International Stroke Genetics Consortium recommendations for studies of genetics of stroke outcome and recovery

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium

Updated Stroke Gene Panels : Rapid evolution of knowledge on monogenic causes of stroke

This article updates our previous Stroke Gene Panels (SGP) from 2017. Online Mendelian Inheritance in Man and PubMed were searched. We divided detected genes into two SGP groups, SGP1: genes reported in at least one person with stroke and associated with one or more clinical subgroups: large artery atherosclerotic, large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection or occlusion), cerebral small vessel diseases, cardio-embolic (arrhythmia, heart defect, cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma, arteriovenous malformations) and metabolism disorders; and SGP2: genes related to diseases that may predispose to stroke. We identified 168 SGP1 genes, 70 of these were validated for clinical practice. We also detected 72 SGP2 genes. Nine genes were removed because of conflicting evidence. The number of genes increased from 168 to 240 during 4.5-years, reflecting a dynamic evolution and the need for regular updates for research and clinical use.Peer reviewe

ESO Guideline on Covert Cerebral Small Vessel Disease

'Covert' cerebral small vessel disease (ccSVD) is common on neuroimaging in persons without overt neurological manifestations, and increases the risk of future stroke, cognitive impairment, dependency, and death. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist with clinical decisions about management of ccSVD, specifically white matter hyperintensities and lacunes, to prevent adverse clinical outcomes. The guidelines were developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We prioritised the clinical outcomes of stroke, cognitive decline or dementia, dependency, death, mobility and mood disorders, and interventions of blood pressure lowering, antiplatelet drugs, lipid lowering, lifestyle modifications, glucose lowering and conventional treatments for dementia. We systematically reviewed the literature, assessed the evidence, formulated evidence-based recommendations where feasible, and expert consensus statements. We found little direct evidence, mostly of low quality. We recommend patients with ccSVD and hypertension to have their blood pressure well controlled; lower blood pressure targets may reduce ccSVD progression. We do not recommend antiplatelet drugs such as aspirin in ccSVD. We found little evidence on lipid lowering in ccSVD. Smoking cessation is a health priority. We recommend regular exercise which may benefit cognition, and a healthy diet, good sleep habits, avoiding obesity and stress for general health reasons. In ccSVD, we found no evidence for glucose control in the absence of diabetes or for conventional Alzheimer dementia treatments. Randomised controlled trials with clinical endpoints are a priority for ccSVD.Peer reviewe

Diversity in genetic risk of recurrent stroke: a genome-wide association study meta-analysis

IntroductionStroke is a leading cause of death and disability worldwide. Recurrent strokes are seven times more lethal than initial ones, with 54% leading to long-term disability. Substantial recurrent stroke risk disparities exist among ancestral groups. Notably, Africans face double the risk and higher fatality rates compared to Europeans. Although genetic studies, particularly GWAS, hold promise for uncovering biological insights into recurrent stroke, they remain underexplored. Our study addresses this gap through meta-analyses of recurrent stroke GWAS, considering specific ancestral groups and a combined approach.MethodsWe utilized four independent study cohorts for African, European, and Combined ancestry recurrent stroke GWAS with genotyping, imputation, and strict quality control. We harmonized recurrent stroke phenotype and effect allele estimates across cohorts. The logistic regression GWAS model was adjusted for age, sex, and principal components. We assessed how well genetic risk of stroke informs recurrent stroke risk using Receiver Operating Characteristic (ROC) curve analysis with the GIGASTROKE Consortium's polygenic risk scores (PRS).ResultsHarmonization included 4,420 participants (818 African ancestry and 3,602 European ancestry) with a recurrent stroke rate of 16.8% [median age 66.9 (59.1, 73.6) years; 56.2% male]. We failed to find genome-wide significant variants (p < 5e−8). However, we found 18 distinct suggestive (p < 5e−6) genetic loci with high biological relevance consistent across African and European ancestries, including PPARGC1B, CCDC3, OPRL1, and MYH11 genes. These genes affect vascular stenosis through constriction and dilation. We also observed an association with SDK1 gene, which has been previous linked with hypertension in Nigerian and Japanese populations). ROC analysis showed poor performance of the ischemic stroke PRS in discriminating recurrent stroke status (area under the curve = 0.48).DiscussionOur study revealed genetic associations with recurrent stroke not previously associated with incident ischemic stroke. We found suggestive associations in genes previously linked with hypertension. We also determined that knowing the genetic risk of incident stroke does currently not inform recurrent stroke risk. We urgently need more studies to understand better the overlap or lack thereof between incident and recurrent stroke biology

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Number of addictive substances used related to increased risk of unnatural death: A combined medico-legal and case-record study

<p>Abstract</p> <p>Background</p> <p>Substance use disorders have repeatedly been found to lead to premature death, i.e. drug-related death by disease, fatal intoxications, or trauma (accidents, suicide, undetermined suicide, and homicide). The present study examined the relationship between multi-drug substance use and natural and unnatural death.</p> <p>Methods</p> <p>All consecutive, autopsied patients who had been in contact with the Addiction Centre in Malmö University Hospital from 1993 to 1997 inclusive were investigated. Drug abuse was investigated blindly in the case records and related to the cause of death in 387 subjects.</p> <p>Results</p> <p>Every substance apart from alcohol used previously in life added to the risk of unnatural death in a linear way. There were independent increased risks of fatal heroin overdoses or undetermined suicide. Death by suicide and violent death were unrelated to additional abuse.</p> <p>Conclusion</p> <p>The number of drugs used was related to an increased risk of unnatural death by undetermined suicide (mainly fatal intoxications) and heroin overdose.</p

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source : Design of the NAVIGATE ESUS randomized trial

Peer reviewe

Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p 5 7.12 3 10-11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p 5 0.695).Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 case