James F Meschia

University of Alabama at Birmingham, Birmingham, Alabama, United States

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Publications (297)2283.82 Total impact

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    ABSTRACT: Background and purpose: Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels-associated genetic variant MTHFR C677T for association with magnetic resonance imaging-confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. Methods: We included 1359 magnetic resonance imaging-confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. Results: MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). Conclusions: MTHFR C677T was associated with magnetic resonance imaging-confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes.
    Full-text · Article · Feb 2016 · Stroke
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    ABSTRACT: Background: Stroke symptoms in the general adult population are common and associated with stroke risk factors, lower physical and mental functioning, impaired cognitive status, and future stroke. Our objective was to determine the association of stroke symptoms with self-reported hospitalization or emergency department (ED) visit. Methods: Lifetime history of stroke symptoms (sudden weakness, numbness, unilateral or general loss of vision, loss of ability to communicate or understand) was assessed at baseline in a national, population-based, longitudinal cohort study of 30,239 blacks and whites younger than 45 years, enrolled from 2003 to 2007. Self-reported hospitalization or ED visit and reason were collected during follow-up through March 2013. The symptom–hospitalization association was assessed by proportional hazards analysis in persons who were stroke/transient ischemic attack-free at baseline (27,126) with adjustment for sociodemographics and further adjustment for risk factors. Results: One or more stroke symptoms were reported by 4758 (17.5%). After adjustment for sociodemographics, stroke symptoms were most strongly associated with greater risk of hospitalization/ED for cardiovascular disease (CVD) (hazard ratio [HR] = 1.87, 95% confidence interval [CI]: 1.78-1.96), stroke (HR = 1.69, 95% CI: 1.55-1.85), and any reason (HR = 1.39, 95% CI: 1.34-1.44). These associations remained significant and only modestly reduced after risk factor adjustment. Conclusions: Stroke symptoms are a marker for future hospitalization and ED visit not only for stroke but also for CVD in general. Findings suggest a role for stroke symptom assessment as a novel and simple approach for identifying individuals at high risk for CVD including stroke in whom preventive strategies could be implemented.
    No preview · Article · Jan 2016 · Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association
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    ABSTRACT: Background and purpose: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. Methods: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. Results: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. Conclusions: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
    No preview · Article · Jan 2016 · Stroke
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    Full-text · Article · Dec 2015 · The Lancet Neurology
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    ABSTRACT: Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)). Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.
    Preview · Article · Dec 2015 · Neurology
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    ABSTRACT: Background: The value of neuron-specific enolase (NSE) in predicting clinical outcomes has been investigated in a variety of neurological disorders. Objective: To investigate the associations of serum NSE with severity of bleeding and functional outcomes in patients with subarachnoid hemorrhage (SAH). Methods: We retrospectively reviewed the records of patients with SAH from June 2008 to June 2012. The severity of SAH bleeding at admission was measured radiographically with the Fisher scale and clinically with the Glasgow Coma Scale, Hunt and Hess grade, and World Federation of Neurologic Surgeons scale. Outcomes were assessed with the modified Rankin Scale at discharge. Results: We identified 309 patients with nontraumatic SAH, and 71 had NSE testing. Median age was 54 years (range, 23-87 years), and 44% were male. In multivariable analysis, increased NSE was associated with a poorer Hunt and Hess grade (P = .003), World Federation of Neurologic Surgeons scale score (P < .001), and Glasgow Coma Scale score (P = .003) and worse outcomes (modified Rankin Scale at discharge; P = .001). There was no significant association between NSE level and Fisher grade (P = .81) in multivariable analysis. Conclusion: We found a significant association between higher NSE levels and poorer clinical presentations and worse outcomes. Although it is still early for any relevant clinical conclusions, our results suggest that NSE holds promise as a tool for screening patients at increased risk of poor outcomes after SAH. Abbreviations: BMI, body mass indexGCS, Glasgow Coma ScalemRS, modified Rankin ScaleNSE, neuron-specific enolaseSAH, subarachnoid hemorrhageWFNS, World Federation of Neurologic Surgeons.
    No preview · Article · Nov 2015 · Neurosurgery
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    ABSTRACT: Background and purpose: Prior meta-analysis showed that carotid endarterectomy benefits decline with increasing surgical delay following symptoms. For symptomatic patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), we assessed if differences in time between symptoms and carotid endarterectomy or carotid artery stenting are associated with differences in risk of periprocedural stroke or death. Methods: We analyzed the 1180 symptomatic patients in CREST who received their assigned procedure and had clearly defined timing of symptoms. Patients were classified into 3 groups based on time from symptoms to procedure: <15, 15 to 60, and >60 days. Results: For carotid endarterectomy, risk of periprocedural stroke or death was not significantly different for the 2 later time periods relative to the earliest time period (hazard ratio, 0.74; 95% confidence interval, 0.22-2.49 for 15-60 days and hazard ratio, 0.91; 95% confidence interval, 0.25-3.33 for >60 days; P=0.89). For carotid artery stenting, risk of periprocedural stroke or death was also not significantly different for later time periods relative to the earliest time period (hazard ratio, 1.12; 95% confidence interval, 0.53-2.40 for 15-60 days and hazard ratio, 1.15; 95% confidence interval, 0.48-2.75 for >60 days; P=0.93). Conclusions: Time from symptoms to carotid endarterectomy or carotid artery stenting did not alter periprocedural safety, supporting early revascularization regardless of modality. Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.
    No preview · Article · Oct 2015 · Stroke

  • No preview · Conference Paper · Oct 2015
  • Kevin M Barrett · Brajesh K Lal · James F Meschia
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    ABSTRACT: Evidence-based therapeutic options for stroke continue to emerge based on results from well-designed clinical studies. Ischemic stroke far exceeds hemorrhagic stroke in terms of prevalence and incidence, both in the USA and worldwide. The public health effect of reducing death and disability related to ischemic stroke justifies the resources that have been invested in identifying safe and effective treatments. The emergence of novel oral anticoagulants for ischemic stroke prevention in atrial fibrillation has introduced complexity to clinical decision making for patients with this common cardiac arrhythmia. Some accepted ischemic stroke preventative strategies, such as carotid revascularization for asymptomatic carotid stenosis, require reassessment, given advances in risk factor management, antithrombotic therapy, and surgical techniques. Intra-arterial therapy, particularly with stent retrievers after intravenous tissue plasminogen activator, has recently been demonstrated to improve functional outcomes and will require investment in system-based care models to ensure that effective treatments are received by patients in a timely fashion. The purpose of this review is to describe recent advances in medical and surgical approaches to ischemic stroke prevention and acute treatment. Results from recently published clinical trials will be highlighted along with ongoing clinical trials addressing key questions in ischemic stroke management and prevention where equipoise remains.
    No preview · Article · Oct 2015 · Current Cardiology Reports
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    ABSTRACT: Background and purpose: There is higher combined risk of stroke or death (S+D) at older ages with carotid stenting. We assess whether this can be attributed to patient or arterial characteristics that are in the pathway between older age and higher risk. Methods: Mediation analysis of selected patient (hypertension, diabetes mellitus, and dyslipidemia) and arterial characteristics assessed at the clinical sites and the core laboratory (plaque length, eccentric plaque, ulcerated plaque, percent stenosis, peak systolic velocity, and location) was performed in 1123 carotid artery stenting-treated patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). We assessed the association of age with these characteristics, the association of these characteristics with stroke risk, and the amount of mediation of the association of age on the combined risk of periprocedural S+D with adjustment for these factors. Results: Only plaque length as measured at the sites increased with age, was associated with increased S+D risk and significantly mediated the association of age on S+D risk. However, adjustment for plaque length attenuated the increased risk per 10 years of age from 1.72 (95% confidence interval, 1.26-2.37) to 1.66 (95% confidence interval, 1.20-2.29), accounting for only 8% of the increased risk. Conclusions: Plaque length seems to be in the pathway between older age and higher risk of S+D among carotid artery stenting-treated patients, but it mediated only 8% of the age effect excess risk of carotid artery stenting in CREST. Other factors and mechanisms underlying the age effect need to be identified as plaque length will not identify elderly patients for whom stenting is safe relative to endarterectomy. Clinical trial registration: URL: http://clinicaltrials.gov. Unique Identifier: NCT00004732.
    No preview · Article · Sep 2015 · Stroke
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    ABSTRACT: Although the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. This analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age < 55 years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age ≥ 55 years). Heritabilities for young-onset stroke and old-onset stroke were estimated at 42% (±8%, P < 0.001) and 34% (±10%, P < 0.001), respectively. Our data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant. © 2015 EAN.
    No preview · Article · Sep 2015 · European Journal of Neurology
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    ABSTRACT: The association between resting heart rate and ischemic stroke remains unclear. To examine the association between resting heart rate and ischemic stroke. A total of 24 730 participants (mean age: 64 ± 9·3 years; 59% women; 41% blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who were free of stroke at the time of enrollment (2003-2007) were included in this analysis. Resting heart rate was determined from baseline electrocardiogram data. Heart rate was examined as a continuous variable per 10 bpm increase and also as a categorical variable using tertiles ( <61 bpm, 61 to 70 bpm, and >70 bpm). First-time ischemic stroke events were identified during follow-up and adjudicated by physician review. Over a median follow-up of 7·6 years, a total of 646 ischemic strokes occurred. In a Cox regression model adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, each 10 bpm increase in heart rate was associated with a 10% increase in the risk of ischemic stroke (hazard ratio = 1·10, 95% confidence interval = 1·02, 1·18). In the categorical model, an increased risk of ischemic stroke was observed for heart rates in the middle (hazard ratio = 1·29, 95% confidence interval = 1·06, 1·57) and upper (hazard ratio = 1·37, 95% confidence interval = 1·12, 1·67) tertiles compared with the lower tertile. The results were consistent when the analysis was stratified by age, gender, race, exercise habits, hypertension, and coronary heart disease. In REGARDS, high resting heart rates were associated with an increased risk of ischemic stroke compared with low heart rates. Further research is needed to examine whether interventions aimed to reduce heart rate decrease stroke risk. © 2015 World Stroke Organization.
    Full-text · Article · Aug 2015 · International Journal of Stroke
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    ABSTRACT: Post-hoc, we hypothesized that over the recruitment period of the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), increasing experience and improved patient selection with carotid stenting, and to a lesser extent, carotid endarterectomy would contribute to lower periprocedural event rates. Three study periods with approximately the same number of patients were defined to span recruitment. Composite and individual rates of periprocedural stroke, myocardial infarction, and death rate were calculated separately by treatment assignment (carotid stenting/carotid endarterectomy). Temporal changes in unadjusted event rates, and rates after adjustment for temporal changes in patient characteristics, were assessed. For patients randomized to carotid stenting, there was no significant temporal change in the unadjusted composite rates that declined from 6.2% in the first period, to 4.9% in the second, and 4.6% in the third (P=0.28). Adjustment for patient characteristics attenuated the rates to 6.0%, 5.9%, and 5.6% (P=0.85). For carotid endarterectomy-randomized patients, both the composite and the combined stroke and death outcome decreased between periods 1 and 2 and then increased in period 3. The hypothesized temporal reduction of stroke+death events for carotid stenting-treated patients was not observed. Further adjustment for changes in patient characteristics between periods, including the addition of asymptomatic patients and a >50% decrease in proportion of octogenarians enrolled, resulted in practically identical rates. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732. © 2015 American Heart Association, Inc.
    No preview · Article · Jul 2015 · Stroke
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    ABSTRACT: The aim of this guideline is to provide a focused update of the current recommendations for the endovascular treatment of acute ischemic stroke. Where there is overlap, the recommendations made here supersede those of previous guidelines. This focused update analyzes results from 8 randomized clinical trials of endovascular treatment and other relevant data published since 2013. It is not intended to be a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that justifies changes in current recommendations. Members of the writing committee were appointed by the American Heart Association/American Stroke Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association/American Stroke Association Manuscript Oversight Committee (MOC). Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statement Oversight Committee and Stroke Council Leadership Committee. Evidence-based guidelines are presented for the selection of patients with acute ischemic stroke for endovascular treatment, the endovascular procedure and for systems of care to facilitate endovascular treatment. Certain endovascular procedures have been demonstrated to provide clinical benefit in selected patients with acute ischemic stroke. Systems of care should be organized to facilitate the delivery of this care. © 2015 American Heart Association, Inc.
    Preview · Article · Jun 2015 · Stroke
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    ABSTRACT: Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage. A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed. No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing. Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for sufficient power except for loci with large effects. © 2015 American Heart Association, Inc.
    No preview · Article · Jun 2015 · Stroke
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    ABSTRACT: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations. © 2015 American Heart Association, Inc.
    Full-text · Article · Jun 2015 · Stroke
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    ABSTRACT: Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confi rm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.
    Full-text · Article · Jun 2015 · The Lancet Neurology
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    ABSTRACT: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk. To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis). We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10-8) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10-7) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.
    No preview · Article · May 2015
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    ABSTRACT: The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly. We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency >0.01 were included in the analysis. A significance level of P<0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method. We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association. Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease. © 2015 The Authors.
    Full-text · Article · May 2015 · Stroke
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    ABSTRACT: Background and Purpose—Although pharmacological treatment of hypertension has important health benefits, it does not capture the benefit of maintenance of ideal health through the prevention or delay of hypertension. Methods—A total of 26 875 black and white participants aged 45+ years were assessed and followed for incident stroke events. The association was assessed between incident stroke and: (1) systolic blood pressure (SBP)categorized as normal (<120 mm Hg), prehypertension (120–139 mm Hg), stage 1 hypertension (140–159 mm Hg), and stage 2 hypertension (160 mm Hg+), and (2) number of classes of antihypertensive medications, classified as none, 1, 2, or 3 or more. Results—During 6.3 years of follow-up, 823 stroke events occurred. Nearly half (46%) of the population were successfully treated (SBP<140 mm Hg) hypertensives. Within blood pressure strata, the risk of stroke increased with each additional class of required antihypertensive medication, with hazard ratio [HR], 1.33; 95% confidence interval, 1.16 to 1.52 for normotensive, HR, 1.15; 95% confidence interval, 1.05 to 1.26 for prehypertension, and HR, 1.22; 95% confidence interval, 1.06 to 1.39 for stage 1 hypertension. A successfully treated (SBP<120 mm Hg) hypertensive person on 3+ antihypertensive medication classes was at marginally higher stroke risk than a person with untreated stage 1 hypertension (HR, 2.48 versus HR=2.19; relative to those with SBP <120 on no antihypertensive medications). Conclusions—Maintaining the normotensive status solely through pharmacological treatment has a profound impact, as nearly half of this general population cohort were treated to guideline (SBP<140 mm Hg) but failed to return to risk levels similar to normotensive individuals. Even with successful treatment, there is a substantial potential gain by prevention or delay of hypertension.
    Full-text · Article · May 2015 · Stroke

Publication Stats

8k Citations
2,283.82 Total Impact Points


  • 2014
    • University of Alabama at Birmingham
      • School of Public Health
      Birmingham, Alabama, United States
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
  • 2013
    • University of Newcastle
      • School of Nursing and Midwifery
      Newcastle, New South Wales, Australia
    • Imperial College London
      Londinium, England, United Kingdom
    • University of Mississippi
      Mississippi, United States
  • 2001-2013
    • Mayo Foundation for Medical Education and Research
      • • Department of Neurology
      • • Department of Pharmacology
      Рочестер, Michigan, United States
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2012
    • St George's, University of London
      • Stroke and Dementia Research Centre
      Londinium, England, United Kingdom
  • 2005-2010
    • Mayo Clinic
      Jacksonville, Florida, United States
  • 2004-2010
    • University of Florida
      Gainesville, Florida, United States
    • Coriell Institute for Medical Research
      Camden, New Jersey, United States
  • 2004-2009
    • University of Cincinnati
      • Department of Neurology
      Cincinnati, Ohio, United States
  • 2008
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 2007
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • Icahn School of Medicine at Mount Sinai
      • Department of Neurology
      Manhattan, New York, United States
  • 2004-2007
    • Emory University
      • Department of Neurology
      Atlanta, Georgia, United States
  • 2000-2007
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
  • 1997-2002
    • Indiana University-Purdue University Indianapolis
      • Department of Neurology
      Indianapolis, Indiana, United States