Major Ischemic Stroke Subtypes Research Articles

Modifiable risk factors mediate the effect of gastroesophageal reflux disease on stroke and subtypes: A Mendelian randomization study

ObjectivesPrevious observational studies have suggested that gastroesophageal reflux disease (GERD) increases the risk of stroke, but the specific underlying mechanisms are unclear. We investigated the causal associations of GERD with stroke and its subtypes using Mendelian randomization (MR), and evaluated the potential mediating effects of modifiable stroke risk factors in the causal pathway. MethodsGenetic instrumental variables for GERD were extracted from the latest genome-wide association study (GWAS) summary level data. We initially performed two-sample MR to examine the association of GERD with stroke and its subtypes, including ischemic stroke, intracranial hemorrhage, and the major subtypes of ischemic stroke. Two-step MR was further employed to investigate the mediating effect of 15 risk factors in the causal pathway. ResultsWe found significant causal associations of genetically predicted GERD with increased risk of stroke (OR: 1.22 95% CI: 1.126–1.322), ischemic stroke (OR: 1.19 95% CI: 1.098–1.299), and large-artery stroke (OR: 1.49 95% CI: 1.214–1.836). Replication and sensitivity analyses yielded consistent effect directions and similar estimates. Further mediation analyses indicated that hypertension (HTN), systolic blood pressure (SBP), and type 2 diabetes (T2D) mediated 36.0%, 9.0%, and 15.8% of the effect of GERD on stroke; 42.9%, 10.8%, and 21.4% for ischemic stroke, and 23.3%; 7.9%, and 18.7% for large-artery stroke, respectively. ConclusionsThis study supports that GERD increases susceptibility to stroke, ischemic stroke, and large-artery stroke, and is partially mediated by HTN, SBP, and T2D.

Evolving ischemic stroke subtypes in 15 years: A hospital-based observational study.

Depicting the time trends of ischemic stroke subtypes may inform healthcare resource allocation on etiology-based stroke prevention and treatment. To reveal the evolving ischemic stroke subtypes from 2004 to 2018. We determined the stroke etiologies of consecutive first-ever transient ischemic attack or ischemic stroke patients admitted to a regional hospital in Hong Kong from 2004 to 2018. We analyzed the age-standardized incidences and the two-year recurrence rate of major ischemic stroke subtypes. Among 6940 patients admitted from 2004 to 2018, age-standardized incidence of ischemic stroke declined from 187.0 to 127.4 per 100,000 population (p < 0.001), driven by the decrease in large artery disease (43.0-9.67 per 100,000 population (p < 0.001)), and small vessel disease (71.9-45.7 per 100,000 population (p < 0.001)). Age-standardized incidence of cardioembolic stroke did not change significantly (p = 0.2). Proportion of cardioembolic stroke increased from 20.4% in 2004-2006 to 29.3% in 2016-2018 (p < 0.001). Two-year recurrence rate of intracranial atherothrombotic stroke reduced from 19.3% to 5.1% (p < 0.001) with increased prescriptions of statin (p < 0.001) and dual antiplatelet therapy (p < 0.001). In parallel with increased anticoagulation use across the study period (p < 0.001), the two-year recurrence of AF-related stroke reduced from 18.9% to 6% (p < 0.001). Etiology-based risk factor control might have led to the diminishing stroke incidences related to atherosclerosis. To tackle the surge of AF-related strokes, arrhythmia screening, anticoagulation usage, and mechanical thrombectomy service should be reinforced. Comparable preventive strategies might alleviate the enormous stroke burden in mainland China.

Risk factor profile associated with major ischemic stroke subtypes in patients managed in a comprehensive stroke unit

Objective — to determine risk factor profiles associated with major ischemic stroke (IS) subtypes in patients managed in a comprehensive stroke unit (CSU).Methods and subjects. 612 patients with IS (mean age 68.1 years, 44.4 % of women) admitted CSU in 2011 — 2018 were enrolled in a retrospective observational study. Patients’ medical history included detailed information about risk factors, and all necessary auxiliary investigations were carried out according to current guidelines, which allowed us to determine the subtype of IS. The c2 criterion was used to compare qualitative indicators in major IS subtypes (posterior comparison was performed using the Marascuilo method), and the Kruskal‑Wallis test was used to compare the quantitative indicators (posterior comparison was performed according to the Dunn’s test). All statistical analysis was performed in MedCalc v. 19.2 software.Results. Risk factors were highly prevalent in IS patients: 86.5 % had arterial hypertension (AH), 59.9 % were elderly or old, 41.1 % had hyperlipidemia, 37.1 % had atrialfibrillation (AF), 30.3 % had diabetesmellitus (DM), and 24.7 % were smokers. 254 patients were assigned to atherothrombotic (AT), 270 to cardioembolic (CE), and 35 to lacunar (LI) subtypesof IS, whereas 53 subjects were diagnosed with IS of otheretiology. In 369 (60.3 %) patients, AH was uncontrolled (only 31 % of the study participants were taking antihypertensive drugs regularly), 163 (60.4 %) patients with CE had not taken anticoagulants. AT was significantly (p &lt; 0.05) associated with AH, smoking, and malesex, CE correlated with older age, female sex, and high rate of AF, while individuals with LI had higher levels of total and low density lipoproteincholesterol. Significant relationships of IS subtypes with the duration of AH or DM, cholesterolor high densityl ipoproteincholesterol levels, obesity, control of AH or a family history of stroke were not found.Conclusions. High prevalence and poor control of risk factors in IS patients was documented, and risk factor profiles associated with major IS subtypes were determined. Identification of the sub patterns may contribute to the further improvement of stroke prevention strategies in Ukraine.

Genetically Determined Platelet Count and Risk of Cardiovascular Disease.

Objective- Cardiovascular disease, including coronary artery disease (CAD) and ischemic stroke, is the leading cause of death worldwide. This Mendelian randomization study uses genetic variants as instruments to investigate whether there is a causal effect of genetically determined platelet count on CAD and ischemic stroke risk. Approach and Results- A genome-wide association study of 166 066 subjects was used to identify instruments and genetic association estimates for platelet count. Genetic association estimates for CAD and ischemic stroke were obtained from genome-wide association studies, including 60 801 CAD cases and 123 504 controls, and 60 341 ischemic stroke cases and 454 450 controls, respectively. The inverse-variance weighted meta-analysis of ratio method Mendelian randomization estimates was the main method used to obtain estimates for the causal effect of genetically determined platelet count on risk of cardiovascular outcomes. We found no significant Mendelian randomization effect of genetically determined platelet count on risk of CAD (odds ratio of CAD per SD unit increase in genetically determined platelet count, 1.01; 95% CI, 0.98-1.04; P=0.60). However, higher genetically determined platelet count was causally associated with an increased risk of ischemic stroke (odds ratio, 1.07; 95% CI, 1.04-1.11; P<1×10-5), including all major ischemic stroke subtypes. Similar results were obtained in sensitivity analyses more robust to the inclusion of pleiotropic genetic variants. Conclusions- This Mendelian randomization study found evidence that higher genetically determined platelet count is causally associated with higher risk of ischemic stroke.

A study on the relationship between changes in serum hs-CRP levels and Chinese ischemic stroke subclassification

Objective: To make sure of the relationship between changes in the serum hs- CRP level and Chinese ischemic stroke subclassification( CISS) to explore the action mechanism of the serum high sensitive C- reactive protein( hs- CRP) in ischemic stroke. Methods: The serum hs- CRP level was measured in 177 ischemic stroke patients. They were classified into2 major ischemic stroke subtypes based on the causes and pathogenesis to explore the relationship between the serum hs- CRP level and CISS. Results: The serum hs- CRP level in ischemic stroke groups was significantly higher than that in the control group( P 0. 05). There was significant difference in the serum hs- CRP level between different Chinese ischemic stroke subtypes( P 0. 05). Conclusion: The level of serum hs- CRP is closely correlated to the incidence of the ischemic stroke and there is significant difference in the serum hs- CRP level between different Chinese ischemic stroke subtypes.

Abstract WP406: Endothelial Function is Impaired in Embolic Stroke of Undetermined Source (ESUS)

Background: Impairment of endothelial function is associated with atherosclerosis and atrial fibrillation, and could underlie several types of ischemic stroke. Recently, embolic stroke of undetermined source (ESUS) has attracted much attention as the major cause of cryptogenic stroke. Objective: The purpose of this study was to clarify the endothelial function in patients with ESUS and compare it with those with other major ischemic stroke subtypes and without a history of stroke. Material and Methods: Between 2015 September and 2017 July, we have prospectively enrolled 402 outpatients with any vascular risk factors or with a history of cerebrovascular events, who had undergone brain MRI within a year and had any sign of cerebral vessel disease. Among them, 230 patients underwent flow-mediated vasodilation (FMD) test to evaluate vascular endothelial function. The subject group was classified into No stroke group and five stroke subtype groups; large artery atherosclerosis (LAA), small vessel disease (SVO), cardiogenic embolism (CE), ESUS, and others (Other stroke). Endothelial function was expressed as percent increase of brachial vessel diameter (%FMD) after interruption of blood flow with mechanical compression for five minutes. Results: The age of subjects was 69.5±10.6 years old, and 61% of them were males. The prevalence of hypertension, diabetes, dyslipidemia, chronic kidney disease, atrial fibrillation, and a history of stroke were 69%, 28%, 51%, 20%, 10%, and 57% respectively. The %FMD of total subjects was 5.16±2.60%; %FMD of stroke subtypes were 5.19±0.32% in No stroke (n=100), 5.02±0.60% in LAA (n=18), 5.19±0.37% in SVO (n = 47), 4.97±0.63% in CE (n=16), 3.55±0.50% in ESUS (n=26), 6.55±0.53% in Other stroke (n=23). The %FMD was significantly lower in ESUS than those in No stroke, SVO, Other stroke (p&lt;0.05). No significant difference in %FMD was observed between ESUS group and LAA or CE group. Conclusion: This study clearly showed that vascular endothelial function of patients with ESUS was significantly impaired. Endothelial dysfunction could underlie development of atrial fibrillation, atherosclerotic plaque or thrombus formation in patients with ESUS.

Differential gene expression profiles between two subtypes of ischemic stroke with blood stasis syndromes.

Ischemic stroke is a cerebrovascular thrombotic disease with high morbidity and mortality. Qi deficiency blood stasis (QDBS) and Yin deficiency blood stasis (YDBS) are the two major subtypes of ischemic stroke according to the theories of traditional Chinese medicine. This study was conducted to distinguish these two syndromes at transcriptomics level and explore the underlying mechanisms. Male rats were randomly divided into three groups: sham group, QDBS/MCAO group and YDBS/MCAO group. Morphological changes were assessed after 24 h of reperfusion. Microarray analysis with circulating mRNA was then performed to identify differential gene expression profile, gene ontology and pathway enrichment analyses were carried out to predict the gene function, gene co-expression and pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and Tunel staining analysis. Three subsets of dysregulated genes were acquired, including 445 QDBS-specific genes, 490 YDBS-specific genes and 1676 blood stasis common genes. Our work reveals for the first time that T cell receptor, MAPK and apoptosis pathway were identified as the hub pathways based on the pathway networks, while Nfκb1, Egfr and Casp3 were recognized as the hub genes by co-expression networks. This research helps contribute to a clearer understanding of the pathological characteristics of ischemic stroke with QDBS and YDBS syndrome, the proposed biomarkers might provide insight into the accurate diagnose and proper treatment for ischemic stroke with blood stasis syndrome.

Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study.

The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.

Multiplicity of Risk Factors in Ischemic Stroke Patients: Relations to Age, Sex, and Subtype - A Study of 2,505 Patients from the Lund Stroke Register

Background: The prevalence of risk factors for ischemic stroke may vary between different groups of stroke patients. We examined the distribution of individual well-established risk factors as well as the multiplicity of risk factors in different age groups and among subtypes. Methods: In the Lund Stroke Register, we consecutively enrolled 2,505 patients with first-ever ischemic stroke from 2001 to 2009 and registered hypertension, diabetes mellitus, heart disease, current smoking, hypercholesterolemia as well as stroke subtype. Results: Among young patients (<55 years), at least 50% had ≥2 risk factors and 20-25% had ≥3 risk factors. In patients aged 55 years or older, the proportion with ≥2 risk factors was 70-80% and with ≥3 risk factors 35-45%. Men and women had a similar burden of risk factors. Approximately 50% of the cases classified as cardioembolism (CE) and large artery atherosclerosis (LAA) had ≥3 risk factors, which was significantly more than the other TOAST (Trial of Org 10172 in Acute Stroke Treatment) subtypes (CE p < 0.001, LAA p = 0.001). Conclusions: The prevalence of well-established risk factors is similar among young and old stroke patients with large proportions (50-80%) having ≥2 risk factors. Even though the prevalence of well-established risk factors differs between pathogenetic subtypes, these risk factors as well as the multiplicity of risk factors seem to be of clinical importance in all major subtypes of ischemic stroke.

Abstract 26: Agreement Between TOAST and CCS Classification in SiGN

Background: The heterogeneity of ischemic stroke has relevance for determination of risk for recurrence, prediction of outcomes, and identification of genetic risk factors. Among the many systems created for classifying patients into subtypes of stroke, the Trial of Org10172 Acute Stroke Trial (TOAST) and Causative Classification of Stroke (CCS) systems are among the most commonly used. Both systems generate similar subtype diagnoses although the two systems use different criteria for subtype assignment. The purpose of this study was to assess the level of agreement between subtype classification made using these two systems. Methods: Study subjects included 14,106 adult men and women accrued in the NINDS Stroke Genetics Network (SiGN) across 21 centers in the US and Europe classified independently using both with TOAST and CCS. Kappa statistics were calculated for the five major ischemic stroke subtypes common to both systems. Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; kappa = 0.60, 95% confidence interval [CI], 0.59 to 0.61). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large artery atherosclerosis (kappa, 0.71; 95% CI, 0.70 to 0.73) and lowest for small artery occlusion (kappa = 0.56, 95%CI, 0.54 to 0.58). Conclusion: Agreement between TOAST and CCS diagnoses was only moderate. Caution is warranted when comparing or combining results based upon the two systems. Re-phenotyping using one system should be encouraged when possible to ensure valid results. Table: Cross-classification of stroke subtypes by TOAST and CCS

An Interactive Association of Common Sequence Variants in the Neuropeptide Y Gene With Susceptibility to Ischemic Stroke

Knowledge of the genetic architecture of ischemic stroke has been quite limited. Most significant associations of candidate genes with ischemic stroke have been difficult to replicate. This might be because the associations were not strong enough for results to be consistent, and testing a mixture of heterogeneous ischemic strokes might lead to confounded genetic associations. A preliminary association analysis with 28 sequence variants in 18 candidate genes (ACE, AGT, AGTR1, BDNF, CRP, F13B, LIF, MMP9, NPPA, NPY, PTGS2, SELP, SERPINE1, SREBF2, TFPI, THBD, VCAM1, and VEGF) revealed that NPY might be the most responsible for the susceptibility of ischemic stroke. Forty-five variants were discovered in the NPY gene by full sequencing, and 5 polymorphisms were selected based on their allele frequency and linkage disequilibrium estimates to conduct a thorough examination of their associations with ischemic stroke and its subtypes classified by TOAST. This study was conducted with 271 patients with ischemic stroke and 455 control subjects. In contrast to a slight significance for an allelic association with ischemic stroke, remarkable discrepancies between haplotype frequencies of control subjects and patients were found. Especially, TA and CC of the haplotypes composed of C4112T and A6411C in the NPY gene were associated with increased risk (P=1.8 x 10(-21), P=2.0 x 10(-13)). The interchanged haplotypes, TC and CA, were protective against the diseases (P=9.3 x 10(-12), P=6.0 x 10(-17)). The associations were also shown in major subtypes of ischemic stroke. This remarkable haplotypic association suggested that the interaction between the 2 common sequence polymorphisms in NPY contributed to a great amount of phenotypic variability of ischemic stroke.

Thrombin Activatable Fibrinolysis Inhibitor Activation Peptide Shows Association With All Major Subtypes of Ischemic Stroke and With TAFI Gene Variation

Thrombin activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis. The aim of the present study was to investigate the possible association between TAFI and overall ischemic stroke and ischemic stroke subtypes. The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 cases (18 to 69 years) and 600 matched population controls. Stroke subtype was defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. TAFI was investigated at the protein level, by analyzing plasma levels of intact TAFI and released activation peptide [AP], and at the genetic level, by genotyping a selection of eleven single nucleotide polymorphisms. After adjustment for traditional risk factors, both TAFI measurements showed association with overall ischemic stroke (AP: odds ratio, 2.22; 95% confidence interval, 1.89 to 2.61; intact TAFI: odds ratio, 1.21; 95% confidence interval, 1.06 to 1.38; for 1-SD increase in AP and intact TAFI, respectively). AP showed associations with all 4 major subtypes of ischemic stroke and intact TAFI to large vessel disease and cryptogenic stroke. TAFI genotypes and haplotypes showed significant associations with both TAFI measurements. In contrast, no association was observed between genetic variants and overall ischemic stroke. TAFI levels show independent association with overall ischemic stroke. This association is stronger for released AP than for intact TAFI, and for released AP, it is present in all ischemic stroke subtypes.

Microalbuminuria in ischemic stroke.

To determine (1) the incidence of microalbuminuria in patients with recent ischemic stroke, (2) its relationship to risk factors for stroke, (3) its prevalence in the major subtypes of ischemic stroke, and (4) its potential for identifying patients at increased risk for recurrent stroke, myocardial infarction, or vascular death. Prospective case-control study. Outpatient clinics at the medical centers affiliated with the Department of Veterans Affairs and Oregon Health Sciences University in Portland, Ore. A total of 186 older men and women (median age, 65 years) who were enrolled in a prospective study of risk factors for recurrent stroke, including 97 patients with recent (6-8 weeks) ischemic stroke, 51 with similar clinical risk factors for stroke, including 24 with a history of remote stroke or transient ischemic attack, and 38 community-dwelling volunteers. Microalbuminuria was 3 times more prevalent in patients with recent stroke (29%) than in those with clinical risk factors for stroke (10%), and was undetectable in healthy elderly controls (P<.001). The presence of microalbuminuria in recent stroke as well as in the combined recent and remote stroke or transient ischemic attack group (n = 121) was predicted by diabetes (odds ratio [OR], 8.4; 95% confidence interval [CI], 2.6-27.0; P<.001; serum albumin levels (OR, 0.12; 95% CI, 0.03-0.50; P<.005); age (OR, 1.1; 95% CI, 1.0-1.2; P<.01), and ischemic heart disease (OR, 3.0; 95% CI, 1.0-9.1; P<.05). Among patients with recent stroke the prevalence of microalbuminuria did not differ among major ischemic stroke subtypes, ie, atheroembolic, 23%; cardioembolic, 30%; and lacunar, 33%. During a mean +/- SD of 1.5 +/- 0.9 years of follow-up, 20% of patients with recent stroke, 14% with risk factors for stroke, and 0% of healthy elderly volunteers had vascular end points (P<.004), with events being as frequent in patients with microalbuminuria (32%) as in patients with macroalbuminuria (33%). After controlling for major clinical risk factors, microalbuminuria remained an independently significant predictor of future stroke in the combined recent stroke and remote stroke or transient ischemic attack group (Cox proportional hazard ratio, 4.9; 95% CI, 1.4-17.6; P<.01). Microalbuminuria is a common finding in patients with cerebrovascular disease and is associated with increased risk for stroke even after correction for the presence of confounding clinical risk factors. These data suggest that microalbuminuria merits further examination as a potentially inexpensive and easily measured marker of increased risk for stroke.

Diabetes, Hypertension and Erythrocyte Aggregation in Acute Stroke

Elevated erythrocyte (RBC) aggregation (RBC-A) may contribute to the pathogenesis of stroke and stroke recurrence. We measured RBC-A at low shear in 55 patients with acute ischemic stroke and in 24 age-balanced controls without cerebrovascular disease or vascular risk factors. RBC-A was significantly elevated in subgroups of stroke patients who were hypertensive, diabetic, or both, compared with either stroke patients lacking these risk factors (p at least < 0.01) or healthy elderly (all p < 0.001). RBC-A was normal in stroke patients (n = 14) free of both diabetes and hypertension. In a multivariate linear regression model glycosylated hemoglobin (p < 0.0001), plasma viscosity (p < 0.006) and systolic blood pressure (p < 0.05) were each independently significant and together accounted for about 52% of the variation in RBC-A in acute stroke patients. No relationship was detected between RBC-A and infarct size or among the major subtypes of ischemic stroke. The results suggest that vigorous control of both blood glucose and blood pressure may reduce the potentially damaging effects of elevated RBC-A in the cerebral vasculature.