Heart Failure in Acute Ischemic Stroke

Heart failure (HF) is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. Due to the aging of the population it has become a growing public health problem in recent decades. Diagnosis of HF is clinical and there is no diagnostic test, although some basic complementary testing should be performed in all patients. Depending on the ejection fraction (EF), the syndrome is classified as HF with low EF or HF with normal EF (HFNEF). Although prognosis in HF is poor, HFNEF seems to be more benign. HF and ischemic stroke (IS) share vascular risk factors such as age, hypertension, diabetes mellitus, coronary artery disease and atrial fibrillation. Persons with HF have higher incidence of IS, varying from 1.7% to 10.4% per year across various cohort studies. The stroke rate increases with length of follow-up. Reduced EF, independent of severity, is associated with higher risk of stroke. Left ventricular mass and geometry are also related with stroke incidence, with concentric hypertrophy carrying the greatest risk

Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood

Apixaban is a new oral anticoagulant with a specific inhibitory action on FXa. No information is available on the reversal of the antihemostatic action of apixaban in experimental or clinical settings. We have evaluated the effectiveness of different factor concentrates at reversing modifications of hemostatic mechanisms induced by moderately elevated concentrations of apixaban (200 ng/ml) added in vitro to blood from healthy donors (n = 10). Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were assessed. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with blood circulating through damaged vascular surfaces, at a shear rate of 600 s−1. The potential of prothrombin complex concentrates (PCCs; 50 IU/kg), activated prothrombin complex concentrates (aPCCs; 75 IU/kg), or activated recombinant factor VII (rFVIIa; 270 μg/kg), at reversing the antihemostatic actions of apixaban, were investigated. Apixaban interfered with TG kinetics. Delayed lag phase, prolonged time to peak and reduced peak values, were improved by the different concentrates, though modifications in TG patterns were diversely affected depending on the activating reagents. Apixaban significantly prolonged clotting times (CTs) in TEM studies. Prolongations in CTs were corrected by the different concentrates with variable efficacies (rFVIIa≥aPCC>PCC). Apixaban significantly reduced fibrin and platelet interactions with damaged vascular surfaces in perfusion studies (p<0.05 and p<0.01, respectively). Impairments in fibrin formation were normalized by the different concentrates. Only rFVIIa significantly restored levels of platelet deposition. Alterations in hemostasis induced by apixaban were variably compensated by the different factor concentrates investigated. However, effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG, and rFVIIa being more effective on TEM and perfusion studies. Our results indicate that rFVIIa, PCCs and aPCCs have the potential to restore platelet and fibrin components of the hemostasis previously altered by apixaban

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

Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL

Inflammatory Response of Ischemic Tolerance in Circulating Plasma : Preconditioning-Induced by Transient Ischemic Attack (TIA) Phenomena in Acute Ischemia Patients (AIS)

Ischemic tolerance (IT) refers to a state where cells are resistant to the damaging effects caused by periods of ischemia. In a clinical scenario, the IT phenomenon would be activated by a recent transient ischemic attack (TIA) before an ischemic stroke (IS). The characterization of inflammatory protein expression patterns will contribute to improved understanding of IT. A total of 477 IS patients from nine hospitals, recruited between January 2011 and January 2016, were included in the current study and divided in three groups: 438 (91.9%) patients without previous TIA (group 1), 22 (4.6%) patients who suffered TIA 24 h before IS (group 2), and 17 (3.5%) patients who suffered TIA between 24 h and 7 days prior to IS (group 3). An inflammatory biomarker panel (IL-6, NT-proBNP, hsCRP, hs-Troponin, NSE, and S-100b) on plasma and a cytokine antibody array was performed to achieve the preconditioning signature potentially induced by TIA phenomena. Primary outcome was modified rankin scale (mRs) score at 90 days. Recent previous TIA was associated with better clinical outcome at 90 days (median mRS of group 1: 2.0 [1.0-4.0]; group 2: 2.0 [0.0-3.0]; group 3: 1.0 [0-2.5]; p = 0.086) and smaller brain lesion (group 1: 3.7 [0.7-18.3]; group 2: 0.8 [0.3-8.9]; group 3: 0.6 [0.1-5.5] mL; p = 0.006). All inflammation biomarkers were down regulated in the groups of recent TIA prior to IS compared to those who did not suffer a TIA events. Moreover, a cytokine antibody array revealed 30 differentially expressed proteins between the three groups. Among them, HRG1-alpha (Fold change 74.4 between group 1 and 2; 74.2 between group 1 and 3) and MAC-1 (Fold change 0.05 between group 1 and 2; 0.06 between group 1 and 3) expression levels would better stratify patients with TIA 7 days before IS. These two proteins showed an earlier inflammation profile that was not detectable by the biomarker panel. Inflammatory pathways were activated by transient ischemic attack, however the period of time between this event and a further ischemic stroke could be determined by a protein signature that would contribute to define the role of ischemic tolerance induced by TIA

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 (

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

Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study

Background and purpose: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. Methods: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (Delta NIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10(-06)) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH. Results: The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 x 10(-08)) and in MERTK (p value = 1.56 x 10(-07)). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 x 10(-06) and p value = 1.3 x 10(-02), respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = - 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = - 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells. Conclusions: DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation

Comparison of the impact of atrial fibrillation on the risk of early death after stroke in women versus men

BACKGROUND: Atrial fibrillation (AF) is considered a predictive factor of poor clinical outcome in patients with an ischemic stroke (IS). This study addressed whether the impact of AF on the in-hospital mortality after first ever IS is different according to the patient’s gender. METHODS: We prospectively studied 1678 patients with first ever IS consecutively admitted to two University Hospitals. We recorded demographic data, vascular risk factors, and the stroke severity (NIHSS) at admission analyzing their impact on the in-hospital mortality and on the combined mortality-dependency at discharge using a Cox proportional hazards model. Two variable interactions between those factors independently related to in-hospital mortality and combined mortality-dependency at discharge were tested. RESULTS: Overall in-hospital mortality was 11.3%. Cox proportional hazards model showed that NIHSS at admission (HR: 1.178 [95% CI 1.149–1.207]), age (HR: 1.044 [95% CI 1.026–1.061]), AF (HR: 1.416 [95% CI 1.048–1.913]), male gender (HR: 1.853 [95% CI 1.323–2.192) and ischemic heart disease (HR: 1.527 [95% CI 1.063–2.192]) were independent predictors of in-hospital mortality. A significant interaction between gender and AF was found (p = 0.017). Data were stratified by gender, showing that AF was an independent predictor of poor outcome just for woman (HR: 2.183 [95% CI 1.403–3.396]; p < 0.001). The independent predictors of combined mortality-disability at discharge were NIHSS at admission (HR: 1.052 [95% CI 1.041–1.063]), age (HR: 1.011 [95% CI 1.004–1.018]), AF (HR: 1.197 [95% CI 1.031–1.390]), ischemic heart disease (HR: 1.222 [95% CI 1.004–1.488]), and smoking (HR: 1.262 [95% CI 1.033–1.541]). CONCLUSIONS: The impact of AF is different in the twogenders and appears as a specific ischemic stroke predictor of in-hospital mortality just for women

Variants at APOE influence risk of deep and lobar intracerebral hemorrhage

Objective Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50–2.23, p = 6.6 × 10 −10 ; and OR = 2.20, 95%CI = 1.85–2.63, p = 2.4 × 10 −11 , respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08–1.36, p = 2.6 × 10 −4 ). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78478/1/22134_ftp.pd