RESUMO
OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown. METHODS: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk. RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk. INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337.
Assuntos
Doenças de Pequenos Vasos Cerebrais , Semaforinas , Acidente Vascular Cerebral Lacunar , Humanos , Estudo de Associação Genômica Ampla , Hemorragia Cerebral/genética , Hemorragia Cerebral/complicações , Doenças de Pequenos Vasos Cerebrais/genética , Doenças de Pequenos Vasos Cerebrais/complicações , Acidente Vascular Cerebral Lacunar/complicações , Cromatina , Semaforinas/genéticaRESUMO
BACKGROUND: As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States. METHODS: We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the International Classification of Diseases, Ninth Revision codes 430-436 and Tenth Revision codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population. RESULTS: Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients. CONCLUSIONS: An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke.
Assuntos
Procedimentos Endovasculares , Acidente Vascular Cerebral , Trombectomia , Humanos , Procedimentos Endovasculares/tendências , Feminino , Idoso , Masculino , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Estudos Transversais , Acidente Vascular Cerebral/cirurgia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Idoso de 80 Anos ou mais , AVC Isquêmico/cirurgia , AVC Isquêmico/epidemiologia , AVC Isquêmico/terapia , Adulto , Definição da ElegibilidadeRESUMO
BACKGROUND: Intracerebral hemorrhage (ICH) has an estimated heritability of 29%. We developed a genomic risk score for ICH and determined its predictive power in comparison to standard clinical risk factors. METHODS: We combined genome-wide association data from individuals of European ancestry for ICH and related traits in a meta-genomic risk score ([metaGRS]; 2.6 million variants). We tested associations with ICH and its predictive performance in addition to clinical risk factors in a held-out validation dataset (842 cases and 796 controls). We tested associations with risk of incident ICH in the population-based UK Biobank cohort (486 784 individuals, 1526 events, median follow-up 11.3 years). RESULTS: One SD increment in the metaGRS was significantly associated with 31% higher odds for ICH (95% CI, 1.16-1.48) in age-, sex- and clinical risk factor-adjusted models. The metaGRS identified individuals with almost 5-fold higher odds for ICH in the top score percentile (odds ratio, 4.83 [95% CI, 1.56-21.2]). Predictive models for ICH incorporating the metaGRS in addition to clinical predictors showed superior performance compared to the clinical risk factors alone (c-index, 0.695 versus 0.686). The metaGRS showed similar associations for lobar and nonlobar ICH, independent of the known APOE risk locus for lobar ICH. In the UK Biobank, the metaGRS was associated with higher risk of incident ICH (hazard ratio, 1.15 [95% CI, 1.09-1.21]). The associations were significant within both a relatively high-risk population of antithrombotic medications users, as well as among a relatively low-risk population with a good control of vascular risk factors and no use of anticoagulants. CONCLUSIONS: We developed and validated a genomic risk score that predicts lifetime risk of ICH beyond established clinical risk factors among individuals of European ancestry. Whether implementation of the score in risk prognostication models for high-risk populations, such as patients under antithrombotic treatment, could improve clinical decision making should be explored in future studies.
Assuntos
Fibrinolíticos , Estudo de Associação Genômica Ampla , Humanos , Fatores de Risco , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/genética , GenômicaRESUMO
BACKGROUND: Hemoglobin concentration and diffusion-weighted imaging (DWI) ischemic lesions are separately known to be associated with poor intracerebral hemorrhage (ICH) outcomes. While hemoglobin concentrations have known relationships with ischemic stroke, it is unclear whether hemoglobin concentration is associated with DWI ischemic lesions after ICH. We sought to investigate the hypothesis that hemoglobin concentrations would associate with DWI lesions after ICH and further investigated their relationships with clinical outcomes. METHODS: Supratentorial ICH patients enrolled between 2010 and 2016 to a prospective, multicenter, observational cohort study (ERICH study [Ethnic/Racial Variations of Intracerebral Hemorrhage]) were assessed. Patients from this study with baseline, admission hemoglobin, and hospitalization magnetic resonance imaging were analyzed. Hemoglobin was examined as the primary exposure variable defined as a continuous variable (g/dL). Magnetic resonance imaging DWI ischemic lesion presence was assessed as the primary radiographic outcome. Primary analyses assessed relationships of hemoglobin with DWI lesions. Secondary analyses assessed relationships of DWI lesions with poor 3-month outcomes (modified Rankin Scale score, 4-6). These analyses were performed using separate multivariable logistic regression models adjusting for relevant covariates. RESULTS: Of 917 patients with ICH analyzed, mean baseline hemoglobin was 13.8 g/dL (±1.9), 60% were deep ICH, and DWI lesions were identified in 27% of the cohort. In our primary analyses, increased hemoglobin, defined as a continuous variable, was associated with DWI lesions (adjusted odds ratio, 1.21 per 1 g/dL change in hemoglobin [95% CI, 1.07-1.37]) after adjusting for sex, race, ICH severity, time to magnetic resonance imaging, and acute blood pressure change. In secondary analyses, DWI lesions were associated with poor 3-month outcomes (adjusted odds ratio, 1.83 [95% CI, 1.24-2.69]) after adjusting for similar covariates. CONCLUSIONS: We identified novel relationships between higher baseline hemoglobin concentrations and DWI ischemic lesions in patients with ICH. Further studies are required to clarify the role of hemoglobin concentration on both cerebral small vessel disease pathophysiology and ICH outcomes.
Assuntos
Hemorragia Cerebral , Imageamento por Ressonância Magnética , Humanos , Estudos Prospectivos , Hemorragia Cerebral/complicações , Imagem de Difusão por Ressonância Magnética/métodos , HemoglobinasRESUMO
BACKGROUND: Our primary objective was to evaluate if disparities in race, sex, age, and socioeconomic status (SES) exist in utilization of advanced neuroimaging in year 2015 in a population-based study. Our secondary objective was to identify the disparity trends and overall imaging utilization as compared with years 2005 and 2010. METHODS: This was a retrospective, population-based study that utilized the GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) data. Patients with stroke and transient ischemic attack were identified in the years 2005, 2010, and 2015 in a metropolitan population of 1.3 million. The proportion of imaging use within 2 days of stroke/transient ischemic attack onset or hospital admission date was computed. SES determined by the percentage below the poverty level within a given respondent's US census tract of residence was dichotomized. Multivariable logistic regression was used to determine the odds of advanced neuroimaging use (computed tomography angiogram/magnetic resonance imaging/magnetic resonance angiogram) for age, race, gender, and SES. RESULTS: There was a total of 10 526 stroke/transient ischemic attack events in the combined study year periods of 2005, 2010, and 2015. The utilization of advanced imaging progressively increased (48% in 2005, 63% in 2010, and 75% in 2015 [P<0.001]). In the combined study year multivariable model, advanced imaging was associated with age and SES. Younger patients (≤55 years) were more likely to have advanced imaging compared with older patients (adjusted odds ratio, 1.85 [95% CI, 1.62-2.12]; P<0.01), and low SES patients were less likely to have advanced imaging compared with high SES (adjusted odds ratio, 0.83 [95% CI, 0.75-0.93]; P<0.01). A significant interaction was found between age and race. Stratified by age, the adjusted odds of advanced imaging were higher for Black patients compared with White patients among older patients (>55 years; adjusted odds ratio, 1.34 [95% CI, 1.15-1.57]; P<0.01), but no racial differences among the young. CONCLUSIONS: Racial, age, and SES-related disparities exist in the utilization of advanced neuroimaging for patients with acute stroke. There was no evidence of a change in trend of these disparities between the study periods.
Assuntos
Disparidades em Assistência à Saúde , Ataque Isquêmico Transitório , Neuroimagem , Acidente Vascular Cerebral , Humanos , Pessoa de Meia-Idade , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/epidemiologia , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/epidemiologia , Brancos , Negro ou Afro-AmericanoRESUMO
BACKGROUND: In 2015, endovascular therapy (EVT) for large vessel occlusions became standard of care for acute ischemic stroke. Lower utilization of IV alteplase has been reported in women, but whether sex differences in EVT use in the United States exists has not been established. METHODS: We identified all acute ischemic stroke discharges from Get With The Guidelines-Stroke hospitals between 2012 and 2019 who were potentially eligible for EVT, based on National Institutes of Health Stroke Scale score ≥6 and arrival <6 hours, according to 2018 American Heart Association/ASA guidelines. Multivariable regression analyses were used to determine the association between sex and EVT utilization, and outcomes (including mortality, discharge home, functional status) after EVT. Separate analyses were conducted for the 2 time periods: 2012 to 2014, and 2015 to 2019. RESULTS: Of 302 965 patients potentially eligible for EVT, 42 422 (14%) received EVT. Before 2015, EVT treatment rates were 5.3% in women and 6.6% in men. From 2015 to 2019, treatment rates increased in both sexes to 16.7% in women and 18.5% in men. The adjusted odds ratio for EVT in women compared with men was 0.93 (95% CI, 0.87-0.99) before 2015, and 0.98 (95% CI, 0.96-1.01) after 2015. There were no significant sex differences in outcomes except that after 2015, women were less able to ambulate at discharge (adjusted odds ratio, 0.95 [95% CI, 0.95-0.99]) and had lower in-hospital mortality (adjusted odds ratio, 0.93 [95% CI, 0.88-0.99]). CONCLUSIONS: EVT utilization has increased dramatically in both women and men since EVT approval in 2015. Following statistical adjustment, women were less likely to receive EVT initially, but after 2015, women were as likely as men to receive EVT. After EVT, women were more likely to be disabled at discharge but less likely to experience in-hospital death compared with men.
Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/cirurgia , Procedimentos Endovasculares/métodos , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Sistema de Registros , Caracteres Sexuais , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Though stroke risk factors such as substance use may vary with age, less is known about trends in substance use over time or about performance of toxicology screens in young adults with stroke. METHODS: Using the Greater Cincinnati Northern Kentucky Stroke Study, a population-based study in a 5-county region comprising 1.3 million people, we reported the frequency of documented substance use (cocaine/marijuana/opiates/other) obtained from electronic medical record review, overall and by race/gender subgroups among physician-adjudicated stroke events (ischemic and hemorrhagic) in adults 20 to 54 years of age. Secondary analyses included heavy alcohol use and cigarette smoking. Data were reported for 5 one-year periods spanning 22 years (1993/1994-2015), and trends over time were tested. For 2015, to evaluate factors associated with performance of toxicology screens, multiple logistic regression was performed. RESULTS: Overall, 2152 strokes were included: 74.5% were ischemic, mean age was 45.7±7.6, 50.0% were women, and 35.9% were Black. Substance use was documented in 4.4%, 10.4%, 19.2%, 24.0%, and 28.8% of cases in 1993/1994, 1999, 2005, 2010, and 2015, respectively (Ptrend<0.001). Between 1993/1994 and 2015, documented substance use increased in all demographic subgroups. Adjusting for gender, comorbidities, and National Institutes of Health Stroke Scale, predictors of toxicology screens included Black race (adjusted odds ratio, 1.58 [95% CI, 1.02-2.45]), younger age (adjusted odds ratio, 0.70 [95% CI, 0.53-0.91], per 10 years), current smoking (adjusted odds ratio, 1.62 [95% CI, 1.06-2.46]), and treatment at an academic hospital (adjusted odds ratio, 1.80 [95% CI, 1.14-2.84]). After adding chart-reported substance use to the model, only chart-reported substance abuse and age were significant. CONCLUSIONS: In a population-based study of young adults with stroke, documented substance use increased over time, and documentation of substance use was higher among Black compared with White individuals. Further work is needed to confirm race-based disparities and trends in substance use given the potential for bias in screening and documentation. Findings suggest a need for more standardized toxicology screening.
Assuntos
Isquemia Encefálica , Cocaína , Alcaloides Opiáceos , Acidente Vascular Cerebral , Transtornos Relacionados ao Uso de Substâncias , Isquemia Encefálica/terapia , Criança , Feminino , Humanos , Kentucky/epidemiologia , Masculino , Acidente Vascular Cerebral/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto JovemRESUMO
BACKGROUND: There are limited data about the epidemiology and secondary stroke prevention strategies used for patients with depressed left ventricular ejection fraction (LVEF) and sinus rhythm following an acute ischemic stroke (AIS). We sought to describe the prevalence of LVEF ≤40% and sinus rhythm among patients with AIS and antithrombotic treatment practice in a multi-center cohort from 2002 to 2018. METHODS: This was a multi-center, retrospective cohort study comprised of patients with AIS hospitalized in the Greater Cincinnati Northern Kentucky Stroke Study and 4 academic, hospital-based cohorts in the United States. A 1-stage meta-analysis of proportions was undertaken to calculate a pooled prevalence. Univariate analyses and an adjusted multivariable logistic regression model were performed to identify demographic, clinical, and echocardiographic characteristics associated with being prescribed an anticoagulant upon AIS hospitalization discharge. RESULTS: Among 14 338 patients with AIS with documented LVEF during the stroke hospitalization, the weighted pooled prevalence of LVEF ≤40% and sinus rhythm was 5.0% (95% CI, 4.1-6.0%; I2, 84.4%). Of 524 patients with no cardiac thrombus and no prior indication for anticoagulant who survived postdischarge, 200 (38%) were discharged on anticoagulant, 289 (55%) were discharged on antiplatelet therapy only, and 35 (7%) on neither. There was heterogeneity by site in the proportion discharged with an anticoagulant (22% to 45%, P<0.0001). Cohort site and National Institutes of Health Stroke Severity scale >8 (odds ratio, 2.0 [95% CI, 1.1-3.8]) were significant, independent predictors of being discharged with an anticoagulant in an adjusted analysis. CONCLUSIONS: Nearly 5% of patients with AIS have a depressed LVEF and are in sinus rhythm. There is significant variation in the clinical practice of antithrombotic therapy prescription by site and stroke severity. Given this clinical equipoise, further study is needed to define optimal antithrombotic treatment regimens for secondary stroke prevention in this patient population.
Assuntos
Fibrilação Atrial , AVC Isquêmico , Acidente Vascular Cerebral , Assistência ao Convalescente , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrinolíticos/uso terapêutico , Humanos , Alta do Paciente , Prevalência , Estudos Retrospectivos , Volume Sistólico , Função Ventricular EsquerdaRESUMO
BACKGROUND AND PURPOSE: In intracerebral hemorrhage (ICH), preexisting cognitive impairment has been identified as a risk factor for increased mortality and morbidity. However, previous studies examined predominantly White populations; therefore, the prevalence and effect of preICH cognitive impairment has not been studied in a multiethnic cohort. This limits the generalizability of previous findings. We sought to investigate the role of preexisting cognitive impairment in a multiethnic population on short-term mortality and functional outcomes after ICH. METHODS: Patients with ICH were prospectively enrolled as cases for the GERFHS III (Genetic and Environmental Risk Factors for Hemorrhagic Stroke) Study and the Ethnic/Racial Variations of ICH (ERICH) Study. Cognitive impairment before ICH was defined as positive history of dementia or treatment with donepezil, galantamine, memantine, or rivastigmine on chart abstraction or baseline interview. Specific outcomes-modified Rankin Scale score at 3 months (0-2 versus ≥3), Barthel Index score (<100 versus 100) at 3 months, and withdrawal of care-were analyzed using multivariable logistic regression. Propensity score matching and analysis was done because of imbalances between cognitively impaired and cognitively intact groups. RESULTS: Of the 3537 cases of ICH, 304 patients had cognitive impairment predating ICH. Cognitively impaired subjects were more likely to experience withdrawal of care during hospitalization, and for survivors, greater disability (modified Rankin Scale score of ≥3) and lower Barthel scores after ICH. After propensity score matching, preexisting cognitive impairment was associated with a lower modified Rankin Scale at 3 months in the White, Black, and Hispanic subgroups. CONCLUSIONS: Preexisting cognitive impairment was associated with loss of independence 3-month post-ICH, when matching for risk factors of cognitive impairment, in the White, Black, and Hispanic subgroups. This suggests that preexisting cognitive impairment has a negative effect in obtaining functional independence following ICH, irrespective of race/ethnicity.
Assuntos
Hemorragia Cerebral/complicações , Hemorragia Cerebral/mortalidade , Disfunção Cognitiva/complicações , Adulto , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , População Negra , Estudos de Coortes , Etnicidade , Feminino , Hispânico ou Latino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Pontuação de Propensão , Estudos Prospectivos , Grupos Raciais , Fatores de Risco , Resultado do Tratamento , População Branca , Suspensão de Tratamento/estatística & dados numéricosRESUMO
BACKGROUND AND PURPOSE: Anecdotal evidence suggests that the coronavirus disease 2019 (COVID-19) pandemic mitigation efforts may inadvertently discourage patients from seeking treatment for stroke with resultant increased morbidity and mortality. Analysis of regional data, while hospital capacities for acute stroke care remained fully available, offers an opportunity to assess this. We report regional Stroke Team acute activations and reperfusion treatments during COVID-19 mitigation activities. METHODS: Using case log data prospectively collected by a Stroke Team exclusively serving ≈2 million inhabitants and 30 healthcare facilities, we retrospectively reviewed volumes of consultations and reperfusion treatments for acute ischemic stroke. We compared volumes before and after announcements of COVID-19 mitigation measures and the prior calendar year. RESULTS: Compared with the 10 weeks prior, stroke consultations declined by 39% (95% CI, 32%-46%) in the 5 weeks after announcement of statewide school and restaurant closures in Ohio, Kentucky, and Indiana. Results compared with the prior year and time trend analyses were consistent. Reperfusion treatments also appeared to decline by 31% (95% CI, 3%-51%), and specifically thrombolysis by 33% (95% CI, 4%-55%), but this finding had less precision. CONCLUSIONS: Upon the announcement of measures to mitigate COVID-19, regional acute stroke consultations declined significantly. Reperfusion treatment rates, particularly thrombolysis, also appeared to decline qualitatively, and this finding requires further study. Urgent public education is necessary to mitigate a possible crisis of avoiding essential emergency care due to COVID-19.
Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Pneumonia Viral/complicações , Pneumonia Viral/terapia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , COVID-19 , Infecções por Coronavirus/epidemiologia , Humanos , Indiana/epidemiologia , Kentucky/epidemiologia , Ohio/epidemiologia , Pandemias , Equipe de Assistência ao Paciente , Pneumonia Viral/epidemiologia , Estudos Prospectivos , Encaminhamento e Consulta/estatística & dados numéricos , Reperfusão , Acidente Vascular Cerebral/epidemiologia , Trombectomia , Terapia Trombolítica/estatística & dados numéricos , Tempo para o Tratamento , Resultado do TratamentoRESUMO
Background and Purpose- Sex differences in stroke incidence over time were previously reported from the GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study). We aimed to determine whether these differences continued through 2015 and whether they were driven by particular age groups. Methods- Within the GCNKSS population of 1.3 million, incident (first ever) strokes among residents ≥20 years of age were ascertained at all local hospitals during 5 periods: July 1993 to June 1994 and calendar years 1999, 2005, 2010, and 2015. Out-of-hospital cases were sampled. Sex-specific incidence rates per 100 000 were adjusted for age and race and standardized to the 2010 US Census. Trends over time by sex were compared (overall and age stratified). Sex-specific case fatality rates were also reported. Bonferroni corrections were applied for multiple comparisons. Results- Over the 5 study periods, there were 9733 incident strokes (56.3% women). For women, there were 229 (95% CI, 215-242) per 100 000 incident strokes in 1993/1994 and 174 (95% CI, 163-185) in 2015 (P<0.05), compared with 282 (95% CI, 263-301) in 1993/1994 to 211 (95% CI, 198-225) in 2015 (P<0.05) in men. Incidence rates decreased between the first and last study periods in both sexes for IS but not for intracerebral hemorrhage or subarachnoid hemorrhage. Significant decreases in stroke incidence occurred between the first and last study periods for both sexes in the 65- to 84-year age group and men only in the ≥85-year age group; stroke incidence increased for men only in the 20- to 44-year age group. Conclusions- Overall stroke incidence decreased from the early 1990s to 2015 for both sexes. Future studies should continue close surveillance of sex differences in the 20- to 44-year and ≥85-year age groups, and future stroke prevention strategies should target strokes in the young- and middle-age groups, as well as intracerebral hemorrhage.
Assuntos
Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Kentucky/epidemiologia , Masculino , Pessoa de Meia-Idade , Ohio/epidemiologia , Fatores Sexuais , Fatores de TempoRESUMO
Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.
Assuntos
Isquemia Encefálica/genética , Hemorragia Cerebral/genética , Doenças de Pequenos Vasos Cerebrais/genética , Encéfalo , Isquemia Encefálica/complicações , Hemorragia Cerebral/complicações , Doenças de Pequenos Vasos Cerebrais/complicações , Feminino , Expressão Gênica/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genéticaRESUMO
Intracranial aneurysms (IA) are weakened outpouchings of the arterial wall in the cerebrovasculature. Rupture of an IA often leads to devastating consequences. The early identification of IA patients is crucial for management of their condition. A genetic variant at rs10230207, located nearby the HDAC9, TWIST1, and FERD3L genes, is associated with IA. HDAC9 is a class IIa histone deacetylase that mediates vascular smooth muscle cell dysfunction. TWIST1 is a mechanosensitive transcription factor and its expression is reduced in unstable carotid atherosclerotic plaques. In this study, the expression of the HDAC9, TWIST1, and FERD3L genes was characterized and associated with the presence of the rs10230207 genetic variant. Allelic discrimination and gene expression analysis were performed using lymphoblasts from 85 population controls and 109 IA patients. Subjects that were heterozygous (GT) within rs10230207 were 4.32 times more likely to have an IA than those that were homozygous for the reference allele (GG; 95%CI 1.23 to 14.16). Subjects that were homozygous (TT) were 8.27 times more likely to have an IA than those that were GG (95%CI 2.45 to 27.85). While the presence of the risk allele was not associated with changes in FERD3L gene expression, the risk allele was associated with increased HDAC9 and decrease in TWIST1 mRNA expression. The significant inverse correlation between HDAC9 and TWIST1 gene expression suggests that changes in the expression of both of genes may contribute to the formation of IAs.
Assuntos
Doenças das Artérias Carótidas/genética , Histona Desacetilases/genética , Aneurisma Intracraniano/genética , Linfócitos/metabolismo , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Proteína 1 Relacionada a Twist/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND AND PURPOSE: Computed tomographic angiography and conventional angiography provide timely vascular anatomic information in patients with stroke. However, iodinated contrast dye may cause acute kidney injury (AKI). Within a large, biracial population, we examined in-hospital incidence of new or worsening kidney disease in patients with stroke and its association with administration of intravenous dye. METHODS: All adult residents of the Greater Cincinnati/Northern Kentucky region with acute ischemic stroke or intracerebral hemorrhage who presented to an emergency department in 2010 were included. Prevalence of unsuspected kidney disease at the time of emergency department presentation and the incidence of AKI after admission in 2 groups of patients-those who did and those who did not receive intravenous dye-were determined. RESULTS: In 2010, 2299 patients met inclusion criteria (89% ischemic stroke and 11% intracerebral hemorrhage); mean age 69 years (SD 15), 22% black, and 54% women. Among these patients, 37% had kidney disease at baseline, including 22% (516/2299) in whom this was unsuspected. Two percent (2%; 15/853) of patients with baseline kidney disease developed AKI during the hospital stay. Of those with no baseline kidney disease, 1% (14/14 467) developed AKI. There was no association between dye administration and new or worsening kidney disease. CONCLUSIONS: Although 22% of patients in the Greater Cincinnati/Northern Kentucky stroke population had unsuspected kidney disease, the incidence of new or worsening kidney disease was low, and AKI was not associated with dye administration. These findings confirm single-center reports that the risk of severe renal complications after contrast dye is small.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Isquemia Encefálica/diagnóstico por imagem , Angiografia Cerebral/efeitos adversos , Hemorragia Cerebral/diagnóstico por imagem , Meios de Contraste/efeitos adversos , Nefropatias , Acidente Vascular Cerebral/diagnóstico por imagem , Injúria Renal Aguda/epidemiologia , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/epidemiologia , Hemorragia Cerebral/epidemiologia , Feminino , Halogenação , Humanos , Kentucky/epidemiologia , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Ohio/epidemiologia , Acidente Vascular Cerebral/epidemiologiaAssuntos
Avaliação da Deficiência , Registros Eletrônicos de Saúde , Estado Funcional , AVC Isquêmico/diagnóstico , Qualidade de Vida , Características de Residência , Inquéritos e Questionários , Sobreviventes/psicologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Entrevistas como Assunto , AVC Isquêmico/epidemiologia , AVC Isquêmico/fisiopatologia , AVC Isquêmico/psicologia , Masculino , Saúde Mental , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Telefone , Estados Unidos/epidemiologiaRESUMO
BACKGROUND AND PURPOSE: The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (r-tPA; CLEAR) in Acute Ischemic Stroke (AIS) and CLEAR-Enhanced Regimen (CLEAR-ER) trials demonstrated safety of reduced dose r-tPA plus the glycoprotein 2b/3a inhibitor, eptifibatide, in AIS compared with r-tPA alone. The objective of the CLEAR-Full Dose Regimen (CLEAR-FDR) trial was to estimate the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients treated with the combination of full-dose r-tPA plus eptifibatide. METHODS: CLEAR-FDR was a single-arm, prospective, open-label, multisite study. Patients aged 18 to 85 years treated with 0.9 mg/kg IV r-tPA within 3 hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 µg/kg bolus and 2-hour infusion at 0.75 µg/kg per minute) was administered. The primary end point was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if an sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was 3 sICHs within the first 19 patients or 4 sICHs within 29 patients. RESULTS: From October 2013 to December 2014, 27 patients with AIS were enrolled. Median age was 73 years (range, 34-85; interquartile range, 65-80) and median National Institute of Health stroke scale score was 12 (range, 6-26; interquartile range, 9-16). One sICH (3.7%; 95% confidence interval, 0.7%-18%) was observed. CONCLUSIONS: These results demonstrate comparable safety of full-dose r-tPA plus eptifibatide with historical rates of sICH with r-tPA alone and support proceeding with a phase 3 trial evaluating full-dose r-tPA combined with eptifibatide to improve outcomes after AIS.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Hemorragia Cerebral/induzido quimicamente , Fibrinolíticos/efeitos adversos , Peptídeos/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada/efeitos adversos , Eptifibatida , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do TratamentoRESUMO
We tested the hypothesis that vascular macrophage infiltration and O2 (-) release impairs sympathetic nerve α2-adrenergic autoreceptor (α2AR) function in mesenteric arteries (MAs) of DOCA-salt hypertensive rats. Male rats were uninephrectomized or sham operated (sham). DOCA pellets were implanted subcutaneously in uninephrectomized rats who were provided high-salt drinking water or high-salt water with apocynin. Sham rats received tap water. Blood pressure was measured using radiotelemetry. Treatment of sham and DOCA-salt rats with liposome-encapsulated clodronate was used to deplete macrophages. After 3-5, 10-13, and 18-21 days of DOCA-salt treatment, MAs and peritoneal fluid were harvested from euthanized rats. Norepinephrine (NE) release from periarterial sympathetic nerves was measured in vitro using amperometry with microelectrodes. Macrophage infiltration into MAs as well as TNF-α and p22(phox) were measured using immunohistochemistry. Peritoneal macrophage activation was measured by flow cytometry. O2 (-) was measured using dihydroethidium staining. Hypertension developed over 28 days, and apocynin reduced blood pressure on days 18-21. O2 (-) and macrophage infiltration were greater in DOCA-salt MAs compared with sham MAs after day 10. Peritoneal macrophage activation occurred after day 10 in DOCA-salt rats. Macrophages expressing TNF-α and p22(phox) were localized near sympathetic nerves. Impaired α2AR function and increased NE release from sympathetic nerves occurred in MAs from DOCA-salt rats after day 18. Macrophage depletion reduced blood pressure and vascular O2 (-) while restoring α2AR function in DOCA-salt rats. Macrophage infiltration into the vascular adventitia contributes to increased blood pressure in DOCA-salt rats by releasing O2 (-), which disrupts α2AR function, causing enhanced NE release from sympathetic nerves.
Assuntos
Pressão Sanguínea/imunologia , Hipertensão/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos , Artérias Mesentéricas/inervação , Receptores Adrenérgicos alfa 2/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Ácido Clodrônico/farmacologia , Acetato de Desoxicorticosterona , Hipertensão/etiologia , Hipertensão/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/imunologia , Mineralocorticoides , NADPH Oxidases/imunologia , NADPH Oxidases/metabolismo , Nefrectomia , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/metabolismo , Cloreto de Sódio na Dieta , Superóxidos , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Ischemic stroke, which accounts for 87% of cerebrovascular accidents, is responsible for massive global burden both in terms of economic cost and personal hardship. Many stroke survivors face long-term disability-a phenotype associated with an increasing number of genetic variants. While clinical variables such as stroke severity greatly impact recovery, genetic polymorphisms linked to functional outcome may offer physicians a unique opportunity to deliver personalized care based on their patient's genetic makeup, leading to improved outcomes. A comprehensive catalogue of the variants at play is required for such an approach. In this review, we compile and describe the polymorphisms associated with outcome scores such as modified Rankin Scale and Barthel Index. Our search identified 74 known genetic polymorphisms spread across 48 features associated with various poststroke disability metrics. The known variants span diverse biological systems and are related to inflammation, vascular homeostasis, growth factors, metabolism, the p53 regulatory pathway, and mitochondrial variation. Understanding how these variants influence functional outcome may be helpful in maximizing poststroke recovery.
Assuntos
AVC Isquêmico , Humanos , AVC Isquêmico/genética , Recuperação de Função Fisiológica/fisiologia , Polimorfismo GenéticoRESUMO
BACKGROUND: Dysphagia after stroke is common and can impact morbidity and death. The purpose of this population-based study was to determine specific epidemiological and health risk factors that impact development of dysphagia after acute stroke. METHODS AND RESULTS: Ischemic and hemorrhagic stroke cases from 2010 and 2015 were identified via chart review from the GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study), a representative sample of ≈1.3 million adults from southwestern Ohio and northern Kentucky. Dysphagia status was determined on the basis of clinical assessments and necessity for alternative access to nutrition via nasogastric or percutaneous endoscopic gastrostomy tube placement. Comparisons between patients with and without dysphagia were made to determine differences in baseline characteristics and premorbid conditions. Multivariable logistic regression determined factors associated with increased risk of dysphagia. Dysphagia status was ascertained from 4139 cases (1709 with dysphagia). Logistic regression showed that increased age, Black race, higher National Institutes of Health Stroke Scale score at admission, having a hemorrhagic stroke (versus infarct), and right hemispheric stroke increased the risk of developing dysphagia after stroke. Factors associated with reduced risk included history of high cholesterol, lower prestroke modified Rankin Scale score, and white matter disease. CONCLUSIONS: This study replicated previous findings of variables associated with dysphagia (older age, worse stroke, right-sided hemorrhagic lesions), whereas other variables identified were without clear biological rationale (eg, Black race, history of high cholesterol, and presence of white matter disease) and should be investigated in future studies to determine biological relevance and potential influence in stroke recovery.
Assuntos
Transtornos de Deglutição , Acidente Vascular Cerebral Hemorrágico , Leucoencefalopatias , Acidente Vascular Cerebral , Adulto , Humanos , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/epidemiologia , Transtornos de Deglutição/etiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , ColesterolRESUMO
BACKGROUND AND OBJECTIVES: Few studies have examined trends and disparities in long-term outcome after stroke in a representative US population. We used a population-based stroke study in the Greater Cincinnati Northern Kentucky region to examine trends and racial disparities in poststroke 5-year mortality. METHODS: All patients with acute ischemic strokes (AISs) and intracerebral hemorrhages (ICHs) among residents ≥20 years old were ascertained using ICD codes and physician-adjudicated using a consistent case definition during 5 periods: July 1993-June 1994 and calendar years 1999, 2005, 2010, and 2015. Race was obtained from the medical record; only those identified as White or Black were included. Premorbid functional status was assessed using the modified Rankin Scale, with a score of 0-1 being considered "good." Mortality was assessed with the National Death Index. Trends and racial disparities for each subtype were analyzed with logistic regression. RESULTS: We identified 8,428 AIS cases (19.3% Black, 56.3% female, median age 72) and 1,501 ICH cases (23.5% Black, 54.8% female, median age 72). Among patients with AIS, 5-year mortality improved after adjustment for age, race, and sex (53% in 1993/94 to 48.3% in 2015, overall effect of study year p = 0.009). The absolute decline in 5-year mortality in patients with AIS was larger than what would be expected in the general population (5.1% vs 2.8%). Black individuals were at a higher risk of death after AIS (odds ratio [OR] 1.23, 95% CI 1.08-1.39) even after adjustment for age and sex, and this effect was consistent across study years. When premorbid functional status and comorbidities were included in the model, the primary effect of Black race was attenuated but race interacted with sex and premorbid functional status. Among male patients with a good baseline functional status, Black race remained associated with 5-year mortality (OR 1.4, 95% CI 1.1-1.7, p = 0.002). There were no changes in 5-year mortality after ICH over time (64.4% in 1993/94 to 69.2% in 2015, overall effect of study year p = 0.32). DISCUSSION: Long-term survival improved after AIS but not after ICH. Black individuals, particularly Black male patients with good premorbid function, have a higher mortality after AIS, and this disparity did not change over time.