Identification of pathogenic variants in the Brazilian cohort with Familial hypercholesterolemia using exon-targeted gene sequencing.

Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n = 210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3'UTR and 5'UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.

Genomics, epigenomics and pharmacogenomics of familial hypercholesterolemia (FHBGEP): A study protocol.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide. OBJECTIVES: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH). METHODS: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients. SUMMARY: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients.

Dysregulation of microRNAs and target genes networks in human abdominal aortic aneurysm tissues.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a pathological enlargement of infrarenal aorta close to the aortic bifurcation, and it is an important cause of mortality in the elderly. Therefore, the biomarker identification for early diagnosis is of great interest for clinical benefit. It is known that microRNAs (miRNAs) have important roles via target genes regulation in many diseases. This study aimed to identify miRNAs and their target genes involved in the pathogenesis of AAA. METHODS: Tissue samples were obtained from patients who underwent AAA surgery and from organ donors (control group). Quantitative PCR Array was applied to assess 84 genes and 384 miRNAs aiming to identify differentially expressed targets (AAA n = 6, control n = 6), followed by validation in a new cohort (AAA n = 18, control n = 6) by regular qPCR. The functional interaction between validated miRNAs and target genes was performed by the Ingenuity Pathway Analysis (IPA) software. RESULTS: The screening cohort assessed by PCR array identified 10 genes and 59 miRNAs differentially expressed (≥2-fold change, p<0.05). Among these, IPA identified 5 genes and 9 miRNAs with paired interaction. ALOX5, PTGIS, CX3CL1 genes, and miR-193a-3p, 125b-5p, 150-5p maintained a statistical significance in the validation cohort. IPA analysis based on the validated genes and miRNAs revealed that eicosanoid and metalloproteinase/TIMP synthesis are potentially involved in AAA. CONCLUSION: Paired interactions of differentially expressed ALOX5, PTGIS, CX3CL1 genes, and miR-193b-3p, 125b-5p, 150-5p revealed a potentially significant role of the eicosanoid synthesis and metalloproteinase/TIMP pathways in the AAA pathogenesis.

Brazilian guidelines on prevention of cardiovascular disease in patients with diabetes: a position statement from the Brazilian Diabetes Society (SBD), the Brazilian Cardiology Society (SBC) and the Brazilian Endocrinology and Metabolism Society (SBEM).

BACKGROUND: Since the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical risk-based approach on treatment for patients with diabetes. MAIN BODY: The Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy. CONCLUSIONS: Diabetes is a heterogeneous disease. Although cardiovascular risk is increased in most patients, those without risk factors or evidence of sub-clinical atherosclerosis are at a lower risk. Optimal management must rely on an approach that will cover both cardiovascular disease prevention in individuals in the highest risk as well as protection from overtreatment in those at lower risk. Thus, cardiovascular prevention strategies should be individualized according to cardiovascular risk while intensification of treatment should focus on those at higher risk.

Identification of mildly oxidized low-density lipoprotein (electronegative LDL) and its auto-antibodies IgG in children and adolescents hypercholesterolemic offsprings.

BACKGROUND: Oxidative modification of low-density lipoproteins (LDL) is an essential step in atherogenesis, generating minimally oxidized LDL, also called electronegative LDL [LDL(-)], which has chemotactic, cytotoxic and immunogenic properties. METHODS AND RESULTS: Serum LDL(-) and anti-LDL(-) auto-antibodies (IgG) were evaluated in 28 children and adolescents with familial hypercholesterolemia (FH) antecedents, with or without early coronary artery disease in first-degree relatives (eCAD), hypercholesterolemic (hc) or normocholesterolemic (nc) versus a control group of normocholesterolemic children without pathologic antecedents (C). ELISA method was used for detection of LDL(-) and anti-LDL(-) IgG. LDL(-) serum levels did not differ among the four groups (FH-eCAD-hc 41.4 +/- 24.9 microg/dl; FH-hc 38.3 +/- 11.2 microg/dl; FH-nc 47.3 +/- 17.0 microg/dl and C 44.2 +/- 28.8 microg/dl, p = 0.659). However, IgG anti-LDL(-) auto-antibodies were significantly higher in the control group in comparison to the FH groups with or without eCAD, independent of hypercholesterolemia or normocholesterolemia (FH-eCAD-hc 0.825 +/- 0.289 microg/dl; FH-hc 0.667 +/- 0.307 microg/dl; FH-nc 0.763 +/- 0.204 microg/dl and C 1.105 +/- 0.233 microg/dl, p = 0.006). When the auto-antibodies of groups with FH, with or without eCAD and with or without hypercholesterolemia were compared, no differences were found (p = 0.509). CONCLUSION: These results showed that FH and/or eCAD children and adolescents have lower titers of auto-antibodies anti-LDL(-) than children from normal families, independent of serum LDL-cholesterol or serum LDL(-).

Effects of soy germ isoflavones and hormone therapy on nitric oxide derivatives, low-density lipoprotein oxidation, and vascular reactivity in hypercholesterolemic postmenopausal women.

OBJECTIVE: To evaluate the effects of soy germ isoflavones and hormone therapy on vascular reactivity, the formation of nitric oxide derivatives, and lipid peroxidation in hypercholesterolemic postmenopausal women. DESIGN: Women were treated with soy germ, 17beta-estradiol or 17beta-estradiol + noretisterone acetate for 3 months after taking placebo for 1 month. The plasma concentrations of nitrite + nitrate and S-nitrosothiols were evaluated by gaseous phase chemiluminescence; nitrotyrosine, electronegative low-density lipoprotein, and estradiol levels were determined by enzyme-linked immunosorbent assay; cholesterol oxides and isoflavones were determined by gas chromatography and high-performance liquid chromatography, respectively. Vascular reactivity was analyzed by high-resolution ultrasonography. RESULTS: Soy germ isoflavones and hormone therapy induced a decrease in nitrite + nitrate, electronegative low-density lipoprotein, and cholesterol oxides, as well as an increase in S-nitrosothiols. Soy germ isoflavones lowered electronegative low-density lipoprotein, and cholesterol oxides more efficiently than did hormone therapy. Only soy isoflavones inhibited nitrotyrosine formation. A significant improvement of vascular reactivity was only seen in women treated with 17beta-estradiol. CONCLUSIONS: The soy germ isoflavones and 17beta-estradiol, alone or associated with noretisterone acetate, in the doses and forms used here, have similar effects on the bioavailability of nitric oxide. Soy germ treatment inhibited lipid peroxidation more effectively than hormone therapy.

[Mechanisms of hepatotoxicity]. / Mecanismos de hepatotoxicidade.

Liver disease following the use of hypolipidemic drugs has been reported as a cellular damage (increases in AST or ALT enzymes) without cholestatic alterations (bilirubin and or alkaline phosphatase increases). Six mechanisms were proposed for hepatotoxicity: 1. High energy reactions on P450 cytochrome impairing calcium homeostasis with rupture of intracellular fibrils and hepatocyte lysis. 2. Impairment of transporter proteins related to the bile acids flux (mechanism proposed for fibrate liver toxicity). 3. Immune reactions due to the formation of metabolites linked to enzymes following liver metabolism of hypolipidemic drugs. 4. Hepatotoxicity by T cells with additional inflammation mediated by neutrophils. 5. Apoptosis mediated by TNF and Fas (immune mediated). 6. Oxidative stress due to damage of intracellular organelles. In addition, advanced age, alcohol in excess, high doses of hypolipidemic drugs, interaction with other drugs, and previous active liver disease might increase liver toxicity.

Predictive Potential of Twenty-Two Biochemical Biomarkers for Coronary Artery Disease in Type 2 Diabetes Mellitus.

We investigated the potential of a panel of 22 biomarkers to predict the presence of coronary artery disease (CAD) in type 2 diabetes mellitus (DM2) patients. The study enrolled 96 DM2 patients with (n = 75) and without (n = 21) evidence of CAD. We assessed a biochemical profile that included 22 biomarkers: total cholesterol, LDL, HDL, LDL/HDL, triglycerides, glucose, glycated hemoglobin, fructosamine, homocysteine, cysteine, methionine, reduced glutathione, oxidized glutathione, reduced glutathione/oxidized glutathione, L-arginine, asymmetric dimethyl-L-arginine, symmetric dimethyl-L-arginine, asymmetric dimethyl-L-arginine/L-arginine, nitrate plus nitrite, S-nitrosothiols, nitrotyrosine, and n-acetyl-ß-glucosaminidase. Prediction models were built using logistic regression models. We found that eight biomarkers (methionine, nitratate plus nitrite, n-acetyl-ß-glucosaminidase, BMI, LDL, HDL, reduced glutathione, and L-arginine/asymmetric dimethyl-L-arginine) along with gender and BMI were significantly associated with the odds of CAD in DM2. These preliminary findings support the notion that emerging biochemical markers might be used for CAD prediction in patients with DM2. Our findings warrant further investigation with large, well-designed studies.

Progesterone abolishes estrogen and/or atorvastatin endothelium dependent vasodilatory effects.

UNLABELLED: This double blind randomized placebo controlled study assessed the effects of atorvastatin, estradiol and norethisterone, isolated and in combination, on the lipid profile and on vascular reactivity, in post-menopausal women with hypercholesterolemia and arterial hypertension. Ninety-four women aged 50-65 were selected. All have received dietary counseling (4 weeks), placebo (4 weeks), and drug therapy (12 weeks): 17-beta estradiol 2mg/day (E) (n=17); E + norethisterone acetate 1mg/day (P) (n=18); Atorvastatin 10mg/day (A) (n=20); E + A (n=21) and E + P + A (n=18). All treatment modalities have significantly reduced total cholesterol (TC) (E=8.8%, E + P=10.1%, A=27.9%, A + E=29.4% and E + P + A=35.7%) and LDL-cholesterol (LDL-c) levels (E + P + A=46.6%, E + A=45.9%, A=40.2%, E=20.3%, and E + P=12.1%). As concerns HDL-cholesterol (HDL-c), Groups E and E + A had increases of 15.5% and 13.1%, respectively. The addition of a progesterone compound reduced its concentration (Group E + P=-9.1%, and Group E + P + A=-9.5%). By random, approximately half of the patients in each group were designated to the endothelial function evaluation (brachial artery ultrasound). We observed that in Group A (n=10), in Group E (n=10) and with the association (Group E + A) (n=7), there was a significant increase in the flow-mediated vasodilatation as compared to basal measurements. The addition of a progestin has annulled these benefits. CONCLUSIONS: Atorvastatin has promoted more beneficial effects on TC and LDL-c, whereas estradiol was responsible for an increase in HDL-c. The addition of a progesterone derivative abolished these benefits. Atorvastatin, estradiol or both together improved endothelial function, an effect suppressed by the addition of norethisterone.

Lipid peroxidation and nitric oxide inactivation in postmenopausal women.

OBJECTIVE: To assess the effect of endogenous estrogens on the bioavailability of nitric oxide (.NO) and in the formation of lipid peroxidation products in pre- and postmenopausal women. METHODS: NOx and S-nitrosothiols were determined by gaseous phase chemiluminescence, nitrotyrosine was determined by ELISA, COx (cholesterol oxides) by gas chromatography, and cholesteryl linoleate hydroperoxides (CE18:2-OOH), trilinolein (TG18:2-OOH), and phospholipids (PC-OOH) by HPLC in samples of plasma. RESULTS: The concentrations of NOx, nitrotyrosine, COx, CE18:2-OOH, and PC-OOH were higher in the postmenopausal period (33.8+/-22.3 microL; 230+/-130 nM; 55+/-19 ng/microL; 17+/-8.7 nM; 2775+/-460 nM, respectively) as compared with those in the premenopausal period (21.1+/-7.3 microM; 114+/-41 nM; 31+/-13 ng/microL; 6+/-1.4 nM; 1635+/-373 nM). In contrast, the concentration of S-nitrosothiols was lower in the postmenopausal period (91+/-55 nM) as compared with that in the premenopausal p in the premenopausal period (237+/-197 nM). CONCLUSION: In the postmenopausal period, an increase in nitrotyrosine and a reduction of S-nitrosothiol formation, as well as an increase of COx, CE18:2-OOH and PC-OOH formation occurs. Therefore, NO inactivation and the increase in lipid peroxidation may contribute to endothelial dysfunction and to the greater risk for atherosclerosis in postmenopausal women.

Improvement of atherosclerotic markers in non-diabetic patients after bariatric surgery.

BACKGROUND: The objective of this study was to assess the impact of bariatric surgery performed in extremely obese non-diabetic subjects on the following parameters: endothelial function, inflammatory processes (assessed by high-sensitivity C-reactive protein [hs-CRP]), carotid artery intima-media thickness (CIMT), and glucose and lipid profiles. METHODS: Forty-seven obese individuals with body mass index >40 kg/m(2) underwent bariatric surgery and returned for post-procedure assessment between 6 and 19 months after surgery. Ninety-three percent of patients were female. Their age ranged from 18 to 65 (mean 41) years old at baseline. Baseline was defined as the maximum of 30 days before surgery. Before and after surgery, all patients were subjected to a brachial artery ultrasound examination to evaluate endothelial-dependent dilation, CIMT by ultrasound, and laboratory analyses including glucose, lipid and inflammatory profiles were performed. RESULTS: Subjects lost an average of 33 % of their original weight (p < 0.001). Flow-mediated dilation showed significant improvement after surgery from 7.4 % to 18.9 % (p < 0.001) on average. There was regression of CIMT, with the median being reduced from 0.8 to 0.5 mm (p < 0.001). The median Hs-CRP reduced from 0.83 to 0.18 mg/dl (p < 0.001), while glucose and lipid profiles were also improved after surgery. CONCLUSIONS: This study shows that severely obese, non-diabetic patients who had pronounced weight loss after bariatric surgery had an overall improvement in brachial flow-mediated dilation, CIMT, high-sensitivity CRP, and glucose and lipid metabolism. The best responses of the brachial flow-mediated dilation after surgery were observed in non-smokers and in younger subjects.

Diretriz brasileira baseada em evidências sobre prevenção de doenças cardiovasculares em pacientes com diabetes: posicionamento da Sociedade Brasileira de Diabetes (SBD), da Sociedade Brasileira de Cardiologia (SBC) e da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) / Brazilian evidence-based guideline on cardiovascular disease prevention in patients with diabetes: positioning of the Brazilian Society of Diabetes (SBD), the Brazilian Society of Cardiology (SBC) and the Brazilian Society of Endocrinology and Metabology (SBEM)

Resumo Fundamentação: desde o primeiro posicionamento da Sociedade Brasileira de Diabetes (SBD) sobre diabetes e prevenção cardiovascular, em 2014,1 importantes estudos têm sido publicados na área de prevenção cardiovascular e tratamento do diabetes,2 os quais contribuíram para a evolução na prevenção primária e secundária nos pacientes com diabetes. Ferramentas de estratificação de risco mais precisas, novos fármacos hipolipemiantes e novos antidiabéticos com efeitos cardiovasculares e redução da mortalidade, são parte desta nova abordagem para os pacientes com diabetes. O reconhecimento de que o diabetes é uma doença heterogênea foi fundamental, sendo claramente demonstrado que nem todos os pacientes diabéticos pertencem a categorias de risco alto ou muito alto. Um porcentual elevado é composto por pacientes jovens, sem os fatores de risco clássicos, os quais podem ser classificados adequadamente em categorias de risco intermediário ou mesmo em baixo risco cardiovascular. O presente posicionamento revisa as melhores evidências atualmente disponíveis e propõe uma abordagem prática, baseada em risco, para o tratamento de pacientes com diabetes. Estruturação: perante este desafio e reconhecendo a natureza multifacetada da doença, a SBD uniu-se à Sociedade Brasileira de Cardiologia (SBC) e à Sociedade Brasileira de Endocrinologia e Metabolismo (SBEM), e formou um painel de especialistas, constituído por 28 cardiologistas e endocrinologistas, para revisar as melhores evidências disponíveis e elaborar uma diretriz contendo recomendações práticas para a estratificação de risco e prevenção da Doença Cardiovascular (DVC) no Diabetes Melito (DM). As principais inovações incluem: (1) considerações do impacto de novos hipolipemiantes e das novas medicações antidiabéticas no risco cardiovascular; (2) uma abordagem prática, baseada em fator de risco, para orientar o uso das estatinas, incluindo novas definições das metas da Lipoproteína de Baixa Densidade-colesterol (LDL-colesterol) e colesterol não Lipoproteína de Alta Densidade HDL; (3) uma abordagem baseada em evidências, para avaliar a isquemia miocárdica silenciosa (IMS) e a aterosclerose subclínica em pacientes com diabetes; (4) as abordagens mais atuais para o tratamento da hipertensão; e (5) recomendação de atualizações para o uso de terapia antiplaquetária. Esperamos que esta diretriz auxilie os médicos no cuidado dedicado aos pacientes com diabetes. Métodos: inicialmente, os membros do painel foram divididos em sete subcomitês para definirem os tópicos principais que necessitavam de uma posição atualizada das sociedades. Os membros do painel pesquisaram e buscaram no PubMed estudos clínicos randomizados e metanálises de estudos clínicos e estudos observacionais de boa qualidade, publicados entre 1997 e 2017, usando termos MeSH: [diabetes], [diabetes tipo 2], [doença cardiovascular], [estratificação de risco cardiovascular] [doença arterial coronária], [rastreamento], [isquemia silenciosa], [estatinas], [hipertensão], [ácido acetilsalicílico]. Estudos observacionais de baixa qualidade, metanálises com alta heterogeneidade e estudos transversais não foram incluídos, embora talvez tenham impactado no Nível de Evidência indicado. A opinião de especialistas foi usada quando os resultados das buscas não eram satisfatórios para um item específico. É importante salientar que este posicionamento não teve a intenção de incluir uma revisão sistemática rigorosa. Um manuscrito preliminar, destacando recomendações de graus e níveis de evidência (Quadro 1), foi esboçado. Este passo levou a várias discussões entre os membros dos subcomitês, que revisaram os achados e fizeram novas sugestões. O manuscrito foi, então, revisto pelo autor líder, encarregado da padronização do texto e da inclusão de pequenas alterações, sendo submetido à apreciação mais detalhada pelos membros dos comitês, buscando uma posição de consenso. Depois desta fase, o manuscrito foi enviado para a banca editorial e edição final, sendo encaminhado para publicação. Quadro 1 Graus de recomendações e níveis de evidências adotados nesta revisão Grau de recomendação Classe I A evidência é conclusiva ou, se não, existe consenso de que o procedimento ou tratamento é seguro e eficaz Classe II Há evidências contraditórias ou opiniões divergentes sobre segurança, eficácia, ou utilidade do tratamento ou procedimento Classe IIa As opiniões são favoráveis ao tratamento ou procedimento. A maioria dos especialistas aprova Classe IIb A eficácia é bem menos estabelecida, e as opiniões são divergentes Classe III Há evidências ou consenso de que o tratamento ou procedimento não é útil, eficaz, ou pode ser prejudicial Níveis de Evidência A Múltiplos estudos clínicos randomizados concordantes e bem elaborados ou metanálises robustas de estudos clínicos randomizados B Dados de metanálises menos robustas, um único estudo clínico randomizado ou estudos observacionais C Opinião dos especialistas

Terapêutica hipolipemiante na hipercolesterolemia familiar / Lipid-lowering therapy in familial hypercholesterolemia

A hipercolesterolemia familiar (HF) é doença metabólica muito comum, mas não reconhecida e tratada adequadamente. Sua forma homozigótica, mais rara, leva a aumentos muito importantes do LDL-colesterol e à evolução dramática da aterosclerose e suas complicações em fases muito precoces da vida. Na sua forma mais branda, muito mais comum, a heterozigótica, o aparecimento de manifestações ateroscleróticas costuma ser mais tardio, dependendo da intensidade das alterações do perfil lipídico e dos outros fatores de risco eventualmente presentes. Os recursos terapêuticos para controle da HF vão desde as mudanças do estilo de vida até os medicamentos de uso comum como estatinas potentes em altas doses, na maioria das vezes combinadas à ezetimiba e/ou resina, niacina e fibratos. Novos produtos foram aprovados para uso em outros países, como a lomitapida e o mipomersen, mas apenas para a HF na forma homozigótica. Os inibidores da PCSK9 são importante esperança no controle desses pacientes. As pesquisas com os inibidores da CETP têm sido marcadas por decepções, mas um estudo clínico envolvendo um deles ainda está em andamento. Nosso país não dispõe da LDL-aférese, recurso que se tem mostrado fundamental para a melhora do prognóstico dos portadores das formas graves da HF

Familial hypercholesterolemia (FH) is a common metabolic disease, although not adequately recognized and treated. Its rarer, homozygous form leads to a significant increase in LDL-cholesterol and marked development of atherosclerosis and its complications in very early phases of life. In its milder, much more common, heterozygous form, the appearance of clinical manifestations usually occurs later, depending on the intensity of the changes in lipid profile and the presence of other risk factors. Therapeutic resources for FH control range from changes in lifestyle to medications commonly used as high potency statins in high dosages, in most cases combined with ezetimibe and/or resins, niacin and fibrates. New products have recently been approved for use in other countries such as lomitapide and mipomersen, but only for homozygous FH. PCSK9 inhibitors are an important hope for the control of these patients.Research with CETP inhibitors has failed to demonstrate clinical benefits to date, but a clinical study evaluating one of them is still ongoing. Our country does not have availability of LDL-apheresis, a resource that has proven fundamental for improving the prognosis of patients with more severe forms of FH

Effect of n-3 fatty acids and statins on oxidative stress in statin-treated hypercholestorelemic and normocholesterolemic women.

INTRODUCTION: Although the combination of statins with n-3 fatty acids seems to be beneficial under the lipid profile aspect, there is little information about the interaction of these two compounds on oxidative stress. OBJECTIVE: Evaluate the interaction between statins and n-3 fatty acids on oxidative stress in women, using a 2² factorial design. METHODS: Forty-three women participated in this crossover design. They were separated into two groups in which 20 were under statin treatment for more than 6 months, and 23 were normolipidemic. Within each group, half of the patients received capsules containing 2.4 g/day of a mixture of EPA and DHA for 6 weeks, while the other half received a mixture of soya and corn oil. After a period of 90 days of washout, the groups were switched, and received the supplementation for 6 weeks more. RESULTS: Statins reduced serum LDL and increased SOD expression. n-3 fatty acids increased the plasma malondialdehyde and SOD activity but reduced catalase expression (p<0.05). The interaction involving statins and n-3 fatty acids was nearly significant to the serum triacylglycerol reduction (p=0.054). CONCLUSION: Combining statins and n-3 fatty acids is an excellent strategy to reduce plasma cholesterol and triacylglycerol concentration in women. However, n-3 fatty acids increased the oxidative stress and the pleiotropic effect of statins seemed to be not enough to counterbalance this result. Our data also suggested that the mechanism by which n-3 fatty acids interfere in oxidative stress can be associated with antioxidant enzymes expression and activity.