Implementación de un programa de angioplastia coronaria ambulatoria en pacientes con riesgo incrementado / Implementation of an Ambulatory Percutaneous Coronary Intervention Program in Higher Risk Patients

RESUMEN: Introducción: La hipercolesterolemia familiar es una hiperlipidemia primaria. Se trata de un trastorno genético autosómico dominante del metabolismo de las lipoproteínas, caracterizado por concentraciones plasmáticas elevadas de colesterol unido a lipoproteínas de baja densidad y presencia de xantomas tendinosos, y está asociado con el desarrollo prematuro de enfermedad cardiovascular. Objetivos: Investigar la presencia de mutaciones en el principal gen asociado al desarrollo de hipercolesterolemia familiar (LDLR) en un grupo de pacientes identificados como "casos índices", de entre aquellos que concurren al Servicio de Lípidos del Hospital Universitario Fundación Favaloro con diagnóstico clínico de hipercolesterolemia familiar. Determinar la composición ancestral de la población estudiada. Material y métodos: Se estudió una población de 38 pacientes con diagnóstico clínico de hipercolesterolemia familiar. La región codificante y las zonas intrónicas adyacentes del gen LDLR se secuenciaron automáticamente por el método de Sanger. Se investigó el componente ancestral de la población estudiada a partir del análisis de 46 marcadores informativos de ancestralidad (AIM-Indel). Resultados: Se identificaron 50 variantes diferentes, de las cuales el 48% se consideraron patogénicas. Se logró establecer una correlación genotipo-gravedad del fenotipo en el 60,5% de los pacientes estudiados. El componente ancestral de la población estudiada fue predominantemente europeo, seguido de un componente nativo-americano y, en menor proporción, africano. Conclusiones: El análisis genético por secuenciación del gen LDLR en pacientes identificados como "casos índices" con diagnóstico clínico de hipercolesterolemia familiar permite correlacionar el dato genético con la gravedad del fenotipo observado clínicamente y efectuar un diagnóstico en cascada en los miembros de la familia que presentan los criterios de inclusión considerados.

ABSTRACT: Background: Familial hypercholesterolemia is a primary hyperlipidemia. It is an autosomal dominant genetic disorder of lipoprotein metabolism, characterized by elevated plasma low-density lipoprotein cholesterol and presence of tendon xanthomas, and is associated with early cardiovascular disease. Objectives: The aim of this study was to investigate the presence of mutations in the main gene associated with the development of familial hypercholesterolemia (LDLR) in a group of patients identified as "index cases" attending the Lipid Clinic of the Hospital Universitario Fundación Favaloro with clinical diagnosis of familial hypercholesterolemia. The ancestral composition of the study population was determined. Methods: We evaluated 38 patients with clinical diagnosis of familial hypercholesterolemia. Mutation screening of the LDLR gene coding regions and adjacent intronic areas was performed using Sanger sequencing. The ancestral component of the study population was investigated using 46 ancestry inference markers (AIM-Indel). Results: Fifty different variants were identified, 48% of which were considered pathogenic. A genotype-phenotype severity correlation was established in 60.5% of the patients evaluated. The ancestral component of the study population was predominantly European, followed by native-American and African in lower proportion. Conclusions: Genetic testing by LDLR gene sequencing in patients identified as "index cases" with clinical diagnosis of familial hypercholesterolemia allows the correlation between the genetic information and the severity of the clinical phenotype to a cascade testing of the family members presenting the inclusion criteria considered.

Estudio genético de hipercolesterolemia familiar en una población hospitalaria de la Ciudad de Buenos Aires / Genetic Testing of Familial Hypercholesterolemia in a Hospital-Based Population of the City of Buenos Aires

RESUMEN: Introducción: La hipercolesterolemia familiar es una hiperlipidemia primaria. Se trata de un trastorno genético autosómico dominante del metabolismo de las lipoproteínas, caracterizado por concentraciones plasmáticas elevadas de colesterol unido a lipoproteínas de baja densidad y presencia de xantomas tendinosos, y está asociado con el desarrollo prematuro de enfermedad cardiovascular. Objetivos: Investigar la presencia de mutaciones en el principal gen asociado al desarrollo de hipercolesterolemia familiar (LDLR) en un grupo de pacientes identificados como "casos índices", de entre aquellos que concurren al Servicio de Lípidos del Hospital Universitario Fundación Favaloro con diagnóstico clínico de hipercolesterolemia familiar. Determinar la composición ancestral de la población estudiada. Material y métodos: Se estudió una población de 38 pacientes con diagnóstico clínico de hipercolesterolemia familiar. La región codificante y las zonas intrónicas adyacentes del gen LDLR se secuenciaron automáticamente por el método de Sanger. Se investigó el componente ancestral de la población estudiada a partir del análisis de 46 marcadores informativos de ancestralidad (AIM-Indel). Resultados: Se identificaron 50 variantes diferentes, de las cuales el 48% se consideraron patogénicas. Se logró establecer una correlación genotipo-gravedad del fenotipo en el 60,5% de los pacientes estudiados. El componente ancestral de la población estudiada fue predominantemente europeo, seguido de un componente nativo-americano y, en menor proporción, africano. Conclusiones: El análisis genético por secuenciación del gen LDLR en pacientes identificados como "casos índices" con diagnóstico clínico de hipercolesterolemia familiar permite correlacionar el dato genético con la gravedad del fenotipo observado clínicamente y efectuar un diagnóstico en cascada en los miembros de la familia que presentan los criterios de inclusión considerados.

ABSTRACT: Background: Familial hypercholesterolemia is a primary hyperlipidemia. It is an autosomal dominant genetic disorder of lipoprotein metabolism, characterized by elevated plasma low-density lipoprotein cholesterol and presence of tendon xanthomas, and is associated with early cardiovascular disease. Objectives: The aim of this study was to investigate the presence of mutations in the main gene associated with the development of familial hypercholesterolemia (LDLR) in a group of patients identified as "index cases" attending the Lipid Clinic of the Hospital Universitario Fundación Favaloro with clinical diagnosis of familial hypercholesterolemia. The ancestral composition of the study population was determined. Methods: We evaluated 38 patients with clinical diagnosis of familial hypercholesterolemia. Mutation screening of the LDLR gene coding regions and adjacent intronic areas was performed using Sanger sequencing. The ancestral component of the study population was investigated using 46 ancestry inference markers (AIM-Indel). Results: Fifty different variants were identified, 48% of which were considered pathogenic. A genotype-phenotype severity correlation was established in 60.5% of the patients evaluated. The ancestral component of the study population was predominantly European, followed by native-American and African in lower proportion. Conclusions: Genetic testing by LDLR gene sequencing in patients identified as "index cases" with clinical diagnosis of familial hypercholesterolemia allows the correlation between the genetic information and the severity of the clinical phenotype to a cascade testing of the family members presenting the inclusion criteria considered.

Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management / Estratificação de Risco Cardiovascular e Elegibilidade para Estatina com Base na Diretriz Brasileira vs. Norte-Americana para Manejo do Colesterol

Abstract Background: The best way to select individuals for lipid-lowering treatment in the population is controversial. Objective: In healthy individuals in primary prevention: to assess the relationship between cardiovascular risk categorized according to the V Brazilian Guideline on Dyslipidemia and the risk calculated by the pooled cohort equations (PCE); to compare the proportion of individuals eligible for statins, according to different criteria. Methods: In individuals aged 40-75 years consecutively submitted to routine health assessment at one single center, four criteria of eligibility for statin were defined: BR-1, BR-2 (LDL-c above or at least 30 mg/dL above the goal recommended by the Brazilian Guideline, respectively), USA-1 and USA-2 (10-year risk estimated by the PCE ≥ 5.0% or ≥ 7.5%, respectively). Results: The final sample consisted of 13,947 individuals (48 ± 6 years, 71% men). Most individuals at intermediate or high risk based on the V Brazilian Guideline had a low risk calculated by the PCE, and more than 70% of those who were considered at high risk had this categorization because of the presence of aggravating factors. Among women, 24%, 17%, 4% and 2% were eligible for statin use according to the BR-1, BR-2, USA-1 and USA-2 criteria, respectively (p < 0.01). The respective figures for men were 75%, 58%, 31% and 17% (p < 0.01). Eighty-five percent of women and 60% of men who were eligible for statin based on the BR-1 criterion would not be candidates for statin based on the USA-1 criterion. Conclusions: As compared to the North American Guideline, the V Brazilian Guideline considers a substantially higher proportion of the population as eligible for statin use in primary prevention. This results from discrepancies between the risk stratified by the Brazilian Guideline and that calculated by the PCE, particularly because of the risk reclassification based on aggravating factors.

Resumo Fundamento: Existe controvérsia sobre a melhor forma de selecionar indivíduos para tratamento hipolipemiante na população. Objetivos: Em indivíduos saudáveis em prevenção primária: avaliar a relação entre o risco cardiovascular segundo a V Diretriz Brasileira de Dislipidemias e o risco calculado pelas pooled cohort equations (PCE); comparar a proporção de indivíduos elegíveis para estatinas, de acordo com diferentes critérios. Métodos: Em indivíduos de 40 a 75 anos submetidos consecutivamente a avaliação rotineira de saúde em um único centro, quatro critérios de elegibilidade para estatina foram definidos: BR-1, BR-2 (LDL-c acima ou pelo menos 30 mg/dL acima da meta preconizada pela diretriz brasileira, respectivamente), EUA-1 e EUA-2 (risco estimado pelas PCE em 10 anos ≥ 5,0% ou ≥ 7,5%, respectivamente). Resultados: Foram estudados 13.947 indivíduos (48 ± 6 anos, 71% homens). A maioria dos indivíduos de risco intermediário ou alto pela V Diretriz apresentou risco calculado pelas PCE baixo e mais de 70% daqueles considerados de alto risco o foram devido à presença de fator agravante. Foram elegíveis para estatina 24%, 17%, 4% e 2% das mulheres pelos critérios BR-1, BR-2, EUA-1 e EUA-2, respectivamente (p < 0,01). Os respectivos valores para os homens foram 75%, 58%, 31% e 17% (p < 0,01). Oitenta e cinco por cento das mulheres e 60% dos homens elegíveis para estatina pelo critério BR-1 não seriam candidatos pelo critério EUA-1. Conclusões: Comparada à diretriz norte-americana, a V Diretriz Brasileira considera uma proporção substancialmente maior da população como elegível para estatina em prevenção primária. Isso se relaciona com discrepâncias entre o risco estratificado pela diretriz brasileira e o calculado pelas PCE, particularmente devido à reclassificação de risco baseada em fatores agravantes.

Endothelial Effect of Statin Therapy at a High Dose Versus Low Dose Associated with Ezetimibe / Efeito Endotelial da Terapia com Estatina em Alta Dose versus Baixa Dose Associada à Ezetimiba

Abstract Background: The effect of statins on the endothelial function in humans remains under discussion. Particularly, it is still unclear if the improvement in endothelial function is due to a reduction in LDL-cholesterol or to an arterial pleiotropic effect. Objective: To test the hypothesis that modulation of the endothelial function promoted by statins is primarily mediated by the degree of reduction in LDL-cholesterol, independent of the dose of statin administered. Methods: Randomized clinical trial with two groups of lipid-lowering treatment (16 patients/each) and one placebo group (14 patients). The two active groups were designed to promote a similar degree of reduction in LDL-cholesterol: the first used statin at a high dose (80 mg, simvastatin 80 group) and the second used statin at a low dose (10 mg) associated with ezetimibe (10 mg, simvastatin 10/ezetimibe group) to optimize the hypolipidemic effect. The endothelial function was assessed by flow-mediated vasodilation (FMV) before and 8 weeks after treatment. Results: The decrease in LDL-cholesterol was similar between the groups simvastatin 80 and simvastatin 10/ezetimibe (27% ± 31% and 30% ± 29%, respectively, p = 0.75). The simvastatin 80 group presented an increase in FMV from 8.4% ± 4.3% at baseline to 11% ± 4.2% after 8 weeks (p = 0.02). Similarly, the group simvastatin 10/ezetimibe showed improvement in FMV from 7.3% ± 3.9% to 12% ± 4.4% (p = 0.001). The placebo group showed no variation in LDL-cholesterol level or endothelial function. Conclusion: The improvement in endothelial function with statin seems to depend more on a reduction in LDL-cholesterol levels, independent of the dose of statin administered, than on pleiotropic mechanisms.

Resumo Fundamento: O efeito das estatinas na função endotelial em seres humanos permanece em discussão. Particularmente, ainda carece resposta se a melhora na função endotelial deve-se à redução do LDL-colesterol ou a um efeito pleiotrópico arterial. Objetivo: Testar a hipótese de que a modulação da função endotelial promovida por estatinas é prioritariamente mediada pelo grau de redução do LDL-colesterol, independente da dose de estatina utilizada. Métodos: Ensaio clínico randomizado com dois grupos de tratamento hipolipemiante (16 pacientes/cada) e um grupo placebo (14 pacientes). Os dois grupos ativos foram desenhados para promover graus semelhantes de redução de LDL-colesterol: o primeiro utilizou estatina em alta dose (80 mg, grupo sinvastatina 80) e o segundo em baixa dose (10 mg) associada a ezetimiba (10 mg, grupo sinvastatina 10/ezetimiba) para otimizar o efeito hipolipemiante. A função endotelial foi analisada pela vasodilatação mediada por fluxo (VMF) antes e após 8 semanas de tratamento. Resultados: A redução no LDL-colesterol foi semelhante entre os grupos sinvastatina 80 e sinvastatina 10/ezetimiba (27% ± 31% e 30% ± 29%, respectivamente, p = 0,75). O grupo sinvastatina 80 apresentou incremento da VMF de 8,4% ± 4,3% no basal para 11% ± 4,2% após 8 semanas (p = 0,02). Da mesma forma, o grupo sinvastatina 10/ezetimiba apresentou melhora da VMF de 7,3% ± 3,9% para 12% ± 4,4% (p = 0,001). O grupo placebo não apresentou variação no nível de LDL-colesterol ou da função endotelial. Conclusão: A melhora da função endotelial com uso de estatina parece depender mais da redução do LDL-colesterol, independente da dose de estatina utilizada, do que de mecanismos pleiotrópicos.

Efeitos pleiotrópicos das estatinas na sepse / Pleiotropic effects of statins in sepsis

O objetivo do presente estudo foi revisar os efeitos da terapia com estatinas em pacientes com quadro de sepse. Foi realizada uma busca bibliográfica de artigos na base de dados MEDLINE/PubMed, SciELO e LILACS, no período de publicação delimitado entre 2009 e 2013. Foram incluídos artigos referentes a ensaios clínicos randomizados controlados e estudos de coorte observacionais clínicos. Foram encontrados diversos estudos clínicos e observacionais que investigaram o efeito do uso de estatinas em infecções e em sepse, tanto de uso contínuo pré-hospitalar (com ou sem interrupção durante internação) ou com início imediato pós-internação. Alguns estudos descrevem prováveis efeitos positivos e benéficos da terapia com estatinas no quadro de sepse, dentre eles a melhora dos parâmetros inflamatórios e da taxa de mortalidade, porém, esses resultados não se sustentam quando são aplicados métodos estatísticos que levamem conta diferentes variáveis, tais como idade, sexo, comorbidades e gravidade da doença. Até o momento nenhum estudo demonstrou evidências sólidas e significativas quanto à redução de mortalidadee morbidade no quadro séptico associado ao uso de estatinas, indicando que seu efeito benéfico e protetor ainda não foi plenamente delimitado, sendo necessários mais estudos que confirmem os resultados até agora encontrados.

The objective of this study was to review the effects of statin therapy in patients with signs of sepsis. A bibliographic search of articles published between 2009-2013 was performed in the MEDLINE/PubMed, SciELO and LILACS databases. Randomized controlled trials and observational clinical cohort studies were included. The results show that several clinical and observational studies have investigated the effect of statin in infection and sepsis, both pre-hospital continuous use (with or without interruption during hospitalization) or starting immediately post-hospitalization. Some studies describe positive and beneficial effects of statin therapy in the contextof sepsis, including improvement on inflammatory parameters and mortality rates. However, these results do not hold on when statistic methods, which take into account different variables such as age, sex, comorbidities and severity disease, are applied. To date, no study has demonstrated strong and significant evidence regarding the reduction of morbidity and mortality in sepsis associated with the use of statin. This indicates that beneficial and protective effects have not been fully defined yet. More researches are required to confirm the results found so far.

Effectiveness of lipid-lowering therapy among a sample of patients in Colombia / Eficacia del tratamiento hipolipemiante en una muestra de pacientes de Colombia

OBJECTIVE: To determine the effectiveness of lipid-lowering therapy in a sample of patients affiliated with the Sistema General de Seguridad Social en Salud (the Colombian health system). METHODS: A cross-sectional study was conducted from 1 January 2010-30 June 2011. From a total of 8 316 patients in 10 cities, a random sample of 600 was stratified according to dyslipidemia. Information on sociodemographic and anthropometric characteristics, risk factors, and pharmacological and laboratory variables were obtained from medical records. RESULTS: Subjects were predominantly female (56.2%), with a mean age of 65.1 ± 11.5 years; 93.2% had hypertension; 29.0%, diabetes mellitus; and 10.2%, a history of myocardial infarction. The patients were being treated with lovastatin (84.1%) or gemfibrozil (12.3%)-both at doses below what is recommended-or atorvastatin (1.8%). In patients with high cardiovascular risk, 38.6% achieved goals for low-density lipoprotein cholesterol (LDL-C) levels (<100 mg/dL). Among those at moderate risk, 49.4% reached the target level (< 130 mg/dL). On average, there was a 4.9% reduction in LDL-C. Sex, age, history of cardiovascular disease and/or diabetes mellitus, use of hydrochlorothiazide, and poor therapy adherence were statistically associated with a lack of dyslipidemia control. CONCLUSIONS: Because a lack LDL-C control occurred in patients with two or more of the following variables: male, more than 55 years of age, diabetes and/or a history of cardiovascular disease, received lower doses of lovastatin, or non-adherent to treatment, it is recommended that medication be increased based on clearly-defined therapeutic goals and that comorbidities be assessed and effectively treated.

OBJETIVO: Determinar la eficacia del tratamiento hipolipemiante en una muestra de pacientes afiliados al Sistema General de Seguridad Social en Salud de Colombia. MÉTODOS: Se llevó a cabo un estudio transversal desde el 1 de enero del 2010 al 30 de junio del 2011. De un total de 8 316 pacientes de 10 ciudades seleccionadas, se estratificó una muestra aleatoria de 600 pacientes en función de la dislipidemia. A partir de los expedientes médicos, se obtuvo información sobre las características sociodemográficas y antropométricas, los factores de riesgo y las variables farmacológicas y de laboratorio. RESULTADOS: En la muestra predominaban las mujeres (56,2%) y la media de la edad era de 65,1 ± 11,5 años; 93,2% de los pacientes eran hipertensos; 29,0% eran diabéticos; y 10,2% tenían antecedentes de infarto de miocardio. Los pacientes recibían tratamiento con lovastatina (84,1%) o gemfibrozilo (12,3%) -ambos a dosis inferiores a las recomendadas- o atorvastatina (1,8%). El 38,6% de los pacientes con alto riesgo de enfermedad cardiovascular alcanzaron los objetivos de reducción de los niveles de colesterol unido a lipoproteínas de baja densidad (C-LDL) (< 100 mg/dL). El 49,4% de los pacientes que presentaban un riesgo moderado también alcanzaron los niveles fijados como objetivo (< 130 mg/dL). En promedio, hubo una reducción de 4,9% del C-LDL. El sexo, la edad, los antecedentes personales de enfermedad cardiovascular y diabetes, la administración de hidroclorotiazida y la deficiente adherencia al tratamiento se asociaron estadísticamente con una falta de control de la dislipidemia. CONCLUSIONES: Dado que se produjo un control deficitario del C-LDL en pacientes con dos o más de las siguientes variables: varones, mayores de 55 años, diabéticos o con antecedentes de enfermedad cardiovascular, que recibían dosis bajas de lovastatina, o mostraban falta de adherencia al tratamiento, se recomienda que se aumente la medicación con base en objetivos terapéuticos claramente definidos y que se evalúen y se traten eficazmente las comorbilidades.

Rosuvastatina e ciprofibrato no tratamento da dislipidemia em pacientes com HIV / Rosuvastatin and ciprofibrate in the treatment of dyslipidemia in patients with HIV

FUNDAMENTO: A dislipidemia secundária à terapia antirretroviral potente nos pacientes com HIV está associada à significativa elevação da morbimortalidade cardiovascular por doença aterosclerótica, sendo, portanto, necessário tratamento imediato e eficaz. OBJETIVO: Demonstrar a efetividade e a segurança da rosuvastatina e do ciprofibrato no tratamento da dislipidemia associada à terapia antirretroviral potente em pacientes com HIV. MÉTODOS: Trezentos e quarenta e seis pacientes com dislipidemia foram submetidos a tratamento farmacológico: 200 pacientes com hipertrigliceridemia receberam ciprofibrato (Grupo I); 79 pacientes com hipercolesterolemia receberam rosuvastatina (Grupo II); e 67 pacientes com dislipidemia mista receberam ciprofibrato associado a rosuvastatina (Grupo III). O perfil lipídico foi avaliado antes e após o tratamento hipolipemiante, sendo feita comparação estatística pelo teste de Wilcoxon. Transaminases hepáticas e creatinofosfoquinase foram dosadas para controle de toxicidade hepática e muscular. RESULTADOS: As concentrações séricas de triglicérides e de colesterol total foram significativamente menores do que as obtidas antes do tratamento, para os três grupos experimentais (p < 0,002). Observou-se aumento significativo do HDL colesterol nos grupos experimentais I e III (p < 0,002). Nos grupos I e II, o LDL-colesterol foi significativamente menor (p < 0,001). Nenhum dos pacientes apresentou elevações de transaminases ou de creatinofosfoquinase a níveis de toxicidade significativa. CONCLUSÃO: Os resultados deste estudo demonstram que ciprofibrato, rosuvastatina ou a combinação de ambos pode ser considerada tratamento hipolipemiante efetivo, seguro e com boa tolerância nos pacientes com Aids submetidos à terapia antirretroviral potente.

BACKGROUND: Dyslipidemia secondary to highly active antiretroviral therapy in patients with HIV is associated with a significant increase in cardiovascular morbidity and mortality due to atherosclerotic disease, requiring, thus, immediate and effective treatment. OBJECTIVE: To demonstrate the effectiveness and safety of rosuvastatin and ciprofibrate in the treatment of dyslipidemia associated with highly active antiretroviral therapy in patients with HIV. METHODS: Three hundred and forty-six patients with dyslipidemia underwent pharmacological treatment as follows: 200 patients with hypertriglyceridemia received ciprofibrate (Group I); 79 patients with hypercholesterolemia received rosuvastatin (Group II); and 67 patients with mixed dyslipidemia received ciprofibrate associated with rosuvastatin (Group III). The lipid profile was assessed before and after the lipid-lowering treatment, and the Wilcoxon test was used for statistical comparison. Liver transaminases and creatine phosphokinase were measured to assess liver and muscle toxicity. RESULTS: The serum concentrations of triglycerides and total cholesterol were significantly lower than those obtained before the lipid-lowering treatment in the three experimental groups (p < 0.002). A significant increase in HDL-cholesterol was observed in Groups I and III (p < 0.002). In Groups I and II, LDL-cholesterol was significantly lower (p < 0.001). None of the patients experienced elevations in transaminases or creatine phosphokinase to significantly toxic levels. CONCLUSION: The results of this study show that ciprofibrate and rosuvastatin or a combination of both can be considered an effective, safe and well-tolerated lipid-lowering treatment for patients with AIDS on highly active antiretroviral therapy.