RESUMO
BACKGROUND: The effectiveness of statin treatment to reduce coronary events and mortality has been hardly examined considering goals of LDL-C. We aimed to analyse such association in secondary cardiovascular prevention. METHODS: Retrospective cohort analysis of electronic health records from the SIDIAP database, Catalonia-Spain. Recruitment period was from 2006 to 2017 and study period finished at the end of 2018. We included 54,175 people aged ≥35 years in cardiovascular secondary prevention starting statin treatment. We analysed the association of achieved LDL-C goals after statin initiation with coronary heart disease and all-cause mortality. RESULTS: Mean age was 69 years and 20,146 (37.2%) were women. Coronary heart disease occurred in 5687 (10.5%) participants, and 10,676 (19.7%) persons passed away. Median follow-up lasted 5.7 years (interquartile range, 3.4-8.1). The coronary heart disease HRs (95% CI) for the LDL-C goals of 70-100, <70-55 and <55 mg/dL were .86 (.81-.92), .83 (.76-.9) and .8 (.72-.88), respectively. They were .89 (.83-.96) in the group with 30%-40% reduction and .86 (.8-.93) in the groups with 40%-50% and ≥50% reduction. We observed no association with mortality. We observed no relevant differences by sex or age. CONCLUSIONS: This population-level retrospective analysis of real-world data observed that treatment with statins is effective to achieve certain LDL-C goals and CHD reduction. The lack of significant difference between LDL-C goals needs confirmation in additional studies with real-world data. The LDL-C target should consider the magnitude of the decrease in coronary events.
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Myogenic regulatory factors of the MyoD family have the ability to reprogram differentiated cells toward a myogenic fate. In this study, we demonstrate that Six1 or Six4 are required for the reprogramming by MyoD of mouse embryonic fibroblasts (MEFs). Using microarray experiments, we found 761 genes under the control of both Six and MyoD. Using MyoD ChIPseq data and a genome-wide search for Six1/4 MEF3 binding sites, we found significant co-localization of binding sites for MyoD and Six proteins on over a thousand mouse genomic DNA regions. The combination of both datasets yielded 82 genes which are synergistically activated by Six and MyoD, with 96 associated MyoD+MEF3 putative cis-regulatory modules (CRMs). Fourteen out of 19 of the CRMs that we tested demonstrated in Luciferase assays a synergistic action also observed for their cognate gene. We searched putative binding sites on these CRMs using available databases and de novo search of conserved motifs and demonstrated that the Six/MyoD synergistic activation takes place in a feedforward way. It involves the recruitment of these two families of transcription factors to their targets, together with partner transcription factors, encoded by genes that are themselves activated by Six and MyoD, including Mef2, Pbx-Meis and EBF.
Assuntos
Reprogramação Celular/genética , Genoma , Proteínas de Homeodomínio/metabolismo , Proteína MyoD/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética , Transativadores/metabolismo , Animais , Sequência de Bases , Sítios de Ligação/genética , Células Cultivadas , Imunoprecipitação da Cromatina , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Luciferases/metabolismo , Camundongos Knockout , Desenvolvimento Muscular/genética , Mutação/genética , Proteínas Nucleares/metabolismo , Motivos de Nucleotídeos/genética , Reprodutibilidade dos Testes , Transativadores/genética , Fatores de Transcrição/metabolismoRESUMO
AIM: The concept of risk age may help overcome an excessive weight of age in cardiovascular risk functions. This study aimed to evaluate the equivalence of risk age with arterial stiffness by comparing people with increased risk age and individuals with the same chronological and risk age. In order to materialize this aim, we categorized individuals based on cardiovascular risk and compared groups with increased risk factors (other than age) and groups with normal levels. METHODS: This is a cross-sectional population-level study carried out in Girona province within the context of the REGICOR study (Girona Heart Registry). In this study, individuals aged 35-90 years who had a brachial-ankle pulse wave velocity measurement and with no previous cardiovascular disease or peripheral arterial disease were included. Cardiovascular risk was estimated with the FRESCO (in 35-79 year-olds), SCORE2 (in 35-69 year-olds), and SCORE2-OP (in 70-90 year-olds) functions and categorized to calculate and compare (in each category) the median chronological age in the group with increased risk factors and the reference. Arterial stiffness was assessed with the brachial-ankle pulse wave velocity (baPWV). The analyses were carried out separately by sex. RESULTS: In this study, 2499 individuals were included, with a mean age of 59.7 and 46.9% of men. Men presented worse health condition, including a higher mean cardiovascular disease risk score. Both men and women with increased levels of risk factors showed worse health condition than the respective men and women with optimal levels. In each risk category, the groups with higher risk age than chronological age (increased risk factors) were similar in baPWV values to the groups with the same chronological and risk ages (reference), who were consistently older. CONCLUSIONS: In categories with the same cardiovascular risk, the arterial stiffness of participants with a higher risk factor burden (increased risk age) matched that of older participants with the rest of the risk factors at optimal levels (same chronological and risk age). These results support the guidelines on the utilization of risk age to explain heightened cardiovascular risk, particularly among individuals in middle age.
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Índice Tornozelo-Braço , Doenças Cardiovasculares , Fatores de Risco de Doenças Cardíacas , Análise de Onda de Pulso , Rigidez Vascular , Humanos , Rigidez Vascular/fisiologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Idoso , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/diagnóstico , Adulto , Idoso de 80 Anos ou mais , Fatores Etários , Fatores de RiscoRESUMO
BACKGROUND: Cardiovascular health has been associated with dementia onset, but little is known about the variation of such association by sex and age considering dementia subtypes. We assessed the role of sex and age in the association between cardiovascular risk and the onset of all-cause dementia, Alzheimer's disease, and vascular dementia in people aged 50-74 years. METHODS: This is a retrospective cohort study covering 922.973 Catalans who attended the primary care services of the Catalan Health Institute (Spain). Data were obtained from the System for the Development of Research in Primary Care (SIDIAP database). Exposure was the cardiovascular risk (CVR) at baseline categorized into four levels of Framingham-REGICOR score (FRS): low (FRS < 5%), low-intermediate (5% ≤ FRS < 7.5%), high-intermediate (7.5% ≤ FRS < 10%), high (FRS ≥ 10%), and one group with previous vascular disease. Cases of all-cause dementia and Alzheimer's disease were identified using validated algorithms, and cases of vascular dementia were identified by diagnostic codes. We fitted stratified Cox models using age parametrized as b-Spline. RESULTS: A total of 51,454 incident cases of all-cause dementia were recorded over a mean follow-up of 12.7 years. The hazard ratios in the low-intermediate and high FRS groups were 1.12 (95% confidence interval: 1.08-1.15) and 1.55 (1.50-1.60) for all-cause dementia; 1.07 (1.03-1.11) and 1.17 (1.11-1.24) for Alzheimer's disease; and 1.34 (1.21-1.50) and 1.90 (1.67-2.16) for vascular dementia. These associations were stronger in women and in midlife compared to later life in all dementia types. Women with a high Framingham-REGICOR score presented a similar risk of developing dementia - of any type - to women who had previous vascular disease, and at age 50-55, they showed three times higher risk of developing dementia risk compared to the lowest Framingham-REGICOR group. CONCLUSIONS: We found a doseâresponse association between the Framingham-REGICOR score and the onset of all dementia types. Poor cardiovascular health in midlife increased the onset of all dementia types later in life, especially in women.
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Doença de Alzheimer , Demência Vascular , População Europeia , Feminino , Humanos , Pessoa de Meia-Idade , Demência Vascular/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Masculino , IdosoRESUMO
Childhood obesity increases the risk of developing metabolic syndrome later in life. Moreover, metabolic dysfunction may be inherited into the following generation through non-genomic mechanisms, with epigenetics as a plausible candidate. The pathways involved in the development of metabolic dysfunction across generations in the context of childhood obesity remain largely unexplored. We have developed a mouse model of early adiposity by reducing litter size at birth (small litter group, SL: 4 pups/dam; control group, C: 8 pups/dam). Mice raised in small litters (SL) developed obesity, insulin resistance and hepatic steatosis with aging. Strikingly, the offspring of SL males (SL-F1) also developed hepatic steatosis. Paternal transmission of an environmentally induced phenotype strongly suggests epigenetic inheritance. We analyzed the hepatic transcriptome in C-F1 and SL-F1 mice to identify pathways involved in the development of hepatic steatosis. We found that the circadian rhythm and lipid metabolic process were the ontologies with highest significance in the liver of SL-F1 mice. We explored whether DNA methylation and small non-coding RNAs might be involved in mediating intergenerational effects. Sperm DNA methylation was largely altered in SL mice. However, these changes did not correlate with the hepatic transcriptome. Next, we analyzed small non-coding RNA content in the testes of mice from the parental generation. Two miRNAs (miR-457 and miR-201) appeared differentially expressed in the testes of SL-F0 mice. They are known to be expressed in mature spermatozoa, but not in oocytes nor early embryos, and they may regulate the transcription of lipogenic genes, but not clock genes, in hepatocytes. Hence, they are strong candidates to mediate the inheritance of adult hepatic steatosis in our murine model. In conclusion, litter size reduction leads to intergenerational effects through non-genomic mechanisms. In our model, DNA methylation does not seem to play a role on the circadian rhythm nor lipid genes. However, at least two paternal miRNAs might influence the expression of a few lipid-related genes in the first-generation offspring, F1.
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Fígado Gorduroso , MicroRNAs , Obesidade Infantil , Masculino , Camundongos , Animais , Modelos Animais de Doenças , Sêmen , Epigênese Genética , Metilação de DNA , LipídeosRESUMO
BACKGROUND: Time restricted feeding (TRF) refers to dietary interventions in which food access is limited during a specific timeframe of the day. TRFs have proven useful in improving metabolic health in adult subjects with obesity. Their beneficial effects are mediated, in part, through modulating the circadian rhythm. Nevertheless, the translation of these dietary interventions onto obese/overweight children and adolescents remains uncharacterized. The objective of this study is to explore the feasibility of temporal dietary interventions for improving metabolic health in the context of childhood obesity. METHODS: We have previously developed a mouse model of early adiposity (i.e., childhood obesity) through litter size reduction. Mice raised in small litters (SL) became obese as early as by two weeks of age, and as adults, they developed several obesity-related co-morbidities, including insulin resistance, glucose intolerance and hepatic steatosis. Here, we explored whether two independent short-term chrono-nutritional interventions might improve metabolic health in 1-month-old pre-pubertal SL mice. Both TRFs comprised 8 h feeding/14 h fasting. In the first one (TRF1) Control and SL mice had access to the diet for 8 h during the dark phase. In the second intervention (TRF2) food was available during the light:dark transitions. RESULTS: TRF1 did not alter food intake nor ameliorate adiposity in SL-TRF1. In contrast, SL-TRF2 mice showed unintentional reduction of caloric intake, which was accompanied by reduced total body weight and adiposity. Strikingly, hepatic triglyceride content was completely normalized in SL-TRF1 and SL-TRF2 mice, when compared to the ad lib-fed SL mice. These effects were partially mediated by (i) clock-dependent signals, which might modulate the expression of Pparg or Cpt1a, and (ii) clock-independent signals, such as fasting itself, which could influence Fasn expression. CONCLUSIONS: Time-restricted feeding is an effective and feasible nutritional intervention to improve metabolic health, namely hepatic steatosis, in a model of childhood obesity. These data open new avenues for future safe and efficient chrono-nutritional interventions aimed to improve metabolic health in children with overweight/obesity.
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Adiposidade , Jejum , Fígado Gorduroso/complicações , Fígado Gorduroso/prevenção & controle , Obesidade Infantil/complicações , Maturidade Sexual , Animais , Relógios Circadianos/genética , Dieta , Modelos Animais de Doenças , Fígado Gorduroso/genética , Regulação da Expressão Gênica , Resistência à Insulina , Tamanho da Ninhada de Vivíparos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Oxirredução , Obesidade Infantil/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/metabolismoRESUMO
Childhood obesity is a strong risk factor for adult obesity, type 2 diabetes, and cardiovascular disease. The mechanisms that link early adiposity with late-onset chronic diseases are poorly characterised. We developed a mouse model of early adiposity through litter size reduction. Mice reared in small litters (SLs) developed obesity, insulin resistance, and hepatic steatosis during adulthood. The liver played a major role in the development of the disease. OBJECTIVE: To gain insight into the molecular mechanisms that link early development and childhood obesity with adult hepatic steatosis and insulin resistance. METHODS: We analysed the hepatic transcriptome (Affymetrix) of control and SL mice to uncover potential pathways involved in the long-term programming of disease in our model. RESULTS: The circadian rhythm was the most significantly deregulated Gene Ontology term in the liver of adult SL mice. Several core clock genes, such as period 1-3 and cryptochrome 1-2, were altered in two-week-old SL mice and remained altered throughout their life course until they reached 4-6 months of age. Defective circadian rhythm was restricted to the periphery since the expression of clock genes in the hypothalamus, the central pacemaker, was normal. The period-cryptochrome genes were primarily entrained by dietary signals. Hence, restricting food availability during the light cycle only uncoupled the central rhythm from the peripheral and completely normalised hepatic triglyceride content in adult SL mice. This effect was accompanied by better re-alignment of the hepatic period genes, suggesting that they might have played a causal role in mediating hepatic steatosis in the adult SL mice. Functional downregulation of Per2 in hepatocytes in vitro confirmed that the period genes regulated lipid-related genes in part through peroxisome proliferator-activated receptor alpha (Ppara). CONCLUSIONS: The hepatic circadian rhythm matures during early development, from birth to postnatal day 30. Hence, nutritional challenges during early life may misalign the hepatic circadian rhythm and secondarily lead to metabolic derangements. Specific time-restricted feeding interventions improve metabolic health in the context of childhood obesity by partially re-aligning the peripheral circadian rhythm.
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Ritmo Circadiano/fisiologia , Lactação , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adiposidade , Adulto , Animais , Ritmo Circadiano/genética , Diabetes Mellitus Tipo 2/metabolismo , Jejum , Feminino , Humanos , Hipotálamo/metabolismo , Recém-Nascido , Resistência à Insulina/fisiologia , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/metabolismo , Obesidade InfantilRESUMO
Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.