Identification of APOB variants in samples from the brazilian population with hypercholesterolemic phenotype

BACKGROUND AND AIMS: Apolipoprotein B plays a crucial role in regulating plasma cholesterol by mediating the interaction of low-density lipoprotein (LDL) with LDL receptors in the liver. Inherited mutations in this gene may increase the risk of developing premature atherosclerotic cardiovascular disease, especially in individuals with familial hypercholesterolemia type 2 (FH2). The aim of this study is to identify APOB variants that may indicate pathogenicity in a sample of the Brazilian population using a data bank exome sequencing study by NGS in a Brazilian population phenotypically diagnosed by clinical and laboratory profile. This finding is going to improve genetic hypercholesteremia diagnosis. METHODS: High-quality DNA samples (n»300) were sequenced using an exon-targeted gene sequencing (ETGS) strategy to identify variants in FHrelated genes. Pathogenicity classification was based on criteria established by the American College of Medical Genetics and Genomics (ACMG), also using information from ClinVar and pathogenicity scores from previous association studies. RESULTS: A total of 121 variants were identified in APOB, of which four are novel variants missense (p.Thr626Asn, p.Ile2750Thr, p.Gln2078Lys and p.Met4184Arg). After curating pathogenicity scores, variants were classified according to the ACMG criteria. Among them four as pathogenic or likely pathogenic (p.Pro2739Leu, p.His1923Arg, p.Pro994Leu and p.Pro877Leu), and 21 variants had uncertain significance. Additionally, 92 previously known variants with uncertain significance were classified as benign or likely benign. The results were submitted to Clinvar for actualization of pathogenicity. CONCLUSIONS: These results improve the molecular diagnosis associating APOB variants with the clinical phenotype of hypercholesterolemia.

Variante no gene LDL-R associada com elevação do LDL-C identificada em um portador de hipercolesterolemia familiar / LDL-R gene variant associated with LDL-C elevation identified in a carrier of familial hypercholesterolemia

INTRODUÇÃO: A hipercolesterolemia familiar (HF) é uma doença hereditária autossômica codominante marcada por altos níveis de colesterol ligado à lipoproteína de baixa densidade (LDL-c). Pode-se apresentar na forma homozigótica, apresentando prevalência de 1/160.000 a 1/1.000.000 ou na forma heterozigótica, um caso em cada 200-250 pessoas. Material e MÉTODO: Paciente do sexo feminino, aos 11 meses foi encaminhada ao setor de Dislipidemia para acompanhamento. Na primeira consulta, apresentava colesterol total (CT): 325 mg/dL, LDL-c: 255 mg/dL, colesterol ligado à lipoproteína de alta densidade (HDL-c): 44 mg/dL, triglicerídeos (TG): 128 mg/ dL. Exame físico: sem alterações. Durante o seguimento, paciente realizou doppler de carótidas e vertebrais sem aumento da espessura médio intimal e tomografia computadorizada com escore de cálcio de zero. Paciente foi incluída no protocolo para o sequenciamento exômico dos principais genes relacionados com a HF. A paciente apresentou 9 diferentes variantes, todos em heterozigose, com cobertura maior que 30 vezes, distribuídas nos 3 genes, no entanto nenhuma previamente associada com HF. RESULTADOS: Trata-se de uma criança cuja alteração do perfil lipídico foi identificada precocemente. A análise do perfil genético identificou uma mutação que está relacionada ao fenótico de HF. As variantes mais comuns relacionadas à HF estão localizadas no gene que codifica o receptor da LDL (LDLR). Dentre as variantes analisadas, somente a variante rs1433099 no gene LDLR foi previamente associada a elevação do LDL-c e maior suscetibilidade a desenvolver doença arterial coronariana. No entanto esse achado nunca havia sido descrito em pacientes com diagnóstico clínico de HF. DISCUSSÃO E CONCLUSÕES: O relato de caso apresentou uma variante genética que não havia sido descrita previamente relacionada à HF. Dessa forma, devido à grande importância da hereditariedade nos quadros de dislipidemias, à pequena parcela de genes descritos e validados, sugere-se que a variante rs1433099 no gene LDLR seja incorporada nos exames genéticos associadas a essa patologia; possibilitando a expansão do diagnóstico, além do tratamento precoce dessa enfermidade tão frequente.

Variabilidade lipídica e risco cardiovascular / Lipid variability and cardiovascular risk

Introdução: As doenças cardiovasculares são a principal causa de óbito no mundo e geram um importante impacto econômico. Hipertensão arterial, diabetes mellitus, dislipidemia, tabagismo e obesidade são os fatores de risco modificáveis mais implicados no aparecimento de infarto agudo do miocárdio (IAM) e acidente vascular encefálico (AVE). A variabilidade nas medidas de parâmetros cardiovasculares tem surgido nos últimos anos como novo fator de risco cardiovascular. Nesse contexto, estudos têm mostrado que uma maior variabilidade de colesterol ligado à lipoproteína de baixa densidade (LDL-C) e colesterol ligado à lipoproteína de alta densidade (HDL-C) está associada com piores desfechos cardiovasculares. Entretanto, nenhum estudo até o momento avaliou o grupo específico de pacientes submetidos à cirurgia de revascularização miocárdica (CRM). Assim, elaborou-se este estudo com o intuito de avaliar se uma maior variabilidade nas medidas de LDL-C e HDL-C em pacientes submetidos à CRM está associada com eventos cardiovasculares maiores, definidos como: IAM não fatal, AVE não fatal, hospitalização por insuficiência cardíaca, hospitalização por angina, nova revascularização (cirúrgica ou percutânea) e morte. Métodos: A população do estudo foi composta de uma coorte de pacientes que foram submetidos à CRM isolada, no período 01 de janeiro de 2012 a 31 de dezembro de 2012. A variabilidade de LDL-C e HDL-C será avaliada por três índices: desvio padrão, coeficiente de variação e variabilidade corrigida independente da média. Resultados: Dos 568 pacientes submetidos à CRM isolada em 2012, 34 pacientes foram a óbito ainda na mesma internação. Também foram excluídos do estudo 50 pacientes que só tiveram uma coleta, e 133 pacientes que não tiveram nenhuma coleta de lípides séricos no período de seguimento, restando 351 pacientes que foram incluídos. Durante o período de seguimento, os pacientes incluídos tiveram total de 2090 coletas de lípides, sendo a média 5,9 coletas. No total, 46 pacientes tiveram somente 2 coletas, e um paciente teve o número máximo de coletas (18). Na primeira medida após a alta hospitalar, o valor médio de colesterol total foi de 155,7 mg/dL, 84,7 mg/dL para LDL-C, 41,8 mg/dL para HDL-C e 152 mg/dL para triglicerídeos. As análises de variabilidade estão sendo realizadas. Conclusão: Espera-se avaliar se uma maior variabilidade nas medidas de LDL-C e HDL-C em pacientes submetidos à CRM está associado com eventos cardiovasculares maiores.

Análise funcional in silico das variantes no gene da APOB em pacientes com hipercolesterolemia familial / In silico functional analysis of variants in the APOB gene in patients with familial hypercholesterolemia

INTRODUÇÃO: O diagnóstico molecular da hipercolesterolemia familial (HF) é atribuído principalmente as variantes nos genes LDLR, LDLRAP1, APOB e PCSK9. O objetivo deste estudo foi realizar análise in silico para investigar o impacto de variantes sem descrição na literatura no gene APOB observado em pacientes com HF. MÉTODOS: Foram selecionados 141 indivíduos com diagnóstico clínico de HF. As variantes no gene da APOB foram selecionadas após sequenciamento dos éxons de 61 genes utilizando a plataforma MiSeq (Illumina). Os dados foram analisados nos programas Real Time Analysis, MiSeq Reporter, BaseSpace Sequence Hub e VariantStudio. Para a análise in silico, as sequências molde das moléculas da apoB-100 e o LDLr foram selecionadas por modelagem comparativa considerando o maior grau de identidade. As sequências proteicas foram alinhadas e os modelos 3D foram construídos utilizando os programas SEAVIEW e MODELLER v9.21. O gráfico de Ramachandran do modelo de menor energia apresenta 0,5% de outliers e análise de regiões de desordem, como principal validação. Os resultados das conformações de ancoragem foram analisados no software PyMol 2.1. Os estudos de docking molecular foram realizados para identificar o melhor complexo de conformação usando o servidor web clusPRO. RESULTADOS: Após a análise molecular dos 141 pacientes foram identificadas 7 variantes missenses sem descrição na literatura no gene APOB (c.433C>T, c.2630C>T, c.2950G>A, c.5743G>A, c.7367C>A, c.9880T>C e c.10780T>C). Os estudos de docking das variantes demonstraram uma maior afinidade entre o LDLr e a apoB-100 (c.2630C> T; Pro877Leu) em comparação com a proteína não mutada. A troca dos resíduos permaneceu como propriedade físico-química, e comparando as distâncias de ligação das proteínas não-mutadas (5Å) e mutadas (3,5Å), sugere-se uma maior afinidade do complexo (LDLr-apoB-100) para a leucina, tal fato é afirmado pela análise da região de desordens da apoB-100, onde a posição 877 está em uma região desorganizada e flexível. Esta maior afinidade poderia levar a uma menor dissociação intracelular deste complexo, resultando em uma alta taxa de degradação do LDLr pelas enzimas lisossômicas, levando ao aumento da concentração plasmática de LDLc. Para as outras variantes não houve alterações significativas. CONCLUSÃO: Os resultados sugerem que estudos in silico baseados na ferramenta de docking molecular podem melhorar o conhecimento da contribuição genética no desenvolvimento da doença HF. Além disso, a variante APOB c.2630C> T deve ser avaliada in vitropara validação do mecanismo proposto. (AU)

Metas lipídicas: mundo real / Lipid goals: real world

INTRODUÇÃO: Frente à crescente evidência da redução de eventos cardiovasculares relacionados à redução do LDL colesterol (LDL-c), a Sociedade Brasileira de Cardiologia (SBC) propôs em 2017 metas mais agressivas de LDL-c. OBJETIVO: Avaliar em um centro terciário de cardiologia a proporção de pacientes que atingiram metas de LDL-c propostas pela Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose da SBC conforme estratificação de risco cardiovascular. METODOLOGIA: Foram analisados 2180 pacientes consecutivos em controle ambulatorial quanto à fatores de risco cardiovascular e terapia medicamentosa vigente. Conforme a diretriz, foram classificados em risco baixo, intermediário, alto e muito alto com metas de LDL-c < 130, 100, 70 e 50 mg/dL, respectivamente. RESULTADOS: A média de idade foi de 65 anos, sendo 53% dos pacientes do sexo feminino. Do total, 1225 (56.2%) eram de risco muito alto, 900 (41.3%) alto, 50 (2.3%) intermediário e 5 (0.2%) de baixo risco. Trezentos e noventa e nove pacientes (18.3%) atingiram as metas de LDL-c estabelecidas pela diretriz, sendo 11.1%, 26.2%, 46% e 80% de cada faixa de risco, respectivamente. Destes, 74.5% dos pacientes de muito alto risco, 56.2% de alto risco, 86% de risco intermediário e 40% de baixo risco estavam em uso de estatinas na intensidade e doses preconizadas pela diretriz. Apenas 148 (6.8%) pacientes não usavam estatina. (AU)

Genetic variants in genes related to lipid metabolism and atherosclerosis, dyslipidemia and atorvastatin response.

OBJECTIVE: Using candidate gene approach, we have investigated the effect of single nucleotide polymorphism (SNP) in genes related to lipid metabolism and atherosclerosis on dyslipidemia and atorvastatin response. METHODS: The study included 157 patients treated with atorvastatin and 145 controls. Genomic DNA was isolated and genotyped using SNPlex technology. RESULTS: Allele and genotype disease association test revealed that APOB rs693 (OR: 2.2 [1.5-3.2], p=0.0001) and CD36 rs1984112 (OR: 3.7 [1.9-7.0], p=0.0002) SNPs were independent risk factors for hypercholesterolemia. Only APOB rs693 T variant allele was associated with increased LDL cholesterol levels (>160mg/dL). After atorvastatin treatment (10mg/day/4weeks), LIPC -514T allele was positively associated with LDL cholesterol reduction. CONCLUSION: The current study reinforces the current knowledge that carrying APOB rs693 is an independent risk factor for dyslipidemia and higher LDL levels. Furthermore, we found that a variant of CD36 was associated with dyslipidemia as a risk (rs1984112) factor. Finally, atorvastatin response could be predicted by LIPC -514C>T SNP and physical activity. In conclusion, our data evidences the contribution of genetic markers and their interaction with environmental factor in the variability of statin response.

Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus.

BACKGROUND: Oxidative stress plays an important role in the pathophysiology of diabetes mellitus. The aim of this study was to evaluate the formation of cholesterol oxides (ChOx) as biomarkers of oxidative stress in subjects with impaired glucose tolerance (IGT) and diabetes. METHODS: Blood plasma levels of cholesterol oxidation products were determined in the following groups: type 1 diabetes mellitus (DM1), type 2 diabetes (DM2), impaired glucose tolerance (IGT), children without diabetes (C1) and adults without diabetes (C2). The serum levels of cholest-5-ene-3alpha,7alpha-diol (7alpha-hydroxycholesterol, 7alpha-OH), cholest-5-ene-3beta,7beta-diol (7beta-hydroxycholesterol, 7beta-OH), 3beta-hydroxycholest-5-7-one (7-ketocholesterol, 7-K), 5alpha-cholestane-3beta,5,6beta-triol (cholestanetriol), 5,6alpha-epoxy-5alpha-cholestan-3alpha-ol (cholesterol-5alpha,6alpha-epoxide,), 5,6beta-epoxy-5beta-cholestan-3beta-ol (cholesterol-5beta,6beta-epoxide) and cholest-5-eno-3beta,25-diol (25-hydroxycholesterol, 25-OH) (trivial name and abbreviations indicated in parentheses) were quantified by gas chromatography using flame ionization detection. RESULTS: The levels of total ChOx were elevated in the DM1 and DM2 groups compared to age-matched subjects without diabetes (p < 0.05). The concentrations of 7beta-hydroxycholesterol, cholesterol-alpha-epoxide and cholesterol-beta-epoxide were higher in the blood plasma of subjects in the DM2 group than in the blood plasma of subjects in the C2 and IGT groups (p < 0.05). Treatment of type 2 diabetic patients with oral hypoglycemic drugs associated with insulin resulted in lower concentrations of nitrotyrosine in the blood plasma without significant changes in the concentrations of glucose and glycated hemoglobin. Moreover, combination with statins in both treatments decreased the concentrations of ChOx. CONCLUSIONS: ChOx are suitable biomarkers of oxidative stress and may be useful in clinical studies to follow drug effects on lipid oxidative modifications in diabetic patients.

Eff ect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial / Eff ect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial

Background Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion.

The aim of this study was to assess prospectively the drug’s ability to prevent type 2 diabetes in individuals at high risk

of developing the condition.

Methods 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and

no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive

rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was

a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at

Findings At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo

group. 306 (11·6%) individuals given rosiglitazone and 686 (26·0%) given placebo developed the composite primary

outcome (hazard ratio 0·40, 95% CI 0·35–0·46; p<0·0001); 1330 (50·5%) individuals in the rosiglitazone group and

798 (30·3%) in the placebo group became normoglycaemic (1·71, 1·57–1·87; p<0·0001). Cardiovascular event rates

were much the same in both groups, although 14 (0·5%) participants in the rosiglitazone group and two (0·1%) in the

Interpretation Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the

likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or

Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus / Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus

Background Oxidative stress plays an important role in the pathophysiology of diabetes mellitus. The aim of this study was to evaluate the formation of cholesterol oxides (ChOx) as biomarkers of oxidative stress in subjects with impaired glucose tolerance (IGT) and diabetes. Methods Blood plasma levels of cholesterol oxidation products were determined in the following groups: type 1 diabetes mellitus (DM1), type 2 diabetes (DM2), impaired glucose tolerance (IGT), children without diabetes (C1) and adults without diabetes (C2). The serum levels of cholest-5-ene-3£/,7£/-diol (7£/-hydroxycholesterol, 7£/-OH), cholest- 5-ene-3£],7£]-diol (7£]-hydroxycholesterol, 7£]-OH), 3£]-hydroxycholest-5-7- one (7-ketocholesterol, 7-K), 5£/-cholestane-3£],5,6£]-triol (cholestanetriol), 5,6£/-epoxy-5£/-cholestan-3£/-ol (cholesterol-5£/,6£/-epoxide,), 5,6£]-epoxy- 5£]-cholestan-3£]-ol (cholesterol-5£],6£]-epoxide) and cholest-5-eno-3£],25-diol (25-hydroxycholesterol, 25-OH) (trivial name and abbreviations indicated in parentheses) were quantified by gas chromatography using flame ionization detection. Results The levels of total ChOx were elevated in the DM1 and DM2 groups compared to age-matched subjects without diabetes (p < 0.05).The concentrations of 7£]-hydroxycholesterol, cholesterol-£/-epoxide and cholesterol-£]-epoxide were higher in the blood plasma of subjects in the DM2 group than in the blood plasma of subjects in the C2 and IGT groups (p < 0.05). Treatment of type 2 diabetic patients with oral hypoglycemic drugs associated with insulin resulted in lower concentrations of nitrotyrosine in the blood plasma without significant changes in the concentrations of glucose and glycated hemoglobin. Moreover, combination with statins in both treatments decreased the concentrations of ChOx.Conclusions ChOx are suitable biomarkers of oxidative stress and may be useful in clinical studies to follow drug effects on lipid oxidative modifications in diabetic patients. Copyright ÆÉ 2006 John Wiley & Sons, Ltd.

High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent.

The MDR1 gene encodes the P-glycoprotein, an efflux transporter with broad substrate specificity. P-glycoprotein has raised great interest in pharmacogenetics because it transports a variety of structurally divergent drugs, including lipid-lowering drugs. The synonymous single-nucleotide polymorphism C3435T and the nonsynonymous single-nucleotide polymorphism G2677T/A in MDR1 have been indicated as potential determinants of variability in drug disposition and efficacy. In order to evaluate the effect of G2677T/A and C3435T MDR1 polymorphisms on serum levels of lipids before and after atorvastatin administration, 69 unrelated hypercholesterolemic individuals from São Paulo city, Brazil, were selected and treated with 10 mg atorvastatin orally once daily for four weeks. MDR1 polymorphisms were analyzed by PCR-RFLP. C3435T and G2677T polymorphisms were found to be linked. The allelic frequencies for C3435T polymorphism were 0.536 and 0.464 for the 3435C and 3435T alleles, respectively, while for G2677T/A polymorphism allele frequencies were 0.580 for the 2677G allele, 0.384 for the 2677T allele and 0.036 for the 2677A allele. There was no significant relation between atorvastatin response and MDR1 polymorphisms (repeated measures ANOVA; P > 0.05). However, haplotype analysis revealed an association between T/T carriers and higher basal serum total (TC) and LDL cholesterol levels (TC: 303 +/- 56, LDL-C: 216 +/- 57 mg/dl, respectively) compared with non-T/T carriers (TC: 278 +/- 28, LDL-C: 189 +/- 24 mg/dl; repeated measures ANOVA/Tukey test; P < 0.05). These data indicate that MDR1 polymorphism may have an important contribution to the control of basal serum cholesterol levels in Brazilian hypercholesterolemic individuals of European descent.

High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent

The MDR1 gene encodes the P-glycoprotein, an efflux transporter with broad substrate specificity. P-glycoprotein has raised great interest in pharmacogenetics because it transports a variety of structurally divergent drugs, including lipid-lowering drugs. The synonymous single-nucleotide polymorphism C3435T and the nonsynonymous single-nucleotide polymorphism G2677T/A in MDR1 have been indicated as potential determinants of variability in drug disposition and efficacy. In order to evaluate the effect of G2677T/A and C3435T MDR1 polymorphisms on serum levels of lipids before and after atorvastatin administration, 69 unrelated hypercholesterolemic individuals from São Paulo city, Brazil, were selected and treated with 10 mg atorvastatin orally once daily for four weeks. MDR1 polymorphisms were analyzed by PCR-RFLP. C3435T and G2677T polymorphisms were found to be linked. The allelic frequencies for C3435T polymorphism were 0.536 and 0.464 for the 3435C and 3435T alleles, respectively, while for G2677T/A polymorphism allele frequencies were 0.580 for the 2677G allele, 0.384 for the 2677T allele and 0.036 for the 2677A allele. There was no significant relation between atorvastatin response and MDR1 polymorphisms (repeated measures ANOVA; P > 0.05). However, haplotype analysis revealed an association between T/T carriers and higher basal serum total (TC) and LDL cholesterol levels (TC: 303 ± 56, LDL-C: 216 ± 57 mg/dl, respectively) compared with non-T/T carriers (TC: 278 ± 28, LDL-C: 189 ± 24 mg/dl; repeated measures ANOVA/Tukey test; P < 0.05). These data indicate that MDR1 polymorphism may have an important contribution to the control of basal serum cholesterol levels in Brazilian hypercholesterolemic individuals of European descent.

Acute in vivo chylomicron metabolism and postalimentary lipoprotein alterations in normolipidemic male smokers.

Increased postprandial lipemia has been stated as one of the mechanisms responsible for atherogenesis in smokers. We measured the postalimentary lipid response and the in vivo intravascular delipidation index of an artificial chylomicron emulsion in healthy adult smokers and controls. The blood was collected in the fasting state immediately after the smokers smoked one cigarette. The lipemia was measured 2, 4, 6 and 8 h postalimentarily in smokers (S, n = 8) and in non-smoking controls (C, n = 8) and the chylomicron metabolism rate was measured 2, 4, 6, 8, 12, 16, 20, 24 and 30 min after the injection of an artificial emulsion to S (n = 10) and to C (n = 10). The lipoproteins were isolated in the fasting period and 4 h after the fatty meal and their chemical composition in cholesterol, triglycerides, phospholipids and protein was determined. Smokers showed an increased lipolysis percentage value (mean +/- S.E.M.) of the artificial chylomicron (39.1 +/- 3.1) compared to controls (26.5 +/- 3.3) and higher levels of HDL(2)-PL: 28.4 +/- 4.3 (S) versus 16.2 +/- 2.0 (C) mg/dl (mean +/- S.E.M.). In conclusion, the oral fat tolerance was not altered in smokers but an upregulation of the rate of metabolism of the TG-rich lipoproteins was elicited immediately after smoking one cigarette.

Evaluation of the effects of a new fermented milk product (Gaio) on primary hypercholesterolemia.

OBJECTIVE: To verify the effects on the lipid profile of a product of fermented milk (Gaio) in patients with mild to moderate primary hypercholesterolemia. DESIGN: The study was prospective, randomized, double-blinded and placebo controlled, with a crossover design. SUBJECTS: Thirty-two patients (21 women and 11 men) with ages ranging between 36 and 65 years old were included in the study. All of them were on a controlled diet for at least 8 weeks. INTERVENTION: Patients began, after clinical and laboratory analysis, in a randomized and double-blind manner to take 200 g daily of Gaio or its placebo. After 8 weeks blood was collected again for lipid profile evaluation and the crossover was made. After an additional 8 weeks blood was collected for another lipid profile determination. RESULTS: All patients included completed the study. Comparisons were made between means of lipid profile constituents after the placebo and active product periods. These showed significant mean reduction of 5.3% (P = 0.004) for total cholesterol, 6.15% (P = 0.012) for LDL-cholesterol and no significant variation for HDL-cholesterol and triglycerides. The majority of patients presented no variation or had a decrease in their total cholesterol level. However, during the active product period, three patients showed an increase in cholesterol level by more than 5%. CONCLUSION: The fermented milk (Gaio) produced a small but statistically significant decrease in total and LDL-cholesterol mean. However, not all subjects seem to respond to the product, and a few subjects showed a cholesterol increment. Further investigations are necessary to clarify this aspect.

Atuaçäo do exercício físico sobre os fatores de risco para doenças cardiovasculares / Acuation of physical exercise over risk factors for cardiovascular diseases

Etudos têm demonstrado que o sedentarismo está associado com maior incidência de doença coronária. Inversamente, a prática regular de atividade física é útil na prevençäo primária e secundária dessa importante doença. Os mecanismos pelos quais os exercícios físicos influem sobre a doença coronária näo estäo total totalmente elucidados. Sabe-se que a açäo benéfica da atividade física pode depender da melhora da capacidade cardiorrespiratória e da atuaçäo sobre vários fatores de risco importantes paro desencadeamento da aterosclerose coronária. Tem sido demonstrado que a intensidade de exercício capas de melhorar o perfil metabólico é menor do que a necessária para levar o incremento importante da capacidade cardiorrespiratória.

[Randomized, double-blind comparative study between pravastatin and lovastatin. Evaluation of efficacy and safety]. / Estudo comparativo duplo-cego, randomizado entre pravastatina e lovastatina. Análise da eficácia e segurança.

PURPOSE: To verify eventual difference observed in the efficacy and safety of lovastatin (L) when compared to pravastatin (P), considering increasing doses up to the maximum and recommended ones in clinical practice. METHODS: Forty-eight hypercholesterolemic patients (LDL-C > 160 mg/dl after a placebo seven-day period) were studied and randomly assigned to constitute groups of 24 patients (GL and GP groups). The patients from GL group received L 20 mg/day and those from GP group P 10 mg/day, in a double-blind fashion. Six and 12 weeks later, the those were doubled. At the end of the placebo period and at weeks 6, 12 and 18 they were evaluated for clinical data and laboratorial parameters, such as: lipid profile (TC, TG, HDL-C and LDL-C); enzymes AST, ALT, CPK, gamma-GT, alkalin phosphatase); biochemical data (urea, creatinine, bilirubin, uric acid, glucose); complete blood count and urinalysis. RESULTS: Both drugs have shown significant reductions in TC and LDL-C levels at the lowest clinical doses (L 20 mg/day; P 10 mg/day), which became more marked as doses were gradually increased. However, the responses were always significantly greater for L in all doses employed. No adverse effects requiring treatment discontinuation were observed for both drugs. CONCLUSION: L showed a higher TC and LDL-C lowering effect than that observed with P, when the doses recommended by the respective manufacturers were compared.

[Lipid profile of metallurgic industry employees and its relationship with other risk factors]. / Perfil lipídico de funcionários de indústria metalúrgica e sua relação com outros fatores de risco.

PURPOSE: To study the lipid profile and its relation with other risk factors for coronary heart disease in a population of metallurgic workers in São Bernardo do Campo, SP. METHODS: In 1966 employees were determined: lipid profile after 12h fasting, height and weight and they answered a questionnaire about other risk factors. Diabetic and hypertensive were excluded, remaining 1586 cases, 1384 males, mean age 34. The variables of the lipid profile were related with other risk factors (sex, age, smoking, body mass index, physical activity at work and at leisure time) and alcohol intake. RESULTS: Five hundred and eighty people (36.6%) had total cholesterol > 200mg/dl, 104 (6.4%) triglycerides > 250mg/dl, 273 (17.2%) HDL-cholesterol < 35mg/dl and 579 (36.9%) LDL-cholesterol > 130mg/dl, levels considered ideals for the different lipid variables. The different relations between lipid levels and the other variable analysed: age, sex, body mass index, smoking, alcohol intake, physical activity at work and leisure time were described. CONCLUSION: The frequency of lipid abnormalities is high in the assessed population. For primary prevention, a strategy has to be taken to modify this picture.

[Comparison between lovastatin and gemfibrozil in treatment of primary hyperlipidemias]. / Comparação entre a lovastatina e o gemfibrozil no tratamento de hiperlipidemias primárias.

PURPOSE: To compare the effects of lovastatin and gemfibrozil in patients with primary hyperlipidemias. PATIENTS AND METHODS: Forty patients with cholesterolemia over 200 mg/dl and triglyceridemia not higher than 350 mg/dl, excluded secondary causes, were selected. Twenty patients received lovastatin and 20 gemfibrozil. In order to establish the lipid profile, blood samples were taken after 2 months without medication, after 4 weeks of diet and placebo and after 6 and 12 weeks of active treatment. Biochemical profile was determined before and after the treatment with active drug. RESULTS: Thirty nine patients completed the study. Total and LDL-cholesterol were significantly reduced (p less than 0.05) by both drugs but lovastatin had greater effect. Only gemfibrozil reduced triglycerides significantly. Neither drug had significant effects on HDL-cholesterol. The tolerance was satisfactory; only one patient (using gemfibrozil) needed to stop the treatment due to gastrointestinal side effects. The biochemical profile did not present any significant alteration. CONCLUSION: Both drugs produced useful effects on the lipid profile. Lovastatin produced greater reductions of total and LDL-cholesterol, while gemfibrozil was more active reducing triglycerides. Neither drug changed significantly the HDL-cholesterol.