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1.
Praxis (Bern 1994) ; 109(10): 755-762, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32752965

RESUMO

CME: Primary and Secondary Hypercholesterolemia Abstract. In patients with hypercholesterolemia and an LDL-cholesterol level >5 mmol/l, familial hypercholesterolemia (primary hypercholesterolemia) should be considered. This genetically determined illness should lead to medical therapy and screening for hypercholesterinemia in close relatives. Beside the superelevated LDL-cholesterol levels, additional clinically diagnostic findings and family anamnesis can support the diagnosis of familial hypercholesterolemia. The likelihood of familial hypercholesterolemia can be estimated using the Lipid Clinic Network Score. Additionally, a variety of exogenous factors may have an impact on lipoprotein metabolism and may lead to secondary hypercholesterolemia. Hypothyroidism, cholestasis, nephrotic syndrome or specific medications, among others, should be considered as potential factors leading to high cholesterol levels before familial hypercholesterolemia is suspected or lipid-lowering treatment is started.


Assuntos
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , LDL-Colesterol , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/terapia , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/terapia , Lipídeos , Programas de Rastreamento
2.
Am J Cardiol ; 128: 28-34, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32650921

RESUMO

Involvement of atherosclerosis in extracardiac vascular territories may identify coronary artery disease (CAD) patients at higher risk for adverse events. We investigated the long-term prognostic implications of polyvascular disease in patients with CAD, and further analyzed lipid goal attainment and its relation to patient outcomes. The study was a retrospective analysis of 10,297 patients who underwent coronary revascularization, categorized as having CAD alone (83.1%) or with multisite artery disease (MSAD) (16.9%) including cerebrovascular disease (CBVD) and/or peripheral artery disease (PAD). Incidence rates and hazard ratios (HR) for major adverse cardiovascular events (MACE) (myocardial infarction, ischemic stroke, or all-cause death) according to vascular territories involved, and in relation to most-recent lipid levels attained, were analyzed. Patients with MSAD were older with higher burden of co-morbidities. The rate of MACE (myocardial infarction, ischemic stroke, or all-cause death) and its individual components increased with the number of affected vascular beds. Adjusted HR (95% confidence interval) for MACE was 1.41 (1.24 to 1.59) in patients with CAD and CBVD, 1.46 (1.33 to 1.62) in CAD and PAD, and 1.69 (1.49 to 1.92) in those with CAD and CBVD and PAD, compared with CAD alone. Most-recent low-density lipoprotein cholesterol (LDL-C) levels <55 mg/dl and <70 mg/dl were attained by 21.8% and 44.6% of patients with CAD alone, in comparison to 22.7% and 43.3% in MSAD. Compared with patients with most-recent LDL-C > 100 mg/dl, attaining LDL-C < 70 mg/dl had an adjusted HR for MACE of 0.52 (0.47 to 0.57) in CAD only patients and 0.66 (0.57 to 0.78) in MSAD patients. In conclusion, the presence of CBVD and/or PAD in patients with CAD is associated with higher burden of co-morbidities and progressive increase in long-term MACE. More than half of CAD patients with or without MSAD do not achieve lipid goals, which are associated with a significantly lower risk for adverse events.


Assuntos
Transtornos Cerebrovasculares/epidemiologia , Doença da Artéria Coronariana/cirurgia , Hipercolesterolemia/terapia , Infarto do Miocárdio/epidemiologia , Revascularização Miocárdica , Doença Arterial Periférica/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Angina Instável/epidemiologia , Angina Instável/cirurgia , Aneurisma da Aorta Abdominal/epidemiologia , Causas de Morte , LDL-Colesterol/sangue , Comorbidade , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/epidemiologia , Incidência , Israel/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio sem Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio sem Supradesnível do Segmento ST/cirurgia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia
3.
Clín. investig. arterioscler. (Ed. impr.) ; 32(2): 49-58, mar.-abr. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-187146

RESUMO

Background and aims: The first line of therapy in children with hypercholesterolaemia is therapeutic lifestyle changes (TLSC). The efficacy of lifestyle intervention in children with familial hypercholesterolaemia (FH), where LDL-C levels are genetically driven, deserves a focused study. Aims: To evaluate the impact of a lifestyle education program, focused on food patterns and physical activity, on lipid profiles assessed by nuclear magnetic resonance (NMR) in children with FH vs. non-FH. Methods: Phase 1 was a cross-sectional study of baseline characteristics, and phase 2 was a prospective TLSC intervention study. In total, the study included 238 children (4 to 18 years old; 47% girls) attending the lipid unit of our hospital due to high cholesterol levels. Eighty-five were diagnosed with FH (72% genetic positive), and 153 were diagnosed with non-Familial hypercholesterolaemia. A quantitative food frequency questionnaire (FFQ) including 137 items was used. Physical activity (PA) was assessed by the Minnesota questionnaire. The lipid profile was assessed using the 2D-1H-NMR (Liposcale test). A total of 127 children (81 in the FH group) participated in the prospective phase and were re-assessed after 1 year of the TLSC intervention, consisting of education on lifestyle changes delivered by a specialized nutritionist. Results: The FH and non-FH groups were similar in anthropometry and clinical data, except that those in the FH were slightly younger than those in the non-FH group. Both the FH and non-FH groups showed a similar diet composition characterized by a high absolute calorie intake and a high percentage of fat, mainly saturated fat. The PA was below the recommended level in both groups. After one year of TLSC, the percentage of total and saturated fats was reduced, and the amount of fiber increased significantly in both groups. The percentage of protein increased slightly. The number of children engaged in at least 1 hour/day of PA increased by 56% in the FH group and by 53% in the non-FH group, and both these increases were significant. The total and small-LDL particle numbers were reduced in both groups, although the absolute change was greater in the FH group than in the non-FH group. Conclusions: Educational strategies to implement TLSC in children lead to empowerment, increased adherence, and overall metabolic improvement in children with high blood cholesterol, including those with FH


Antecedentes y objetivos: La primera línea de terapia en niños con hipercolesterolemia son los cambios terapéuticos en el estilo de vida (TLSC). La eficacia de la intervención en el estilo de vida en niños con hipercolesterolemia familiar (HF), en los que los niveles de LDL-C son generados genéticamente, merece un estudio específico. Objetivos: Evaluar el impacto de un programa de educación sobre el estilo de vida, centrado en los patrones alimentarios y la actividad física, sobre el perfil lipídico evaluado por resonancia magnética nuclear (RMN) en niños con HF versus no HF. Métodos: La fase 1 fue un estudio transversal de las características basales, y la fase 2 fue un estudio prospectivo de intervención mediante TLSC. En total, el estudio incluyó a 238 niños (de 4 a 18 años; 47% niñas) que asistieron a la unidad de lípidos de nuestro hospital debido a los altos niveles de colesterol. Ochenta y cinco fueron diagnosticados con HF (72% genéticamente positivos), y 153 fueron diagnosticados de no HF. Se utilizó un cuestionario cuantitativo de frecuencia de alimentos (FFQ) que incluye 137 ítems. La actividad física (AF) se evaluó mediante el cuestionario de Minnesota. El perfil lipídico se evaluó mediante la prueba 2D-1H-NMR (Liposcale Test). Un total de 127 niños (81 en el grupo HF) participaron en la fase prospectiva y fueron reevaluados después de 1 año de la intervención mediante TLSC, que consistió en educación sobre cambios en el estilo de vida impartida por una nutricionista especializada. Resultados: Los grupos HF y no HF fueron similares en los datos antropométricos y clínicos, excepto que los HF eran ligeramente más jóvenes que los no HF. Los participantes de ambos grupos mostraron una composición de dieta similar caracterizada por un alto consumo de calorías totales y un alto porcentaje de grasas, principalmente grasas saturadas. La AF estuvo por debajo del nivel recomendado en ambos grupos. Después de un año de TLSC, se redujo el porcentaje de grasas totales y saturadas, y la cantidad de fibra aumentó significativamente en ambos grupos. El porcentaje de proteína aumentó ligeramente. El número de niños involucrados en al menos 1 hora/día de AF aumentó en un 56% en el grupo de HF y en un 53% en el grupo sin HF, y ambos aumentos fueron significativos. Los números de partículas LDL totales y pequeñas se redujeron en ambos grupos, aunque el cambio absoluto fue mayor en el grupo HF que en el grupo no HF. Conclusiones: Las estrategias educativas para implementar TLSC en niños conducen al empoderamiento, al aumento de la adherencia y a la mejora metabólica general en niños con colesterol alto en sangre, incluidos aquellos con HF


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Hipercolesterolemia/sangue , Hipercolesterolemia/terapia , Estilo de Vida , Educação de Pacientes como Assunto , Lipoproteínas LDL/sangue , Dietoterapia , Terapia por Exercício , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/terapia , Ressonância Magnética Nuclear Biomolecular , Estudos Transversais , Estudos Prospectivos , Resultado do Tratamento
4.
J Nutr Sci Vitaminol (Tokyo) ; 65(5): 421-429, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31666479

RESUMO

Diosgenin (Dio) is a steroid sapogenin found in plants such as Dioscorea species, and is recognized as a phytochemical against various disorders as well as a natural precursor of steroidal drugs. The present study used rats fed high-cholesterol (Chol) diets supplemented with or without 0.5% Dio for 6 wk to investigate the effects of dietary Dio on lipid metabolism. Dio supplementation significantly increased serum high-density lipoprotein Chol concentrations and fecal Chol content, and significantly decreased fecal bile acid content compared rats fed a high-Chol diet alone, showing that dietary Dio may facilitate excretion of Chol rather than bile acids. A reduction in the liver triglyceride content and intra-abdominal visceral fat was observed in Dio-supplemented rats. Interestingly, dietary Dio also significantly increased the skeletal muscle-fiber diameter and area in the thigh muscles of the rats. Mouse myoblast-derived C2C12 cells were used to examine whether Dio directly affected skeletal muscle. Dio promoted fusion of myoblasts into multinucleated cells or myotubes. Furthermore, in myotube C2C12 cells, protein levels of phosphorylated AMP-activated protein kinase (AMPK) increased with Dio treatment in a dose-dependent manner. These results indicate that Dio may not only induce myoblast fusion and enhance skeletal muscle as an energy expenditure organ, but may also activate the catabolic pathway via AMPK in skeletal muscle cells. Thus, these effects of Dio on skeletal muscles may contribute to inhibition of visceral fat accumulation.


Assuntos
Suplementos Nutricionais , Diosgenina/administração & dosagem , Hipercolesterolemia/terapia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ácidos e Sais Biliares/análise , Colesterol/análise , HDL-Colesterol/sangue , Dieta Hiperlipídica , Fezes/química , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Hipertrofia , Gordura Intra-Abdominal/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Ratos , Coxa da Perna/patologia , Triglicerídeos/análise
6.
Int J Clin Pharmacol Ther ; 57(12): 575-589, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31549625

RESUMO

OBJECTIVE: Bococizumab, a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, has been shown to reduce low-density lipoprotein cholesterol (LDL-C). Here, we describe the pharmacokinetics and pharmacodynamics of bococizumab and its effect on lipoprotein particle composition and other biomarkers, based on a double-blind, placebo-controlled, randomized, dose-ranging study. MATERIALS AND METHODS: The study consisted of two populations: Japanese subjects with uncontrolled LDL-C (LDL-C ≥ 100 mg/dL) despite treatment with atorvastatin (n = 121) and Japanese subjects naïve to lipid-lowering agents with LDL-C ≥ 130 mg/dL (n = 97). Subjects were randomized to receive either bococizumab 50, 100, or 150 mg or placebo, every 2 weeks. One arm of subjects in the ator-vastatin-treated population received ezetimibe 10 mg instead of bococizumab. RESULTS: In both populations, bococizumab exposure increased with increasing dose, and subjects with lower body weights tended to have higher exposures. Bococizumab treatment was associated with a dose-dependent reduction in LDL particles and a small increase in total high-density lipoprotein (HDL) particles. Significant reductions in lipoprotein-associated phospholipase A2 (Lp-PLA2) were observed for bococizumab-treated subjects but not for subjects treated with placebo or ezetimibe. CONCLUSION: Increased bococizumab dosage resulted in increased exposure. Levels of LDL and HDL particles and biomarkers such as Lp-PLA2 were also altered with bococizumab treatment. (ClinicalTrials.gov identifier: NCT02055976).
.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticolesterolemiantes/farmacocinética , Hipercolesterolemia/terapia , Pró-Proteína Convertase 9/antagonistas & inibidores , Atorvastatina/uso terapêutico , Biomarcadores/sangue , Método Duplo-Cego , Humanos , Japão , Resultado do Tratamento
7.
Food Funct ; 10(9): 6098-6109, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31495848

RESUMO

Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD). Probiotics are one of the most popular dietary supplements for hypercholesterolemia, but there are questions as to whether there are differences between probiotics and cholesterol-lowering drugs like atorvastatin (ATO) both in effectiveness and in the underlying mechanisms. In this study, the hypocholesterolemia effects of 4 probiotic strains were investigated and compared with ATO, focusing on their impacts on the gut microbiota. A hypercholesterolemia model was established via high-fat diet (HFD) in golden hamsters after which ATO and the 4 probiotics were orally administered individually for 8 weeks. All probiotics were effective, but less than ATO, on body weight, serum parameters (TG, TC, LDL, INS, HbA1c) and expression of inflammatory factors (INF-α, IL-1ß, CRP), with strain JQII-5 being most significant. Besides, these effects were associated with restoration of microbiota dysbiosis induced by HFD. It was worth noting that ATO and probiotics induced different shifts of the gut microbiota in both structure and key phylotypes. Most interestingly, Allobaculum, a HFD-suppressed genus, reported to be involved in alleviating oxidative stress, was enriched by all tested probiotic strains, but not by ATO. Furthermore, Prevotella, also a HFD-suppressed genus, was uniquely reversed by JQII-5. Importantly, most of the alerted genera and reversed genera were found to be correlated with the inflammatory state and serum lipid level. Compared with ATO, the probiotic strains were less effective on body weight, hypercholesterolemia, and inflammation. However, probiotics exert additional favorable effects on the gut microbiota, making them excellent potential complements to cholesterol-lowering drugs like ATO.


Assuntos
Atorvastatina/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Hipercolesterolemia/terapia , Lactobacillus plantarum/fisiologia , Pediococcus/fisiologia , Animais , Anticolesterolemiantes/uso terapêutico , Bactérias/classificação , Bactérias/isolamento & purificação , Cricetinae , Citocinas/análise , Disbiose/etiologia , Disbiose/terapia , Fezes/microbiologia , Glucose/metabolismo , Hipercolesterolemia/tratamento farmacológico , Masculino , Mesocricetus , Pediococcus acidilactici/fisiologia , Pediococcus pentosaceus/fisiologia , Probióticos/uso terapêutico , Ganho de Peso/efeitos dos fármacos
8.
Atheroscler Suppl ; 39: e1-e8, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31451336
9.
Med. clín (Ed. impr.) ; 153(1): 1-5, jul. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-183350

RESUMO

Antecedentes y objetivo: Varios estudios han puesto de manifiesto un cumplimiento terapéutico subóptimo en la población general, sobre todo en ancianos y en enfermos crónicos. El objetivo de este estudio es describir la adherencia al tratamiento de diabetes mellitus, dislipidemia e hipertensión arterial, e identificar los factores que la influencian. Material y métodos: Estudio observacional transversal retrospectivo sobre 16.208 pacientes mayores de 65 años de la Cohorte EpiChron, que iniciaron tratamiento en monoterapia de un antidiabético, un hipolipidemiante o un antihipertensivo en 2010. La adherencia se midió mediante el cálculo de la relación de posesión de medicación durante un año de seguimiento, considerándose adherentes los casos con posesión de medicación ≥80%. Se realizó un estudio descriptivo y un modelo de regresión logística para identificar los factores predictores de baja adherencia. Resultados: La adherencia a los antidiabéticos, antihipertensivos e hipolipidemiantes fue del 72,4; 50,7 y 44,3%, respectivamente. Se observó un aumento en la adherencia del 3-8% por cada enfermedad crónica adicional del paciente. La presencia de enfermedad mental no afectó a la adherencia, y el sexo, edad y número de fármacos prescritos no presentaron efectos consistentes. Conclusiones: Los resultados obtenidos ponen de manifiesto una adherencia al tratamiento subóptima en las enfermedades crónicas estudiadas. La adherencia aumentó con el número de enfermedades crónicas, mientras que sexo, edad y número de fármacos no presentaron un efecto consistente. Es necesario investigar si existen otros factores que puedan influir en la adherencia terapéutica, ya que su mejora puede tener mayor impacto en la salud que cualquier avance en las terapias


Background and objective: Sub-optimal adherence to treatment in the general population has been highlighted in several studies, especially in the elderly and/or chronic patients. This study aims to describe the adherence to treatment of diabetes mellitus, dyslipidaemia and hypertension, and to identify the factors that influence adherence. Material and method: Retrospective, cross-sectional observational study on 16,208 patients aged ≥65 years from the EpiChron Cohort who initiated monotherapy treatment of an antidiabetic, a lipid-lowering or an antihypertensive medication in 2010. Adherence was measured by calculating the medication possession ratio during one year, considering those cases with medication possession ratio ≥80% to be adherent. We performed a descriptive study, and a logistic regression model was used to identify the predictors of low adherence. Results: Adherence to antidiabetics, antihypertensive and lipid-lowering drugs was 72.4%, 50.7% and 44.3%, respectively. An increase in adherence of 3-8% was observed for each additional chronic disease suffered by the patient. The presence of mental illness did not affect adherence, and sex, age and number of prescribed drugs did not present consistent effects. Conclusion: The results obtained show a sub-optimal adherence to treatment for the 3chronic diseases studied. Adherence increased with the number of chronic diseases, while sex, age and number of drugs did not show a consistent effect. It is necessary to investigate if there are other factors that may influence therapeutic adherence, since improving adherence may have a greater impact on health than any progress in therapies


Assuntos
Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Cooperação e Adesão ao Tratamento , Hipertensão/terapia , Hipercolesterolemia/terapia , Diabetes Mellitus/terapia , Estudos de Coortes , Estudos Transversais , Estudos Retrospectivos , Modelos Logísticos , Doença Crônica/tratamento farmacológico , Doença Crônica/epidemiologia
10.
Stroke ; 50(7): 1819-1824, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31167621

RESUMO

Background and Purpose- Risk factor control and treatment compliance in the following months after stroke are poor. We aim to validate a digital platform for smartphones to raise awareness among patients about the need to adopt healthy lifestyle, improve communication with medical staff, and treatment compliance. Methods- Farmalarm is an application (app) for smartphones designed to increase stroke awareness by medication alerts and compliance control, chat communication with medical staff, didactic video files, exercise monitoring. Patients with stroke discharged home were screened for participation and divided into groups: to follow the FARMALARM program for 3 to 4 weeks or standard of care follow-up. We determined achievement of risk factor control goals at 90 days. Results- From August 2015 to December 2016, from the 457 patients discharged home, 159 (34.8%) were included: Farmalarm (n=107); age 57±12, Control (n=52), age 59±10; without significant differences in baseline characteristics between groups. At 90 days, knowledge of vascular risk factors was higher in FARMALARM group (86.0% versus 69.2%, P<0.01). The rate of patients with diabetes mellitus (83.2% versus 63.5%, P<0.01) and hypercholesterolemia (80.3% versus 63.5%, P=0.03) under control and the rate of patients with 4 out of 4 risk factors under control was higher in FARMALARM group (50.4% versus 30.7%, P=0.02). A regression model showed that the use of Farmalarm was independently associated with all risk factors under control at 90 days (odds ratio, 2.3; 95% CI, 1.14-4.6; P=0.02). Conclusions- In patients with stroke discharged home, the use of mobile apps to monitor medication compliance and increase stroke awareness is feasible and seems to improve the control of vascular risk factors.


Assuntos
Aplicativos Móveis , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/terapia , Idoso , Comunicação , Complicações do Diabetes/terapia , Exercício Físico , Feminino , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/terapia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Fatores de Risco , Prevenção Secundária , Smartphone
11.
Appl Microbiol Biotechnol ; 103(15): 5993-6006, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201452

RESUMO

Atherosclerosis is the major cause of cardiovascular diseases, which are considered the fatal ailment globally. Hypercholesterolaemia plays a critical role in the development of atherosclerosis and cardiovascular diseases. Many studies have been stated that probiotics could affect hypercholesterolemia via cholesterol metabolism. Probiotics are live bacteria which are good for our health when administered orally in high amounts. Recently, many studies have revealed the beneficial effects of the nutritional ingestion of probiotics which can decrease serum cholesterol levels. The aim of this review is, firstly, to explore the hypercholesterolemia effect of how it progresses into atherosclerosis and, secondly, to summarize the hypocholesterolaemia effect of probiotics on atherosclerosis and the up-to-date information on their basic mechanisms. The most important mechanisms responsible for the hypocholesterolemic effect of probiotics are the suppression of the reabsorption of bile acids and inhibition of the intestinal cholesterol absorption. Current studies indicate that numerous mechanisms within the cholesterol metabolism, e.g., ones involving the Niemann-Pick C1-Like 1 protein, 3-hydroxy-3-methylglutaryl-CoA reductase, and 7α- and 27α-hydroxylases, have been recommended where regulation may take place after oral intake of probiotics. However, these mechanisms are still poorly understood. Thus, further studies are required to examine the possible mechanisms, whereby probiotics can be utilized safely and considered for the treatment of hypercholesterolemia.


Assuntos
Aterosclerose/prevenção & controle , Aterosclerose/fisiopatologia , Hipercolesterolemia/complicações , Hipercolesterolemia/terapia , Probióticos/administração & dosagem , Probióticos/farmacologia , Animais , Colesterol/metabolismo , Humanos
12.
Biomater Sci ; 7(7): 2777-2792, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31041934

RESUMO

Cationic liposomes have shown great potential in efficient siRNA delivery, and their positive charge is crucial for tight extracellular siRNA binding, effective intracellular siRNA disassembly and physiological toxicity. Thus, the development of novel cationic lipids with a suitable positive charge is desirable for safe and efficient siRNA delivery. Herein, we fabricated a library of 21 tertiary amine-derived cationic lipids (TA) to achieve a balance between effectiveness and safe siRNA delivery. The screened TA13 liposomes, which consisted of TA13 and helper lipid DOPE at a mole ratio of 1 : 1, readily condensed siRNA to form lipoplexes (TA13 LPs), achieving stronger gene silencing in diverse cells than the commercially available vector Lipo2000. Moreover, the TA13 LPs demonstrated effective in vivo gene silencing and good safety in normal mice. The improved gene silencing efficiency of the TA13 LPs is ascribed to their capability of sequentially conquering the barriers met by in vivo siRNA delivery. Notably, the TA13 LPs delivered ApoB-siRNA and obviously decreased ApoB mRNA expression in the liver and the total cholesterol and low-density lipoprotein in the serum of hypercholesterolemia mice, indicating a potential siRNA therapeutic for hypercholesterolemia treatment. It is anticipated that these novel tertiary amine-based liposomes can provide a simple and widely-used platform for the safe and effective delivery of siRNA, and their structure-activity relationships can aid in the further development of effective cationic lipids.


Assuntos
Aminas/química , Portadores de Fármacos/química , Lipídeos/química , RNA Interferente Pequeno/química , Segurança , Animais , Portadores de Fármacos/toxicidade , Inativação Gênica , Células HeLa , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/terapia , Lipídeos/toxicidade , Células MCF-7 , Masculino , Camundongos , RNA Interferente Pequeno/genética
13.
Curr Atheroscler Rep ; 21(7): 26, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31041550

RESUMO

PURPOSE OF REVIEW: Lipoprotein apheresis is a very efficient but time-consuming and expensive method of lowering levels of low-density lipoprotein cholesterol, lipoprotein(a)) and other apoB containing lipoproteins, including triglyceride-rich lipoproteins. First introduced almost 45 years ago, it has long been a therapy of "last resort" for dyslipidaemias that cannot otherwise be managed. In recent years new, very potent lipid-lowering drugs have been developed and the purpose of this review is to define the role of lipoprotein apheresis in the current setting. RECENT FINDINGS: Lipoprotein apheresis still plays an important role in managing patients with homozygous FH and some patients with other forms of hypercholesterolaemia and cardiovascular disease. In particular, patients not achieving treatment goals despite modern lipid-lowering drugs, either because these are not tolerated or the response is insufficient. Recently, lipoprotein(a) has emerged as an important cardiovascular risk factor and lipoprotein apheresis has been used to decrease lipoprotein(a) concentrations in patients with marked elevations and cardiovascular disease. However, there is considerable heterogeneity concerning the recommendations by scientific bodies as to which patient groups should be treated with lipoprotein apheresis. Lipoprotein apheresis remains an important tool for the management of patients with severe drug-resistant dyslipidaemias, especially those with homozygous FH.


Assuntos
Remoção de Componentes Sanguíneos/métodos , LDL-Colesterol/sangue , Hipercolesterolemia/terapia , Hiperlipoproteinemia Tipo II/terapia , Lipoproteína(a)/sangue , Lipoproteínas/sangue , Triglicerídeos/sangue , Remoção de Componentes Sanguíneos/efeitos adversos , Remoção de Componentes Sanguíneos/economia , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/genética , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores
14.
Int J Mol Sci ; 20(9)2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31064116

RESUMO

Hypercholesterolemia may be causally related to heart failure with preserved ejection fraction (HFpEF). We aimed to establish a HFpEF model associated with hypercholesterolemia and type 2 diabetes mellitus by feeding a high-sucrose/high-fat (HSHF) diet to C57BL/6J low-density lipoprotein receptor (LDLr)-/- mice. Secondly, we evaluated whether cholesterol-lowering adeno-associated viral serotype 8 (AAV8)-mediated LDLr gene transfer prevents HFpEF. AAV8-LDLr gene transfer strongly (p < 0.001) decreased plasma cholesterol in standard chow (SC) mice (66.8 ± 2.5 mg/dl versus 213 ± 12 mg/dl) and in HSHF mice (84.6 ± 4.4 mg/dl versus 464 ± 25 mg/dl). The HSHF diet induced cardiac hypertrophy and pathological remodeling, which were potently counteracted by AAV8-LDLr gene transfer. Wet lung weight was 19.0% (p < 0.001) higher in AAV8-null HSHF mice than in AAV8-null SC mice, whereas lung weight was normal in AAV8-LDLr HSHF mice. Pressure-volume loop analysis was consistent with HFpEF in AAV8-null HSHF mice and showed a completely normal cardiac function in AAV8-LDLr HSHF mice. Treadmill exercise testing demonstrated reduced exercise capacity in AAV8-null HSHF mice but a normal capacity in AAV8-LDLr HSHF mice. Reduced oxidative stress and decreased levels of tumor necrosis factor-α may mediate the beneficial effects of cholesterol lowering. In conclusion, AAV8-LDLr gene therapy prevents HFpEF.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Terapia Genética/métodos , Insuficiência Cardíaca/prevenção & controle , Hipercolesterolemia/terapia , Receptores de LDL/genética , Animais , Colesterol/sangue , Dependovirus/genética , Diabetes Mellitus Tipo 2/etiologia , Cardiomiopatias Diabéticas/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/efeitos adversos , Feminino , Insuficiência Cardíaca/fisiopatologia , Hipercolesterolemia/complicações , Hipercolesterolemia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Receptores de LDL/metabolismo , Volume Sistólico , Fator de Necrose Tumoral alfa/sangue
15.
Benef Microbes ; 10(5): 555-567, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31090460

RESUMO

Hypercholesterolemia is a main risk factor of cardiovascular disease. Probiotics are a safe approach to reduce elevated cholesterol without any deleterious effect to human health. Saccharomyces boulardii CNCM I-745 probiotic properties are well documented in a context of intestinal dysbiosis. Recent in vitro and preclinical studies have suggested its potential effects on dyslipidemia. This is the first controlled study investigating the effects of S. boulardii CNCM I-745 on lipidemic profile and gut microbiota in a hamster hypercholesterolemic model. Daily administration (3 g/kg) of S. boulardii for 21 or 39 days in hamsters fed a 0.3% cholesterol-diet significantly reduced total plasma cholesterol (P<0.001) and increased faecal total cholesterol (P<0.05) compared to vehicle-treated animals. S. boulardii significantly modified the gut microbiota composition of the hamster fed a 0.3% cholesterol-diet. These microbial abundancy modifications of the microbiota were correlated to variations of lipidemic values or liver genes expressions. In particularly we found that abundance of g_Allobaculum, the most modified taxon after S. boulardii treatment (+236%; P<0.05), was correlated to variations in plasmatic lipoproteins level and ABCG5 hepatic gene expression. We also observed a not previously described correlation between the levels of g_Oxalobacter in the gut microbiota and total cholesterol plasma concentration. In conclusion, we confirmed the cholesterol-lowering effects of S. boulardii intake and we demonstrated for the first time the S. boulardii effect on gut microbiota in the context of hypercholesterolemia in hamsters. Our results provide new insights for a beneficial and safe approach of hypercholesterolemia treatment and could be considered for clinical development, alone or in addition to conventional treatment.


Assuntos
Disbiose/complicações , Disbiose/terapia , Hipercolesterolemia/terapia , Lipídeos/análise , Plasma/química , Probióticos/administração & dosagem , Saccharomyces boulardii/crescimento & desenvolvimento , Animais , Cricetinae , Modelos Animais de Doenças , Fezes/química , Microbioma Gastrointestinal , Resultado do Tratamento
16.
Dtsch Med Wochenschr ; 144(5): 322-328, 2019 03.
Artigo em Alemão | MEDLINE | ID: mdl-30836403

RESUMO

Atherosclerotic cardiovascular disease is the leading cause of premature mortality and morbidity worldwide. Dyslipidemia is a commonly encountered clinical condition and is an important determinant of cardiovascular disease. The causality of plasma low-density lipoprotein-cholesterol (LDL-C) in the pathophysiology of cardiovascular disease has been established beyond any reasonable doubt. In this context, individual risk estimation, the determination of target values and lipid-lowering strategies represent an essential part and a challenge in the daily clinical practice to prevent cardiovascular events. Statins are recommended as first-line therapy for patients with hypercholesterolemia in secondary prevention. Controversies remain in the context of primary prevention, however, as to which kind of subjects to treat, the magnitude of the benefit, and potential harm. This article gives a brief overview of the current evidence, guideline recommendations and strategies for lowering of LDL-C in the primary prevention of cardiovascular disease.


Assuntos
Hipercolesterolemia , Prevenção Primária , Humanos , Hipercolesterolemia/prevenção & controle , Hipercolesterolemia/terapia , Guias de Prática Clínica como Assunto
17.
J Clin Apher ; 34(4): 423-433, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30817043

RESUMO

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition with monoclonal antibodies has complemented the armamentarium of lipid-lowering therapy (LLT) before the final step of commencing chronic lipoprotein apheresis (LA). Data are scarce on patients who, after escalation of LLT with PCSK9 antibodies, have commenced chronic LA or PCSK9 antibody treatment during ongoing long-term LA. PATIENTS AND METHODS: In this study, a cohort of 110 patients with established atherosclerotic cardiovascular disease (ASCVD) due to hypercholesterolemia or concomitant lipoprotein(a)-hyperlipoproteinemia, who received PCSK9 antibodies for the first time during routine care, were consecutively identified. RESULTS: Mean LDL-C concentration prior to initiation of LA or PCSK9 antibody treatment was 5.3 ± 2.6 mmol/L (205 ± 102 mg/dL). Due to established ASCVD, the risk-adjusted LDL-C target value was <1.8 mmol/L (<70 mg/dL) in all patients. Use of PCSK9 antibodies increased the proportion of patients attaining the LDL-C target concentration by 41.8% overall. Treatment emergent adverse events (TEAE) associated with PCSK9 antibody medication were reported in 35 patients (31.8%). Discontinuation of PCSK9 antibody therapy due to TEAEs occurred in 25 patients (22.7%). CONCLUSION: Finally, 55.5% of patients received a combination of PCSK9 antibody therapy and LA at individually optimized treatment frequencies resulting in an increase of target attainment in 54.1% of patients. About 18.1% of chronic LA patients terminated LA treatment in this real-world study. The termination of long-term LA therapy, which has hitherto prevented the progression of ASCVD, requires careful individual risk assessment and cannot be recommended by the general criteria of LDL-C reduction.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Remoção de Componentes Sanguíneos/métodos , Terapia Combinada/métodos , Lipoproteínas/isolamento & purificação , Pró-Proteína Convertase 9/antagonistas & inibidores , Aterosclerose/terapia , LDL-Colesterol/isolamento & purificação , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Hipercolesterolemia/terapia , Lipídeos/isolamento & purificação , Lipoproteína(a)/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/imunologia
19.
Blood Purif ; 47(4): 301-316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799420

RESUMO

BACKGROUND AND AIM: Elevated low-density lipoprotein cholesterol and/or lipoprotein(a) are established risk factors for cardiovascular disease (CVD). Management of hypercholesterolemia consists of drug therapies, including statins and proprotein convertase subtilisin/kexin type 9 inhibitors. In patients with familial hypercholesterolemia (FH), lipoprotein apheresis (LA) is utilized to control lipid levels. However, LA is not currently a standard therapy for non-FH. This review summarizes the literature regarding LA therapy in CVD prevention. METHODS: PubMed/MEDLINE databases were searched using the keywords "LA" and "CVD". Citations were individually reviewed for relevance. RESULTS: The efficacy of LA was clearly demonstrated, largely based on evidence from observational studies. In patients who are unresponsive to traditional lipid-lowering medications, LA effectively reduced serum lipoprotein levels and adverse cardiovascular events. CONCLUSION: It was concluded that LA is a safe and effective technique that could be considered in the management of hypercholesterolemia and future risk. Randomized control trials would further support a role for LA as a therapeutic option.


Assuntos
Doenças Cardiovasculares/terapia , Lipoproteína(a)/sangue , Plasmaferese , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Aterosclerose/terapia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipercolesterolemia/terapia , Plasmaferese/efeitos adversos , Plasmaferese/métodos , Fatores de Risco , Padrão de Cuidado , Resultado do Tratamento
20.
Appl Microbiol Biotechnol ; 103(7): 3181-3191, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30783721

RESUMO

Hypercholesterolemia plays a critical role in the development of atherosclerosis and cardiovascular diseases. Many works have been reported that gut microbiota could affect hypercholesterolemia through cholesterol metabolism. However, the role of gut microbiota on cholesterol transportation remains unclear. In this study, 8-week-old C57BL/6J mice were fed with high-cholesterol diet to build the hypercholesterolemic mice. Then, the hypercholesterolemic mice got the oral administration of Enterococcus faecalis ATCC19433 at a dose of 109 CFU/mL/day or PBS with high-cholesterol diet for 4 weeks. Serum was collected to detect the concentration of total cholesterol (TC). Meanwhile, pathology, histology, real-time polymerase chain reaction, Western blot, and immunofluorescence were used to evaluate the expression of ABCG5 and ABCG8 in the liver and small intestine. We also analyzed the composition of gut microbiota through high-throughput sequencing method. Oral administration of E. faecalis ATCC19433 significantly decreased the concentration of serum cholesterol in hypercholesterolemic mice. Furthermore, E. faecalis ATCC19433 reduced the concentration of liver cholesterol and improved cholesterol by increasing the expression of ABCG5 and ABCG8. Moreover, oral administration of E. faecalis ATCC19433 modulated the composition of gut microbiota and increased the counts of Lactobacillus, Bifidobacterium, and Akkermansia. Our results showed that E. faecalis ATCC19433 could exert hypocholesterolemic effect on hypercholesterolemic mice by improving transporter ABCG5 and ABCG8. E. faecalis ATCC19433 maybe contribute to the transportation of cholesterol potentially and modulate the composition of gut microbiota.


Assuntos
Colesterol/metabolismo , Enterococcus faecalis/metabolismo , Microbioma Gastrointestinal , Interações Microbianas , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Administração Oral , Animais , Bifidobacterium/isolamento & purificação , Transporte Biológico , Colesterol/sangue , Hipercolesterolemia/terapia , Lactobacillus/isolamento & purificação , Metabolismo dos Lipídeos , Lipoproteínas/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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