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1.
Eur J Prev Cardiol ; : 2047487319876765, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537123
2.
J Clin Lipidol ; 13(3): 397-401, 2019 May - Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30948303

RESUMO

We report for the first time the efficiency and safety of a 49-month compassionate use of the microsomal transfer protein inhibitor lomitapide in a child with homozygous familial hypercholesterolemia. On average, 20 mg of lomitapide caused a 37% reduction in low-density lipoprotein cholesterol levels on top of ezetimibe and atorvastatin. The drug was well tolerated with no changes in liver enzymes and occurrence of steatosis on hepatic ultrasound. The patient presented adequate growth and sexual maturation. Nonetheless, there was progression in either subclinical atherosclerotic carotid or aortic valve diseases. Further studies are necessary to test the impact and safety of lomitapide in children with homozygous familial hypercholesterolemia.

7.
Atherosclerosis ; 263: 257-262, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28689098

RESUMO

BACKGROUND AND AIMS: There is controversy on the accuracy of different diagnostic criteria for familial hypercholesterolemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. METHODS: All index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age ≥18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. RESULTS: Overall, 753 ICs were included and an FH causing mutation was found in 34% (n = 257) of the subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values ≥ 230 mg/dL (5.9 mmol/L) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were 0.744 (95% CI: 0.704-0.784) and 0.730 (95% CI: 0.687-0.774), respectively, p=0.014. CONCLUSIONS: In our population, LDL ≥230 mg/dL is a feasible criterion to indicate ICs to genetic testing.


Assuntos
LDL-Colesterol/sangue , Análise Mutacional de DNA , Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Mutação , Adulto , Idoso , Arco Senil/sangue , Arco Senil/genética , Área Sob a Curva , Biomarcadores/sangue , Brasil , Distribuição de Qui-Quadrado , Tomada de Decisão Clínica , Estudos de Viabilidade , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco , Regulação para Cima , Xantomatose/sangue , Xantomatose/genética
10.
Atherosclerosis ; 263: 393-397, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28499609

RESUMO

BACKGROUND AND AIMS: Achilles tendon xanthomas (ATX) are a sign of long-term exposure to high blood cholesterol in familial hypercholesterolemia (FH) patients, which have been associated with cardiovascular disease. We evaluated the ATX association with the presence and extent of subclinical coronary atherosclerosis in heterozygous FH patients. METHODS: 102 FH patients diagnosed by US-MEDPED criteria (67% with genetically proven FH), with median LDL-C 279 mg/dL (interquartile range: 240; 313), asymptomatic for cardiovascular disease, underwent computed tomography angiography and coronary artery calcium (CAC) quantification. Subclinical coronary atherosclerosis was quantified by CAC, segment-stenosis (SSS) and segment-involvement (SIS) scores. Adjusted Poisson regression was used to assess the association of ATX with subclinical atherosclerosis burden as continuous variables. RESULTS: Patients with ATX (n = 21, 21%) had higher LDL-C and lipoprotein(a) [Lp(a)] concentrations as well as greater CAC scores, SIS and SSS (p < 0.05). After adjusting for age, sex, smoking, hypertension, previous statin use, HDL-C, LDL-C and Lp(a) concentrations, there was an independent positive association of ATX presence with CAC scores (ß = 1.017, p < 0.001), SSS (ß = 0.809, p < 0.001) and SIS (ß = 0.640, p < 0.001). CONCLUSIONS: ATX are independently associated with the extension of subclinical coronary atherosclerosis quantified by tomographic scores in FH patients.


Assuntos
Tendão do Calcâneo , Apolipoproteína B-100/genética , Doença da Artéria Coronariana/etiologia , Heterozigoto , Hiperlipoproteinemia Tipo II/genética , Mutação , Receptores de LDL/genética , Xantomatose/etiologia , Tendão do Calcâneo/diagnóstico por imagem , Adulto , Doenças Assintomáticas , Biomarcadores/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Estudos Transversais , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Projetos Piloto , Índice de Gravidade de Doença , Xantomatose/diagnóstico por imagem
12.
Curr Med Res Opin ; 33(2): 239-251, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27776432

RESUMO

In the last two decades, statin therapy has proved to be the most potent isolated therapy for attenuation of cardiovascular risk. Its frequent use has been seen as one of the most important elements for the reduction of cardiovascular mortality in developed countries. However, the recurrent incidence of muscle symptoms in statin users raised the possibility of causal association, leading to a disease entity known as statin associated muscle symptoms (SAMS). Mechanistic studies and clinical trials, specifically designed for the study of SAMS have allowed a deeper understanding of the natural history and accurate incidence. This set of information becomes essential to avoid an unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents overdiagnosis and an inadequate suspension of one of the most powerful prevention strategies of our times. In this context, the Luso-Latin American Consortium gathered all available information on the subject and presents them in detail in this document as the basis for the identification and management of SAMS.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de Risco
13.
Int J Mol Sci ; 17(9)2016 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-27563889

RESUMO

The purpose of our work was to select phages displaying peptides capable of binding to vascular markers present in human atheroma, and validate their capacity to target the vascular markers in vitro and in low-density lipoprotein receptor knockout (LDLr(-/-)) mouse model of atherosclerosis. By peptide fingerprinting on human atherosclerotic tissues, we selected and isolated four different peptides sequences, which bind to atherosclerotic lesions and share significant similarity to known human proteins with prominent roles in atherosclerosis. The CTHRSSVVC-phage peptide displayed the strongest reactivity with human carotid atherosclerotic lesions (p < 0.05), when compared to tissues from normal carotid arteries. This peptide sequence shares similarity to a sequence present in the fifth scavenger receptor cysteine-rich (SRCR) domain of CD163, which appeared to bind to CD163, and subsequently, was internalized by macrophages. Moreover, the CTHRSSVVC-phage targets atherosclerotic lesions of a low-density lipoprotein receptor knockout (LDLr(-/-)) mouse model of atherosclerosis in vivo to High-Fat diet group versus Control group. Tetraazacyclododecane-1,4,7,10-tetraacetic acid-CTHRSSVVC peptide (DOTA-CTHRSSVVC) was synthesized and labeled with (111)InCl3 in >95% yield as determined by high performance liquid chromatography (HPLC), to validate the binding of the peptide in atherosclerotic plaque specimens. The results supported our hypothesis that CTHRSSVVC peptide has a remarkable sequence for the development of theranostics approaches in the treatment of atherosclerosis and other diseases.


Assuntos
Aterosclerose/diagnóstico , Imagem Molecular/métodos , Peptídeos/metabolismo , Animais , Antígenos CD/química , Antígenos de Diferenciação Mielomonocítica/química , Aterosclerose/metabolismo , Modelos Animais de Doenças , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos/química , Receptores de Superfície Celular/química , Receptores de LDL/deficiência , Receptores de LDL/genética
14.
Atherosclerosis ; 248: 76-83, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26987068

RESUMO

BACKGROUND AND AIMS: Regular intake of phytosterols (PS) is proven to dose-dependently lower LDL-cholesterol (LDL-C). Whether PS consumption can also impact low-grade inflammation is unclear. Considering the low feasibility of outcomes studies involving PS consumption, investigation of surrogate markers of atherosclerosis represents a valuable approach. This study assessed the anti-inflammatory effect of PS consumption, according to inflammatory biomarkers, mainly C-reactive protein (CRP). METHODS AND RESULTS: A systematic search of Medline, Cab Abstracts, and Food Science & Technology Abstracts was conducted through January 2015. Our study selection included randomized controlled trials (RCT), involving intake of PS-enriched foods as active treatment, and measurement of plasma inflammatory biomarkers. Random-effects meta-analyses were performed using average baseline and end-of-intervention concentrations and control-adjusted absolute changes in CRP and blood lipids. There were 20 eligible RCTs including a total of 1308 subjects. The absolute change of plasma CRP levels with PS consumption was -0.10 mg/L (95%CI -0.26; 0.05), a non-significant change, and heterogeneity had borderline significance (I(2) = 29.1; p-value = 0.073). The absolute reduction of LDL-C was -14.3 mg/dL (95%CI -17.3; -11.3). Meta-regression analyses showed that both the dose and duration of PS intake significantly influenced the absolute changes in plasma CRP (ß = -0.35, p = 0.0255 and ß = -0.03, p = 0.0209, respectively). CONCLUSIONS: In this meta-analysis, regular intake of PS-enriched foods did not significantly change CRP, whilst LDL-C concentrations were significantly reduced. Further studies with higher PS doses may provide more definite conclusions on a potential anti-inflammatory effect of PS intake.


Assuntos
Biomarcadores/metabolismo , Inflamação/metabolismo , Fitosteróis/química , Anti-Inflamatórios/química , Colesterol/sangue , LDL-Colesterol/metabolismo , Humanos , Lipídeos/sangue , Plantas/química , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Triglicerídeos/sangue
15.
J Lipid Res ; 56(2): 358-68, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25510249

RESUMO

Inflammation of adipose tissue induces metabolic derangements associated with obesity. Thus, determining ways to control or inhibit inflammation in adipose tissue is of clinical interest. The present study tested the hypothesis that in mouse adipose tissue, endogenous prostaglandin E2 (PGE2) negatively regulates inflammation via activation of prostaglandin E receptor 4 (EP4). PGE2 (5-500 nM) attenuated lipopolysaccharide-induced mRNA and protein expression of chemokines, including interferon-γ-inducible protein 10 and macrophage-inflammatory protein-1α in mouse adipose tissue. A selective EP4 antagonist (L161,982) reversed, and two structurally different selective EP4 agonists [CAY10580 and CAY10598] mimicked these actions of PGE2. Adipose tissue derived from EP4-deficient mice did not display this response. These findings establish the involvement of EP4 receptors in this anti-inflammatory response. Experiments performed on adipose tissue from high-fat-fed mice demonstrated EP4-dependent attenuation of chemokine production during diet-induced obesity. The anti-inflammatory actions of EP4 became more important on a high-fat diet, in that EP4 activation suppressed a greater variety of chemokines. Furthermore, adipose tissue and systemic inflammation was enhanced in high-fat-fed EP4-deficient mice compared with wild-type littermates, and in high-fat-fed untreated C57BL/6 mice compared with mice treated with EP4 agonist. These findings provide in vivo evidence that PGE2-EP4 signaling limits inflammation. In conclusion, PGE2, via activation of EP4 receptors, functions as an endogenous anti-inflammatory mediator in mouse adipose tissue, and targeting EP4 may mitigate adipose tissue inflammation.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Quimiocinas/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Quimiocina CCL3/metabolismo , Quimiocina CXCL10/metabolismo , Dinoprostona/análogos & derivados , Dinoprostona/farmacologia , Técnicas In Vitro , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Interleucina-8/farmacologia , Masculino , Pirrolidinonas/farmacologia , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Proteína Amiloide A Sérica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tetrazóis/farmacologia , Tiofenos/farmacologia , Triazóis/farmacologia
16.
Atherosclerosis ; 238(1): 101-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25461735

RESUMO

BACKGROUND: There is little knowledge about familial hypercholesterolemia in Brazil. This study presents the first results of genetic cascade screening performed in the city of Sao Paulo. MATERIAL AND METHODS: Two-hundred and forty-eight suspected index cases were initially included. DNA was extracted from peripheral blood and the complete coding sequence of low-density lipoprotein receptor, exon 7 of proprotein convertase subtilisin/kexin type 9 gene and part of exon 26 of apolipoprotein B genes were sequenced. Multiplex Ligation-dependent Probe Amplification was performed on cases where a causal mutation was not identified through sequencing. After the identification of a causal mutation screening in first-degree relatives was pursued. RESULTS: From 248 index cases, a mutation was found in 125 individuals (50.4%). 394 relatives were included in the cascade screening program and a mutation was identified in 59.4%. Seventy different causal mutations in the low-density lipoprotein receptor gene (97.2%) and 2 in the apolipoprotein B gene (2.8%) were found. No mutations were encountered in the proprotein convertase subtilisin/kexin type 9 gene. Mutations in exons 14 and 4 were the most prevalent and, 10 cases of true homozygotes (8 index cases and 2 relatives) and 1 compound heterozygote were identified. The most frequent mutation found was of Lebanese origin, the p.(Cys681*) mutation in exon 14 (8.5%). CONCLUSION: Genetic familial hypercholesterolemia cascade screening is feasible in Brazil and leads to identification of a mutation in approximately half of the index cases with higher rates of success in their relatives.


Assuntos
Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Adulto , Idoso , Apolipoproteínas B/sangue , Apolipoproteínas B/genética , Índice de Massa Corporal , Brasil/epidemiologia , Éxons , Feminino , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/epidemiologia , Líbano , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética
18.
Arq Bras Cardiol ; 102(5 Suppl 1): 1-41, 2014 05.
Artigo em Português | MEDLINE | ID: mdl-27223869
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