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1.
Mol Med Rep ; 21(3): 1431-1438, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016473

RESUMO

Among the mechanisms of action of hyperbaric oxygenation (HBO), the chance of reducing injury by interfering with the mechanisms of redox homeostasis in the heart leads to the possibility of extending the period of viability of the myocardium at risk. This would benefit late interventions for reperfusion to the ischemic area. The objective of the present study was to investigate the changes in the redox system associated with HBO therapy maintained during the first hour after coronary occlusion in an acute myocardial infarction (MI) rat model. Surviving male rats (n=105) were randomly assigned to one of three groups: Sham (SH=26), myocardial infarction (MI=45) and infarction+hyperbaric therapy (HBO=34, 1 h at 2.5 atm). After 90 min of coronary occlusion, a sample of the heart was collected for western blot analysis of total protein levels of superoxide dismutase, catalase, peroxiredoxin and 3­nitrotyrosine. Glutathione was measured by enzyme­linked immunosorbent assay (ELISA). The detection of the superoxide radical anion was carried out by oxidation of dihydroethidium analyzed with confocal microscopy. The mortality rate of the MI group was significantly higher than that of the HBO group. No difference was noted in the myocardial infarction size. The oxidized/reduced glutathione ratio and peroxiredoxin were significantly higher in the SH and MI when compared to the HBO group. Superoxide dismutase enzymes and catalase were significantly higher in the HBO group compared to the MI and SH groups. 3­Nitrotyrosine and the superoxide radical were significantly lower in the HBO group compared to these in the MI and SH groups. These data demonstrated that hyperbaric oxygenation therapy decreased mortality by improving redox control in the hearts of rats in the acute phase of myocardial infarction.

2.
Eur Heart J Cardiovasc Imaging ; 21(3): 251-257, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31702778

RESUMO

AIMS: The objective of this study was to evaluate if vascular age derived from coronary artery calcium (CAC) score improves atherosclerosis cardiovascular disease (ASCVD) risk discrimination in primary prevention asymptomatic heterozygous familial hypercholesterolaemia (FH) patients undergoing standard lipid-lowering therapy. METHODS AND RESULTS: Two hundred and six molecularly confirmed FH individuals (age 45 ± 14 years, 36% males, baseline LDL-cholesterol 6.2 ± 2.2 mmol/L; 239 ± 85mg/dL) were followed by 4.4 ± 2.9 years (median: 3.7 years, interquartile ranges 2.7-6.8). CAC measurement was performed, and lipid-lowering therapy was optimized according to FH guidelines. Vascular age was derived from CAC and calculated according to the Multi Ethnic Study of Atherosclerosis algorithm. Risk estimation based on the Framingham equations was calculated for both biological (bFRS) and vascular (vaFRS) age. During follow-up, 15 ASCVD events (7.2%) were documented. The annualized rate of events for bFRS <10%, 10-20%, and >20% was respectively: 8.45 [95% confidence interval (CI) 3.17-22.52], 23.28 (95% CI 9.69-55.94), and 28.13 (95% CI 12.63-62.61) per 1000 patients. The annualized rate of events for vaFRS <10%, 10-20%, and >20% was respectively: 0, 0, and 50.37 (95% CI 30.37-83.56) per 1000 patients. vaFRS presented a better discrimination for ASCVD events compared to bFRS 0.7058 (95% CI 0.5866-0.8250) vs. vaFRS 0.8820 (95% CI 0.8286-0.9355), P = 0.0005. CONCLUSION: CAC derived vascular age can improve ASCVD risk discrimination in primary prevention FH subjects. This tool may help further stratify risk in FH patients already receiving lipid-lowering medication who might be candidates for further treatment with newer therapies.

3.
BMC Cardiovasc Disord ; 19(1): 251, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31706288

RESUMO

BACKGROUND: Heart failure (HF) is a major public health problem with increasing prevalence worldwide. It is associated with high mortality and poor quality of life due to recurrent and costly hospital admissions. Several studies have been conducted to describe HF risk predictors in different races, countries and health systems. Nonetheless, understanding population-specific determinants of HF outcomes remains a great challenge. We aim to evaluate predictors of 1-year survival of individuals with systolic heart failure from the GENIUS-HF cohort. METHODS: We enrolled 700 consecutive patients with systolic heart failure from the SPA outpatient clinic of the Heart Institute, a tertiary health-center in Sao Paulo, Brazil. Inclusion criteria were age between 18 and 80 years old with heart failure diagnosis of different etiologies and left ventricular ejection fraction ≤50% in the previous 2 years of enrollment on the cohort. We recorded baseline demographic and clinical characteristics and followed-up patients at 6 months intervals by telephone interview. Study data were collected and data quality assurance by the Research Electronic Data Capture tools. Time to death was studied using Cox proportional hazards models adjusted for demographic, clinical and socioeconomic variables and medication use. RESULTS: We screened 2314 consecutive patients for eligibility and enrolled 700 participants. The overall mortality was 6.8% (47 patients); the composite outcome of death and hospitalization was 17.7% (123 patients) and 1% (7 patients) have been submitted to heart transplantation after one year of enrollment. After multivariate adjustment, baseline values of blood urea nitrogen (HR 1.017; CI 95% 1.008-1.027; p < 0.001), brain natriuretic peptide (HR 1.695; CI 95% 1.347-2.134; p < 0.001) and systolic blood pressure (HR 0.982;CI 95% 0.969-0.995; p = 0.008) were independently associated with death within 1 year. Kaplan Meier curves showed that ischemic patients have worse survival free of death and hospitalization compared to other etiologies. CONCLUSIONS: High levels of BUN and BNP and low systolic blood pressure were independent predictors of one-year overall mortality in our sample. TRIAL REGISTRATION: Current Controlled Trials NTC02043431, retrospectively registered at in January 23, 2014.

4.
Eur J Clin Nutr ; 73(12): 1622-1625, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31695140

RESUMO

The association of components of a low saturated fat (SFA) and of a Mediterranean diet was tested with atherosclerosis biomarkers in 190 familial hypercholesterolemia adults (FH) from Brazil (BR) and Spain (SP). Median blood LDL-C, Apolipoprotein B (apoB), and C reactive protein (hs-CRP) concentrations were higher in BR than in SP: 179.0 vs.161 mg/dL; 141 vs. 103 mg/dL; and 1.6 vs. 0.8 mg/L respectively (all p < 0.001). In BR there was lower median total fat (22.3 vs. 38.3%) and SFA (8.1 vs. 12.5%) but higher cholesterol (283.3 mg vs.188.9 mg) and carbohydrate (57.1 vs. 42.5%) consumption (all p < 0.001). Inverse associations were encountered between fibers, mono, and polyunsaturated fats and their ratios to SFA with LDL-C and ApoB (all p < 0.001). There was a direct association respectively of cholesterol with lipid biomarkers and of carbohydrates and trans-fatty acids with hs-CRP while other fats showed inverse relations with the latter (p < 0.001).

6.
PLoS One ; 14(3): e0213764, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883578

RESUMO

INTRODUCTION: Studies on metabolomics and CKD have primarily addressed CKD incidence defined as a decline on eGFR or appearance of albuminuria in the general population, with very few evaluating hard outcomes. In the present study, we investigated the association between metabolites and mortality and ESRD in a CKD cohort. SETTING AND METHODS: Data on 454 participants of the Progredir Cohort Study, Sao Paulo, Brazil were used. Metabolomics was performed by GC-MS (Agilent MassHunter) and metabolites were identified using Agilent Fiehn GC/MS and NIST libraries. After excluding metabolites present in <50% of participants, 293 metabolites were analyzed. An FDR q value <0.05 criteria was applied in Cox models on the composite outcome (mortality or incident renal replacement therapy) adjusted for batch effect, resulting in 34 metabolites associated with the outcome. Multivariable-adjusted Cox models were then built for the composite outcome, death, and ESRD incident events. Competing risk analysis was also performed for ESRD. RESULTS: Mean age was 68±12y, mean eGFR-CKDEPI was 38.4±14.6 ml/min/1.73m2 and 57% were diabetic. After adjustments (GC-MS batch, sex, age, DM and eGFR), 18 metabolites remained significantly associated with the composite outcome. Nine metabolites were independently associated with death: D-malic acid (HR 1.84, 95%CI 1.32-2.56, p = 0.0003), acetohydroxamic acid (HR 1.90, 95%CI 1.30-2.78, p = 0.0008), butanoic acid (HR 1.59, 95%CI 1.17-2.15, p = 0.003), and docosahexaenoic acid (HR 0.58, 95%CI 0.39-0.88, p = 0.009), among the top associations. Lactose (SHR 1.49, 95%CI 1.04-2.12, p = 0.03), 2-O-glycerol-α-D-galactopyranoside (SHR 1.76, 95%CI 1.06-2.92, p = 0.03), and tyrosine (SHR 0.52, 95%CI 0.31-0.88, p = 0.02) were associated to ESRD risk, while D-threitol, mannitol and myo-inositol presented strong borderline associations. CONCLUSION: Our results identify specific metabolites related to hard outcomes in a CKD population. These findings point to the need of further exploration of these metabolites as biomarkers in CKD and the understanding of the underlying biological mechanisms related to the observed associations.


Assuntos
Biomarcadores/análise , Falência Renal Crônica/patologia , Metabolômica , Insuficiência Renal Crônica/patologia , Idoso , Estudos de Coortes , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Taxa de Filtração Glomerular , Humanos , Ácidos Hidroxâmicos/análise , Falência Renal Crônica/metabolismo , Falência Renal Crônica/mortalidade , Malatos/análise , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/mortalidade , Fatores de Risco , Álcoois Açúcares/análise , Taxa de Sobrevida
7.
Shock ; 51(3): 381-388, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29621118

RESUMO

Sepsis is a dynamic disease, displaying an inflammatory profile that varies over time and for each organ. Controlling the inflammatory response based in targeting a single molecule has been proved useless. We hypothesized that treatment with bone marrow-derived mononuclear cells (BMDMCs) may be more efficient to modulate the systemic inflammatory response to infection. Adult male Balb/c mice were subjected to cecal ligation and puncture (CLP) or endotoxemia model of experimental sepsis. BMDMCs were separated under Ficoll gradient and injected intravenously 1 h after the procedures. Cytokines concentration was quantified in plasma, lungs, heart, and gut. Spleens, lymph nodes, and thymus were used for lymphocytes isolation and cell death assessment. All measurements were performed 2 h after BMDMCs injection. RAW264.7 macrophages and BMDMCs were cocultivated in vitro to investigate the mechanisms involved. Our data showed that an early single intravenous injection of BMDMCs in animals submitted to the murine model of endotoxemia led to the improvement of survival rate; BMDMCs persistency in lung, liver, and spleen after 24 h; decreased necrosis and apoptosis of mononuclear cells; lower TNF-α, but increased IL-10 concentration in plasma; and tissue-specific cytokine profile. In vitro experiments demonstrated that IL-6, IL-10, and nitric oxide production depends on direct contact of BMDMCs to macrophages and that TNF-α production is negatively regulated by PGE2. BMDMCs are efficient in protecting animals from endotoxemia and sepsis, reducing systemic inflammation as well as specifically modulating tissue inflammation, producing the necessary immune regulation to re-equilibrate the inflammatory response.

8.
JACC Cardiovasc Imaging ; 12(9): 1797-1804, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30448145

RESUMO

OBJECTIVES: The aim of this study was to evaluate the role of coronary artery calcium (CAC) as a predictor of atherosclerotic cardiovascular disease (ASCVD) (fatal or not myocardial infarction, stroke, unstable angina requiring revascularization, and elective myocardial revascularization) events in asymptomatic primary prevention molecularly proven heterozygous familial hypercholesterolemia (FH) subjects receiving standard lipid-lowering therapy. BACKGROUND: FH is associated with premature ASCVD. However, the clinical course of ASCVD in subjects with FH is heterogeneous. CAC score, a marker of subclinical atherosclerosis burden, may optimize ASCVD risk stratification in FH. METHODS: Subjects with FH underwent CAC measurement and were followed prospectively. The association of CAC with ASCVD was evaluated using multivariate analysis. RESULTS: A total of 206 subjects (mean age 45 ± 14 years, 36.4% men, baseline and on-treatment low-density lipoprotein cholesterol 269 ± 70 mg/dl and 150 ± 56 mg/dl, respectively) were followed for a median of 3.7 years (interquartile range: 2.7 to 6.8 years). CAC was present in 105 (51%), and 15 ASCVD events (7.2%) were documented. Almost one-half of events were hard outcomes, and the others were elective myocardial revascularizations. The annualized rates of events per 1,000 patients for CAC scores of 0 (n = 101 [49%]), 1 to 100 (n = 62 [30%]) and >100 (n = 43 [21%]) were, respectively, 0, 26.4 (95% confidence interval: 12.9 to 51.8), and 44.1 (95% confidence interval, 26.0 to 104.1). In multivariate Cox regression analysis, log(CAC score + 1) was independently associated with incident ASCVD events (hazard ratio: 3.33; 95% CI: 1.635 to 6.790; p = 0.001). CONCLUSIONS: CAC was independently associated with ASCVD events in patients with FH receiving standard lipid-lowering therapy. This may help further stratify near-term risk in patients who might be candidates for further treatment with newer therapies.

9.
Atherosclerosis ; 277: 464-469, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30270086

RESUMO

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder associated with high risk of early major cardiovascular events (MACE) that can impact the health related quality of life (HRQoL), however, this association is unclear. This study evaluated HRQoL in index cases (IC) and first-degree relatives (FDR) of individuals at high risk of FH undergoing genetic cascade screening. METHODS: Data collection was performed before awareness of molecular diagnosis results. Individuals were divided into four groups according to the molecular diagnosis: IC with (IC+) and without (IC-) identified mutations (n = 93 and n = 175, respectively), and affected (FDR+, n = 231) and non-affected (FDR-, n = 159) FDR of IC+. HRQoL measurements, mental (MCS) and physical component (PCS) scores were carried out with SF-12 questionnaire. Associations were tested by generalized linear models. RESULTS: The mean age was 49 ±â€¯15 years, 42.2% were men, MACE had occurred in 30.7%. Overall, both PCS and MCS did not differ between FH and non-FH individuals, however, IC trended to have lower PCS independent of FH presence (p=0.003). Lower PCS were associated with female sex (p=0.018), lower education (p<0.001), professional inactivity (p=0.028), previous MACE occurrence (p<0.001), hypertension (p=0.016), depression (p<0.001) and obesity (p<0.001). Lower MCS were associated with female sex (p=0.009), previous MACE occurrence (p=0.034), depression (p<0.001) and smoking (p=0.009). Neither the presence of FH causing mutations nor pharmacological lipid lowering treatment was associated with HRQoL. CONCLUSIONS: HRQoL is not reduced in both IC and FDR FH individuals in comparison with their non-affected counterparts. Previous MACE and co-morbidities are associated with reduced HRQoL.


Assuntos
LDL-Colesterol/sangue , Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Mutação , Qualidade de Vida , Adulto , Anticolesterolemiantes/uso terapêutico , Biomarcadores/sangue , Brasil , Comorbidade , Estudos Transversais , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Inquéritos e Questionários , Resultado do Tratamento
10.
Arq. bras. cardiol ; 111(4): 578-584, Oct. 2018. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-973776

RESUMO

Abstract Background: Genetic cascade screening is the most cost-effective method for the identification of individuals with familial hypercholesterolemia (FH), but the best strategies for the enrollment of at-risk individuals in a FH screening program are not fully known. Objective: The aim of this study is to identify the best predictors of familial enrollment into genetic screening, using features derived from tested probands. Methods: One hundred and eighty-three index-cases (ICs) with a positive genetic result that had relatives screened from 01/2011 to 07/2015 were included. The response variable was the number of relatives for each enrolled IC. All variables in the study were based on ICs' derived clinical and socioeconomical features. The effect size of predictor variables were obtained through a general linear model using a negative binomial regression link function. Significance was considered with a p < 0.05. Results: Mean IC age when enrolling into the program was 50 years old; 78.1% of individuals reported knowledge of relatives with dyslipidemia. Mean baseline LDL-cholesterol level was 316 ± 90 mg/dL. Referral origin through the cascade program website vs. tertiary care, IC LDL-cholesterol and familial history of high LDL-cholesterol levels were independent predictors associated with a higher number of enrolled relatives. Conclusions: Our data suggest that FH cascade screening programs can predict family enrollment based on IC features. This information may be useful for devising better and more effective screening approaches for at-risk individuals.


Resumo Fundamento: O rastreamento genético em cascata é o método mais economicamente viável para a identificação de indivíduos com hipercolesterolemia familiar, mas as melhores estratégias para o recrutamento de indivíduos em risco em um programa de rastreamento deste tipo não são inteiramente conhecidas. Objetivo: Identificar os melhores preditores de recrutamento familiar em rastreamento genético, usando características derivadas de probandos testados. Métodos: Foram inscritos 183 casos índices com resultado genético positivo, que tiveram familiares rastreados de janeiro de 2011 a julho de 2015. A variável de resposta foi o número de familiares para cada caso índice inscrito. Todas as variáveis do estudo foram baseadas em características clínicas e socioeconômicas derivadas dos casos índices. O tamanho do efeito das variáveis preditoras foi obtido de modelo linear geral utilizando função de associação de regressão binomial negativa. A significância foi considerada com p < 0,05. Resultados: A média de idade dos casos índices ao ingressar no programa foi de 50 anos; 78,1% dos indivíduos relataram conhecimento de familiares com dislipidemia. O nível médio de LDL-colesterol inicial foi de 316 ± 90 mg/dL. Origem de referência por meio do site do programa em cascata vs. cuidados terciários, LDL-colesterol do caso índice e história familiar de níveis elevados de LDL-colesterol foram preditores independentes associados a um maior número de familiares inscritos. Conclusões: Programas de rastreamento genético em cascata da hipercolesterolemia familiar podem prever o recrutamento da família com base nas características do caso índice. Esta informação pode ser útil para criar abordagens de rastreamento melhores e mais eficazes para indivíduos em risco.

11.
Arq Bras Cardiol ; 111(4): 578-584, 2018 Oct.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30156605

RESUMO

BACKGROUND: Genetic cascade screening is the most cost-effective method for the identification of individuals with familial hypercholesterolemia (FH), but the best strategies for the enrollment of at-risk individuals in a FH screening program are not fully known. OBJECTIVE: The aim of this study is to identify the best predictors of familial enrollment into genetic screening, using features derived from tested probands. METHODS: One hundred and eighty-three index-cases (ICs) with a positive genetic result that had relatives screened from 01/2011 to 07/2015 were included. The response variable was the number of relatives for each enrolled IC. All variables in the study were based on ICs' derived clinical and socioeconomical features. The effect size of predictor variables were obtained through a general linear model using a negative binomial regression link function. Significance was considered with a p < 0.05. RESULTS: Mean IC age when enrolling into the program was 50 years old; 78.1% of individuals reported knowledge of relatives with dyslipidemia. Mean baseline LDL-cholesterol level was 316 ± 90 mg/dL. Referral origin through the cascade program website vs. tertiary care, IC LDL-cholesterol and familial history of high LDL-cholesterol levels were independent predictors associated with a higher number of enrolled relatives. CONCLUSIONS: Our data suggest that FH cascade screening programs can predict family enrollment based on IC features. This information may be useful for devising better and more effective screening approaches for at-risk individuals.


Assuntos
Família , Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/genética , Seleção de Pacientes , Adulto , Idoso , Brasil , Diagnóstico Precoce , Feminino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Modelos Lineares , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Valores de Referência , Análise de Regressão , Fatores de Risco
12.
Eur J Clin Pharmacol ; 74(12): 1555-1566, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30051215

RESUMO

PURPOSE: Interpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population. METHODS: Two independent cohorts of patients treated with warfarin (n = 832 and n = 133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan® assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates. RESULTS: The inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%). CONCLUSION: Although our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated.


Assuntos
Algoritmos , Anticoagulantes/administração & dosagem , Família 4 do Citocromo P450/genética , Farmacogenética , Polimorfismo Genético/genética , Varfarina/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Anticoagulantes/farmacocinética , Brasil , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Varfarina/farmacocinética
13.
Front Pharmacol ; 9: 542, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875668

RESUMO

The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan® genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309); and 5.5 (p = 0.006) and 10.2 (p < 0.001) mg/week less, respectively, for the self-declared non-white stable subgroup (n = 76). No statistically significant differences in dose requirements were observed according to CYP4F2 genotypes. In conclusion, our results suggest ABCB1 c.3435C>T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.

14.
J Clin Lab Anal ; 32(9): e22596, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29943480

RESUMO

BACKGROUND: The current transfusion policy recommended for individuals with serologic weak-D phenotype is based on data derived from European-descent populations. Data referring to the distribution of RH alleles underlying weak-D phenotype among people of mixed origin are yet incomplete, and the applicability of European-based transfusion guidelines to this specific population is questionable. GOAL: To evaluate the distribution of RHD variant genotype among individuals with serologic weak-D phenotype of both African and European descent. METHODS: Donors and patients of mixed origin and with serologic weak-D phenotype were selected for the study. They were investigated using conventional RHD-PCR assays and RHD whole-coding region direct sequencing. RESULTS: One hundred and six donors and 58 patients were included. There were 47 donors and 29 patients with partial-D genotype (47/106, 44.3%, and 29/58, 50%, respectively). RHD*DAR and RHD*weak D type 38 represented the most common altered RHD alleles among donors (joint frequency of 39.6%), while weak D types 1-3 accounted for 10.4% of the total D variant samples. RHD*DAR was the most common allele identified in the patient group (frequency of 31%), and weak D types 1-3 represented 29.3% of the total. CONCLUSION: The frequency of partial D among mixed individuals with serologic weak-D phenotype is high. They should be managed as D-negative patients until molecular tests are complete.


Assuntos
Doadores de Sangue , Polimorfismo de Nucleotídeo Único/genética , Sistema do Grupo Sanguíneo Rh-Hr/genética , Imunoglobulina rho(D)/genética , Alelos , Transfusão de Sangue , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Fenótipo , Estudos Retrospectivos , Imunoglobulina rho(D)/sangue
15.
Curr Hypertens Rep ; 20(6): 48, 2018 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-29779058

RESUMO

PURPOSE OF THE REVIEW: Blood pressure regulation in humans has long been known to be a genetically determined trait. The identification of causal genetic modulators for this trait has been unfulfilling at the least. Despite the recent advances of genome-wide genetic studies, loci associated with hypertension or blood pressure still explain a very low percentage of the overall variation of blood pressure in the general population. This has precluded the translation of discoveries in the genetics of human hypertension to clinical use. Here, we propose the combined use of resistant hypertension as a trait for mapping genetic determinants in humans and the integration of new large-scale technologies to approach in model systems the multidimensional nature of the problem. RECENT FINDINGS: New large-scale efforts in the genetic and genomic arenas are paving the way for an increased and granular understanding of genetic determinants of hypertension. New technologies for whole genome sequence and large-scale forward genetic screens can help prioritize gene and gene-pathways for downstream characterization and large-scale population studies, and guided pharmacological design can be used to drive discoveries to the translational application through better risk stratification and new therapeutic approaches. Although significant challenges remain in the mapping and identification of genetic determinants of hypertension, new large-scale technological approaches have been proposed to surpass some of the shortcomings that have limited progress in the area for the last three decades. The incorporation of these technologies to hypertension research may significantly help in the understanding of inter-individual blood pressure variation and the deployment of new phenotyping and treatment approaches for the condition.


Assuntos
Pressão Sanguínea/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Hipertensão/genética , Testes Genéticos , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Fenótipo
16.
Heart ; 104(18): 1522-1528, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523589

RESUMO

BACKGROUND: Chagas cardiomyopathy (ChC) prevalence is decreasing in Brazil and medical therapies for heart failure (HF) have improved in the last decade. Whether these changes modified the prognosis of ChC relative to non-Chagas cardiomyopathies (NChC) remains unknown. This study evaluated the temporal trends in population attributable risk (PAR) of ChC for 2-year mortality among patients with HF enrolled at years 2002-2004 (era 1) and 2012-2014 (era 2) in a Brazilian university hospital. METHODS: We prospectively studied 362 (15% with ChC) and 582 (18% with ChC) HF patients with ejection fraction ≤50% in eras 1 and 2, respectively and estimated the PAR of ChC for 2-year mortality. RESULTS: There were 145 deaths (29 in ChC) in era 1 and 85 deaths (26 in ChC) in era 2. In multivariable Cox-regression analysis adjusted for age, sex, ejection fraction, heart rate, body mass index, hypertension, diabetes mellitus, systolic blood pressure and ischaemic/valvar aetiology, ChC was associated with higher risk of death in era 1 (HR (95% CI)=1.92 (1.00 to 3.71), p=0.05) and era 2 (HR (95% CI)=3.51 (1.94 to 6.36), p<0.001). In fully adjusted analysis, the PAR of ChC for mortality increased twofold from era 1 (PAR (95% CI)=11.0 (2.8 to 18.5)%) to era 2 (PAR (95% CI)=21.9 (16.5 to 26.9)%; p=0.023 versus era 1). CONCLUSION: Although the absolute death rates decreased over time in the ChC and NChC groups, the PAR of ChC for mortality increased among patients with HF, driven by increases in the HR associated with ChC. Our results highlight the need for additional efforts aiming to prevent and treat ChC.


Assuntos
Cardiomiopatia Chagásica/complicações , Insuficiência Cardíaca/mortalidade , Medição de Risco/métodos , Volume Sistólico/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Cardiomiopatia Chagásica/epidemiologia , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo , Adulto Jovem
17.
Hypertension ; 71(4): 681-690, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29463627

RESUMO

The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5-50 mg QD) or clonidine (0.1-0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55-1.88]; P=1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01643434.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Clonidina , Hipertensão , Espironolactona , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/classificação , Monitorização Ambulatorial da Pressão Arterial/métodos , Clonidina/administração & dosagem , Clonidina/efeitos adversos , Monitoramento de Medicamentos/métodos , Resistência a Medicamentos , Quimioterapia Combinada/métodos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Espironolactona/administração & dosagem , Espironolactona/efeitos adversos , Resultado do Tratamento
18.
Clin Sci (Lond) ; 132(4): 437-447, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29343616

RESUMO

Rapamycin, the macrolide immunosuppressant and active pharmaceutic in drug-eluting stents (DES), has a well-recognized antiproliferative action that involves inhibition of the mTOR pathway after binding to the cytosolic protein FKBP12. TGF receptor-type I (TGFRI) spontaneous activation is inhibited by the association with FKBP12. We hypothesized that rapamycin, in addition to inhibition of mTOR signaling, activates TGFRI independent of TGFß. Human umbilical vein endothelial cells (HUVECs) were treated with rapamycin (10 nmol/l) and/or TGFß RI kinase inhibitor (TGFRIi, 100 nmol/l) for 24 h. Rapamycin induced SMAD phosphorylation (SMAD1, SMAD2, and SMAD5) and PAI-1 up-regulation, which was specifically abrogated by SMAD2 knockdown. TGFRIi efficiently blocked phosphorylation of SMAD2, but not SMAD1/5. Interestingly, the inhibitor did not alter cell proliferation arrest induced by rapamycin. Active TGFß secretion was not affected by the treatment. Neutralizing TGFß experiments did not influence SMAD2 phosphorylation or PAI-1 expression indicating that activation of this pathway is independent of the ligand. In addition, rapamycin induction of endothelial-to-mesenchymal transition (EndMT) was potentiated by IL-1ß and efficiently blocked by TGFRIi. In vivo, the prothrombogenic effects of rapamycin and up-regulation of PAI-1 in murine carotid arteries were reduced by TGFRIi treatment. In conclusion, we provide evidence that rapamycin activates TGF receptor independent of its ligand TGFß, in concert with promotion of PAI-1 expression and changes in endothelial phenotype. These undesirable effects, the prothrombogenic state, and activation of EndMT are SMAD2-dependent and independent of the therapeutic rapamycin-induced cell proliferation arrest.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/efeitos dos fármacos , Sirolimo/farmacologia , Proteína Smad2/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos
19.
Transfusion ; 58(2): 317-322, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29193119

RESUMO

BACKGROUND: Molecular tests designed to detect the presence of active RHD gene among D- donors have been successfully applied in people of European ancestry, but not in admixed populations with a considerable frequency of RHD*Ψ. Our goal was to evaluate the performance of a molecular screening tool for identifying active RHD alleles among Brazilian blood donors classified as D- C+ and/or E+. STUDY DESIGN AND METHODS: Pools of five DNA samples of serologically D- C+ and/or E+ donors were checked by a RHD polymerase chain reaction (PCR) assay specific for RHD Intron 4 and Exon 7. When a pool result was positive, samples were genotyped individually for RHD Intron 4 and Exon 7, RHD*Ψ, RHCE*Cc, and RHD zygosity. Donors suspected of active RHD gene were further evaluated by whole-coding region and flanking intron direct sequencing. RESULTS: A total of 405 donors were included. Two percent exhibited active RHD gene, codifying D-weak (38 and 45) or DEL phenotype. The most prevalent DEL allele was RHD*DEL1 (c.1227G>A), which is proven to be immunogenic. A high frequency of RHD*Ψ was detected in the donors with nondeleted RHD alleles (31%), far superior to the frequency of RHD variant alleles (15.5%). The proposed approach presented sensitivity of 100% and specificity of 85.7% for identifying active RHD gene. CONCLUSION: The strategy of checking D- donors with RHD PCR followed by exclusion of RHD*Ψ allele has proved efficient in identifying weak-D and DEL phenotype in the Brazilian population.


Assuntos
Alelos , Doadores de Sangue , Tipagem e Reações Cruzadas Sanguíneas/métodos , Frequência do Gene , Técnicas de Genotipagem/métodos , Reação em Cadeia da Polimerase/métodos , Sistema do Grupo Sanguíneo Rh-Hr/genética , Brasil , Feminino , Humanos , Masculino
20.
Sci Rep ; 7(1): 7899, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801620

RESUMO

Aldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day. A group of untreated sham-operated rats was also studied. Ly markedly raised plasma renin activity (PRA) and aldosterone, and exerted more effective anti-albuminuric and renoprotective action than eplerenone. In Protocol 2, Nx rats remained untreated until Day 60, when they were divided into: Nx+V receiving vehicle; Nx+L treated with losartan, 50 mg/kg/day; Nx+L+Eple, given losartan and eplerenone, and Nx+L+Ly, given losartan and Ly. Treatments lasted for 90 days. As an add-on to losartan, Ly normalized blood pressure and albuminuria, and prevented CKD progression more effectively than eplerenone. This effect was associated with strong stimulation of PRA and aldosterone. Despite exhibiting higher affinity for the MR than either eplerenone or spironolactone, Ly caused no hyperkalemia. Ly may become a novel asset in the effort to detain the progression of CKD.


Assuntos
Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Albuminúria/prevenção & controle , Aldosterona/sangue , Animais , Pressão Sanguínea , Eplerenona/administração & dosagem , Losartan/administração & dosagem , Nefrectomia , Ratos Wistar , Renina/sangue , Resultado do Tratamento
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