Navegando por Palavras-chave "Hipercolesterolemia Familiar"

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    Estudo do perfil genético e molecular do sistema calicreína-cininas em pacientes portadores de hipercolesterolemia familiar
    (Universidade Federal de São Paulo (UNIFESP), 2019-03-28) Bittencourt, Clarissa Azevedo [UNIFESP]; Pesquero, Joao Bosco [UNIFESP]; http://lattes.cnpq.br/0856630824759511; http://lattes.cnpq.br/6475256598464720; Universidade Federal de São Paulo (UNIFESP)
    Familial hypercholesterolemia is an autosomal dominant genetic disorder characterized by increased serum levels of total cholesterol and low-density lipoprotein cholesterol. Familial hypercholesterolemia is directly related to the development of cardiovascular diseases, such as hypertension, atherosclerosis, myocardial infarction and coronary disease. In this context, the kallikrein-kinin system actively participates in the regulation of cardiovascular system functions, as demonstrated in studies with angiotensin-converting enzyme inhibitors and has cardioprotective effects mediated by the direct release of nitric oxide by endothelium or stimulated by prostaglandins. No study has so far associated the contribution of the kallikrein-kinin system in the modulation of symptoms or in the pathogenesis of familial hypercholesterolemia. Thus, in this work we investigated the genetic profile of the kallikrein-kinin system in patients with familial hypercholesterolemia. The new generation sequencing of eleven genes related to the kallikrein-kinin system were carried out in 102 patients with familial hypercholesterolemia. 22 rare variants were identified, with nine variants classified as pathogenic by in silico predictors; and 14 polymorphisms. Eight of these variants, present in the ACE, KLK1 and KNG1 genes may be candidate variants to be related to systemic arterial hypertension. Despite the limitations of the association between genotype and phenotype, the results obtained in this work open the opportunity to expand knowledge about the possible modulation of the kallikrein-kinin system in the development of cardiovascular diseases, particularly hypertension, in the context of familial hypercholesterolemia.
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    Papel da Resposta Imune Inata e Adaptativa na Doença Coronária Aterosclerótica em Portadores de Hipercolesterolemia Familiar
    (Universidade Federal de São Paulo (UNIFESP), 2019-08-29) Lopes, Waleria Simone Toledo Fonzar [UNIFESP]; Izar, Maria Cristina De Oliveira [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    BACKGROUND: For hundreds of thousands of years, part of our genomic heritage was primarily developed to combat infectious agents. However, the participation of our immune system modulating the progression of atherosclerosis was only recently recognized in the differential role of lymphocyte subtypes,with B1 lymphocytes with an important antiatherogenic role, due to the production of IgM antibodies that interact with oxidized epitopes of apolipoprotein B, and B2 lymphocytes contributing to atherosclerosis progression favoring interactions of oxidized LDL with dendritic cells, thus contributing for the immune complex deposition in the intima layer and plaque instabilization. Familial Hypercholesterolemia (FH) is an inherited condition characterized by lifetime exposure to high LDL-c, premature atherosclerotic cardiovascular disease (ASCVD) and cutaneous stigmata. However, in spite of LDL-c burden and exposure to aggressive lipid-lowering therapy, there is heterogeneity on atherosclerosis presentation that cannot be explained by classical risk factors. Though, we postulated that the imune-inflammatory system could modulate the burden of atherosclerosis in FH patients. OBJECTIVES:Evaluate if the imune-inflammatory system can modulate the development of coronary atherosclerosis in FH patients under high-intensity lipidlowering therapy. METHODS: One-hundred and two patients with definite or probable diagnosis of FH (Dutch Lipid Clinic Network) were selected. Blood samples for laboratory tests (lipids, biochemistry, apolipoproteins A1, B and Lp(a), immune profile (absolute count and %of lymphocytes TCD4+, TCD8+, B memory cells, B naive, B1, ELISPOT assays, quantification of cytokines TNF-α, IFN-, IL-10, IL-6, IL-4, and IL-2 produced by B memory, B naive and T cells), quantification of monocitic, endothelial and platelet microparticles (flow citometry), and titers of autoantibodies of IgG and IgM isotype anti-oxLDL and anti-Apo B-D (ELISA) were assayed. Genetic study used NGS and a gene pannel with LDLR, APOB, PCSK9, LDLRAP1, APOL1andLIPAgenes. Coronary angiotomography and coronary calcium score (CCS) were performed for the evaluation of the extent and severity of coronary atherosclerosis. Data was compared among individuals with CCS = 0 vs. > 0, among categories of CCS (0; 1-99; 100-399; xxiv 400-999; > 1000 UA), CCS percentiles ( P75) and CAD-RADS categories (0-5). Statistical analysis used parametric and non-parametric tests, as appropriate, with significance set at a P-value < 0,05. RESULTS: CCS> 0 was more prevalent in males (P=0.015), smokers (P=0.016), in those with higher CAD-RADS score (P<0.001), but did not differ among intensities of treatment, presence of cardiovascular risk factors or clinical manifestations of ASCVD. Lipid parameters were similar among participants with CCS = 0 vs. CCS >0 (LDL-c 149 + 61 vs. 158 + 63, respectively; P=0.471). There was heterogeneity in the presentation of ASCVD, with mean and maximal CCS of 173 and 2139 UA, respectively. Immune profile variables, autoantibodies of IgG and IgM isotypes anti- LDLox and anti-Apo B-D, and microparticles did not differ among CCS and CADRADS score categories, although there were trends for diferences for some variables. CONCLUSION: Although there is a clear role of the immune-adaptive system in the development, progression and complications of ASCVD, it does not seem to significantly influence the expression of coronary atherosclerosis evaluated by angiotomography, in subjects with familial hypercholesterolemia under high-intensity lipid-lowering therapy. The expression of ASCVD in those individuals seems to result fromthe balance between long-term exposure to very high levels of LDL-c and highintensity lipid-lowering treatment.