RESUMO
Abstract: Postprandial lipemia can lead to an accumulation of atherogenic lipoproteins in the circulation associated with systemic low-grade inflammation and an increased risk of cardiovascular disease. Lifestyle and pharmacological treatments are usually prescribed for prevention. Vitamin D3 (cholecalciferol), as an anti-atherogenic agent, is being taken into consideration due to its potential beneficial effects in lipid metabolism and its anti-inflammatory potency. To assess the effects of vitamin D3 in the postprandial lipid profile in obese, vitamin D-deficient women, a non-targeted lipidomics approach using liquid chromatography coupled to a quadrupole time-of flight mass spectrometer was used to identify and quantitate a wide-range of circulating lipid species, including diglycerides, lysophosphatidylcholines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The most important changes were found in plasmatic sphingomyelin levels, which experience a decrease after vitamin D3 intake. Our results suggest a turnover of sphingomyelins, probably due to an increased activity of neutral sphingomyelinases, and, therefore, with implications in the clearance of chylomicrons, LDL and VLDL, decreasing postprandial inflammation and macrophage adherence to endothelia, potentially improving cardiovascular disease risk.
Assuntos
Colecalciferol/administração & dosagem , Suplementos Nutricionais , Lipidômica/métodos , Lipídeos/sangue , Obesidade/sangue , Período Pós-Prandial , Deficiência de Vitamina D/tratamento farmacológico , Adulto , Biomarcadores/sangue , Colecalciferol/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Obesidade/diagnóstico , Resultado do Tratamento , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnósticoRESUMO
BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD). No long-term intervention trials on CVD risk factors have been published, and a debate on the efficacy of controlling traditional risk factors in RA is ongoing. We aimed to evaluate a treat-to-target approach versus usual care regarding traditional CVD risk factors in patients with RA. METHODS: In this open-label, randomised controlled trial, patients with RA aged <70 years without prior CVD or diabetes mellitus were randomised 1:1 to either a treat-to-target approach or usual care of traditional CVD risk factors. The primary outcome was defined as change in carotid intima media thickness (cIMT) over 5 years, and the secondary outcome was a composite of first occurrence of fatal and non-fatal cardiovascular events. RESULTS: A total of 320 patients (mean age 52.4 years; 69.7% female) with RA underwent randomisation and 219 patients (68.4%) completed 5 years of follow-up. The mean cIMT progression was significantly reduced in the treat-to-target group compared with usual care (0.023 [95% CI 0.011 to 0.036] mm vs 0.045 [95% CI 0.030 to 0.059] mm; p=0.028). Cardiovascular events occurred in 2 (1.3%) of the patients in the treat-to-target group vs 7 (4.7%) in those receiving usual care (p=0.048 by log-rank test). CONCLUSION: This study provides evidence on the benefit of a treat-to-target approach of traditional CVD risk factors for primary prevention in patients with well-treated RA. TRIAL REGISTRATION NUMBER: NTR3873.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Aterosclerose/etiologia , Doenças Cardiovasculares/etiologia , Adulto , Idoso , Artrite Reumatoide/complicações , Artrite Reumatoide/fisiopatologia , Espessura Intima-Media Carotídea , Gerenciamento Clínico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Planejamento de Assistência ao Paciente , Fatores de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
AIMS/HYPOTHESIS: The blood triacylglycerol level is one of the main determinants of blood Mg2+ concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg2+ concentration <0.7 mmol/l) has serious consequences as it increases the risk of developing type 2 diabetes and accelerates progression of the disease. This study aimed to determine the mechanism by which triacylglycerol levels affect blood Mg2+ concentrations. METHODS: Using samples from 285 overweight individuals (BMI >27 kg/m2) who participated in the 300-Obesity study (an observational cross-sectional cohort study, as part of the Human Functional Genetics Projects), we investigated the association between serum Mg2+ with laboratory variables, including an extensive lipid profile. In a separate set of studies, hyperlipidaemia was induced in mice and in healthy humans via an oral lipid load, and blood Mg2+, triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg2+-containing solutions to study the direct interaction between Mg2+ and NEFAs. RESULTS: In the cohort of overweight individuals, serum Mg2+ levels were inversely correlated with triacylglycerols incorporated in large VLDL particles (r = -0.159, p ≤ 0.01). After lipid loading, we observed a postprandial increase in plasma triacylglycerol and NEFA levels and a reciprocal reduction in blood Mg2+ concentration both in mice (Δ plasma Mg2+ -0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg2+ -0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg2+ may be explained by direct binding of Mg2+ to NEFAs. Moreover, Mg2+ was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg2+ did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg2+ concentration was not affected by the presence of physiological concentrations of other cations. CONCLUSIONS/INTERPRETATION: This study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg2+ levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg2+ concentration, and therefore, our data challenge how the fractional excretion of Mg2+ is calculated and interpreted in the clinic.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Ácidos Graxos não Esterificados/sangue , Magnésio/sangue , Sobrepeso/sangue , Triglicerídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Animais , Glicemia/metabolismo , Estudos Transversais , Diabetes Mellitus Experimental/sangue , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND AIMS: Rheumatoid arthritis (RA) has been associated with an increased risk of atherosclerosis. We aimed to evaluate the progression of carotid intima media thickness (cIMT) in RA patients subject to a cardiovascular treat-to-target intervention. In addition, the presence of the metabolic syndrome (MetS) on cIMT outcomes was evaluated. METHODS: We performed a cohort analysis of FRANCIS, in which RA patients ≤70 years without CVD or diabetes mellitus were randomized for either a treat-to-target intervention or usual care concerning CVD risk factors. MetS was scored at baseline. RESULTS: Three-year data was available in 212 well-controlled RA patients. The treat-to-target intervention resulted in a lower cIMT progression over three years compared to the usual care. However, there was no difference in cIMT at three years between groups. MetS was present in 40.1% of RA patients. Baseline cIMT was significantly higher in RA patients with MetS compared to those without (0.619 (0.112) versus 0.557 (0.104) mm; pâ¯<â¯0.001). After three years, cIMT progression was comparable (0.043 (0.071) versus 0.043 (0.072) mm; pâ¯=â¯0.96). In RA patients with MetS, the presence of plaques increased over three years from 12.9% to 23.5% (pâ¯=â¯0.01). The type of intervention had no effect on cIMT progression in RA patients with MetS. However, in subjects without MetS, treat-to-target resulted in a lower progression. CONCLUSIONS: RA patients with MetS showed an increased CVD risk profile based on both a higher prevalence of CVD risk factors and structural vascular changes. A treat-to-target approach of CVD risk factors reduced cIMT progression only in RA patients without MetS.
Assuntos
Artrite Reumatoide/epidemiologia , Doenças das Artérias Carótidas/epidemiologia , Artéria Carótida Primitiva , Síndrome Metabólica/epidemiologia , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/mortalidade , Artrite Reumatoide/terapia , Doenças Assintomáticas , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/mortalidade , Doenças das Artérias Carótidas/prevenção & controle , Artéria Carótida Primitiva/diagnóstico por imagem , Espessura Intima-Media Carotídea , Progressão da Doença , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/mortalidade , Síndrome Metabólica/terapia , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Placa Aterosclerótica , Prevalência , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Leucocyte activation is an obligatory factor in the development of atherosclerosis. The postprandial situation has been associated to increased leucocyte activation in several disorders, such as type 2 diabetes mellitus and familial combined hyperlipidaemia. Our study aim was to evaluate the effect of post-OGTT hyperglycaemia on leucocyte activation in patients with familial hypercholesterolemia (FH). MATERIALS AND METHODS: Patients who met the diagnostic criteria for heterozygous FH and healthy volunteers were asked to undergo an oral glucose tolerance test. Leucocyte activation markers CD11b and CD66b were determined by flow cytometry. Post-OGTT changes were calculated as area under the curve (AUC) and the incremental area under the curve corrected for baseline values (dAUC). The impact of being an FH patient and using statins on the time-dependent profile of the leucocyte activation markers was studied with repeated measurements analysis. RESULTS: Thirteen FH patients using statins, nine FH patients without statins and 14 healthy volunteers were included. FH subjects on statins had a slightly higher HbA1c than those not using these drugs or controls. Post-OGTT glucose levels were significantly higher in patients with FH when compared to healthy controls (P = 0·001). These effects were independent from the use of statins. CONCLUSIONS: Surprisingly, our study shows impaired post-OGTT glucose excursions in patients with FH compared to healthy volunteers. Post-OGTT hyperglycaemia may be related to persistent post-OGTT activation of monocytes in FH patients compared to healthy controls, and therefore, it may contribute to the development of cardiovascular disease in patients with FH.
Assuntos
Glicemia/fisiologia , Hiperglicemia/fisiopatologia , Hiperlipoproteinemia Tipo II/fisiopatologia , Leucócitos/fisiologia , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Jejum/sangue , Feminino , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/metabolismo , Humanos , Hiperglicemia/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neutrófilos/fisiologia , Estudos ProspectivosRESUMO
BACKGROUND: The binding of apolipoprotein (apo) B-containing lipoproteins to circulating erythrocytes (ery-apoB) is associated with a decreased prevalence of atherosclerosis. In this study, we evaluated ery-apoB as a possible prognostic factor in cardiovascular events and all-cause mortality, in a prospective cohort study. MATERIALS AND METHODS: Ery-apoB was measured by flow cytometry in subjects with and without cardiovascular disease (CVD). The primary endpoint was the cardiovascular event rate. Secondary endpoints were all-cause mortality and the combined endpoint of all-cause mortality and cardiovascular events (any event rate). A Cox regression analysis with univariate and multivariate analyses and Kaplan-Meier survival analysis was performed. RESULTS: Follow-up data were available of 384 subjects. Subjects were divided according to high (> 2·0 au, n = 60), intermediate (0·2-2·0 au, n = 274) or low (< 0·2 au, n = 50) ery-apoB. Median follow-up was 1767 days (IQR 1564-2001). In univariate analysis, low ery-apoB was associated with increased all-cause mortality [HR 9·9 (1·2-79·0), P = 0·031] and any event rate [HR 3·4 (95% CI 1·3-8·7), P = 0·012]. In a Cox regression analysis, only a history of CVD was significantly associated with any event rate [HR 3·6 (1·6-8·0), P = 0·002], while low ery-apoB showed a trend [HR 2·4 (0·9-6·4), P = 0·07]. In a subgroup analysis, in subjects with a history of CVD, ery-apoB was significantly associated with all-cause mortality (log rank P = 0·021) and any event rate (log rank P = 0·009). CONCLUSIONS: Low ery-apoB is associated with increased mortality and cardiovascular risk, especially in patients with a prior history of CVD. These subjects may benefit from more aggressive secondary prevention treatment.
Assuntos
Apolipoproteínas B/metabolismo , Aterosclerose/mortalidade , Eritrócitos/metabolismo , Aterosclerose/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
CONTEXT: Cholecalciferol (vitamin D3) improves vascular function and inflammation, potentially providing an explanation for the proposed cardiovascular protection of vitamin D. OBJECTIVE: We investigated whether cholecalciferol supplementation reduces postprandial arterial dysfunction and inflammation. DESIGN: Randomized, 1:1, double-blind trial. SETTING: Diabetes and Vascular Center, Franciscus Gasthuis, Rotterdam, The Netherlands. PATIENTS: Twenty-four healthy, premenopausal, overweight or obese, vitamin D-deficient women. INTERVENTIONS: A single high (300,000 IU) or low dose (75,000 IU) of cholecalciferol. MAIN OUTCOME MEASURES: The effect of low- and high-dose cholecalciferol on postprandial leukocyte activation markers, pulse wave velocity (PWV), and augmentation index (AIx) during an oral fat loading test, expressed as area under the curve (AUC). RESULTS: High- and low-dose supplementation increased vitamin D by 163% ± 134% (P < 0.001) and 66% ± 59% (P < 0.001), respectively. Monocyte CD11b-AUC slightly increased after low but not high dose (6% ± 2%, P = 0.012, and 4% ± 1%, P = 0.339, respectively). There were no significant effects on postprandial PWV or AIx by high- or low-dose vitamin D. Fasting complement component 3 (C3) levels decreased by 5.9% (P = 0.004) in the high-dose group and by 4.0% (P = 0.018) in the low-dose group. CONCLUSION: A single dose of vitamin D does not seem to reduce arterial stiffness and leukocyte activation in overweight, vitamin D-deficient women. Vitamin D may decrease fasting C3. Possibly, higher vitamin D concentrations may be needed to decrease inflammation and improve vascular function in overweight or obese vitamin D-deficient women.
Assuntos
Colecalciferol/administração & dosagem , Obesidade/metabolismo , Período Pós-Prandial , Rigidez Vascular , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas/administração & dosagem , Adulto , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/metabolismo , Área Sob a Curva , Proteína C-Reativa/imunologia , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Complemento C3/imunologia , Método Duplo-Cego , Feminino , Humanos , Inflamação , Contagem de Leucócitos , Monócitos/imunologia , Neutrófilos/imunologia , Obesidade/complicações , Obesidade/fisiopatologia , Sobrepeso/complicações , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Análise de Onda de Pulso , Triglicerídeos/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/fisiopatologia , Adulto JovemRESUMO
BACKGROUND AND AIMS: Inflammation plays a key role in atherosclerosis. The complement system is involved in atherogenesis, and the complement receptor 1 (CR1) plays a role facilitating the clearance of immune complexes from the circulation. Limited evidence suggests that CR1 may be involved in cardiovascular disease. We investigated the relationship between CR1 gene polymorphisms and cardiovascular risk. METHODS: Single nucleotide polymorphisms (SNPs) within the CR1 region (n = 73) on chromosome 1 were assessed in 5244 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and followed for a mean of 3.2 years. Logistic regression, adjusted for gender, age, country and use of pravastatin, was used to assess the association between the SNPs and cardiovascular disease. RESULTS: All 73 SNPs within the genomic region of the CR1 gene on chromosome 1 were extracted. In this region, strong LD was present leading to the occurrence of two haploblocks. Twelve of the 73 investigated CR1 SNPs were significantly associated with the risk of fatal or nonfatal myocardial infarction (all p < 0.05). Moreover, most of the associated SNPs were also associated with levels of serum C-reactive protein (CRP). The global p-value for the tail strength method to control for multiple testing was 0.0489, implying that the null hypothesis of no associated SNPs can be rejected. CONCLUSIONS: These data indicate that genetic variation within the CR1 gene is associated with inflammation and the risk of incident coronary artery disease.
Assuntos
Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único , Receptores de Complemento 3b/genética , Idoso , Biomarcadores/sangue , Proteína C-Reativa/análise , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Mediadores da Inflamação/sangue , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/imunologia , Fenótipo , Estudos Prospectivos , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Atherosclerosis is a pro-inflammatory condition, in which leucocyte activation plays an important role. The interaction between circulating leucocytes and apolipoprotein (apo) B-containing lipoproteins results in pro-inflammatory changes of these cells. We aimed to evaluate the relationship between apo B bound to circulating leucocytes and atherosclerosis. METHODS: Apo B on circulating leucocytes was measured by flow cytometry in subjects with and without cardiovascular disease (CVD), expressed as mean fluorescent intensity in arbitrary units (au). Carotid intima-media thickness (cIMT) was measured using B-mode ultrasound. Data are given as median (interquartile range). RESULTS: A total of 396 subjects were included, of whom 183 had a history of CVD. Compared to subjects without CVD, patients with CVD had lower apo B bound to neutrophils (12·7 au (9·8-16·2) and 14·2 au (10·1-17·5), respectively, P = 0·038) and to monocytes (2·5 au (1·7-3·1) and 2·7 (1·9-3·6) au, respectively, P = 0·025). No differences were found for lymphocyte-bound apo B. Neutrophil- and monocyte-bound apo B were inversely correlated with cIMT (Spearman's rho: -0·123, P = 0·017 and -0·108, P = 0·035, respectively). Both monocyte- and neutrophil-bound apo B were inversely associated with different factors related to the metabolic syndrome, such as body mass index, triglycerides and complement C3. There was a positive association between erythrocyte-bound apo B and apo B bound to each of the leucocyte classes, possibly reflecting a similar mechanism. Discontinuation of statins in 54 subjects did not influence leucocyte-bound apo B. CONCLUSION: Unexpectedly, the presence of noninternalized apo B-containing lipoproteins on circulating neutrophil and monocyte membranes may represent a protective mechanism against atherosclerosis.
Assuntos
Apolipoproteínas B/metabolismo , Aterosclerose/etiologia , Leucócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/tratamento farmacológico , Espessura Intima-Media Carotídea , Estudos Transversais , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: To investigate the prevalence of underdiagnosis and undertreatment of traditional cardiovascular risk factors in RA patients. METHODS: RA patients ⩽70 years of age without cardiovascular disease (CVD) or diabetes mellitus were included. Systolic blood pressure and a fasting lipid profile were measured. The 10-year CVD risk was estimated using the Dutch Cardiovascular Risk Management (CVRM) guideline and EULAR modifications of the Systemic Coronary Risk Evaluation tables. RESULTS: A total of 327 patients were included (female gender: 68%). The mean age was 53 (11) years [mean (s.d.)]. The median disease duration was 7 years (inter quartile range: 2-14 years). According to the CVRM guideline, 52% of the patients had a CVD risk ⩾20% and according to the EULAR guidelines, 18% of the patients had a CVD risk ≥ 20%. Low-density lipoprotein cholesterol (LDL-C) >2.5 mmol/l was found in >80% of the patients with a CVD risk ⩾10% as estimated by both the CVRM and EULAR guidelines, and 32-42% of the patients with a CVD risk ⩾10% had a systolic blood pressure >140 mmHg, depending on the risk model used. Statins were used in 6% and antihypertensives in 23-25%, and 50-86% of these patients did not reach the recommended treatment targets. CONCLUSION: Regardless of the adapted risk assessment model used, untreated hypertension and hypercholesterolaemia were frequently found in RA patients with increased CVD risk. Treatment of these cardiovascular risk factors deserves more attention in RA. TRIAL REGISTRATION: The Dutch Trial Register, www.trialregister.nl, NTR3873.
Assuntos
Artrite Reumatoide/complicações , Hipercolesterolemia/epidemiologia , Hipertensão/epidemiologia , Adulto , Anti-Hipertensivos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/fisiopatologia , Pressão Sanguínea , Proteína C-Reativa/análise , LDL-Colesterol/sangue , Estudos Transversais , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/tratamento farmacológico , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prevalência , Medição de Risco/métodos , Fatores de RiscoRESUMO
Leukocyte activation has been linked to atherogenesis, but there is little in vivo evidence for its role in the progression of atherosclerosis. We evaluated the predictive value for progression of coronary artery disease (CAD) of leukocyte activation markers in the coronary circulation. Monocyte and neutrophil CD11b, neutrophil CD66b expression and intracellular neutrophil myeloperoxidase (MPO) in the coronary arteries were determined by flow cytometry in patients undergoing coronary angiography. The primary outcome included fatal and nonfatal myocardial infarction or arterial vascular intervention due to unstable angina pectoris. In total 99 subjects who were included, 70 had CAD at inclusion (26 patients had single-vessel disease, 18 patients had twovessel disease and 26 patients had three-vessel disease). The median follow-up duration was 2242 days (interquartile range: 2142-2358). During follow-up, 13 patients (13%) developed progression of CAD. Monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO measured in blood obtained from the coronary arteries were not associated with the progression of CAD. These data indicate that coronary monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO do not predict the risk of progression of CAD.
Assuntos
Doença da Artéria Coronariana/patologia , Leucócitos/fisiologia , Idoso , Antígenos CD/análise , Antígeno CD11b/análise , Moléculas de Adesão Celular/análise , Progressão da Doença , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/análise , Humanos , Leucócitos/química , Masculino , Pessoa de Meia-Idade , Monócitos/química , Monócitos/fisiologia , Peroxidase/metabolismoRESUMO
BACKGROUND AND AIMS: The postprandial situation is a pro-inflammatory condition most likely linked to the development of atherosclerosis. We evaluated the relationship between apolipoprotein (apo) B48 and fasting and postprandial leukocyte activation markers. METHODS: Leukocyte activation markers and apo B48 were determined in 80 subjects with and without coronary artery disease (CAD). Twelve healthy subjects underwent an oral fat loading test (up to 8 h). RESULTS: Fasting apo B48 was significantly higher in patients with CAD (n = 47, 8.1 ± 5.2 mg/L) than in subjects without CAD (n = 33, 5.9 ± 3.9 mg/L, p = 0.022). Fasting apo B48 and triglycerides correlated positively with fasting monocyte CD11b and neutrophil CD66b expression. Plasma apo B48 and leukocyte activation markers increased after an oral fat load. No correlations were found between fasting or postprandial triglycerides and postprandial leukocyte activation markers. We observed no correlations between postprandial apo B48 and postprandial neutrophil CD11b or CD66b expression. CONCLUSION: This study suggests that chylomicron remnants may be responsible for postprandial leukocyte activation in the circulation. The postprandial chylomicron response may be a stronger mediator of postprandial inflammation than postprandial triglyceridemia.
Assuntos
Remanescentes de Quilomícrons/sangue , Doença da Artéria Coronariana/sangue , Gorduras na Dieta/sangue , Mediadores da Inflamação/sangue , Inflamação/sangue , Leucócitos/metabolismo , Período Pós-Prandial , Adulto , Idoso , Antígenos CD/sangue , Apolipoproteína B-48/sangue , Antígeno CD11b/sangue , Estudos de Casos e Controles , Moléculas de Adesão Celular/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Estudos Transversais , Gorduras na Dieta/administração & dosagem , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Inflamação/diagnóstico , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Triglicerídeos/sangueRESUMO
OBJECTIVES: Rheumatoid arthritis (RA) has been identified as an independent cardiovascular risk factor. The importance of risk factors such as hypertension and hyperlipidemia in the generation of atherosclerosis in RA patients is unclear. This study analyzed clinical parameters associated with carotid intima media thickness (cIMT) in patients with RA. METHODS: Subjects with RA and healthy controls without RA, both without known cardiovascular disease, were included. Participants underwent a standard physical examination and laboratory measurements including a lipid profile. cIMT was measured semi-automatically by ultrasound. RESULTS: In total 243 RA patients and 117 controls were included. The median RA disease duration was 7 years (IQR 2-14 years). The median DAS28 was 2.4 (IQR 1.6-3.2) and 114 (50.4%) of the RA patients were in remission. The presence of RA and cIMT were not associated (univariate analysis). Multivariable regression analysis showed that cIMT in RA patients was associated with age (B = 0.006, P<0.001) and systolic blood pressure (B = 0.003, P = 0.003). In controls, cIMT was associated with age (B = 0.006, P<0.001) and smoking (B = 0.097, P = 0.001). CONCLUSION: cIMT values were similar between RA patients and controls. Hypertension was strongly associated with cIMT in RA patients. After adjustment, no association between cIMT and specific RA disease characteristics was found in this well treated RA cohort.
Assuntos
Artrite Reumatoide/diagnóstico por imagem , Doenças Cardiovasculares/etiologia , Espessura Intima-Media Carotídea , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/complicações , Doenças Cardiovasculares/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
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 , Hemoglobinas Glicadas/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 CimaRESUMO
Lipoproteins can induce complement activation resulting in opsonization and binding of these complexes to complement receptors. We investigated the binding of opsonized native LDL and acetylated LDL (acLDL) to the complement receptor 1 (CR1). Binding of complement factors C3b, IgM, C1q, mannose-binding lectin (MBL), and properdin to LDL and acLDL were investigated by ELISA. Subsequent binding of opsonized LDL and acLDL to CR1 on CR1-transfected Chinese Hamster Ovarian cells (CHO-CR1) was tested by flow cytometry. Both native LDL and acLDL induced complement activation with subsequent C3b opsonization upon incubation with normal human serum. Opsonized LDL and acLDL bound to CR1. Binding to CHO-CR1 was reduced by EDTA, whereas MgEGTA only reduced the binding of opsonized LDL, but not of acLDL suggesting involvement of the alternative pathway in the binding of acLDL to CR1. In vitro incubations showed that LDL bound C1q, whereas acLDL bound to C1q, IgM, and properdin. MBL did neither bind to LDL nor to acLDL. The relevance of these findings was demonstrated by the fact that ex vivo up-regulation of CR1 on leukocytes was accompanied by a concomitant increased binding of apolipoprotein B-containing lipoproteins to leukocytes without changes in LDL-receptor expression. In conclusion, CR1 is able to bind opsonized native LDL and acLDL. Binding of LDL to CR1 is mediated via the classical pathway, whereas binding of acLDL is mediated via both the classical and alternative pathways. Binding of lipoproteins to CR1 may be of clinical relevance due to the ubiquitous cellular distribution of CR1.
Assuntos
Ativação do Complemento , Complemento C3b/metabolismo , Lipoproteínas LDL/metabolismo , Receptores de Complemento 3b/metabolismo , Animais , Apolipoproteínas B/metabolismo , Células CHO , Células Cultivadas , Complemento C1q/metabolismo , Via Alternativa do Complemento , Via Clássica do Complemento , Cricetinae , Cricetulus , Ácido Edético/farmacologia , Citometria de Fluxo , Humanos , Imunoglobulina M/metabolismo , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Lipopolissacarídeos/farmacologia , Proteínas Opsonizantes/metabolismo , Properdina/metabolismo , Ligação Proteica/efeitos dos fármacos , Receptores de Complemento 3b/genéticaRESUMO
Many risk factors have been identified as being responsible for the process of atherogenesis. Several of these risk factors are related to inflammation, which is an obligatory feature of the atherosclerotic plaque. Increasing evidence suggests that postprandial lipoproteins and glucose may be involved in the inflammatory process preceding the development of atherosclerosis. During the postprandial situation, remnants of chylomicrons and very low-density lipoproteins bind to circulating leukocytes and endothelial cells, leading to a state of acute activation with the expression of integrins on different cells, the generation of oxidative stress, production of cytokines and complement activation. Elevated plasma glucose levels may also induce leukocyte activation in humans. In addition, advanced glycation end products, formed during hyperglycemia, cause inflammation and endothelial damage. This chain of events results in a situation of acute inflammation causing endothelial dysfunction, which may be one of the earliest defects in atherogenesis. Interestingly, while this may occur several times each day after each meal, there is only limited information on the contribution of different nutrients on the postprandial inflammatory processes. In this review, we will focus on the available evidence and we will discuss the role of lifestyle and pharmaceutical interventions in modulating postprandial inflammation.
Assuntos
Aterosclerose/mortalidade , Glicemia/metabolismo , Quilomícrons/sangue , Lipoproteínas IDL/sangue , Placa Aterosclerótica/metabolismo , Período Pós-Prandial , Animais , Aterosclerose/patologia , Aterosclerose/terapia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Inflamação/sangue , Inflamação/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Estresse Oxidativo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/terapiaRESUMO
Hepatitis E virus genotype 3 is not rare in developed countries, and may cause chronic hepatitis in immunocompromised patients. This may not only lead to abnormalities in liver test and malaise, but to severe neurological symptoms as well. In this case, chronic hepatitis E infection caused encephalopathy, an atactic gait, Lhermitte's sign, incomplete bladder emptying and peripheral sensory neuropathy in a renal transplant recipient. The diagnosis was not performed until years after the onset of first symptoms and several months after the onset of neurological symptoms. If treated adequately, viral load can be reduced in over two-thirds of patients and neurological symptoms are often resolved. More widespread knowledge about this virus and its extrahepatic manifestations may lead to a quicker diagnosis, and may limit pathology. Serological screening should be added to standard pretransplant virological screening, so that, in the future, patients without antibodies could be vaccinated.
Assuntos
Encefalopatia Hepática/diagnóstico , Hepatite E/diagnóstico , Hepatite E/tratamento farmacológico , Falência Renal Crônica/imunologia , Ribavirina/uso terapêutico , Idoso , Biópsia por Agulha , Doença Crônica , Progressão da Doença , Eletromiografia/métodos , Feminino , Seguimentos , Sobrevivência de Enxerto , Encefalopatia Hepática/terapia , Hepatite E/imunologia , Humanos , Hospedeiro Imunocomprometido , Imuno-Histoquímica , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Testes de Função Hepática , Imageamento por Ressonância Magnética/métodos , Índice de Gravidade de Doença , Transplantados , Imunologia de Transplantes , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
Postprandial lipemia has been associated with cardiovascular disease. The current pathophysiological concept is that postprandial remnant lipoproteins migrate into the subendothelial space and that remnants activate circulating leukocytes and endothelial cells. Activated monocytes adhere to endothelial adhesion molecules, facilitating subendothelial migration of monocytes. These cells differentiate into macrophages, with the risk of foam cell formation, due to uptake of remnants and modified lipoproteins. Evidence is emerging that specific interventions may reduce the atherogenic postprandial inflammation. Fruits rich in polyphenols, virgin olive oil, carotenoids and exercise have recently been found to reduce postprandial inflammation. Pharmaceutical interventions with fibrates or statins not only improve the overall lipid profile, but reduce postprandial inflammation as well. This review will deal with the current concept of postprandial inflammation in relation to the development of atherosclerosis and potential interventions to reduce postprandial inflammation.