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1.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
3.
Clin Chim Acta ; 490: 194-199, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30201373

RESUMO

BACKGROUND: Familial Combined Hyperlipidemia (FCH) is related to different metabolic disorders. The objective of this study was to evaluate the presence of alterations of hydrocarbonated metabolism and lipid profile together with inflammatory and adhesion molecules in subjects with FCH compared to controls. METHODS: 75 HFC patients and 75 healthy individuals were studied. Glucose, insulin, HOMA-IR index and lipid parameters, in addition to anti-oxidized LDL antibodies (Anti ox-LDL), small and dense LDL (sdLDL) and HDL subfractions, proinflammatory cytokines and adhesion molecules were measured. RESULTS: FCH patients showed higher levels of hydrocarbonated metabolism parameters, total cholesterol, triglycerides, LDLc, Apolipoprotein B and non-HDLc (p < .001), and lower levels of HDLc (p < .001) and Apolipoprotein AI (p < .05) than controls. In addition, the inflammatory markers hsCRP, IL-6, IL-8, P-selectin, E-selectin and ICAM were all higher with (p < .05) respect to controls. The increase of sdLDL was correlated with the presence of IR and IL-6 levels. Significant differences in diameter and percentage of phenotype B LDL, small HDL subfractions and Anti ox-LDL were also detected between patients and controls. CONCLUSIONS: The lipid characteristics of FCH are confirmed by IR and a low grade inflammatory state in patients, and are associated with the predominance of sdLDL and Anti ox-LDL.


Assuntos
Hiperlipidemia Familiar Combinada/complicações , Adulto , HDL-Colesterol/sangue , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Inflamação/complicações , Masculino , Fenótipo
4.
Nutrients ; 10(12)2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30513705

RESUMO

This review covers the current knowledge about plant stanol esters as a dietary treatment option for heterozygous familial hypercholesterolemia (he-FH) children. The current estimation of the prevalence of he-FH is about one out of 200⁻250 persons. In this autosomal dominant disease, the concentration of plasma low-density lipoprotein cholesterol (LDL-C) is strongly elevated since birth. Quantitative coronary angiography among he-FH patients has revealed that stenosing atherosclerotic plaques start to develop in he-FH males in their twenties and in he-FH females in their thirties, and that the magnitude of the plaque burden predicts future coronary events. The cumulative exposure of coronary arteries to the lifelong LDL-C elevation can be estimated by calculating the LDL-C burden (LDL-C level × years), and it can also be used to demonstrate the usefulness of dietary stanol ester treatment. Thus, when compared with untreated he-FH patients, the LDL-C burden of using statin from the age of 10 is 15% less, and if he-FH patients starts to use dietary stanol from six years onwards and a combination of statin and dietary stanol from 10 years onwards, the LDL-C burden is 21% less compared to non-treated he-FH patients. We consider dietary stanol treatment of he-FH children as a part of the LDL-C-lowering treatment package as safe and cost-effective, and particularly applicable for the family-centered care of the entire he-FH families.


Assuntos
LDL-Colesterol/sangue , Hipercolesterolemia/dietoterapia , Hiperlipoproteinemia Tipo II/dietoterapia , Sitosteroides/uso terapêutico , Criança , Feminino , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/dietoterapia , Hiperlipoproteinemia Tipo II/sangue , Masculino
5.
Atherosclerosis ; 277: 204-210, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29970255

RESUMO

BACKGROUND AND AIMS: A novel method to estimate low density lipoprotein cholesterol (LDL-C) has been proposed by Martin et al. This may permit a more accurate estimation of cardiovascular risk, however, external validation is needed. Here, the performance of LDL-C using this new method (LDL-N) is compared with LDL-C estimated with Friedewald equation (LDL-F) in familial combined hyperlipidemia (FCHL), a common primary dyslipidemia in which apolipoprotein B containing particle composition is abnormal and interferes with LDL-C estimation. METHODS: A total of 410 FCHL subjects were included. LDL-C was estimated with both the Friedewald equation (LDL-F) and the novel formula (LDL-N). Apolipoprotein B levels and non- HDL-C were recorded. The correlation and concordance between LDL-F and LDL-N and both Apolipoprotein B and non-HDL-C levels were calculated. Analysis stratifying for triglyceride tertiles and FCHL lipid phenotypes was also carried out. RESULTS: The correlations between LDL-N and Apo B and non-HDL-C were ρ = 0.777 (95%CI 0.718-0.825) and ρ = 0.735 (95%CI 0.648-0.816), respectively. The corresponding correlations for LDL-F were ρ = 0.551(95%CI 0.454-0.637) and ρ = 0.394 (95%CI 0.253-0.537), respectively. In mixed dyslipidemia or isolated hypertriglyceridemia, these correlations were significantly better using LDL-N. With respect to concordance, LDL-N performed significantly better than LDL-F when considering apoB <90 mg/dL (κLDL-N = 0.495 vs. κLDL-F = 0.165) and non-HDL-C <130 (κLDL-N = 0.724 vs. κLDL-F = 0.253). CONCLUSIONS: In FCHL, LDL-C estimation using Martin's formula showed greater correlation and concordance with non-HDL-C and Apo B compared with the Friedewald equation.


Assuntos
LDL-Colesterol/sangue , Hiperlipidemia Familiar Combinada/diagnóstico , Modelos Biológicos , Adulto , Apolipoproteína B-100/sangue , Biomarcadores/sangue , Estudos Transversais , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Triglicerídeos/sangue
6.
J Investig Med ; 66(1): 17-21, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28822973

RESUMO

Familial combined hyperlipidemia (FCH) is a primary atherogenic dyslipidemia with insulin resistance and increased cardiovascular risk. Plasminogen activator inhibitor type 1 (PAI-1) and myeloperoxidase (MPO) activity are associated with proinflammatory and atherothrombotic risk. Our aim was to study the role played by PAI-1 and MPO activity in the carotid atherosclerosis prevalence in FCH subjects. 36 FCH unrelated subjects (17 women) were matched by age and body weight with 36 healthy normolipidemic subjects (19 female). Blood lipids, glucose, insulin, insulin resistance (homeostasis model assessment (HOMA)), MPO, and PAI-1 were determined in both groups. Carotid intima media thickness (IMT) was measured by the same investigator by standardized protocol. No differences in age, body mass index (BMI) or waist circumference were observed between the two groups. HOMA and PAI-1 values were higher in the FCH group, reaching statistical significance in those subjects with insulin resistance. In addition, PAI-1 values correlated significantly with metabolic syndrome components and carotid IMT. It is known that the elevated cardiovascular risk that characterizes FCH is frequently associated with insulin resistance. We have detected that two known proinflammatory and proatherothrombotic factors (MPO and PAI-1) are significantly elevated in FCH subjects with insulin resistance. These results could partly explain the high cardiovascular risk present in FCH subjects.


Assuntos
Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/complicações , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/complicações , Resistência à Insulina , Inibidor 1 de Ativador de Plasminogênio/sangue , Adulto , Doenças das Artérias Carótidas/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Hiperlipidemia Familiar Combinada/metabolismo , Masculino , Pessoa de Meia-Idade , Peroxidase/metabolismo
7.
Arterioscler Thromb Vasc Biol ; 37(12): 2356-2363, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29074587

RESUMO

OBJECTIVE: Bilirubin is a potent antioxidant that has been inversely related to cardiovascular disease. There is little information on serum total bilirubin (TB) in relation to atherosclerosis in familial dyslipidemia. We assessed the association between TB and carotid and femoral atherosclerosis in this high-risk group. APPROACH AND RESULTS: We evaluated 464 individuals with familial dyslipidemia (56% men; median age, 48 years), 322 with familial hypercholesterolemia, and 142 with familial combined hyperlipidemia. Carotid and femoral arteries were imaged bilaterally with a standardized ultrasonographic protocol. Mean and maximum intima-media thickness and plaque presence (≥1.2 mm) and height were recorded. Cross-sectional associations between TB and atherosclerosis variables were investigated in multivariable-adjusted models, including lipid values and hypolipidemic drug use. Inflammatory markers (C-reactive protein, total leukocyte count, and lipoprotein[a]) were also determined. Increasing TB levels were associated with decreasing intima-media thickness of all carotid segments (P<0.05, all). TB also related to carotid plaque, present in 78% of individuals, and to plaque burden (≥3 plaques), with odds ratios (95% confidence interval) 0.59 (0.36-0.98) and 0.57 (0.34-0.96) for each increase of 0.5 mg in TB, respectively. Findings were confirmed in a validation cohort of 177 subjects with nonfamilial dyslipidemia. Only the familial combined hyperlipidemia group, with higher inflammation-related markers, showed an inverse association between TB and femoral plaque height (ß=-0.183; P=0.030). CONCLUSIONS: TB was inversely and independently associated with carotid plaque burden in familial and nonfamilial dyslipidemia. These findings support the use of TB as a biomarker of atherosclerosis in this high-risk group.


Assuntos
Bilirrubina/sangue , Doenças das Artérias Carótidas/etiologia , Artéria Femoral , Hiperlipidemia Familiar Combinada/sangue , Hiperlipoproteinemia Tipo II/sangue , Doença Arterial Periférica/etiologia , Placa Aterosclerótica , Adulto , Biomarcadores/sangue , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Artéria Femoral/diagnóstico por imagem , Humanos , Hiperlipidemia Familiar Combinada/complicações , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico por imagem , Prognóstico , Medição de Risco , Fatores de Risco , Ultrassonografia Doppler em Cores
8.
PLoS Genet ; 12(5): e1006078, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27227539

RESUMO

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.


Assuntos
Apolipoproteínas B/genética , Doença da Artéria Coronariana/genética , Dislipidemias/genética , Hiperlipidemia Familiar Combinada/genética , Adulto , HDL-Colesterol/sangue , HDL-Colesterol/genética , Doença da Artéria Coronariana/sangue , Dislipidemias/sangue , Dislipidemias/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/patologia , Lipoproteínas LDL/sangue , Lipoproteínas LDL/genética , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Triglicerídeos/genética
9.
Atheroscler Suppl ; 18: 80-4, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25936309

RESUMO

BACKGROUND: A chronic lipoprotein apheresis therapy leads to an expressed reduction in the incidence of cardiovascular events in high-risk patients. In addition to the elimination of atherogenic lipoproteins such as LDL and lipoprotein(a), an antioxidative effect of lipoprotein apheresis has been suspected. OBJECTIVES AND METHODS: We investigated long-term biochemical effects in sixteen patients undergoing lipoprotein apheresis - lipid filtration (LF, n = 7) or dextran sulfate adsorption (DSA, n = 9). Systemic oxidative stress markers (blood phagocyte chemiluminescence, levels of oxidized LDL and antioxLDL antibodies) were examined at the 1st, 40th and 80th apheresis sessions. RESULTS: In DSA patients, the 80th apheresis session was associated with significantly higher LDL cholesterol removal and lower HDL cholesterol deprivation as compared to LF patients. In contrast to LF patients, DSA patients showed a long-term progressive decrease in circulating oxidant generating activity as evaluated by whole blood chemiluminescence (p < 0.05). Moreover, a single LF apheresis session was associated with higher systemic generation of reactive oxygen species over time. CONCLUSION: Compared to LF, long-term DSA apheresis is associated with a gradual reduction of circulating oxidative burden and may be considered a beneficial molecular mechanism of this technique.


Assuntos
Remoção de Componentes Sanguíneos/métodos , Hipercolesterolemia/terapia , Hiperlipidemia Familiar Combinada/terapia , Técnicas de Imunoadsorção , Lipoproteínas/sangue , Estresse Oxidativo , Idoso , Autoanticorpos/sangue , Biomarcadores/sangue , LDL-Colesterol/sangue , Sulfato de Dextrana/uso terapêutico , Feminino , Filtração , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/imunologia , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/imunologia , Lipoproteína(a)/sangue , Lipoproteínas/imunologia , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Fagócitos/metabolismo , Fatores de Tempo , Resultado do Tratamento
10.
Atherosclerosis ; 240(1): 190-6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25797312

RESUMO

BACKGROUND/OBJECTIVE: Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner. METHODS: 623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria. RESULTS: The proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score. CONCLUSION: These criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH.


Assuntos
Apolipoproteína B-100/genética , Análise Mutacional de DNA , Testes Genéticos/métodos , Hiperlipidemia Familiar Combinada/genética , Hiperlipoproteinemia Tipo II/genética , Mutação , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Serina Endopeptidases/genética , Adulto , Idoso , Anticolesterolemiantes/uso terapêutico , Biomarcadores/sangue , LDL-Colesterol/sangue , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipidemia Familiar Combinada/epidemiologia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Linhagem , Fenótipo , Valor Preditivo dos Testes , Pró-Proteína Convertase 9 , Medição de Risco , Fatores de Risco , Triglicerídeos/sangue , País de Gales/epidemiologia
11.
Metabolism ; 64(2): 213-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25456098

RESUMO

BACKGROUND: Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity. METHODS: Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC). RESULTS: 51 Subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p=0.004 and p=0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearman's rho 0.481, p<0.001) and HbA1c (rho 0.433, p=0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p=0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p=0.022) and HbA1c (rho 0.319, p=0.023). CONCLUSIONS: These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Hiperglicemia/etiologia , Hiperlipidemia Familiar Combinada/imunologia , Resistência à Insulina , Leucócitos/imunologia , Antígenos CD/sangue , Antígenos CD/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Glicemia/análise , Antígeno CD11b/sangue , Antígeno CD11b/metabolismo , Moléculas de Adesão Celular/sangue , Moléculas de Adesão Celular/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/metabolismo , Teste de Tolerância a Glucose , Hemoglobina A Glicada/análise , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/metabolismo , Hiperlipidemia Familiar Combinada/fisiopatologia , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Regulação para Cima
12.
Mol Cell Probes ; 29(1): 19-24, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25308402

RESUMO

BACKGROUND: Familial combined hyperlipidemia (FCH) is a polygenic and multifactorial disease characterized by a variable phenotype showing increased levels of triglycerides and/or cholesterol. The aim of this study was to identify single nucleotides (SNPs) in lipid-related genes associated with FCH. METHODS AND RESULTS: Twenty SNPs in lipid-related genes were studied in 142 control subjects and 165 FCH patients after excluding patients with mutations in the LDLR gene and patients with the E2/E2 genotype of APOE. In particular, we studied the 9996G > A (rs2073658) and 11235C > T (rs3737787) variants in the Upstream Stimulatory Factor 1 gene (USF1), and the -1131T > C (rs662799) and S19W (rs3135506) variants in the Apolipoprotein A-V gene (APOA5). We found that the frequencies of these variants differed between patients and controls and that are associated with different lipid profiles. At multivariate logistic regression SNP S19W in APOA5 remained significantly associated with FCH independently of age, sex, BMI, cholesterol and triglycerides. CONCLUSIONS: Our results show that the USF1 and APOA5 polymorphisms are associated with FCH and that the S19W SNP in the APOA5 gene is associated to the disease independently of total cholesterol, triglycerides and BMI. However, more extensive studies including other SNPs such as rs2516839 in USF1, are required.


Assuntos
Apolipoproteínas A/genética , Grupo com Ancestrais do Continente Europeu/genética , Hiperlipidemia Familiar Combinada/genética , Fatores Estimuladores Upstream/genética , Adulto , Apolipoproteína A-V , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hiperlipidemia Familiar Combinada/sangue , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue
13.
Clin Chim Acta ; 438: 160-5, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25172037

RESUMO

BACKGROUND: In familial combined hyperlipidemia (FCHL) the severity of the dyslipidemia is determined by an overproduction of VLDL (very low density lipoprotein) particles and by its abnormal lipid composition. However, few are known regarding the metabolic factors that determine these abnormalities. We investigated the impact of metabolic factors on the number of atherogenic particles (apolipoprotein B level (apoB)) and the triglyceride content of very low-density lipoproteins (VLDLs-TG). METHODS: A cross-sectional study done in FCHL subjects and gender and age-matched healthy subjects. A clinical assessment, lipid profile and plasma concentrations of insulin, apolipoprotein CIII (apo CIII), apolipoprotein AII (apo AII), high sensitive C-reactive protein (HS-CRP), adiponectin and leptin were documented in 147 FCHL patients and 147 age-matched healthy subjects. Multivariate regression models were performed to investigate the independent determinants of VLDL-TG and apo B levels adjusting for confounding factors. RESULTS: The variables that determined the VLDL-triglyceride content as a surrogate of VLDL composition were apo CIII (ß=0.365, p<0.001), insulin (ß=0.281, p<0.001), Apo AII (ß=0.145, p<0.035), and adiponectin levels (ß=-0.255, p<0.001). This model explained 34% of VLDL composition (VLDL-TG) variability. However, none of these variables were independent contributors of apo B-containing particles. CONCLUSIONS: In patients with FCHL apo CIII, apo AII and adiponectin are major novel factors determining the VLDL particle composition. However, such factors do not explain apo B-containing particles.


Assuntos
Apolipoproteínas B/sangue , Biomarcadores/sangue , Hiperlipidemia Familiar Combinada/diagnóstico , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Adulto , Idoso , Apolipoproteína C-III/sangue , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico
14.
BMC Endocr Disord ; 14: 90, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25425215

RESUMO

BACKGROUND: Alterations in postprandial metabolism have been described in familial combined hyperlipidemia (FCH); however, their underlying mechanisms are not well characterized. We aimed to identify factors related to the magnitude of postprandial lipemia and apolipoprotein (apo) A-V levels in subjects with FCH. METHODS: FCH cases (n = 99) were studied using a standardized meal test. Abdominal obesity was assessed using the waist to hip ratio (WHR). A linear regression model was performed to investigate the variables associated with the triglycerides incremental area under the curve (iAUC). Independent associations between metabolic variables and apo A-V iAUC were also investigated in a randomly selected subgroup (n = 44). The study sample was classified according to the presence of fasting hypertriglyceridemia (≥150 mg/dL) and abdominal obesity (WHR ≥0.92 in men and ≥0.85 in women) to explore differences in parameters. RESULTS: The fasting apo B-48 levels (r = 0.404), and the WHR (r = 0.359) were independent factors contributing to the triglycerides iAUC (r2 = 0.29, P < 0.001). The triglycerides iAUC was independently associated with the apo A-V iAUC (r2 = 0.54, P < 0.01). Patients with both hypertriglyceridemia and abdominal obesity showed the most robust triglycerides and apo A-V postprandial responses. CONCLUSIONS: In patients with FCH the fasting apo B-48 level is the main factor associated with postprandial lipemia. Abdominal obesity also contributes to the magnitude of the postprandial response.The triglycerides postprandial increment is the principal factor associated with the apo A-V postprandial response.


Assuntos
Apolipoproteínas/sangue , Colesterol/sangue , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemias/sangue , Hipertrigliceridemia/sangue , Lipoproteínas/sangue , Obesidade Abdominal/sangue , Período Pós-Prandial , Triglicerídeos/sangue , Adulto , Estudos Transversais , Feminino , Humanos , Hiperlipidemia Familiar Combinada/epidemiologia , Hiperlipidemias/epidemiologia , Hipertrigliceridemia/epidemiologia , Masculino , México/epidemiologia , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologia
15.
J Nutr ; 144(8): 1219-26, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24899155

RESUMO

The effect of weight loss on lipids differs among individuals, although whether it can modify the management of hereditary hyperlipidemias has not yet been explored. The objective of this study was to examine the effect of weight loss on cholesterol metabolism, assessed by circulating noncholesterol sterols, in overweight adults with familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). We conducted a 6-mo weight loss intervention in untreated individuals (FH: n = 28; FCHL: n = 50) with a body mass index of >25 kg/m(2) and mean age of 46.9 ± 11.3 y, of whom 53.8% were men. A hypocaloric diet was implemented and serum lipid analyses, including noncholesterol sterols, were assessed. Global significant mean weight losses of 5.7 kg (-6.6%) and 6.6 kg (-7.6%) were achieved after 3 and 6 mo, respectively. Mean non-HDL cholesterol and triglyceride (TG) changes at 3 and 6 mo compared with baseline were -5.8% (P = 0.004) and -7.1% (P = 0.014), and -30.1% (P < 0.001) and -31.4% (P < 0.001), respectively. Among participants who lost ≥5% body weight, only significant changes in TGs and non-HDL cholesterol were observed in FCHL participants. Sterol precursors of cholesterol synthesis decreased significantly by 10.4% at 6 mo in FCHL participants, mostly because of a 23.9% lathosterol reduction. Baseline synthesis precursors were associated with TG reduction in FCHL participants (P = 0.039; R(2) = 0.20), and intestinally derived sterols were inversely associated with non-HDL cholesterol changes in FH participants (P = 0.036; R(2) = 0.21). Thus, FCHL participants had a better lipid-lowering response to weight loss than did FH participants. This response was positively associated with baseline cholesterol synthesis, which was reduced by weight loss. Our results confirm the cholesterol overproduction mechanism of FCHL and its interaction with fat mass, while also supporting the differential management of familial hyperlipidemias if obesity coexists. This trial was registered at clinicaltrials.gov as NCT01995149.


Assuntos
Hiperlipidemia Familiar Combinada/sangue , Hiperlipoproteinemia Tipo II/sangue , Sobrepeso/sangue , Perda de Peso , Adulto , Índice de Massa Corporal , Colesterol/sangue , HDL-Colesterol/sangue , Feminino , Humanos , Hiperlipidemia Familiar Combinada/complicações , Hiperlipoproteinemia Tipo II/complicações , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Triglicerídeos/sangue
16.
Biochem Biophys Res Commun ; 446(3): 731-5, 2014 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-24406166

RESUMO

Familial combined hyperlipidemia (FCHL), the most common inherited disorder of lipid metabolism is characterized by increasing cholesterol synthesis precursors due to hepatic overproduction of cholesterol. The bile acids synthesis pathway has not been previously studied in FCHL. The aim of this work was to study the oxysterol levels which are involved in the bile acids synthesis from cholesterol in FCHL. Clinical parameters and subclinical atherosclerosis were studied in a total of 107 FCHL patients and 126 normolipidemic controls. Non cholesterol sterols (desmosterol and lanosterol) and oxysterols (27-hydroxycholesterol and 24S-hydroxycholesterol) were measured by high performance liquid chromatography tandem mass spectrometry. Desmosterol and lanosterol, markers of cholesterol synthesis, had a positive correlation with BMI and apo B. However, no correlation was found for 24S-hydroxycholesterol and 27-hydroxycholesterol, precursors of bile acids, with these clinical parameters. Only 27-hydroxycholesterol had a positive correlation with apo B, ρ=0.204 (P=0.037). All oxysterol levels were higher in FHCL as compared to normal controls. A total of 59 FCHL subjects (59%) presented values of 24S-hydroxycholesterol above the 95th percentile of this oxysterol in the control population. All oxysterols showed no association with fat mass in contrast with non-cholesterol sterols. FCHL subjects with oxysterol overproduction had less carotid intima media thickness (cIMT), which suggests less atherosclerosis in these subjects. In summary, our data indicate that high oxysterol levels might be good markers of FCHL, unrelated to fat mass, and may exert a protective mechanism for cholesterol accumulation.


Assuntos
Hidroxicolesteróis/sangue , Hiperlipidemia Familiar Combinada/sangue , Adolescente , Adulto , Idoso , Ácidos e Sais Biliares/biossíntese , Índice de Massa Corporal , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Desmosterol/sangue , Feminino , Humanos , Hiperlipidemia Familiar Combinada/diagnóstico por imagem , Lanosterol/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Clin Sci (Lond) ; 126(9): 679-84, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24308640

RESUMO

Homozygous carriers of the apolipoprotein ε2 allele are at risk of type III hyperlipidaemia, but do not necessarily develop this lipid disorder. In the present study, we have investigated the role of circulating PCSK9 (pro-protein convertase subtilisin kexin type 9), an important regulator of LDL (low-density lipoprotein) receptor expression, in the development of this hyperlipidaemic phenotype. In an observational study, plasma PCSK9 was measured in homozygous carriers of apolipoprotein ε2 (ε2/ε2; n=12), normal controls (n=72) and hypertriglyceridaemic patients with FCHL (familial combined hyperlipidaemia; n=38), who served as a hyperlipidaemic reference group. Cholesterol, triacylglycerols (triglycerides) and apolipoprotein B content in VLDL (very-low-density lipoprotein) and LDL particles was determined by ultracentrifugation in ε2/ε2 and FCHL patients. Median circulating PCSK9 levels did not differ between ε2/ε2 carriers compared with controls and hypertriglyceridaemic FCHL patients (84.5 compared with 82.0 and 84.9 ng/ml; P=0.2 and 0.6 respectively). Circulating PCSK9 was associated with total cholesterol and triacylglycerols levels in ε2/ε2 carriers (P<0.05). These associations were stronger in ε2/ε2 carriers when compared with controls (P values for interaction=0.01 and 0.02 respectively). A direct comparison with FCHL patients demonstrated a similar discrepancy for the association with plasma triacylglycerols and also VLDL-apolipoprotein B, cholesterol and triacylglycerols (P value for interaction=0.01, 0.01, 0.03 and 0.03 respectively). Plasma PCSK9 is associated with type III hyperlipidaemia. Its strong relationship with plasma triacylglycerols and total cholesterol distinguishes ε2/ε2 carriers from controls and another type of dyslipidaemia, which provides valuable information regarding the pathogenesis of this complex dyslipidaemia. Furthermore, these results suggest that patients with type III hyperlipidaemia may benefit from PCSK9-antagonizing therapy.


Assuntos
Apolipoproteína E2/genética , Colesterol/sangue , Homozigoto , Hiperlipidemia Familiar Combinada/genética , Pró-Proteína Convertases/sangue , Serina Endopeptidases/sangue , Triglicerídeos/sangue , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/enzimologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo , Pró-Proteína Convertase 9
18.
Nutr Metab Cardiovasc Dis ; 23(11): 1115-21, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23333725

RESUMO

BACKGROUND AND AIMS: Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL. METHODS AND RESULTS: Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001). CONCLUSIONS: The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.


Assuntos
Colesterol/biossíntese , Hiperlipidemia Familiar Combinada/metabolismo , Modelos Biológicos , Pró-Proteína Convertases/sangue , Serina Endopeptidases/sangue , Regulação para Cima , Adulto , Biomarcadores/sangue , Colesterol/sangue , Estudos de Coortes , Desmosterol/sangue , Família , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Isomerismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Países Baixos , Pró-Proteína Convertase 9 , Análise de Regressão , Reprodutibilidade dos Testes
19.
Circ J ; 77(1): 163-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23018766

RESUMO

BACKGROUND: Familial combined hyperlipidemia (FCH) is an inherited lipid disorder associated with premature cardiovascular disease. It has not been established whether the cardiometabolic risk factors, which frequently accompany FCH, such as diabetes, metabolic syndrome (MetS) and hypertension, modulate cardiovascular risk in FCH patients. METHODS AND RESULTS: In this single-center, retrospective study, 695 FCH patients with adequate follow-up were enrolled (mean age, 48.9 years; 455 male). Risk factors including lipid levels were evaluated before the initiation of treatment. Acute myocardial infarction (AMI) and cardiovascular death were recorded during a mean follow-up of 9 years. The combined endpoint (AMI and/or cardiovascular death) occurred in 41 patients (5.9% of the total). Those FCH patients who reached the combined endpoint had lower high-density lipoprotein cholesterol (HDL-C) than those who did not, but levels of other lipid variables were similar. Presence of hypertension, diabetes or MetS was a predictor of the combined endpoint on univariate Kaplan-Meier analysis (all P<0.005). Multivariate Cox proportional analysis showed that hypertension and MetS were associated with the combined endpoint independently of age, gender, HDL-C and presence of coronary artery disease at enrollment (adjusted hazard ratios [HRs], 3.00; 95% confidence interval [CI]: 1.46-6.17, P=0.003; HR, 2.43; 95CI%: 1.11-5.33, P=0.026, respectively). CONCLUSIONS: Cardiometabolic risk factors such as hypertension and MetS are independent predictors of major cardiovascular events in FCH patients.


Assuntos
HDL-Colesterol/sangue , Doença da Artéria Coronariana , Diabetes Mellitus , Hiperlipidemia Familiar Combinada , Hipertensão , Infarto do Miocárdio , Adulto , Fatores Etários , Idoso , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus/sangue , Diabetes Mellitus/etiologia , Diabetes Mellitus/mortalidade , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/complicações , Hiperlipidemia Familiar Combinada/mortalidade , Hipertensão/sangue , Hipertensão/etiologia , Hipertensão/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Estudos Retrospectivos , Fatores Sexuais
20.
Atherosclerosis ; 224(1): 177-86, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22795978

RESUMO

OBJECTIVES: Phospholipids (PLs) are increasingly recognized as key molecules with potential diagnostic value in acute inflammation, CVD and atherosclerosis. We introduce a pioneer mass spectrometry (MS)-based approach aiming to investigate the relationship of specific plasma PL-subsets with atherogenic blood parameters in young patients with familial hyperlipidemia representing high-CVD-risk groups. METHODS: Plasma of carefully phenotyped FH and FCH patients as well as normolipidemic subjects (age 13 ± 5 years, n = 20) was used. Clinical parameters were assessed using standard laboratory techniques and lipids were subjected to a direct targeted monitoring using LC-ESI-SRM- and MALDI-QIT-TOF-MS/MS, respectively. Statistical analysis was performed to evaluate correlations between PL data and the clinical parameters. RESULTS: Most characteristically significant differences of SM/PC and PC/LPC ratios and positive correlations between SM vs. LDL-C (r = 0.946; p = 0.004) and LPC vs. VLDL-C (r = 0.669; p = 0.218) were observed in FH in contrast to the other study groups. OxPC levels were found in the range of ∼2-20 µmol/L with predominance of short-chain aldehydic species (e.g. SOVPC). A positive correlation of OxPCs with IMT (r = 0.952; p = 0.052) and HDL-C (r = 0.893; p = 0.016) but negative correlation with OxLDL (r = -0.910; p = 0.096) was observed. CONCLUSIONS: Our study was a first attempt to use a MALDI-QIT-TOF-MS/MS based clinical lipidomics approach to investigate atherogenic dyslipidemia in young patients with familial hyperlipidemia. This technique represents a promising platform for clinical screening of lipid biomarkers in the future.


Assuntos
Hiperlipidemia Familiar Combinada/sangue , Hiperlipoproteinemia Tipo II/sangue , Lipoproteínas/sangue , Fosfolipídeos/sangue , Adolescente , Aterosclerose/sangue , Biomarcadores/sangue , Criança , LDL-Colesterol , Feminino , Humanos , Lisofosfatidilcolinas/sangue , Masculino , Fosfatidilcolinas/sangue , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Esfingomielinas/sangue , Espectrometria de Massas em Tandem , Adulto Jovem
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