RESUMO
BACKGROUND: The cardiac-brain connection has been identified as the basis for multiple cardio-cerebral diseases. However, effective therapeutic targets for these diseases are still limited. Therefore, this study aimed to identify pleiotropic and specific therapeutic targets for cardio-cerebral diseases using Mendelian randomization (MR) and colocalization analyses. METHODS: This study included two large protein quantitative trait loci studies with over 4,000 plasma proteins were included in the discovery and replication cohorts, respectively. We initially used MR to estimate the associations between protein and 20 cardio-cerebral diseases. Subsequently, Colocalization analysis was employed to enhance the credibility of the results. Protein target prioritization was based solely on including highly robust significant results from both the discovery and replication phases. Lastly, the Drug-Gene Interaction Database was utilized to investigate protein-gene-drug interactions further. RESULTS: A total of 46 target proteins for cardio-cerebral diseases were identified as robust in the discovery and replication phases by MR, comprising 7 pleiotropic therapeutic proteins and 39 specific target proteins. Followed by colocalization analysis and prioritization of evidence grades for target protein, 6 of these protein-disease pairs have achieved the highly recommended level. For instance, the PILRA protein presents a pleiotropic effect on sick sinus syndrome and Alzheimer's disease, whereas GRN exerts specific effects on the latter. APOL3, LRP4, and F11, on the other hand, have specific effects on cardiomyopathy and ischemic stroke, respectively. CONCLUSIONS: This study successfully identified important therapeutic targets for cardio-cerebral diseases, which benefits the development of preventive or therapeutic drugs.
Assuntos
Análise da Randomização Mendeliana , Proteoma , Locos de Características Quantitativas , Humanos , Proteoma/metabolismo , Pleiotropia Genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Estudo de Associação Genômica Ampla , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/tratamento farmacológicoRESUMO
FMR1 premutation carriers (55-200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. In the general population, enlarged perivascular spaces (PVS) are biomarkers of small vessel disease and glymphatic dysfunction and are associated with cognitive decline. Our aim was to determine if premutation carriers show higher ratings of PVS than controls and whether enlarged PVS are associated with motor and cognitive impairment, MRI features of neurodegeneration, cerebrovascular risk factors and CGG repeat length. We evaluated 655 MRIs (1-10 visits/participant) from 229 carriers (164 with FXTAS and 65 without FXTAS) and 133 controls. PVS in the basal ganglia (BG-EPVS), centrum semiovale, and midbrain were evaluated with a semiquantitative scale. Mixed-effects models were used for statistical analysis adjusting for age. In carriers with FXTAS, we revealed that (1) BG-PVS ratings were higher than those of controls and carriers without FXTAS; (2) BG-PVS severity was associated with brain atrophy, white matter hyperintensities, enlarged ventricles, FXTAS stage and abnormal gait; (3) age-related increase in BG-PVS was associated with cognitive dysfunction; and (4) PVS ratings of all three regions showed robust associations with CGG repeat length and were higher in carriers with the MCP sign than carriers without the sign. This study demonstrates clinical relevance of PVS in FXTAS especially in the basal ganglia region and suggests microangiopathy and dysfunctional cerebrospinal fluid circulation in FXTAS physiopathology.
Assuntos
Ataxia , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Sistema Glinfático , Imageamento por Ressonância Magnética , Tremor , Humanos , Masculino , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Síndrome do Cromossomo X Frágil/patologia , Pessoa de Meia-Idade , Idoso , Proteína do X Frágil da Deficiência Intelectual/genética , Tremor/genética , Tremor/diagnóstico por imagem , Tremor/patologia , Ataxia/genética , Ataxia/diagnóstico por imagem , Ataxia/patologia , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/patologia , Fatores de Risco , Heterozigoto , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/etiologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Cardiovascular and cerebrovascular diseases are the leading causes of death worldwide and interact closely with each other. Danhong Injection (DHI) is a widely used preparation for the co-treatment of brain and heart diseases (CTBH). However, the underlying molecular endotype mechanisms of DHI in the CTBH remain unclear. AIM OF THIS STUDY: To elucidate the underlying endotype mechanisms of DHI in the CTBH. MATERIALS AND METHODS: In this study, we proposed a modular-based disease and drug-integrated analysis (MDDIA) strategy for elucidating the systematic CTBH mechanisms of DHI using high-throughput transcriptome-wide sequencing datasets of DHI in the treatment of patients with stable angina pectoris (SAP) and cerebral infarction (CI). First, we identified drug-targeted modules of DHI and disease modules of SAP and CI based on the gene co-expression networks of DHI therapy and the protein-protein interaction networks of diseases. Moreover, module proximity-based topological analyses were applied to screen CTBH co-module pairs and driver genes of DHI. At the same time, the representative driver genes were validated via in vitro experiments on hypoxia/reoxygenation-related cardiomyocytes and neuronal cell lines of H9C2 and HT22. RESULTS: Seven drug-targeted modules of DHI and three disease modules of SAP and CI were identified by co-expression networks. Five modes of modular relationships between the drug and disease modules were distinguished by module proximity-based topological analyses. Moreover, 13 targeted module pairs and 17 driver genes associated with DHI in the CTBH were also screened. Finally, the representative driver genes AKT1, EDN1, and RHO were validated by in vitro experiments. CONCLUSIONS: This study, based on clinical sequencing data and modular topological analyses, integrated diseases and drug targets. The CTBH mechanism of DHI may involve the altered expression of certain driver genes (SRC, STAT3, EDN1, CYP1A1, RHO, RELA) through various enriched pathways, including the Wnt signaling pathway.
Assuntos
Medicamentos de Ervas Chinesas , Mapas de Interação de Proteínas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Animais , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/genética , Redes Reguladoras de Genes/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Transcriptoma/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , InjeçõesRESUMO
Background: Mounting evidence has demonstrated the associations between gut microbiota, gut microbiota-derived metabolites, and cerebrovascular diseases (CVDs). The major categories of CVD are ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). However, the causal relationship is still unclear. Methods: A two-sample Mendelian randomization (MR) study was conducted leveraging the summary data from genome-wide association studies. The inverse variance-weighted, maximum likelihood, weighted median, and MR.RAPS methods were performed to detect the causal relationship. Several sensitivity analyses were carried out to evaluate potential horizontal pleiotropy and heterogeneity. Finally, reverse MR analysis was conducted to examine the likelihood of reverse causality, and multivariable MR was performed to adjust the potential confounders. Results: We collected 1,505 host single nucleotide polymorphisms (SNPs) linked to 119 gut microbiota traits and 1,873 host SNPs associated with 81 gut metabolite traits as exposure data. Among these, three gut bacteria indicated an elevated risk of IS, two of ICH, and one of SAH. In contrast, five gut bacteria were associated with a reduced risk of IS, one with ICH, and one with SAH. Our study also demonstrated the potential causal associations between 11 gut microbiota-derived metabolites and CVD. Conclusions: This study provided evidence of the causal relationship between gut microbiota, gut microbiota-derived metabolites, and CVD, thereby offering novel perspectives on gut biomarkers and targeted prevention and treatment for CVD.
Assuntos
Transtornos Cerebrovasculares , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos Cerebrovasculares/genética , CausalidadeRESUMO
BACKGROUND: Despite an increase in the number of genes associated with pediatric stroke, imaging phenotypes in children have not been well reported. Guidelines are needed to facilitate the identification and treatment of patients with monogenic causes of cerebrovascular disorders. METHODS: We performed a retrospective review of imaging and medical records of patients aged zero to 21 years with monogenic causes of vascular malformations, small or large vessel disease, transient ischemic attacks, and/or ischemic or hemorrhagic stroke. We classified patients according to their imaging phenotype and reviewed neurological and systemic features and management strategies. We reviewed the literature to identify genes associated with cerebrovascular disorders presenting in childhood. RESULTS: We identified 18 patients with monogenic causes of cerebrovascular disorders and classified each patient as belonging to one or more of three cerebrovascular phenotypes according to predominant imaging characteristics: small vessel disease, large vessel disease, and/or vascular malformations. Preventative treatments included aspirin, N-acetylcysteine, tocilizumab, therapeutic low-molecular-weight heparin, and resection of vascular malformations. CONCLUSIONS: Classifying pediatric patients with cerebrovascular disorders by imaging phenotype can aid in determining the next steps in genetic testing and treatment.
Assuntos
Transtornos Cerebrovasculares , Ataque Isquêmico Transitório , Acidente Vascular Cerebral , Malformações Vasculares , Humanos , Criança , Idoso , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/terapia , AcetilcisteínaRESUMO
Cardiovascular and cerebrovascular diseases are the leading causes of the mortality of humans in the 21st century [...].
Assuntos
Sistema Cardiovascular , Transtornos Cerebrovasculares , Doenças Metabólicas , Humanos , Transtornos Cerebrovasculares/genética , Genômica , Doenças Metabólicas/genética , Biologia MolecularRESUMO
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an extremely rare hereditary cerebral small vessel disease caused by homozygous or compound heterozygous mutations in the gene coding for high-temperature requirement A serine peptidase 1 (HtrA1). Given the rare nature of the disease, delays in diagnosis and misdiagnosis are not uncommon. In this article, we reported the first case of CARASIL from Saudi Arabia with a novel homozygous variant c.1156C>T in exon 7 of the HTRA1 gene. The patient was initially misdiagnosed with primary progressive multiple sclerosis and treated with rituximab. CARASIL should be considered in the differential diagnosis of patients with suspected atypical progressive multiple sclerosis who have additional signs such as premature scalp alopecia and low back pain with diffuse white matter lesions in brain MRI. Genetic testing is important to confirm the diagnosis.
Assuntos
Doenças Arteriais Cerebrais , Transtornos Cerebrovasculares , Leucoencefalopatias , Esclerose Múltipla , Humanos , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/genética , Infarto Cerebral/patologia , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Transtornos Cerebrovasculares/genética , Alopecia/diagnóstico , Alopecia/genética , Mutação , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genéticaRESUMO
BACKGROUND: It is still not clear that whether the expression levels of matrix metalloproteinases (MMPs) family are associated with cardiovascular and cerebrovascular diseases (CCDs) in genetic level. We explored the causal role of 12 members of MMPs in CCDs with mendelian randomization (MR) method to facilitate further exploring the underlying mechanisms. METHODS: The relationship between MMPs and CCDs including intracerebral hemorrhage (ICH), hypertension, coronary heart disease (CHD), atrial fibrillation (AF), and outstanding risk factors of type II diabetes were determined with the inverse variance-weighted (IVW) method. The sensitivity analyses including MR-Egger regression, weighted median estimation, and MR pleiotropy residual sum and outlier were utilized to test the robustness of the results generated from the MR method. RESULTS: We found that a higher serum level of MMP-12 was related to a lower risk of ICH (OR = 0.8287, 95% CI: 0.7526-0.9125, p = 0.00013), but not hypertension, CHD, type II diabetes or AF. And our study also revealed that a higher serum level of MMP-8 could result in a lower risk of hypertension (OR = 0.9976, 95% CI: 0.9964-0.9988, p = 0.00012) and AF (OR = 0.9851, 95% CI: 0.9741-0.9963, p = 0.0092), but not ICH, CHD or type II diabetes. All other members of MMPs other than MMP-8 and MMP-12 showed no statistical association with CCDs according to this study. Sensitivity analyses confirmed the reliability of our results. CONCLUSIONS: We provided statistical evidences for a potential causal relationship between MMP-12 and ICH, as well as MMP-8 and hypertension, while other MMPs showed weaker association with CCDs. The underlying mechanisms need to be established in the future.
Assuntos
Fibrilação Atrial , Doenças Cardiovasculares , Transtornos Cerebrovasculares , Diabetes Mellitus Tipo 2 , Hipertensão , Humanos , Diabetes Mellitus Tipo 2/genética , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 8 da Matriz , Análise da Randomização Mendeliana , Reprodutibilidade dos Testes , Doenças Cardiovasculares/genética , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/genética , Hipertensão/genética , Estudo de Associação Genômica AmplaRESUMO
Objective: To comprehensively evaluate the characteristics of the circulating microRNA expression profile in type 2 diabetic patients with acute ischemic cerebrovascular disease by systematic evaluation and meta-analysis. Methods: The literatures up to March 2022 related to circulating microRNA and acute ischemic cerebrovascular disease in type 2 diabetes mellitus were searched and screened from multiple databases. The NOS quality assessment scale was used to evaluate methodological quality. Heterogeneity tests and statistical analyses of all data were performed by Stata 16.0. The differences in microRNA levels between groups were illustrated by the standardized mean difference (SMD) and 95% confidence interval (95% CI). Results: A total of 49 studies on 12 circulating miRNAs were included in this study, including 486 cases of type 2 diabetes complicated with acute ischemic cerebrovascular disease and 855 controls. Compared with the control group (T2DM group), miR-200a, miR-144, and miR-503 were upregulated and positively correlated with acute ischemic cerebrovascular disease in type 2 diabetes mellitus patients. Their comprehensive SMD and 95% CI were 2.71 (1.64~3.77), 5.77 (4.28~7.26) and 0.73 (0.27~1.19), respectively. MiR-126 was downregulated and negatively correlated with acute ischemic cerebrovascular disease in type 2 diabetes mellitus patients, its comprehensive SMD and 95% CI were -3.64 (-5.56~-1.72). Conclusion: In type 2 diabetes mellitus patients with acute ischemic cerebrovascular disease, the expression of serum miR-200a, miR-503, plasma and platelet miR-144 was upregulated and the expression of serum miR-126 was downregulated. It may have diagnostic value in the early identification of type 2 diabetes mellitus with acute ischemic cerebrovascular disease.
Assuntos
Transtornos Cerebrovasculares , MicroRNA Circulante , Diabetes Mellitus Tipo 2 , MicroRNAs , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , MicroRNAs/genética , Plaquetas , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/genéticaRESUMO
OBJECTIVE: Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene. Cardinal clinical manifestations are pre- and postnatal growth retardation and craniofacial and limb malformations. Here, we report RBS in a Chinese adolescent with novel biallelic ESCO2 variations and complex cerebrovascular diseases. METHODS: Medical history, neurological examinations, neuroimaging, and pathology were collected in the proband and the family. Whole exome sequencing (WES) with copy number variation analysis was performed to screen for genetic variations. RESULTS: The clinical features of the proband were craniofacial and limb malformations together with complex cerebrovascular diseases. She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old. Besides, neuroimaging showed the triad of leukoencephalopathy, calcifications, and cysts. Brain histopathology revealed angiomatous changes and perivascular cysts suggesting chronic small cerebral vasculopathy. Whole exome sequencing (WES) identified novel biallelic variations in the ESCO2 gene (c.1220A>T, p.H407L and c.1562delC, p.A521fs). CONCLUSIONS: We describe complex cerebrovascular diseases in Roberts syndrome caused by novel ESCO2 biallelic variations. This case expands not only the cerebral involvement in Roberts syndrome but also the disease spectrum of the neuroimaging triad with leukoencephalopathy, calcifications, and cysts.
Assuntos
Acetiltransferases , Transtornos Cerebrovasculares , Proteínas Cromossômicas não Histona , Anormalidades Craniofaciais , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/genética , Humanos , Feminino , Adolescente , Acetiltransferases/genética , Proteínas Cromossômicas não Histona/genética , População do Leste Asiático , Transtornos Cerebrovasculares/genéticaRESUMO
OBJECTIVES: To utilize the UK Biobank to identify genetic variants associated with the ICD10 (International Classification of Diseases10)-based diagnosis of cerebrovascular disease (CeVD). BACKGROUND: Cerebrovascular disease occurs because of a complex interplay between vascular, environmental, and genetic factors. It is the second leading cause of disability worldwide. Understanding who may be genetically predisposed to cerebrovascular disease can help guide preventative efforts. Moreover, there is considerable interest in the use of real-world data, such as EHR (electronic health records) to better understand disease mechanisms and to discover new treatment strategies, but whether ICD10-based diagnosis can be used to study CeVD genetics is unknown. METHODS: Using the UK Biobank, we conducted a genome-wide association study (GWAS) where we analyzed the genomes of 11,155 cases and 122,705 controls who were sex, age and ancestry-matched in a 1:11 case: control design. Genetic variants were identified by Plink's firth logistic regression and assessed for association with the ICD10 codes corresponding to CeVD. RESULTS: We identified two groups of SNPs closely linked to PITX2 and LRRTM4 that were significantly associated with CeVD in this study (p < 5 x 10-8) and had a minor allele frequency of > 0.5%. DISCUSSION: Disease assignment based on ICD10 codes may underestimate prevalence; however, for CeVD, this does not appear to be the case. Compared to the age- and sex-matched control population, individuals with CeVD were more frequently diagnosed with comorbid conditions, such as hypertension, hyperlipidemia & atrial fibrillation or flutter, confirming their contribution to CeVD. The UK Biobank based ICD10 study identified 2 groups of variants that were associated with CeVD. The association between PITX2 and CeVD is likely explained by the increased rates of atrial fibrillation and flutter. While the mechanism explaining the relationship between LRRTM4 and CeVD is unclear, this has been documented in previous studies.
Assuntos
Fibrilação Atrial , Transtornos Cerebrovasculares , Fibrilação Atrial/complicações , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Cerebrovascular disease involves a range of conditions including ischemic and hemorrhagic stroke, vascular malformations, and vascular cognitive impairment and dementia (VCID) [...].
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Transtornos Cerebrovasculares , Disfunção Cognitiva , Demência Vascular , Transtornos Cerebrovasculares/genética , Disfunção Cognitiva/etiologia , Demência Vascular/etiologia , HumanosRESUMO
Noncoding RNAs (ncRNAs), such as microRNAs, long noncoding RNAs, and circular RNAs, play an important role in the pathophysiology of cerebrovascular diseases (CVDs). They are effectively detectable in body fluids, potentially suggesting new biomarkers for the early detection and prognosis of CVDs. In this review, the physiological functions of circulating ncRNAs and their potential role as diagnostic and prognostic markers in patients with cerebrovascular diseases are discussed, especially in acute ischemic stroke, subarachnoid hemorrhage, and moyamoya disease.
Assuntos
Transtornos Cerebrovasculares , AVC Isquêmico , Biomarcadores , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/genética , Humanos , Prognóstico , RNA não Traduzido/genéticaRESUMO
Long non-coding RNAs (lncRNAs) regulate neurological damage in cerebral ischemia-reperfusion injury (CIRI). This study aimed to investigate the biological roles of lncRNA CEBPA-AS1 in CIRI. Middle cerebral artery occlusion and ischemia-reperfusion injury (MCAO/IR) rat model and oxygen-glucose deprivation and reoxygenation (OGD/R) cell lines were generated; the expression of CEBPA-AS1 was evaluated by qRT-PCR. The effects of CEBPA-AS1 on cell apoptosis and nerve damage were examined. The downstream microRNA (miRNA) and mRNA of CEBPA-AS1 were predicted and verified. We found that overexpression of CEBPA-AS1 could attenuate MCAO/IR-induced nerve damage and neuronal apoptosis in the rat model. Knockdown of CEBPA-AS1 aggravated cell apoptosis and enhanced the production of LDH and MDA in the OGD/R cells. Upon examining the molecular mechanisms, we found that CEBPA-AS1 stimulated APPL1 expression by combining with miR-340-5p, thereby regulating the APPL1/LKB1/AMPK pathway. In the rescue experiments, CEBPA-AS1 overexpression was found to attenuate OGD/R-induced cell apoptosis and MCAO/IR induced nerve damage, while miR-340-5p reversed these effects of CEBPA-AS1. In conclusion, CEBPA-AS1 could decrease CIRI by sponging miR-340-5, regulating the APPL1/LKB1/AMPK pathway.
Assuntos
Quinases Proteína-Quinases Ativadas por AMP/biossíntese , Proteínas Quinases Ativadas por AMP/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Transtornos Cerebrovasculares/metabolismo , MicroRNAs/biossíntese , Proteínas do Tecido Nervoso/biossíntese , RNA Longo não Codificante/biossíntese , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Quinases Proteína-Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , MicroRNAs/genética , Proteínas do Tecido Nervoso/genética , RNA Longo não Codificante/genética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologiaRESUMO
BACKGROUND AND PURPOSE: The age, body mass index, chronic kidney disease, diabetes, and genotyping (ABCD-GENE) score is a validated risk score integrating CYP2C19 genotypes with clinical risk factors influencing clopidogrel response that would allow the more precise identification of subjects at risk for high platelet reactivity and adverse clinical outcomes. Our objective was to further verify application of the ABCD-GENE score and investigate appropriate cutoff value in patients with minor stroke or transient ischemic attack. METHODS: In this post-analysis of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), the ABCD-GENE score was calculated for all patients enrolled in this study. By using the proposed cutoff of 10, patients were stratified as being at high risk for high platelet reactivity or not. We further categorized the ABCD-GENE score to 0 to 5, 6 to 24, and >24 to investigate the cutoff value of this scale in clinical application. Stroke recurrence at 3 months was considered as the primary outcome. RESULTS: Among a total of 2923 patients with minor stroke/transient ischemic attack, there were 2273 (77.76%) with ABCD-GENE score <10 and 650 (22.24%) patients with ABCD-GENE score ≥10. Compared with the aspirin alone, hazard ratios (95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 0.70 (0.54-0.91) and 0.76 (0.46-1.24), among patients of ABCD-GENE scores <10 and ABCD-GENE scores ≥10, respectively. Stratified analyses by ABCD-GENE score 0 to 5, 6 to 24, and >24, hazard ratios of the clopidogrel-aspirin therapy for stroke recurrence were 0.57 (95% CI, 0.38-0.85), 0.78 (0.58-1.06), and 1.20 (0.44-3.28) (P value for trend=0.0052). CONCLUSIONS: Among Chinese minor stroke/transient ischemic attack population, the efficacy of clopidogrel-aspirin therapy was decreased in patients with higher ABCD-GENE score. Our study suggests that CYP2C19 genotypes and clinical risk factors can be integrated by ABCD-GENE score to estimate the efficacy of clopidogrel-aspirin therapy.
Assuntos
Transtornos Cerebrovasculares/tratamento farmacológico , Clopidogrel/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Fatores Etários , Idoso , Aspirina/uso terapêutico , Índice de Massa Corporal , Transtornos Cerebrovasculares/genética , Citocromo P-450 CYP2C19/genética , Diabetes Mellitus , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Ataque Isquêmico Transitório/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva , Insuficiência Renal Crônica/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do TratamentoRESUMO
Serum biomarkers are associated with hemorrhagic transformation and brain edema after cerebral infarction. However, whether serum biomarkers predict hemorrhagic transformation in large vessel occlusion stroke even after mechanical thrombectomy, which has become widely used, remains uncertain. In this prospective study, we enrolled patients with large vessel occlusion stroke in the anterior circulation. We analyzed 91 patients with serum samples obtained on admission. The levels of matrix metalloproteinase-9 (MMP-9), amyloid precursor protein (APP) 770, endothelin-1, S100B, and claudin-5 were measured. We examined the association between serum biomarkers and hemorrhagic transformation within one week. Fifty-four patients underwent mechanical thrombectomy, and 17 patients developed relevant hemorrhagic transformation (rHT, defined as hemorrhagic changes ≥ hemorrhagic infarction type 2). Neither MMP-9 (no rHT: 46 ± 48 vs. rHT: 15 ± 4 ng/mL, P = 0.30), APP770 (80 ± 31 vs. 85 ± 8 ng/mL, P = 0.53), endothelin-1 (7.0 ± 25.7 vs. 2.0 ± 2.1 pg/mL, P = 0.42), S100B (13 ± 42 vs. 12 ± 15 pg/mL, P = 0.97), nor claudin-5 (1.7 ± 2.3 vs. 1.9 ± 1.5 ng/mL, P = 0.68) levels on admission were associated with subsequent rHT. When limited to patients who underwent mechanical thrombectomy, the level of claudin-5 was higher in patients with rHT than in those without (1.2 ± 1.0 vs. 2.1 ± 1.7 ng/mL, P = 0.0181). APP770 levels were marginally higher in patients with a midline shift ≥ 5 mm than in those without (79 ± 29 vs. 97 ± 41 ng/mL, P = 0.084). The predictive role of serum biomarkers has to be reexamined in the mechanical thrombectomy era because some previously reported serum biomarkers may not predict hemorrhagic transformation, whereas the level of APP770 may be useful for predicting brain edema.
Assuntos
Edema Encefálico/diagnóstico , Infarto Cerebral/diagnóstico , Transtornos Cerebrovasculares/diagnóstico , Acidente Vascular Cerebral/diagnóstico , Trombectomia/métodos , Idoso , Idoso de 80 Anos ou mais , Precursor de Proteína beta-Amiloide/sangue , Precursor de Proteína beta-Amiloide/genética , Biomarcadores/sangue , Edema Encefálico/genética , Edema Encefálico/patologia , Edema Encefálico/cirurgia , Infarto Cerebral/genética , Infarto Cerebral/patologia , Infarto Cerebral/cirurgia , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/patologia , Transtornos Cerebrovasculares/cirurgia , Claudina-5/sangue , Claudina-5/genética , Endotelina-1/sangue , Endotelina-1/genética , Feminino , Expressão Gênica , Humanos , Masculino , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/genética , Valor Preditivo dos Testes , Estudos Prospectivos , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/cirurgiaRESUMO
Background and Purpose: Hypertension is a leading risk factor for cerebrovascular disease and loss of brain health. While the brain renin-angiotensin system (RAS) contributes to hypertension, its potential impact on the local vasculature is unclear. We tested the hypothesis that activation of the brain RAS would alter the local vasculature using a modified deoxycorticosterone acetate (DOCA) model. Methods: C57BL/6 mice treated with DOCA (50 mg SQ; or shams) were given tap H2O and H2O with 0.9% NaCl for 1 to 3 weeks. Results: In isolated cerebral arteries and parenchymal arterioles from DOCA-treated male mice, endothelium- and nitric oxide-dependent dilation was progressively impaired, while mesenteric arteries were unaffected. In contrast, cerebral endothelial function was not significantly affected in female mice treated with DOCA. In males, mRNA expression of renal Ren1 was markedly reduced while RAS components (eg, Agt and Ace) were increased in both brain and cerebral arteries with central RAS activation. In NZ44 reporter mice expressing GFP (green fluorescent protein) driven by the angiotensin II type 1A receptor (Agtr1a) promoter, DOCA increased GFP expression ≈3-fold in cerebral arteries. Impaired endothelial responses were restored to normal by losartan, an AT1R (angiotensin II type 1 receptor) antagonist. Last, DOCA treatment produced inward remodeling of parenchymal arterioles. Conclusions: These findings suggest activation of the central and cerebrovascular RAS impairs endothelial (nitric oxide dependent) signaling in brain through expression and activation of AT1R and sex-dependent effects. The central RAS may be a key contributor to vascular dysfunction in brain in a preclinical (low renin) model of hypertension. Because the brain RAS is also activated during aging and other diseases, a common mechanism may promote loss of endothelial and brain health despite diverse cause.
Assuntos
Transtornos Cerebrovasculares/metabolismo , Endotélio Vascular/metabolismo , Hipertensão/metabolismo , Óxido Nítrico Sintase Tipo III/biossíntese , Receptor Tipo 1 de Angiotensina/biossíntese , Sistema Renina-Angiotensina/fisiologia , Animais , Transtornos Cerebrovasculares/induzido quimicamente , Transtornos Cerebrovasculares/genética , Acetato de Desoxicorticosterona/toxicidade , Feminino , Hipertensão/induzido quimicamente , Hipertensão/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo III/genética , Receptor Tipo 1 de Angiotensina/genética , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
Central nervous system (CNS) injuries are one of the leading causes of morbidity and mortality worldwide, accompanied with high medical costs and a decreased quality of life. Brain vascular disorders are involved in the pathological processes of CNS injuries and might play key roles for their recovery and prognosis. Recently, increasing evidence has shown that long non-coding RNAs (lncRNAs), which comprise a very heterogeneous group of non-protein-coding RNAs greater than 200 nucleotides, have emerged as functional mediators in the regulation of vascular homeostasis under pathophysiological conditions. Remarkably, lncRNAs can regulate gene transcription and translation, thus interfering with gene expression and signaling pathways by different mechanisms. Hence, a deeper insight into the function and regulatory mechanisms of lncRNAs following CNS injury, especially cerebrovascular-related lncRNAs, could help in establishing potential therapeutic strategies to improve or inhibit neurological disorders. In this review, we highlight recent advancements in understanding of the role of lncRNAs and their application in mediating cerebrovascular pathologies after CNS injury.