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.

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.