; P=0.437). Ischemic (HR=1.11 [1.05-1.18]; P=0.001), hemorrhagic (HR=1.53 [1.20-1.96]; P=0.001) and combined (HR=1.31 [1.05-1.63]; P=0.016) strokes were associated but not transient ischemic attack. Subarachnoid hemorrhage was associated only in people <60 years (HR=5.73 [1.82-18.06]; P=0.003). Conclusions: Previous stroke was associated with a higher mortality in people younger than 80 years. The association occurred for both ischemic and hemorrhagic stroke but not for transient ischemic attack. These data might help healthcare authorities to establish prioritization strategies for COVID-19 vaccination.This work was supported, in part, by Spain’s Ministry of Health (Instituto de Salud Carlos III FEDER, RD16/0019/0002 and RD16/0019/0010 INVICTUS-PLUS

High prevalence of non-alcoholic fatty liver disease in patients with a first episode of acute ischemic stroke. Impact on disability and death

IntroductionNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is associated with an increased risk of overall mortality being cardiovascular disease the most common cause of mortality. Strategies are needed to identify high risk groups for NAFLD to improve screening approaches. Moreover, there is a lack of information about the prevalence of NAFLD on patients with acute ischemic stroke (AIS) and the influence of NAFLD on the prognosis of the stroke. The aim of the study was to define the prevalence of NAFLD in patients with a first episode of AIS and the secondary aims were to evaluate the prevalence of NAFLD at different ages and its impact on the severity and prognosis of the AIS.Materials and methodsObservational study including consecutive patients admitted for the first AIS from January 2005 to May 2018. Patients with harmful alcohol intake, other liver diseases and malignancies were excluded. Sociodemographic data, cardiovascular risk factors, comorbidities, and blood test at admission were reviewed. NAFLD and liver fibrosis were assessed with the serological scores Fatty Liver Index (FLI) and Fibrosis-4 respectively. NAFLD was defined by a FLI&gt;60. Stroke severity and prognosis were evaluated with the National Institute of Health Stroke Scale and modified Rankin Scale respectively in patients aged from 40 to 79 years old.ResultsWe included 1601 patients, 52.4% were female and median (IQR) age of 77 (66 – 83) years. The 41% of the total cohort had a FLI&gt;60 with different prevalence according to age in decades: in 30-39 years: 35.7%; in 40-49: 47.5%; in 50-59: 51.1%, in 60-69: 56%, in 70-79: 41.4%; in 80-89: 34.9% (p&lt;0.001). The presence of NAFLD did not impact on the severity or the prognosis of stroke. However, patients with NAFLD were younger than those without NAFLD (74 vs. 78; p&lt;0.001).ConclusionPresence of NAFLD did not impact on disability and death after the stroke. However, patients with a first episode of stroke showed a high prevalence of NAFLD, especially at intermediate ages, and therefore, screening for NAFLD should be advisable

Machine learning approximations to predict epigenetic age acceleration in stroke patients

Age acceleration (Age-A) is a useful tool that is able to predict a broad range of health outcomes. It is necessary to determine DNA methylation levels to estimate it, and it is known that Age-A is influenced by environmental, lifestyle, and vascular risk factors (VRF). The aim of this study is to estimate the contribution of these easily measurable factors to Age-A in patients with cerebrovascular disease (CVD), using different machine learning (ML) approximations, and try to find a more accessible model able to predict Age-A. We studied a CVD cohort of 952 patients with information about VRF, lifestyle habits, and target organ damage. We estimated Age-A using Hannum\u27s epigenetic clock, and trained six different models to predict Age-A: a conventional linear regression model, four ML models (elastic net regression (EN), K-Nearest neighbors, random forest, and support vector machine models), and one deep learning approximation (multilayer perceptron (MLP) model). The best-performing models were EN and MLP; although, the predictive capability was modest (

Burden of Risk Alleles for Hypertension Increases Risk of Intracerebral Hemorrhage

Background and Purpose-Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods-We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results-No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. Conclusion-Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. (Stroke. 2012; 43: 2877-2883.

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

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 x 10(-5) were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 x 10(-8)) were characterized by in silica functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 x 10(-8); odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 x 10(-8), OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silica studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.Peer reviewe

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

Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10(-4) ) with no heterogeneity across studies (I(2) = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10(-6) ).INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe