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BACKGROUND AND AIMS: RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases. METHODS: RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. RESULTS: In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60). CONCLUSIONS: PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.
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Aterosclerose , Isquemia Encefálica , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Pancreatite , Acidente Vascular Cerebral , Humanos , Doença Aguda , Doença da Artéria Coronariana/genética , Proteína 3 Semelhante a Angiopoietina , Anticorpos , Apolipoproteínas B/genética , TriglicerídeosRESUMO
BACKGROUND & AIMS: Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies. METHODS: We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis-acting variants on 4719 blood proteins from the deCODE study (N = 35,559) and 4979 blood proteins from the Fenland study (N = 10,708). RESULTS: The meta-analysis identified genome-wide significant variants (P <5 × 10-8) at 5 loci (ABCG5/8, TWIST2, SPINK1, PRSS2 and MORC4). The proteome-wide MR analyses identified 68 unique blood proteins that may causally be associated with AP, including 29 proteins validated in both data sets. Functional annotation of these proteins confirmed expression of many proteins in metabolic tissues responsible for digestion and energy metabolism, such as the esophagus, adipose tissue, and liver as well as acinar cells of the pancreas. Genetic colocalization and investigations into the druggable genome also identified potential drug targets for AP. CONCLUSIONS: This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets for AP.
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Pancreatite , Proteoma , Humanos , Proteoma/genética , Análise da Randomização Mendeliana , Estudo de Associação Genômica Ampla , Doença Aguda , Pancreatite/genética , Proteínas Sanguíneas , Polimorfismo de Nucleotídeo Único , Tripsina/genética , Tripsinogênio/genética , Inibidor da Tripsina Pancreática de Kazal/genética , Proteínas Nucleares/genéticaRESUMO
BACKGROUND: Maple syrup, a minimally transformed sweetener rich in polyphenols, can exert a prebiotic-like action and improve metabolic parameters in animal models. However, no randomized clinical trial has investigated the impact of replacing refined sugars with maple syrup on cardiometabolic risk factors and gut microbiota composition. AIMS, MATERIALS AND METHODS: In a randomized, double-blind, controlled crossover trial with 42 overweight adults with mild cardiometabolic alterations, participants were instructed to substitute 5% of their total caloric intake from added sugars with either maple syrup or an artificially flavored sucrose syrup for eight weeks. The primary outcome included changes in glucose homeostasis while secondary outcomes were changes in other cardiometabolic risk factors such as blood pressure, anthropometric indices, and blood lipid profiles. Exploratory outcomes involved analyzing changes in gut microbiota composition. RESULTS: Replacing refined sugars with maple syrup over eight weeks decreased the glucose area under the curve when compared to substituting refined sugars with sucrose syrup, as determined during the oral glucose tolerance test, leading to a significant difference between the intervention arms (-50.59±201.92 vs 29.93±154.90, P<.047). Substituting refined sugar with maple syrup also significantly decreased android fat mass (-7.83±175.05 vs 67.61± 206.71 g, P = 0.02) and systolic blood pressure (-2.72±8.73 vs 0.87±8.99 mmHg, P=0.03). No changes in the blood lipid profile were observed. As an exploratory outcome, we further observed that substituting refined sugars with maple syrup promoted selective taxonomic changes in the gut microbiota such as a significant reduction in the abundance of Klebsiella and decreased microbial functions associated with bacterial-induced cytokine response, as compared to substitution with sucrose syrup. CONCLUSION: Substituting refined sugars with maple syrup in individuals with mild metabolic alterations resulted in a significantly greater reduction of key cardiometabolic risk factors as compared to substitution with sucrose syrup, in association with specific changes in gut microbiota. The role of the gut microbiota in these effects remains to be further explored. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov as NCT04117802.
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Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to determine whether the gut microbiota influences cardiometabolic traits as well as the risk of chronic diseases and human longevity using a comprehensive 2-Sample Mendelian randomization approach. We included as exposures 10 gut-associated metabolites and pathways and 57 microbial taxa abundance. We included as outcomes nine cardiometabolic traits (fasting glucose, fasting insulin, systolic blood pressure, diastolic blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, body mass index [BMI]), eight chronic diseases previously linked with the gut microbiota in observational studies (Alzheimer's disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease), as well as parental lifespan and longevity. We found 7 associations with evidence of causality before and after sensitivity analyses, but not after multiple testing correction (1198 tests). Most effect sizes (4/7) were small. The two largest exposure-outcome effects were markedly attenuated towards the null upon inclusion of BMI or alcohol intake frequency in multivariable MR analyses. While finding robust genetic instruments for microbiota features is challenging hence potentially inflating type 2 errors, these results do not support a large causal impact of human gut microbita features on cardiometabolic traits, chronic diseases or longevity. These results also suggest that the previously documented associations between gut microbiota and human health outcomes may not always underly causal relations.
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Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Humanos , Longevidade/genética , Microbioma Gastrointestinal/genética , Análise da Randomização Mendeliana , Doença da Artéria Coronariana/genética , Índice de Massa Corporal , Doença Crônica , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica AmplaRESUMO
Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD.
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Doença da Artéria Coronariana , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.
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Estenose da Valva Aórtica , Aterosclerose , Calcinose , Doenças Cardiovasculares , Adulto , Estenose da Valva Aórtica/complicações , Aterosclerose/etiologia , Calcinose/complicações , Doenças Cardiovasculares/complicações , LDL-Colesterol , Humanos , Lipoproteína(a)/genética , Fatores de RiscoRESUMO
BACKGROUND: Heart failure (HF) is a prevalent cause of mortality and morbidity. The molecular drivers of HF are still largely unknown. RESULTS: We aimed to identify circulating proteins causally associated with HF by leveraging genome-wide genetic association data for HF including 47,309 cases and 930,014 controls. We performed two-sample Mendelian randomization (MR) with multiple cis instruments as well as network and enrichment analysis using data from blood protein quantitative trait loci (pQTL) (2,965 blood proteins) measured in 3,301 individuals. Nineteen blood proteins were causally associated with HF, were not subject to reverse causality and were enriched in ligand-receptor and glycosylation molecules. Network pathway analysis of the blood proteins showed enrichment in NF-kappa B, TGF beta, lipid in atherosclerosis and fluid shear stress. Cross-phenotype analysis of HF identified genetic overlap with cardiovascular drugs, myocardial infarction, parental longevity and low-density cholesterol. Multi-trait MR identified causal associations between HF-associated blood proteins and cardiovascular outcomes. Multivariable MR showed that association of BAG3, MIF and APOA5 with HF were mediated by the blood pressure and coronary artery disease. According to the directional effect and biological action, 7 blood proteins are targets of existing drugs or are tractable for the development of novel therapeutics. Among the pathways, sialyl Lewis x and the activin type II receptor are potential druggable candidates. CONCLUSIONS: Integrative MR analyses of the blood proteins identified causally-associated proteins with HF and revealed pleiotropy of the blood proteome with cardiovascular risk factors. Some of the proteins or pathway related mechanisms could be targeted as novel treatment approach in HF.
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Insuficiência Cardíaca , Proteoma , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose , Proteínas Sanguíneas/metabolismo , Insuficiência Cardíaca/genética , Humanos , Análise da Randomização Mendeliana , Proteoma/metabolismo , Fatores de RiscoRESUMO
BACKGROUND: During pregnancy, maternal metabolism undergoes substantial changes to support the developing fetus. Such changes are finely regulated by different mechanisms carried out by effectors such as microRNAs (miRNAs). These small non-coding RNAs regulate numerous biological functions, mostly through post-transcriptional repression of gene expression. miRNAs are also secreted in circulation by numerous organs, such as the placenta. However, the complete plasmatic microtranscriptome of pregnant women has still not been fully described, although some miRNA clusters from the chromosome 14 (C14MC) and the chromosome 19 (C19MC and miR-371-3 cluster) have been proposed as being specific to pregnancy. Our aims were thus to describe the plasma microtranscriptome during the first trimester of pregnancy, by assessing the differences with non-pregnant women, and how it varies between the 4th and the 16th week of pregnancy. METHODS: Plasmatic miRNAs from 436 pregnant (gestational week 4 to 16) and 15 non-pregnant women were quantified using Illumina HiSeq next-generation sequencing platform. Differentially abundant miRNAs were identified using DESeq2 package (FDR q-value ≤ 0.05) and their targeted biological pathways were assessed with DIANA-miRpath. RESULTS: A total of 2101 miRNAs were detected, of which 191 were differentially abundant (fold change < 0.05 or > 2, FDR q-value ≤ 0.05) between pregnant and non-pregnant women. Of these, 100 miRNAs were less and 91 miRNAs were more abundant in pregnant women. Additionally, the abundance of 57 miRNAs varied according to gestational age at first trimester, of which 47 were positively and 10 were negatively associated with advancing gestational age. miRNAs from the C19MC were positively associated with both pregnancy and gestational age variation during the first trimester. Biological pathway analysis revealed that these 191 (pregnancy-specific) and 57 (gestational age markers) miRNAs targeted genes involved in fatty acid metabolism, ECM-receptor interaction and TGF-beta signaling pathways. CONCLUSION: We have identified circulating miRNAs specific to pregnancy and/or that varied with gestational age in first trimester. These miRNAs target biological pathways involved in lipid metabolism as well as placenta and embryo development, suggesting a contribution to the maternal metabolic adaptation to pregnancy and fetal growth.
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MicroRNAs/genética , Primeiro Trimestre da Gravidez/genética , Adolescente , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Idade Gestacional , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Gravidez , Primeiro Trimestre da Gravidez/sangue , Fatores de Tempo , Adulto JovemRESUMO
The risk factors for nonalcoholic fatty liver disease (NAFLD) have not been clearly identified. We conducted a Mendelian randomization (MR) study to explore this. Independent genetic variants strongly associated with 5 lifestyle and 9 metabolic factors were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for NAFLD were obtained from a GWAS meta-analysis of 8434 cases and 770,180 non-cases (discovery dataset) and another GWAS meta-analysis of 1483 cases and 17,781 non-cases (replication dataset). Univariable and multivariable MR analyses were performed. There were associations with NAFLD for lifetime smoking index (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.31-1.93 per SD-increase), body mass index (BMI, OR 1.33, 95% CI 1.23-1.43 per SD-increase), waist circumference (OR 1.82; 95% CI 1.48-2.24 per SD-increase), type 2 diabetes (OR 1.21, 95% CI 1.15-1.27 per unit increase in log-transformed odds), systolic blood pressure (OR 1.17; 95% CI 1.07-1.26 per 10 mmHg increase), high-density lipoprotein cholesterol (OR 0.84, 95% CI 0.77-0.90 per SD-increase), and triglycerides (OR 1.23, 95% CI 1.15-1.33 per SD-increase). The associations for type 2 diabetes, systolic blood pressure, triglycerides, but not for high-density lipoprotein cholesterol remained strong after adjusting for genetically-predicted BMI. Genetic liability to type 2 diabetes mediated 51.4% (95% CI 13.4-89.3%) of the BMI-effects on NAFLD risk. There were suggestive inverse associations of genetically-predicted alcohol, coffee, and caffeine consumption, and vigorous physical activity with NAFLD risk. This study identified several lifestyle and metabolic factors that may be causally implicated in NAFLD.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Índice de Massa Corporal , HDL-Colesterol/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Humanos , Estilo de Vida , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , TriglicerídeosRESUMO
It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, nmax = 40,914) and DIAGRAM (nmax = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.
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LDL-Colesterol/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Análise da Randomização Mendeliana/métodos , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/induzido quimicamente , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , MasculinoRESUMO
AIMS: Calcific aortic valve stenosis (CAVS) is characterized by a fibrocalcific process. Studies have shown an association between CAVS and the activation of platelets. It is believed that shear stress associated with CAVS promotes the activation of platelets. However, whether platelets actively participate to the mineralization of the aortic valve (AV) and the progression of CAVS is presently unknown. To identify the role of platelets into the pathobiology of CAVS. METHODS AND RESULTS: Explanted control non-mineralized and mineralized AVs were examined by scanning electron microscope (SEM) for the presence of activated platelets. In-depth functional assays were carried out with isolated human valve interstitial cells (VICs) and platelets as well as in LDLR-/- apoB100/100 IGFII (IGFII) mice. Scanning electron microscope and immunogold markings for glycoprotein IIb/IIIa (GPIIb/IIIa) revealed the presence of platelet aggregates with fibrin in endothelium-denuded areas of CAVS. In isolated VICs, collagen-activated platelets induced an osteogenic programme. Platelet-derived adenosine diphosphate induced the release of autotaxin (ATX) by VICs. The binding of ATX to GPIIb/IIIa of platelets generated lysophosphatidic acid (LysoPA) with pro-osteogenic properties. In IGFII mice with CAVS, platelet aggregates were found at the surface of AVs. Administration of activated platelets to IGFII mice accelerated the development of CAVS by 2.1-fold, whereas a treatment with Ki16425, an antagonist of LysoPA receptors, prevented platelet-induced mineralization of the AV and the progression of CAVS. CONCLUSIONS: These findings suggest a novel role for platelets in the progression of CAVS.
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Estenose da Valva Aórtica/metabolismo , Valva Aórtica/patologia , Plaquetas/metabolismo , Calcinose/metabolismo , Osteogênese , Animais , Valva Aórtica/metabolismo , Valva Aórtica/ultraestrutura , Apolipoproteína B-100/metabolismo , Progressão da Doença , Humanos , Integrina beta3/metabolismo , Lisofosfolipídeos/metabolismo , Camundongos , Microscopia Eletrônica de Varredura/métodos , Diester Fosfórico Hidrolases/metabolismo , Glicoproteína IIb da Membrana de Plaquetas/metabolismoRESUMO
Targeting metabolic determinants of exercise performance with pharmacological agents that would mimic/potentiate the effects of exercise represents an attractive clinical alternative to counterbalance the poor exercise capacity in patients with type 2 diabetes mellitus (T2DM). We examined the effect of 1-yr treatment with the insulin sensitizer peroxisome proliferator-activated receptor (PPAR)γ agonist rosiglitazone on aerobic exercise capacity and body fat composition/distribution in men with T2DM and stable coronary artery disease (CAD). One-hundred four men (age: 64 ± 7 yr; body mass index: 30.0 ± 4.4 kg/m2) with T2DM and CAD were randomized to receive rosiglitazone or placebo for 1 yr. Aerobic exercise capacity (exercise duration) was assessed with a maximal treadmill test, and body composition/distribution were assessed by dual-energy X-ray absorptiometry/computed tomography scans. At 1 yr, patients with T2DM under PPARγ agonist treatment showed a reduction in aerobic exercise capacity compared with the control group (exercise duration change, -31 ± 8 versus 7 ± 11 s, P = 0.009). Significant increases in body fat mass (3.1 ± 0.4 kg, 12%), abdominal and mid-thigh subcutaneous adipose tissue (AT) levels, and mid-thigh skeletal muscle fat were found (all P < 0.01), whereas no effect on visceral AT levels was observed (P > 0.05) under treatment. Subcutaneous fat mass gained under PPARγ agonist was the strongest predictor of the worsening in aerobic exercise capacity (P > 0.0001); no association was found with skeletal muscle fat infiltration nor visceral AT. Treatment with the insulin sensitizer PPARγ agonist rosiglitazone in patients with T2DM and CAD is associated with a worsening in aerobic exercise capacity, which seems to be mainly attributable to weight gain and subcutaneous fat mass expansion.
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Distribuição da Gordura Corporal , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Tolerância ao Exercício/efeitos dos fármacos , Rosiglitazona/farmacologia , Idoso , Composição Corporal/efeitos dos fármacos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/terapia , Exercício Físico/fisiologia , Humanos , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , PPAR gama/agonistas , Rosiglitazona/uso terapêutico , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismoRESUMO
Cholesterol efflux capacities (CECs) are negatively associated with cardiovascular disease risk, irrespective of plasma high-density lipoprotein (HDL) cholesterol levels. Whether interventions targeting lifestyle improve HDL-CECs is unknown. Our objective was to determine whether improving dietary quality and increasing physical activity levels improves HDL-CECs in men with abdominal obesity and dyslipidemia. Our study sample included men (48 ± 8.5 yr) with an elevated waist circumference (≥90 cm) associated with dyslipidemia (triglycerides ≥1.69 and/or HDL cholesterol <1.03 mmol/l); 113 men completed a 1-yr intervention, consisting of a healthy eating and physical activity/exercise program, and 32 were included in a control group. An oral lipid tolerance test (OLTT) was performed in a subsample of 28 men who completed the intervention, and blood was collected every 2 h for 8 h. HDL-CECs were measured using [3H]cholesterol-labeled J774 macrophages and HepG2 hepatocytes. The lifestyle modification program led to an overall improvement in the cardiometabolic risk profile, increases in J774-HDL-CEC by 14.1% (+0.88 ± 1.09%, P < 0.0001), HepG2-HDL-CEC by 3.4% (+0.17 ± 0.75%, P = 0.01), and HDL cholesterol and apolipoprotein A-1 levels (13.5%, P < 0.0001 and 14.9%, P < 0.0001, respectively). J774-HDL-CECs and HepG2-HDL-CECs did not change in the control group. The best predictor for changes in HDL-CEC was apolipoprotein A-1 level. The lifestyle modification program also improved HDL-CEC response in postprandial lipemia during an OLTT. HDL-CEC did not change during the OLTT. Our results suggest that increasing physical activity levels and improving diet quality can have a positive impact on both HDL quantity and quality in men with abdominal obesity and dyslipidemia.
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Restrição Calórica , HDL-Colesterol/metabolismo , Dieta Saudável , Dislipidemias/terapia , Exercício Físico , Obesidade Abdominal/terapia , Triglicerídeos/metabolismo , Adiponectina/metabolismo , Adulto , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/metabolismo , Aptidão Cardiorrespiratória , Colesterol/metabolismo , Dislipidemias/metabolismo , Células Hep G2 , Humanos , Estilo de Vida , Macrófagos , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/metabolismo , Pró-Proteína Convertase 9/metabolismo , TrítioRESUMO
Background: Recent evidence suggests that the association between dietary saturated fatty acids (SFAs) and coronary artery disease risk varies according to food sources. How SFAs from butter and cheese influence HDL-mediated cholesterol efflux capacity (CEC), a key process in reverse cholesterol transport, is currently unknown. Objective: In a predefined secondary analysis of a previously published trial, we have examined how diets rich in SFAs from either cheese or butter influence HDL-mediated CEC, compared with diets rich in either monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids (PUFAs). Methods: In a randomized crossover controlled consumption trial, 46 men and women with abdominal obesity consumed 5 isocaloric diets, each for 4 wk. Two diets were rich in SFAs either from cheese (CHEESE) or butter (BUTTER) [12.4-12.6% of energy (%E) as SFAs, 32%E as fat, 52%E as carbohydrates]. In 2 other diets, SFAs (5.8%E) were replaced with either MUFAs from refined olive oil (MUFA) or PUFAs from corn oil (PUFA). Finally, a lower fat and carbohydrate diet was used as a control (5.8%E as SFAs, 25.0%E as fat, 59%E as carbohydrates; CHO). Post-diet HDL-mediated CEC was determined ex vivo using radiolabelled J774 macrophages incubated with apolipoprotein B-depleted serum from the participants. Results: Mean (±SD) age was 41.4 ± 14.2 y, and waist circumference was 107.6 ± 11.5 cm in men and 94.3 ± 12.4 cm in women. BUTTER and MUFA increased HDL-mediated CEC compared with CHEESE (+4.3%, P = 0.026 and +4.7%, P = 0.031, respectively). Exploring the significant diet × sex interaction (P = 0.044) revealed that the increase in HDL-mediated CEC after BUTTER compared with CHEESE was significant among men (+6.0%, P = 0.047) but not women (+2.9%, P = 0.19), whereas the increase after MUFA compared with CHEESE was significant among women (+9.1%, P = 0.008) but not men (-0.6%, P = 0.99). Conclusion: These results provide evidence of a food matrix effect modulating the impact of dairy SFAs on HDL-mediated CEC with potential sex-related differences that deserve further investigation. This trial was registered at clinicaltrials.gov as NCT02106208.
Assuntos
Adulto , Manteiga , Queijo , HDL-Colesterol/metabolismo , Dieta , Ácidos Graxos/farmacologia , Obesidade Abdominal/metabolismo , Apolipoproteínas B/metabolismo , Manteiga/efeitos adversos , Queijo/efeitos adversos , Colesterol/sangue , Óleo de Milho/metabolismo , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Estudos Cross-Over , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/metabolismo , Gorduras na Dieta/farmacologia , Ácidos Graxos/administração & dosagem , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos Insaturados/metabolismo , Ácidos Graxos Insaturados/farmacologia , Comportamento Alimentar , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/complicações , Azeite de Oliva/metabolismo , Fatores de Risco , Circunferência da CinturaRESUMO
AIMS: We aimed to determine the effect of 1-year treatment with the insulin sensitizer peroxisome proliferator-activated receptor (PPAR)-γ agonist rosiglitazone on exercise capacity and blood pressure (BP) response to exercise in men with coronary artery disease (CAD) and type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 116 men (age, 64 ± 7 years; body mass index, 30.0 ± 4.4 kg/m2 ) with CAD and T2D were randomized to receive rosiglitazone or placebo for 1 year. Exercise capacity (VO2peak ) and BP response to exercise were assessed with a maximal treadmill test, prior to the intervention and at 1-year follow-up. Exercise-induced hypertension (EIH) was defined as maximal systolic BP ≥ 220 mm Hg and/or diastolic BP ≥ 100 mm Hg. RESULTS: PPAR-γ agonist-treated patients showed improvements in fasting glucose, HbA1c and insulin sensitivity (Homeostasis model assessment of insulin resistance [HOMA-IR]) (all P < .05). Resting BPs, maximal exercise diastolic BP and resting rate-pressure product (RPP) were all reduced in the PPAR-γ agonist group (P < .05). Maximal exercise duration was unchanged. T2D patients who displayed the greatest improvement in insulin sensitivity (HOMA-IR) under PPAR-γ agonist treatment experienced a greater reduction in exercise BP and RPP (P < .05). The proportion of men with EIH decreased in the PPAR-γ agonist group during follow-up (39.00% ± 0.06% vs 21.00% ± 0.05%). In the subgroup with EIH that was treated with a PPAR-γ agonist, resting and exercise diastolic BP, as well as resting RPP, were all reduced at 1-year follow-up (P < .05). CONCLUSIONS: The insulin sensitizer rosiglitazone has a beneficial effect on resting and BP response to exercise in men with CAD and T2D, especially in those with an exaggerated BP response to exercise.
Assuntos
Pressão Sanguínea , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exercício Físico , Hipertensão/fisiopatologia , Hipoglicemiantes/uso terapêutico , Rosiglitazona/uso terapêutico , Idoso , Glicemia/metabolismo , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Teste de Esforço , Tolerância ao Exercício , Hemoglobinas Glicadas/metabolismo , Humanos , Hipertensão/complicações , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , PPAR gama/agonistas , DescansoRESUMO
OBJECTIVE: Carriers of the PCSK9 (proprotein convertase subtilisin/kexin 9) R46L genetic variant (rs11591147) are characterized by low levels of low-density lipoprotein cholesterol and a decreased risk of cardiovascular disease. We studied the impact of the R46L variant on lipoprotein size and composition. APPROACH AND RESULTS: Lipoprotein size and composition were measured by nuclear magnetic resonance spectroscopy in 2373 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. After adjusting for age, sex, and cardiovascular disease status, carriers of the R46L variant (n=77) were characterized by lower concentrations of very low-density lipoprotein particles (85.8±26.2 versus 99.0±33.3 nmol/L; P<0.001), low-density lipoprotein particles (1479.7±396.8 versus 1662.9±458.3 nmol/L; P<0.001), and lipoprotein(a) (11.1 [7.2-28.6] versus 12.4 [6.7-29.1] mg/dL; P<0.001) compared with noncarriers. Total high-density lipoprotein particle and very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particle sizes were comparable in carriers and noncarriers. Carriers were characterized by lower secretory phospholipase A2 (4.2±0.9 versus 4.6±1.3 nmol/mL/min; P=0.004) and lipoprotein-associated phospholipase A2 activity (47.5±14.1 versus 52.4±16.2 nmol/mL/min; P=0.02) compared with noncarriers. CONCLUSIONS: Results of this study suggest that carriers of the PCSK9 R46L genetic variant have lower very low-density lipoprotein and low-density lipoprotein particle concentrations, lower lipoprotein(a) levels, and lower secretory phospholipase A2 and lipoprotein-associated phospholipase A2 activity compared with noncarriers.
Assuntos
Aterosclerose/prevenção & controle , Heterozigoto , Lipoproteínas/sangue , Espectroscopia de Ressonância Magnética , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Idoso , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Inglaterra , Feminino , Humanos , Lipoproteína(a)/sangue , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Fenótipo , Fosfolipases A2 Secretórias/sangue , Estudos Prospectivos , Fatores de Proteção , Medição de Risco , Fatores de RiscoAssuntos
Aterosclerose , Doenças Cardiovasculares , Humanos , Análise da Randomização Mendeliana , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Jardins , Aterosclerose/genética , Aterosclerose/prevenção & controle , Fatores de Risco , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo ÚnicoRESUMO
PURPOSE OF REVIEW: Patients with familial hypercholesterolemia, familial combined hyperlipidemia and hyperlipoprotein(a) are at high cardiovascular risk. Increasing evidence suggest that lifestyle-related risk factors such as physical inactivity, and poor diet quality could influence cardiovascular risk in these patients. Our objective is to review the evidence that supports the role of lifestyle-related factors in the prediction of cardiovascular risk in patients with inherited lipid disorders. RECENT FINDINGS: Recent studies have shown that smoking, a poor diet quality, physical inactivity, fitness levels, abdominal obesity, insulin resistance, and type 2 diabetes were associated with the presence of atherosclerosis and long-term cardiovascular outcomes in patients with familial hypercholesterolemia. Recent evidence also suggest that managing other cardiovascular risk factors such as cholesterol levels, obesity, glycemic control, blood pressure, smoking, physical inactivity, and diet quality could reduce long-term cardiovascular risk associated with hyperlipoprotein(a). Whether targeting these risk factors could ultimately decrease cardiovascular risk in these patients remains unknown. SUMMARY: Although reducing the number of atherogenic apolipoprotein-B containing particle with lipid-lowering therapy represents the cornerstone of treatment of patients with inherited lipid disorders, lifestyle-related risk factors such as physical inactivity and poor diet quality need to be targeted for the optimal management of these high-risk patients.