Aplastic or twig-like middle cerebral artery and cardiogenic cerebral embolism mimicking moyamoya disease with RNF213 polymorphism: A case report.

Progressive stenosis and occlusion of the bilateral internal carotid artery terminals and circle of Willis are typical features of Moyamoya disease. However, aplastic or twig-like middle cerebral artery (Ap/T-MCA)-wherein the unilateral main trunk of the middle cerebral artery (MCA) is not depicted, and a plexiform arterial network is formed-is similar to the findings of Moyamoya disease. Here, we describe a 78-year-old man who presented with mild right paralysis and aphasia. Magnetic resonance angiography (MRA) at admission did not show the bilateral MCAs. The findings were similar to those of Moyamoya disease, and his symptoms worsened after hospitalization. Endovascular treatment was performed, and the left MCA was completely recanalized. Later, paroxysmal atrial fibrillation was detected, and we finally determined that left MCA occlusion had occurred due to embolism. The right MCA was completely occluded at its origin, indicating an Ap/T-MCA. Embolic occlusion of the unilateral MCA and contralateral Ap/T-MCA made this case resemble Moyamoya disease in the acute stage. Even when chronic occlusion is suspected on MRA in acute cerebral infarction, endovascular treatment should be considered. Additionally, a heterotypic R4810K polymorphism was later found in the RNF213 gene. To our knowledge, this is the second report of Ap/T-MCA with the RNF213 gene polymorphism; however, their association remains unclear and requires further analyses.

Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial.

Background and Purpose- Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods- The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were ≥4 mm in thickness or had a mobile thrombus present. Results- Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; P<0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; P=0.002), and aortic valvulopathy (10 versus 20 versus 20; P<0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA (P=0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53-2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions- Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

PTPN22 Gene Polymorphisms Are Associated with Susceptibility to Large Artery Atherosclerotic Stroke and Microembolic Signals.

Large artery atherosclerotic stroke (LAAS) is the most common ischemic stroke (IS) subtype, and microemboli may be clinically important for indicating increased risk of IS. The inflammatory process of atherosclerosis is well known, and lymphoid phosphatase (Lyp), which is encoded by the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene, plays an important role in the inflammatory response. Our study was intended to evaluate the relationship between PTPN22 gene and LAAS and microembolic signals (MES). Three loci of the PTPN22 gene (rs2476599, rs1217414, and rs2488457) were analyzed in 364 LAAS patients and 369 control subjects. A genotyping determination was performed using the TaqMan assay. The G allele of rs2488457 might be related to a higher risk for developing LAAS and MES (odds ratio (OR) = 1.456, 95% confidence interval (CI) 1.156-1.833, P = 0.001; OR = 1.652, 95% CI 1.177-2.319, P = 0.004, respectively). In the LAAS group, the prevalence of the GTG haplotype was higher (P < 0.001) and the prevalence of the GCC haplotype was lower (P = 0.001). An interaction analysis of rs2488457 with smoking showed that smokers with the CG/GG genotypes had a higher risk of LAAS, compared to nonsmokers with the rs2488457 CC genotype (OR = 2.492, 95% CI 1.510-4.114, P < 0.001). Our research indicated that the PTPN22 rs2488457 might be related to the occurrence of LAAS and MES in the Han Chinese population. In addition, the rs2488457 polymorphism and the environmental factor of smoking jointly influenced the susceptibility of LAAS.

Variants in matrix metalloproteinase-9 gene are associated with hemorrhagic transformation in acute ischemic stroke patients with atherothrombosis, small artery disease, and cardioembolic stroke.

OBJECTIVE: The potential effect of matrix metalloproteinase-9 (MMP-9) variants and these variants interactions on hemorrhagic transformation (HT) risk after ischemic stroke (IS) remain unclear. The aims of present study were to investigate the associations of six variants in MMP-9 with HT, and these variants interactions whether related to increased HT risk. METHOD: A total of 705 patients with IS who were admitted to the participating hospitals within 48 hr of symptom onset were consecutively enrolled between March 2014 and December 2016. HT was confirmed by brain computed tomography (CT) scan during 14 days from stroke onset. Six variants of MMP-9 gene were measured by mass spectrometry. Interactions of gene variant-gene variant were assessed through generalized multifactor dimensionality reduction method (GMDR). RESULTS: HT occurred in 104 (14.8%) patients. There were no differences in genotypes for the six variants between patients with and without HT using univariate analysis (all p > 0.05). GMDR analysis revealed that there was a synergistic effect of gene variant-gene variant interactions between rs3918242 and rs3787268 in MMP-9 gene. Cox regression analysis showed that high-risk interactions of rs3918242 and rs3787268 were associated with increased risk of HT after adjusting for covariates (hazard ratio: 2.08; 95% confidence interval: 1.34-7.85; p = 0.016). CONCLUSION: Incidence of HT is common in acute IS in Chinese population. The mechanisms leading to HT are most likely multifactorial. Two-loci interactions of rs3918242 and rs3787268 in MMP-9 gene may confer a higher risk for HT.

Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study.

OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

Evidence for Cerebral Embolic Prevention in Transcatheter Aortic Valve Implantation and Thoracic Endovascular Aortic Repair.

BACKGROUND: Embolic stroke is a formidable complication of transcatheter aortic valve implantation (TAVI) and thoracic endovascular aortic repair (TEVAR). Mechanical strategies to reduce the risk of ischemic embolic lesions include embolic protection devices (EPDs) and carbon dioxide flushing (CDF). This study aims to assess the efficacy for EPD and CDF uses in TAVI and TEVAR. METHODS: A literature review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis. All searches were performed via PubMed, OvidSP, MEDLINE, Web of Science Core Collection, and Cochrane Library. Conference abstracts and proceedings were included. Those that were out of scope of interest and review articles were excluded. RESULTS: Eighteen studies fulfilled the inclusion criteria of the 456 articles searched. Regarding EPD use in TAVI, systematic review comparing EPD with no-EPD showed smaller total volume of cerebral lesions and smaller volume per lesion in patients with EPD in all studies. They also performed better in postoperative neurocognitive assessments but could not demonstrate clinical prevention of embolic stroke in all studies. While for EPD use in TEVAR, capture of embolic debris and absence of early postoperative neurocognitive deficit were demonstrated in all cases of 2 prospective pilot studies. Concerning CDF in TEVAR, significant reduction in gaseous emboli released during stent-graft deployment was shown by 1 in vitro study. Successful CDF application in all patients, with only 1 case of postoperative nondisabling stroke, was also demonstrated by 1 cohort study. CONCLUSIONS: This systematic review of medical literature has demonstrated the safety and feasibility of EPD use in TAVI. Although improvements in clinical outcomes have yet been demonstrated, there was level I evidence showing reduced embolic lesions in imaging. The use of EPD and CDF in TEVAR was suggested, but evidence remained inadequate to support routine clinical use.

Implications of Janus Kinase 2 Mutation in Embolic Stroke of Unknown Source.

The role of genetic mutations in cerebral ischemia is not completely understood. Among these genetic variations, Philadelphia-negative gain-of-function mutation in the janus kinase 2 (JAK2) protein leads to overexpression of the genes involved in cell growth and proliferation, and has been linked to development of hematological malignancies, specifically, myeloproliferative neoplasms (MPNs; essential thrombocythemia [ET], polycythemia vera [PV], and primary myelofibrosis). Overt ET and PV are known to induce a prothrombotic state that leads to development of vascular complications, including cerebral arterial or venous thrombosis. Thromboembolism can precede overt presentation of an MPN by 2-3 years. As such, for the selected cases of embolic stroke or cerebrovascular sinus thrombosis with otherwise undetermined source and persistent thrombocytosis or polycythemia, in the absence of a confirmed MPN diagnosis, screening for JAK2 mutation may be reasonable, as early diagnosis and appropriate treatment can influence outcome by preventing recurrent thrombotic events. In this article, we review the literature on the genetics, pathogenesis, clinical manifestations, and treatment of JAK2-associated thrombosis, and present 2 cases of JAK2-associated cerebral arterial infarction and cerebral and systemic venous thromboembolism with otherwise negative etiology workup for stroke.

Rs4612666 Polymorphism of the NLRP3 Gene Is Associated with the Occurrence of Large Artery Atherosclerotic Ischemic Strokes and Microembolic Signals.

PURPOSE: Large artery atherosclerosis (LAA) ischemic stroke (IS) is the most common IS subtype, and microemboli are clinically important for indicating an increased risk of IS. Nucleotide-binding domain-like receptor protein 3 (NLRP3) plays a crucial role in the pathogenesis of atherosclerosis. The aim of this study is to investigate the relationship between NLRP3 gene polymorphisms and susceptibility for LAA IS and microembolic signals (MES) in the Chinese Han population. METHODS: We studied 293 patients diagnosed with LAA IS and 265 controls. Transcranial Doppler (TCD) was used to monitor the MES in all of the patients. Depending on the presence or absence of MES, the patients were divided into MES-positive and MES-negative subgroups. PCR-RFLP or direct sequencing were used to analyze three NLRP3 gene polymorphisms. RESULTS: Seventy-six patients presented with MES and the MES-positive rate was 25.94%. Logistic regression analysis showed that the TT genotype frequency for the rs4612666 gene polymorphism was higher in study patients than in the controls (adjusted P = 0.001) and higher in MES-positive patients compared to MES-negative patients (adjusted P = 0.015). The T allele of rs4612666 was associated with an increased risk for developing LAA IS and MES (P = 0.001; P = 0.015, resp.). Prevalence of the CCC haplotype was higher in the controls than in the patients (P = 0.009) and prevalence of the TGT haplotype was lower in the controls than in the patients (P = 0.019). CONCLUSIONS: The NLRP3 rs4612666 gene polymorphism may be related to the occurrence of LAA IS and MES, suggesting that the NLRP3 gene polymorphism increases the susceptibility of LAA IS by changing the plaque vulnerability.

Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study.

BACKGROUND AND PURPOSE: Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR). METHODS: Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance-weighted MR was used to obtain the causal estimates. Inverse-variance-weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias. RESULTS: A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04-1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10-1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67-0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes. CONCLUSIONS: LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.

The ß-fibrinogen gene 455G/A polymorphism associated with cardioembolic stroke in atrial fibrillation with low CHA2DS2-VaSc score.

Previous work has suggested that ischemic stroke (IS) may be more likely to occur in individuals with a genetic predisposition. In this study, we investigated the potential association of IS-relevant genetic risk factors with cardioembolic stroke (CES) in atrial fibrillation (AF) patients with low CHA2DS2-VaSc score. Genotyping was performed using the GenomeLab SNPstream genotyping platform for five IS-relevant SNPs (MMP-9 C1562T, ALOX5AP SG13S114A/T, MTHFR 677 C/T, FGB 455 G/A, and eNOS G298A) in 479 AF patients with CES and 580 age and sex-matched AF patients without CES. The multivariate analysis adjusted for potential confounders and demonstrated that FGB 455 G/A was independently associated with increased risk of CES in AF patients and the significance remained after Bonferroni correction in the additive, dominant, and recessive models with ORs of 1.548 (95% CI: 1.251-1.915, P = 0.001), 1.588 (95% CI: (1.226-2.057, P = 0.003), and 2.394 (95% CI: 1.357-4.223, P = 0.015), respectively. Plasma fibrinogen levels were significantly higher in patients with the A allele compared with patients with genotype of GG (3.29 ± 0.38 mg/dl vs. 2.87 ± 0.18 mg/dl, P < 0.001). We found for the first time that the A allele of FGB 455 G/A was a risk factor for CES in AF patients, probably by elevating the level of plasma fibrinogen.

Utilidad de la tomografía computarizada como herramienta para detectar potenciales donantes en muerte encefálica / Computed tomography as a tool to detect potential brain-dead donors

Fundamento y objetivo: Evaluar la capacidad de cribado de la tomografía computarizada (TC) de cráneo urgente para detectar a los pacientes que pueden evolucionar a muerte encefálica (ME). Pacientes y método: Se incluyeron los pacientes a los que se realiza TC de cráneo urgente y que cumplían los siguientes criterios: desplazamiento de línea media mayor de 5 mm y/o disminución o ausencia de las cisternas de la base. Estos pacientes fueron sometidos a seguimiento durante 28 días. Se recogieron los datos epidemiológicos (sexo, edad, causa de la lesión encefálica), clínicos (nivel de consciencia, índices de gravedad tomográficos) y la evolución de los pacientes: fallecimiento, ME, alta o traslado. Resultados: Se seleccionaron para su seguimiento 166 estudios, siendo la media (DE) de edad de 60,08 (21,8) años. El 49,4% fueron varones. Del total de casos estudiados, fallecieron por ME el 20,5% (n = 34). En el análisis univariado, la hemorragia cerebral, la puntuación inferior a 8 de la Glasgow Coma Scale y la alteración de las cisternas de la base resultaron ser estadísticamente significativas para predecir ME (p < 0,05). Mediante análisis multivariante observamos que la compresión de cisternas de la base suponía 20 (intervalo de confianza del 95% [IC 95%] 2,61-153,78; p = 0,004) veces más posibilidades de evolucionar a ME, mientras que la ausencia de las mismas, hasta 62,6 (IC 95% 13,1-738,8; p < 0,001) veces más. Conclusiones: Nuestro trabajo demuestra que un dato tan sencillo de interpretar como la compresión/ausencia de las cisternas de la base puede ser una potente herramienta para el cribado de pacientes en riesgo de evolucionar a ME (AU)

Background and objective:To assess the ability of urgent head computed tomography (CT) scan screening to detect patients who can evolve to brain death (BD). Patients and method: Patients who underwent urgent head CT scan and meet the following criteria: midline shift greater than 5 mm and/or decrease or absence of basal cisterns. A follow-up for 28 days of each patient was made. Epidemiological data (sex, age, cause of brain injury), clinical data (level of consciousness, severity index in the CT) and patient outcomes (death, BD, discharge or transfer) were recorded. This was a prospective observational study. Results: One hundred and sixty-six patients were selected for study, with mean age 60.08 (SD 21.8) years. A percentage of 49.4 were men and the rest women. In the follow-up, 20,5% (n = 34) had BD. In univariate analysis, intracerebral hemorrhage, Glasgow Coma Scale score less than 8 and alteration of basal cisterns were statistically significant in predicting BD (P < .05). Multivariate analysis showed that patients with compression of basal cisterns were 20 (95% confidence interval [95% CI] 2.61 to 153.78; P = .004] times more likely to progress to brain death, while the absence there of 62.6 (95% CI 13.1 to 738.8; P < .001] times more. Conclusions: Our work shows that data as easy to interpret as compression/absence of basal cisterns can be a powerful tool for screening patients at risk for progression to BD (AU)

Microemboli alter the acute stress response and cause prolonged expression of MCP-1 in the hippocampus.

Microvascular ischemia is linked to cardiovascular disease pathology, as well as alterations in mood and cognition. Ischemia activates the hypothalamic-pituitary-adrenal (HPA) axis and through chronic activation, alters HPA axis function. Dysregulation of the HPA axis can lead to the chronic release of glucocorticoids, a hyper-inflammatory cerebral response, cell damage, and changes in behavior. Although the interactions between injury and HPA axis activity have been established in global ischemia, HPA-related repercussions of diffuse ischemic damage and subsequent inflammation have not been assessed. The current study used a rat model of microsphere embolism (ME) ischemia to test the hypothesis that microvascular ischemia would lead to long term alterations in HPA axis function and inflammatory activity. Furthermore, given the pro-inflammatory nature of chronic stress, we assessed the implications of chronic stress for gene expression of inflammatory factors and key components of the glucocorticoid receptor response, following microvascular ischemia. Results indicated that ME altered the response to an acute stress fourteen days following ME injury and increased hippocampal expression of monocyte chemoattractant protein 1 (Mcp-1) as long as 4 weeks following ME injury, without concomitant effects on gene expression of the glucocorticoid receptor or its co-chaperones. Furthermore, no exacerbative effects of chronic stress exposure were observed following ME injury beyond the effects of ME injury alone. Together, these results indicate that ME injury is sufficient to alter both HPA axis activity and cerebral inflammation for a prolonged period of time following injury.

Gene expression in peripheral immune cells following cardioembolic stroke is sexually dimorphic.

AIMS: Epidemiological studies suggest that sex has a role in the pathogenesis of cardioembolic stroke. Since stroke is a vascular disease, identifying sexually dimorphic gene expression changes in blood leukocytes can inform on sex-specific risk factors, response and outcome biology. We aimed to examine the sexually dimorphic immune response following cardioembolic stroke by studying the differential gene expression in peripheral white blood cells. METHODS AND RESULTS: Blood samples from patients with cardioembolic stroke were obtained at ≤3 hours (prior to treatment), 5 hours and 24 hours (after treatment) after stroke onset (n = 23; 69 samples) and compared with vascular risk factor controls without symptomatic vascular diseases (n = 23, 23 samples) (ANCOVA, false discovery rate p≤0.05, |fold change| ≥1.2). mRNA levels were measured on whole-genome Affymetrix microarrays. There were more up-regulated than down-regulated genes in both sexes, and females had more differentially expressed genes than males following cardioembolic stroke. Female gene expression was associated with cell death and survival, cell-cell signaling and inflammation. Male gene expression was associated with cellular assembly, organization and compromise. Immune response pathways were over represented at ≤3, 5 and 24 h after stroke in female subjects but only at 24 h in males. Neutrophil-specific genes were differentially expressed at 3, 5 and 24 h in females but only at 5 h and 24 h in males. CONCLUSIONS: There are sexually dimorphic immune cell expression profiles following cardioembolic stroke. Future studies are needed to confirm the findings using qRT-PCR in an independent cohort, to determine how they relate to risk and outcome, and to compare to other causes of ischemic stroke.

Association of GGCX gene polymorphism with warfarin dose in atrial fibrillation population in Xinjiang.

OBJECTIVE: To study the effects of γ-glutamyl carboxylase (GGCX) rs2592551 polymorphism on warfarin dose in atrial fibrillation patients in Xinjiang region. METHODS: Polymerase chain reaction - restriction fragment length polymorphism and direct sequencing methods were used to detect the rs2592551 genotype in 269 atrial fibrillation patients with warfarin administration. The effects of different genotypes on warfarin dose were statistically analyzed. RESULTS: The rs2592551 polymorphism detection results were 136 cases of wild-type homozygous CC genotype (50.56%), 115 cases of heterozygous CT genotype (42.75%), 18 cases of homozygous TT genotype (6.69%). The allele frequency C was 71.93%, T was 28.07%. The stable warfarin dose average was 2.86 ± 0.61 mg/d in patients with CC genotype, 3.59 ± 0.93 mg/d in patients with CT genotype and 4.06 ± 0.88 mg/d in patients with TT genotype. The warfarin dose in different genotypes were compared, there was statistically significant difference between CC and TT, CC and CT (P <0. 05), but the TT and CT showed no significant difference (P > 0.05). CONCLUSION: In atrial fibrillation population in Xinjiang, patients with CT and TT genotypes in GGCX gene rs259251 loci required for significantly higher warfarin dose than those with CC genotype. Therefore, rs2592551 polymorphism may one of the factors affecting the warfarin dose in patients with atrial fibrillation.

Cardioembolic stroke related to limb-girdle muscular dystrophy 1B.

BACKGROUND: Cardioembolic stroke is an under-recognized complication in patients with limb-girdle muscular dystrophy 1B. Here we present a young stroke patient who had a novel lamin A/C gene (LMNA) mutation. CASE PRESENTATION: This is a 39-year-old man who had slowly progressive proximal muscle weakness and cardiac arrhythmia since adolescent and a family history of similar manifestation. He sustained acute ischemic stroke in the left middle cerebral artery territory. Intravenous recombinant tissue plasminogen activator therapy was given with significant neurological improvement. Additionally, genetic sequencing of the LMNA gene of the patient identified a mutation in c.513+1 G>A that resulted in a splicing aberration. CONCLUSION: We suggested that LMNA gene related myopathies should be considered in young stroke patients with long-standing myopathic features.

Correlations between clinical variables and gene-expression profiles in carotid plaque instability.

OBJECTIVE: Strokes, a major cause of disability, are often caused by embolism from unstable carotid plaques. The aim of this study was to validate a biobank of human carotid endarterectomies as a platform for further exploration of pathways for plaque instability. For this purpose, we investigated the relationship between clinical parameters of plaque instability and expression of genes previously shown to be associated with either plaque instability or healing processes in the vessel wall. METHODS: A database of clinical information and gene-expression microarray data from 106 carotid endarterectomies were used. RESULTS: Expression of matrix metalloproteinase (MMP)-9 and MMP-7 was 100-fold higher in plaques than in normal artery. In general, genes associated with inflammation (such as RANKL and CD68) were overexpressed in symptomatic compared with asymptomatic plaques. Plaques obtained from patients undergoing surgery within 2 weeks after an embolic event showed up-regulation of genes involved in healing reactions in the vessel wall (including elastin and collagen). Statin treatment, as well as echodense lesions, were associated with a more stable phenotype. CONCLUSION: Here, we demonstrate that gene-expression profiles reflect clinical parameters. Our results suggest that microarray technology and clinical variables can be used for the future identification of central molecular pathways in plaque instability.

Profiles of lacunar and nonlacunar stroke.

OBJECTIVE: Determining which small deep infarcts (SDIs) are of lacunar, arterial, or cardioembolic etiology is challenging, but important in delivering optimal stroke prevention therapy. We sought to distinguish lacunar from nonlacunar causes of SDIs using a gene expression profile. METHODS: A total of 184 ischemic strokes were analyzed. Lacunar stroke was defined as a lacunar syndrome with infarction <15mm in a region supplied by penetrating arteries. RNA from blood was processed on whole genome microarrays. Genes differentially expressed between lacunar (n = 30) and nonlacunar strokes (n = 86) were identified (false discovery rate ≤ 0.05, fold change >|1.5|) and used to develop a prediction model. The model was evaluated by cross-validation and in a second test cohort (n = 36). The etiology of SDIs of unclear cause (SDIs ≥ 15mm or SDIs with potential embolic source) (n = 32) was predicted using the derived model. RESULTS: A 41-gene profile discriminated lacunar from nonlacunar stroke with >90% sensitivity and specificity. Of the 32 SDIs of unclear cause, 15 were predicted to be lacunar, and 17 were predicted to be nonlacunar. The identified profile represents differences in immune response between lacunar and nonlacunar stroke. INTERPRETATION: Profiles of differentially expressed genes can distinguish lacunar from nonlacunar stroke. SDIs of unclear cause were frequently predicted to be of nonlacunar etiology, suggesting that comprehensive workup of SDIs is important to identify potential cardioembolic and arterial causes. Further study is required to evaluate the gene profile in an independent cohort and determine the clinical and treatment implications of SDIs of predicted nonlacunar etiology.

Common genetic coagulation variants are not associated with ischemic stroke in a case-control study.

OBJECTIVE: Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke patients, especially in young adults with cryptogenic stroke. METHODS: Three common genetic variants within the coagulation cascade were investigated in 500 control subjects and in 167 patients with ischemic stroke defined by TOAST subclassification. Analysed variants were factor V Leiden, prothrombin 20210G-->A and factor XIII Val34Leu. RESULTS: The factor V Leiden mutation was over-represented in patients with cardioembolic stroke for trend, whereas the prothrombin 20210G-->A variant and the factor XIII polymorphism Val34Leu were not associated with stroke of any subtype. The three polymorphisms showed no association with stroke in subgroups of patients defined by age (<40, 40-49, 50-59, > or =60 years). DISCUSSION: This study suggests that the analysis of prothrombin 20210G-->A and factor XIII Val34Leu is not a useful diagnostic procedure in the work-up of ischemic stroke.

MTAP gene is associated with ischemic stroke in Chinese Hans.

Common pathogenic mechanisms may be involved in the prevalence of ischemic stroke and coronary heart disease. Recently, genome-wide association (GWA) studies identified a chromosome region (9p21) that confers the risk of coronary heart disease. In a hospital-based case-control study conducted in Chinese Hans, we tested the hypothesis that the methylthioadenosine phosphorylase (MTAP) gene on chromosome region 9p21 is involved in the aetiology of ischemic stroke using a tagging single nucleotide polymorphism (tSNP) strategy. We observed significant association of rs10118757 in the MTAP gene with ischemic stroke. The G allele of rs10118757 was associated with an increased risk of stroke, with a per-allele OR of 1.31(95% CI, 1.04-1.65, p=0.025). The association remains after controlling for confounding factors including age, gender, body mass index, smoking, alcohol drinking, hypertension, diabetes, and hyperlipidaemia (OR=1.38, 95 CI, 1.02-1.88, p=0.039). In addition, the GA+GG genotype of rs10118757 was associated with the increased risk of an undetermined subtype of ischemic stroke (OR=2.14, 95 CI, 1.35-3.38, p=0.001). Further, we also observed the combined effects of rs10118757 with alcohol drinking and hypertension, which increased the risk of ischemic stroke. Our observations support the hypothesis that the MTAP gene may be involved in the prevalence of ischemic stroke in Chinese Hans.