Citations

Background: Racial and ethnic disparities in stroke care are known to contribute to inequality in stroke outcomes. The goal of the FL-PR CReSD Study is to assess and evaluate Get With The Guidelines-Stroke (GWTG-S) quality improvement data collected among Florida and Puerto Rico hospitals to evaluate for race-ethnic, sex, and regional disparities in stroke performance metrics. We sought to analyze the temporal trends in stroke performance metrics among the 9 hospitals located in Puerto Rico from 2010 to 2013. Methods: Age-adjusted temporal trends were evaluated in the following GWTG-S pre-defined performance measures (IV tPA treatment within 3 hours among eligible patients arriving in 2 hours, in-hospital antithrombotic therapy, DVT prophylaxis, antithrombotic therapy at discharge, anticoagulation therapy, statin medication at discharge, and smoking cessation counseling) and defect-free care (compliance with all 7 performance measures). Results: The mean age of 3,094 registered stroke cases was 69.5 ± 14.0 years, 50% were men, and 2,184 (71%) were diagnosed as ischemic strokes. Defect-free care occurred in 60% of ischemic stroke patients. Lower performance metrics were found for IV tPA treatment (78%), DVT prophylaxis (64%), and statin medication at discharge (83%). An additional IV tPA measure of treatment by 4.5 hours when arriving by 3.5 hours was observed in 65% of patients. The performance metrics that significantly improved over time from 2010 to 2013 included: IV tPA treatment within 3 hours (64% to 87%, p=0.04), DVT prophylaxis (33% to 87%, p<0.0001), statin medication at discharge (78% to 87%, p=0.01), and defect-free care (37% to 79%, p<0.0001). Conclusions: In only four years, Puerto Rico hospitals participating in GWTG-S showed significant improvement across all pre-defined acute stroke performance measures. Wider implementation of quality improvement programs like GWTG-S among the 3.7 million inhabitants of Puerto Rico could further improve acute stroke care.

Background: Epsilon (e) variants in the Apolipoprotein E (APOE) gene are well-established risk factors for spontaneous intracerebral hemorrhage (s-ICH). We tested the hypothesis that APOE-e variants are also associated with warfarin-related ICH (w-ICH) and examined interactions between APOE and warfarin. Methods: Prospective multicenter 2-stage (discovery and replication) study. ICH was classified as lobar and non-lobar based on admission head CT. In the discovery stage, w-ICH cases were matched with warfarin-exposed controls (w-controls). In replication, w-ICH cases were matched with non-warfarin controls (nw-controls). APOE was directly genotyped. Association testing was performed using multivariable logistic regression. Gene-environment interaction between APOE and warfarin was formally tested using a case only approach (combining s-ICH and w-ICH cases). Results: The discovery stage included 316 w-ICHs (43% lobar and 57% non-lobar) and 355 w-controls. Results are presented in the Table: APOE-e2 was associated with lobar and non-lobar w-ICH, and APOE-e4 was associated with lobar but not with non-lobar w-ICH. In case-only analysis, 885 s-ICHs were combined with w-ICHs (total n=1201) and no evidence of interaction between APOE and warfarin was found (all p>0.20). The replication included 63 w-ICHs (44% lobar and 56% non-lobar) and 990 nw-controls. The distribution of APOE variants was similar in w-controls (discovery) and nw-controls (replication) for both e2 (p=0.81) and e4 (p=0.88). In replication, APOE-e2 and e4 were associated with lobar but not with non-lobar w-ICH. Conclusions: APOE-e variants constitute strong risk factors for lobar w-ICH. An effect may also exist between APOE-e2 and non-lobar hemorrhages, but given the lack of replication larger sample sizes are required to properly assess this association. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary.

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

Background: We have previously reported that carotid artery stenting (CAS) carries a higher stroke risk than carotid endarterectomy (CEA) in patients over the age of 70. The question arises if advanced age is a surrogate for other factors? If so, can those factors be separately identified such that advanced chronological age alone would not be considered a contra-indication for CAS? Here we consider whether the CAS/CEA choice could be guided by other factors known in the clinical center at the time of patient evaluation, independent of age, in order to provide optimal 4-year outcomes. Methods: Demographic factors (age, sex and race), symptomatic status, patient risk factors (hypertension, diabetes, dyslipidemia, smoking), and arterial characteristics (percent stenosis) were available on 2,502 patients. Additional detailed arterial characteristics (ulcerated plaque, distal tortuosity, sequential lesions, circumferential calcification) were available on 1141 CAS and 438 CEA patients. Potential differential treatment efficacy was assessed by the addition of factor-by-treatment interaction terms to a proportional hazard model containing established predictors of outcome (treatment, symptomatic status, sex, age and age-by-treatment interaction). Results: No other factor was found to mitigate advanced age with evidence of additional treatment effect modification of 4-year outcome (p > 0.10). Discussion: Beyond the previously described differential treatment efficacy by age, there were no other patient or arterial characteristic detected to identify patient subgroups that would differentially benefit from the choice of CAS versus CEA. Our inability to identify factors to guide treatment choices could be due to the low number of stroke and death events, incomplete information regarding arterial characteristics in the CEA population, or the potential exclusion of “high risk” groups (such as those with severe arterial tortuosity) from the study.

Objectives: Genetic and environmental influences contribute to differences in ischemic stroke phenotype across race-ethnic groups. The Causative Classification System (CSS) is an ischemic stroke phenotype characterization tool developed for etiological and causative classification. The CCS phenotypes across ethnic groups were analyzed and compared. Methods: The NINDS S troke G enetics N etwork (SiGN) is a large consortium aimed at identifying subtype-specific ischemic stroke susceptibility genes. Over 12,000 subjects at 22 sites across US and Europe were enrolled, with CSS locally adjudicated. Central CCS quality control was performed on all participants. Analysis was performed on 7,674 patients with complete workups. Findings: Significant ethnic differences were found in stroke etiology across ethnic groups (p <0.0001) with large artery atherosclerosis present most commonly in Asians, cardioembolic sources among Caucasian Europeans, and lacunar strokes among African Americans. African Americans were the youngest ethnic cohort analyzed (see Table 1). Conclusion: Significant differences in stroke subtypes are present across ethnic groups. Future genetic analyses may contribute to our understanding of these differences.

Purpose: Intracerebral hemorrhage (ICH) is the acute manifestation of a progressive disease of the cerebral small vessels. The severity of this disease appears to influence not only risk of ICH, but also the size of the hematoma. As the burden of high blood pressure(BP)-associated alleles is associated with hypertension-related end-organ damage, we sought to determine if this burden influences ICH admission hematoma volume (AHV). Methods: Prospective study undertaken in 441 ICH patients of European ancestry (210 deep and 231 lobar intracranial hematomas). Forty-three single-nucleotide polymorphisms (SNPs) known to be associated with high BP were genotyped in Illumina610-Quad. Single-SNP association analyses with AHV were performed using linear regression. Subsequently, a genetic risk score was calculated as the sum of the products generated by multiplying, at each of the 43 loci, the number risk alleles times the reported effect of that allele on BP. The score was utilized as the independent variable of univariate and multivariate regression models for 2 outcomes: AHV and poor clinical outcome (modified Rankin Scale 3-6). Principal components analysis was utilized to account for population structure. Results: Individually assessed, no single SNP was associated with AHV. In univariate linear regression, the genetic risk score was associated with AHV in all (deep and lobar) and deep locations (Figure 1), but not in lobar hemorrhages. In multivariate regression analyses, each additional standard deviation of the genetic risk score increased mean deep AHV by 21% (or 2.7-milliliter increase, beta=0.21, standard error=0.08, p=0.01) and risk poor clinical outcome by 55% (odds ratio=1.55, 95% confidence interval 1.05-2.28, p=0.03). No significant associations were observed when considering all (deep and lobar) and lobar hemorrhages. Conclusion: In deep ICH, increasing numbers of high BP-related alleles are associated with larger AHV and poor clinical outcome.

Background: Brain diffusion-weighted imaging MRI (DWI) holds promise as a prognostic tool in comatose post-cardiac arrest patients. In a preliminary study we found that more than 10% of whole brain volume with an ADC value of <650x10 -6 mm 2 /sec between 49-108 hours after the arrest identified poor outcome patients (death or vegetative state at 30 days) with 100% specificity and 81% sensitivity. We aimed to validate this threshold in an external dataset. Methods: This is an ongoing multicenter observational study of DWI MRIs of comatose post-cardiac arrest patients obtained between 1 and 5 days (i.e. 25-120 hours) after the arrest. Patient data are systematically recorded on a web-based data entry form and include baseline characteristics, serial neurological examinations, neurophysiological testing, and date and cause of death if applicable. Poor outcome is defined as in hospital death. Assuming a 40% survival rate, and 100% specificity of DWI for poor outcome, 250 patients are needed to achieve a 0% false positive rate for poor outcome with a 95% confidence interval of 0-5%. MRI scans were processed using MIPAV (Medical Image Processing, Analysis and Visualization program). The brain was semi-automatically outlined on the b0 images using a levelset algorithm that analyzes the intensity and then produces the contours of the boundary. If necessary, contours were adjusted manually. The created brain masks were then applied to the corresponding ADC maps, and the ADC values of voxels within the brain were saved for further analysis. We used the ADC maps that we received from the participating centers. If only the b0 and b1000 images were available, we recreated the brain ADC maps using MIPAV. Results: Data from 48 patients from three centers (Northwestern, Mayo Clinic Jacksonville, Stanford) were included in this preliminary analysis: mean age was 57±16 years, 33% female, arrest time 23±23 minutes, 88% of patients were treated with hypothermia. The MRIs were obtained at 73±22 hours after the arrest. Twenty patients (42%) survived to hospital discharge. The median (IQR) percentage of brain volume with ADC<650x10 -6 mm 2 /sec was 5% (3-6) in survivors and 30% (9-46) in non-survivors (P<0.001). Brain volume with an ADC<650x10 -6 mm 2 /sec > 10% was 100% (95%CI 80-100) specific and 68% (95%CI 48-83) sensitive for in hospital death with a positive predictive value of 100% (79-100), and a negative predictive value of 69% (49-84). The risk ratio (RR) of death if >10% of brain volume had an ADC<650x10 -6 mm 2 /sec was 3.2 (95%CI 1.9-5.5). Conclusion: The preliminary results of this multicenter study demonstrate that early quantitative DWI MRI in comatose post-cardiac arrest patients holds great promise as a prognostic adjunct in these patients in the era of hypothermia. Centers who frequently obtain brain DWI MRI in comatose post-cardiac arrest patients are encouraged to participate.

Background: Prior studies have shown an association between mutations within the oxidative phosphorylation (OXPHOS) pathway and familial ischemic stroke syndromes. We investigated whether common autosomal and mitochondrial genetic variants within OXPHOS genes were associated with sporadic ischemic stroke in case-control. Methods: This multicenter association study was performed using a discovery cohort of 1643 individuals and a validation cohort of 2432 individuals from sites participating in the International Stroke Genetics Consortium. We employed a gene-set enrichment analysis (GSEA) using all 95 genes structurally involved in OXPHOS to determine the probability that the OXPHOS gene-set harbored more variants associated with stroke than predicted by chance. We then constructed a genetic score consisting of common variants within these genes. This genetic score was developed in the discovery cohort, and then tested for association with ischemic stroke in the validation cohort. Results: GSEA identified an aggregate association between the OXPHOS gene-set and ischemic stroke (p = 0.012). Based on this result, we constructed and validated a genetic score which demonstrated an association between OXPHOS genetic variation and ischemic stroke (odds ratio (OR) = 1.17, p = 0.008). In order to further distill the association between OXPHOS and stroke, we developed and tested additional scores for each of the five OXPHOS respiratory complexes. This sub-analysis revealed an independent association between OXPHOS Complex I and ischemic stroke (OR = 1.06, p = 0.050). Conclusions: This pathway-based study, informed by GSEA, employing independent discovery and validation cohorts, establishes an association between common genetic variants within OXPHOS genes and ischemic stroke. Analysis of variants within each OXHPOS Complex suggests that Complex I mediates this effect. Further studies are needed to identify the individual variants which influence ischemic stroke risk. Such discoveries offer the promise of new therapeutic targets for the prevention and treatment of stroke.

BACKGROUND AND PURPOSE: Ischemic stroke is a heterogeneous complex disease that results from the interaction between numerous genetic and environmental risk factors. Stroke heritability is approximately 40% in the overall population, similar to that of cancer, although there may be important differences in the etiologies of young (<49 years old) versus older onset ischemic stroke. The goal of this study was to conduct a mechanistic genome-wide association (GWA) analysis contrasting the gene pathways involved in young- and old-onset stroke. METHODS: Our analysis included 946 young subjects (448 ischemic stroke subjects and 498 age and sex matched controls, mean age of stroke onset 41 years) and 2558 older subjects (1070 ischemic stroke subjects and 1488 controls, mean age of stroke onset 66.5 years). All subjects were of European ancestry. The young onset cases and controls were genotyped by Illumina Omni1-Quad array with imputation up to 1.8 M SNPs and the old onset cases and controls by a combination of 550 v1 and v3 as well as 610 Illumina arrays with imputation up to 5.0 M SNPs. Single SNP association testing was performed within each contributing study by logistic regression adjusting for age, sex and population structure. Numbers of genes assigned with significant SNPs (P<=0.0001) were 18 and 25 with young- and old-onset groups, respectively, which were used as an input to pathway analysis by the Pathway Studio (Ariadne Genomics, Co.) RESULTS: SNP-level analyses did not reveal any significant associations with each group that met Bonferroni adjusted thresholds for statistical significance. In analyzing the ‘suggestively associated SNPs’, protein-protein interaction pathway analysis in the young-onset group revealed a strong segregation of significant hub proteins (CAT, RUNX1, and EIF4E) with more than 100 connections, while in the old-onset group the interaction networks were dispersed without much segregation. We observed that protein-protein interaction networks have a power-law connectivity distribution in both young- and old-onset groups. We identified 3 significant and focused pathways, ROS metabolism, melanogenesis, and IGF1R->CdEBPA/FOXO1A signaling, enriched for young-onset stroke (P<0.04). In the old-onset group, 10 pathways were identified involving broader signaling pathways. CONCLUSIONS: Young-onset stroke may involve genetic predisposition characterized by a few distinct and finite pathways. Our data suggests that young onset stroke may involve a few pathways that relate to a small number of key hub proteins, including ROS metabolism, melanogenesis, and IGF1R->CEBPA/FOXO1A signaling. Our analysis is consistent with the hypothesis that different pathways may be involved in young versus old onset stroke.

BACKGROUND: Recent genome-wide association studies (GWAS) have identified a number of novel SNPs associated with blood pressure and hypertension-related traits although studies were very large (approaching 80K participants) and effect sizes were modest with per allele effect sizes as small variants as a single millimeter of mercury difference in blood pressure. However, because hypertension is the most potent modifiable risk factor for ischemic stroke, lowering blood pressure by a few mm Hg can translate into measurable decrease in stroke risk. METHODS: We investigated 22 hypertension (HTN) associated SNPs in a case-control analysis of ischemic stroke in multiple stroke studies including the Siblings With Ischemic Stroke Study (SWISS), the Ischemic Stroke Genetics Study (ISGS), the Bio-Repository of DNA in Stroke (BRAINS), the Vitamin Intervention for Stroke Prevention (VISP) trial, and the Women's Health Initiative (WHI). SWISS/ISGS/BRAINS were analyzed together and included subtype information. Genotyping was funded through the individual studies, the Genomics and Randomized Trials Network (GARNET) consortium, and the SHARe (SNP Health Association Resource). All studies had both raw and imputed GWAS data. Analyses included the following phenotypes: all ischemic stroke, stroke subtypes, and age-at-stroke-onset and were stratified by race. Analyses were minimally adjusted for age, sex and principal components 1 & 2. Alpha was set at 0.05. RESULTS: Eleven of the SNPs from the HTN GWAS were associated with ischemic stroke in European ancestry from one or more of the study populations. Two SNPs on chromosome 12 and one on chromosome 21 were associated in multiple European ancestry cohorts. No SNP was associated in all studies. A SNP previously associated with HTN in African ancestry populations was associated with stroke in African-Americans. Analysis of subtypes found associations with small vessel disease and cardioembolic stroke but not large artery disease. The case-only age-at-stroke-onset analysis also found associations for the two SNPs on chromosome 12. CONCLUSION: These data suggest that candidate SNPs from a HTN GWAS may be associated with ischemic stroke and warrant further investigation. Racial differences were observed. Replication in populations from the other SiGN (Stroke Genetics Network), GENEVA (Gene Environment Association Studies) consortium, and the ISGC (International Stroke Genetics Consortium) studies are underway.