Inhibitors of cholesteryl ester transfer protein - a step forward in the treatment of coronary artery disease?

Although the LDL cholesterol-lowering statins have reduced the mortality and morbidity associated with coronary artery disease (CAD), considerable mortality and morbidity remains. Increasing HDL cholesterol levels is associated with reduced CAD mortality and morbidity. In healthy subjects with mild dyslipidemia, treatment with JTT-705 decreased cholesteryl ester transfer protein (CETP) activity, increased HDL cholesterol and decreased LDL cholesterol. Similarly, another CETP inhibitor, torcetrapib, has recently been shown to increase HDL cholesterol by 46%, decrease LDL cholesterol by 8% and have no effect on triglycerides in subjects with HDL cholesterol levels below 1.0 mmol/l. Increasing HDL cholesterol with inhibitors of CETP represents a new approach to dyslipidemia that requires further investigation, especially in patients with CAD.

Rev-erb beta regulates the expression of genes involved in lipid absorption in skeletal muscle cells - Evidence for cross-talk between orphan nuclear receptors and myokines

Rev-erbbeta is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-alpha (RORalpha). RORalpha has been implicated in the regulation of high density lipoprotein cholesterol, lipid homeostasis, and inflammation. Rev-erbbeta and RORalpha are expressed in similar tissues, including skeletal muscle; however, the pathophysiological function of Rev-erbbeta has remained obscure. We hypothesize from the similar expression patterns, target genes, and overlapping cognate sequences of these nuclear receptors that Rev-erbbeta regulates lipid metabolism in skeletal muscle. This lean tissue accounts for > 30% of total body weight and 50% of energy expenditure. Moreover, this metabolically demanding tissue is a primary site of glucose disposal, fatty acid oxidation, and cholesterol efflux. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. We utilize ectopic expression in skeletal muscle cells to understand the regulatory role of Rev-erbbeta in this major mass peripheral tissue. Exogenous expression of a dominant negative version of mouse Rev-erbbeta decreases the expression of many genes involved in fatty acid/lipid absorption (including Cd36, and Fabp-3 and -4). Interestingly, we observed a robust induction (> 15-fold) in mRNA expression of interleukin-6, an exercise-induced myokine that regulates energy expenditure and inflammation. Furthermore, we observed the dramatic repression (> 20- fold) of myostatin mRNA, another myokine that is a negative regulator of muscle hypertrophy and hyperplasia that impacts on body fat accumulation. This study implicates Rev-erbbeta in the control of lipid and energy homoeostasis in skeletal muscle. In conclusion, we speculate that selective modulators of Rev-erbbeta may have therapeutic utility in the treatment of dyslipidemia and regulation of muscle growth.

Cardiovascular disease and PPARdelta: Targeting the risk factors

Metabolism, in part, is regulated by the peroxisome proliferator-activated receptors (PPARs). The PPARs act as nutritional lipid sensors and three mammalian PPAR subtypes designated PPARalpha (NR1C1), PPARgamma (NR1C3) and PPARdelta (NR1C2) have been identified. This subgroup of nuclear hormone receptors binds DNA and controls gene expression at the nexus of pathways that regulate lipid and glucose homeostasis, energy storage and expenditure in an organ-specific manner. Recent evidence has demonstrated activation of PPARdelta in the major mass peripheral tissue (ie, adipose and skeletal muscle). It enhances glucose tolerance, insulin-stimulated glucose disposal, lipid catabolism, energy expenditure, cholesterol efflux and oxygen consumption. These effects positively influence the blood-lipid profile. Furthermore, PPARdelta activation produces a predominant type I/slow twitch/oxidative muscle fiber phenotype that leads to increased endurance, insulin sensitivity and resistance to obesity. PPARdelta has rapidly emerged as a potential target in the battle against dyslipidemia, insulin insensitivity, type II diabetes and obesity, with therapeutic efficacy in the treatment of cardiovascular disease risk factors. GW-501516 is currently undergoing phase II safety and efficacy trials in human volunteers for the treatment of dyslipidemia. The outcome of these clinical trials are eagerly awaited against a background of conflicting reports about cancer risks in genetically predisposed animal models. This review focuses on the potential pharmacological utility of selective PPARdelta agonists in the context of risk factors associated with metabolic and cardiovascular disease.

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle. Am J Physiol Cell Physiol 291: C203-C217, 2006; doi: 10.1152/ajpcell. 00476.2005.-Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that bind DNA and translate physiological signals into gene regulation. The therapeutic utility of NRs is underscored by the diversity of drugs created to manage dysfunctional hormone signaling in the context of reproductive biology, inflammation, dermatology, cancer, and metabolic disease. For example, drugs that target nuclear receptors generate over $10 billion in annual sales. Almost two decades ago, gene products were identified that belonged to the NR superfamily on the basis of DNA and protein sequence identity. However, the endogenous and synthetic small molecules that modulate their action were not known, and they were denoted orphan NRs. Many of the remaining orphan NRs are highly enriched in energy-demanding major mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and kidney. This review focuses on recently adopted and orphan NR function in skeletal muscle, a tissue that accounts for similar to 35% of the total body mass and energy expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this lean tissue is involved in cholesterol efflux and secretes that control energy expenditure and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal muscle plays a considerable role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, which is the the foremost cause of global mortality (> 16.7 million deaths in 2003). Therefore, it is not surprising that orphan NRs and skeletal muscle are emerging as therapeutic candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease.

Modulation of cholesterol in midlife affords cognitive advantage during ageing - a role for altered redox balance

General practitioners, geriatricians, neurologists and health care professionals all over the world will be facing by 2040 the diagnostic, therapeutic and socioeconomic challenges of over 80 million people with dementia. Dementia is one of the most common diseases in the elderly which drastically affects daily life and everyday personal activities, is often associated with behavioural symptoms, personality change and numerous clinical complications and increases the risk for urinary incontinence, hip fracture, and - most markedly - the dependence on nursing care. The costs of care for patients with dementia are therefore immense. Serum cholesterol levels above 6.5 mmol/L are known to be associated with an increased RR of 1.5 and 2.1 to develop Alzheimeŕs disease, the most common form of dementia, and a reduction of serum cholesterol in midlife is associated with a lowered dementia risk. The aim of this work is to critically discuss some of the main results reported recently in the literature in this respect and to provide the pathophysiological rationale for the control of dyslipidemia in the prevention of dementia onset and progression.

Impact of a comprehensive nutrition and lifestyle education intervention on body weight and health-related outcomes in morbidly-obese Hispanic-Americans following laparoscopic Roux-en-Y gastric bypass

As morbid obesity increasingly affects Hispanic-Americans, the incidence of Roux-en-Y gastric bypass procedures (RYGB) among this population rises. Prospective research on the impact of postoperative educational interventions focused on Hispanic- Americans is needed to prevent premature weight loss plateau, weight regain, nutritional deficiencies, and relapse of obesity-related comorbidities. This randomized-controlled study evaluated the impact of a comprehensive nutrition and lifestyle education intervention (6 biweekly postoperative sessions that incorporated motivational strategies for behavioral change) as compared to a non-comprehensive approach (printed guidelines for healthy lifestyle). The variables to consider are body weight, obesity-related comorbidities (depression, diabetes, dyslipidemia, and others), nutrient status, physical activity, and eating habits in 144 morbidly-obese adult Hispanic-Americans 6 to 12 months following RYGB. Patients were randomly assigned to either the comprehensive intervention (n=72) or the comparison group (n=72). Participants (mean age 44.5 ± 13.5 years) were mainly Cuban-born females (83.3%). Intervention sessions attendance was 64%. At 12 months, both groups lost weight significantly, but those in the comprehensive intervention experienced greater excess weight loss than those in the comparison group (80% vs. 64% from preoperative excess weight, P<.001). Intervention participants were significantly more involved in physical activity (+ 14 min/week vs. – 4 min/week), had decreased depression, joint illness, and required less medication for comorbidities than comparison participants. Additionally, those in the comprehensive intervention had sustained supplement intake experiencing less folate deficiency (P=.014). The non-comprehensive intervention group significantly decreased their protein and supplement intake compared to the intervention group. Patients in the comprehensive intervention had significantly better eating habits reflected by fewer episodes of dumping syndrome, constipation, and night eating, than those in the comparison group who reported greater eating in response to negative emotions (P=.003). These findings support the importance of a comprehensive educational approach to achieve more effective weight reduction and health-related outcomes to prevent relapse of obesity-related comorbidities and nutritional deficiencies in Hispanic-Americans 6 to 12 months following RYGB.

Obesity, cardiovascular disease risk factors and weight loss in a population of adult Mexican Americans

The study of obesity has evolved into one of the most important public health issues in the United States (U.S.), particularly in Hispanic populations. Mexican Americans, the largest Hispanic ethnic subgroup in the U.S., have been significantly impacted by obesity and related cardiovascular diseases. Mexican Americans living in the Lower Rio Grande Valley (the Valley) in the Texas-Mexico border are one of the most disadvantaged and hard-to-reach minority groups. Demographic factors, socioeconomic status, acculturation, and physical activity behavior have been found to be important predictors of health, although research findings are mixed when establishing predictors of obesity in this population. Furthermore, while obesity has long been linked to cardiovascular disease (CVD) risk factors such as hypertension, type 2 diabetes, and dyslipidemia; information on the relationships between obesity and these CVD risk factors have been mostly from non-minority population groups. Overall, research has been mixed in establishing the association between obesity and related CVD risk factors in this population calling attention to the need for further research. Nevertheless, identifying predictors of success for weight loss in this population will be important if health disparities are to be addressed. The overall objective of the findings presented in this dissertation was to attain a more informed profile of obesity and CVD risk factors in this population. In particular, we examined predictors of obesity, measures of obesity and association with cardiovascular disease risk factors in a sample of 975 Mexican Americans participating in a health promotion program in the Valley region. Findings suggest acculturation factors to be one of the most important predictors of obesity in this population. Results also point to the need of identifying other possible risk factors for predicting CVD risk. Finally, initial body mass index is an important predictor of weight loss in this population group. Thus, indicating that this population is not only amenable to change, but that improvements in weight loss are feasible. This finding strengthens the relevance of prevention programs such as Beyond Sabor for Mexican populations at risk, in particular, food bank recipients.

Obesity Indicators by Race/Ethnicity for Diagnosis of Cardiometabolic Diseases for a US Representative Sample of Adults

Background: Obesity, a growing epidemic, is a preventable risk factor for cardiometabolic diseases. Obesity and cardiometabolic diseases affect Hispanics and African Americans more than non-Hispanic Caucasians. This study examined the relationship among race/ethnicity, obesity diagnostic measures (body mass index, waist circumference, subscapular and triceps skinfold thickness), and cardiometabolic risk factors (hyperglycemia, high, non-high-density lipoprotein cholesterol, low, high-density lipoprotein cholesterol, and hypertension) for adults across the United States. Methods: Using data from two-cycles of the National Health and Examination Survey (NHANES) 2007-2010, and accounting for the complex sample design, logistic regression models were conducted comparing obesity indicators in Mexican Americans, other Hispanics, and Black non-Hispanics, with White non-Hispanics and their associations with the presence of cardiometabolic diseases. Results: Differences by race/ethnicity were found for subscapular skinfold thickness and hyperglycemia. Waist circumference and subscapular skinfold were positively associated with the presence of hyperglycemia; dyslipidemia, and hypertension across race/ ethnicity, adjusting for age, gender, smoking, physical activity, education, income to poverty index, and health insurance. Race/ ethnicity did not influence the association of any obesity indicators with the tested cardiometabolic diseases. All obesity measures except triceps skinfold were associated with hyperglycemia. Conclusions: We suggest that subscapular skinfold thickness be considered as an inexpensive non-intrusive screening tool for cardiometabolic risk factors in an adult US population

Prevalência e fatores associados à diminuição da função pulmonar em obesos em pré-operatório de cirurgia bariátrica

Introduction: Obesity shows changes in pulmonary function and respiratory mechanics, however, little is known regarding the prevalence of worsening respiratory function when considering the increase in central or peripheral adiposity or general obesity. Objectives: To analyze the association between anthropometric adiposity and decreased lung function in obese. Materials and Methods: Patients eligible for this study obese individuals (IMC≥30kg/m2) in pre-bariatric surgery and referred for Treatment Clinic of Obesity and Related Diseases, located at the University Hospital Onofre Lopes (HUOL), from October 2005 and July 2014. The evaluation included clinical information and measurement of anthropometric measures (body mass index (BMI), body fat index (BFI) and waist circumference (WC) and neck (NC)) and spirometric. The prevalence and analysis by Poisson regression was performed considering the following outcome variables: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and Maximum Voluntary Ventilation (MVV) and as predictor variables were considered: BMI, IAC, WC and NC and as control variables: age, gender, smoking history and comorbidities (diabetes mellitus, dyslipidemia and hypertension). Statistical analysis was performed using Statistical Package for Social Sciences software (SPSS - version 20.0). Results: We analyzed 384 individuals, 75% women, mean BMI: 46.6 (± 8.7) kg/m2, IAC: 49.26 (± 9.48)%, WC: 130.84 (± 16.23) cm and NC: 42.3 (± 4.6) cm. The higher prevalence of FVC and FEV1 <80% was observed in individuals with NC above 42 cm, followed those with a BMI above 45 kg/m2. Multivariate analysis using Poisson regression showed as risk factors associated with FVC <80%, the variables: NC above 42 cm (odds ratio (OR) 2.41) and BMI over 45Kg/m2 (OR 1.71 ). As for FEV1 <80% predicted, all predictor variables were associated, with the largest odds presented by the NC (3.40). MVVV was not associated with any studied varaible. Conclusion: Individuals with NC above 42 cm had higher prevalence of reduced lung function and the NC was the measure with the highest association with reduced lung function in obese.

A influência da perda de peso no perfil inflamatório de mulheres com síndrome dos ovários policísticos

The polycystic ovary syndrome (PCOS) is considered the most common endocrine disorder in reproductive age women, with a prevalence ranging from 15 to 20%. In addition to hormonal and reproductive changes, it is common in PCOS the presence of risk factors for developing cardiovascular disease (CVD) and diabetes mellitus, insulin resistance (IR), visceral obesity, chronic low-grade inflammation and dyslipidemia. Due to the high frequency of obesity associated with PCOS, weight loss is considered as the first-line treatment for the syndrome by improving metabolic and normalizes serum androgens, restoring reproductive function of these patients. Objectives: To evaluate the inflammatory markers and IR in women with PCOS and healthy ovulatory with different nutritional status and how these parameters are displayed after weight loss through caloric restriction in with Down syndrome. Methods: Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in serum samples from 40 women of childbearing age. The volunteers were divided into four groups: Group I (not eutrophic with PCOS, n = 12); Group II (not eutrophic without PCOS, n = 10), Group III (eutrophic with PCOS, n = 08) and Group IV (eutrophic without PCOS, n = 10). The categorization of groups was performed by body mass index (BMI), according to the World Health Organization (WHO) does not eutrophic, overweight and obesity (BMI> 25 kg / m²) and normal weight (BMI <24.9 kg / m²). IR was determined by HOMA-IR index. In the second phase of the study a controlled dietary intervention was performed and inflammatory parameters were evaluated in 21 overweight and obese women with PCOS, before and after weight loss. All patients received a low-calorie diet with reduction of 500 kcal / day of regular consumption with standard concentrations of macronutrients. Results: Phase 1: PCOS patients showed increased levels of CRP (p <0.01) and HOMAIR (p <0.01). When divided by BMI, both not eutrophic group with PCOS (I) as eutrophic with PCOS (III) showed increased levels of CRP (I = 2.35 ± 0,55mg / L and 2.63 ± III = 0,65mg / L; p <0.01) and HOMA-IR (I = 2.16 ± 2.54 and III = 1.07 ± 0.55; p <0.01). There were no differences in TNF-α and IL-6 between groups. Step 2: After the weight loss of 5% of the initial weight was reduced in all of the components of serum assessed inflammatory profile, PCR (154.75 ± 19:33) vs (78.06 ± 8.9) TNF α (10.89 ± 5.09) vs (6:39 ± 1:41) and IL6 (154.75 ± 19:33) vs (78.06 ± 08.09) (p <0:00) in association with improvement some hormonal parameters evaluated. Conclusion: PCOS contributed to the development of chronic inflammation and changes in glucose metabolism by increasing CRP, insulin and HOMA-IR, independent of nutritional status. The weight loss, caloric restriction has improved the inflammatory condition and hormonal status of the evaluated patients.

Prevalência da síndrome metabólica em receptores de transplante renal de acordo com o gênero e tempo pós-transplante /

Metabolic syndrome (MS) is defined as a set of cardiovascular risk factors including obesity, systemic high blood pressure (SHBP), changes in glucose metabolism and dyslipidemia. The prevalence of MS in renal transplant recipients (RTR) ranges from 15% to 65%, increasing the risk of cardiovascular disease (CVD) and reducing renal allograft survival in the long term. The objectives of this study were to determine the prevalence and frequency of MS in renal transplant patients according to gender and time of transplantation and to evaluate renal function in patients with and without MS. Patients and Methods: Crosssectional study conducted from August 2012 to September 2013 involving 153 renal transplant recipients. MS was defined according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). The sample was divided into two groups: patients with metabolic syndrome (WMS patients) and patients without metabolic syndrome (WoMS patients) and according to gender. The WMS patients were stratified into quartiles according to the renal transplantation period (RTP), and variables related to MS were analyzed for both sexes. Results: MS was diagnosed in 58.1% of the studied population, specifically in MS was found 58.4% of men and 41.6% of women (P ˂ 0.05). The male and female with MS were 48.8 ± 11.6 years old vs. 47.1 ± 12.7 years old and the time of post transplantation was 76.1 ± 76.5 months vs. 84.7 ± 65.4 months, respectively (P >0,05). When we compared the sexes in the WMS group, systolic blood pressure (SBP) was higher in men (137.0 ± 18.1 vs. 128.9 ± 13.6 mmHg, P= 0.029), while the other components of MS did not exhibit significant differences. With respect to renal function, when we compared the sexes in the WMS group, the serum creatinine (sCr) was higher in men (1.73 ± 0.69 vs. 1.31 ± 0.47 mg/dL, P= 0.0012), while the urinary protein/creatinine ratio was higher in women (0.48 ± 0.69 vs. 0.37 ± 0.48 mg/dL, P=0.0150). We found no significant difference in the estimated glomerular filtration rate (eGFR) between WMS and WoMS patients for women and men (50.6 ± 19.1 vs. 50.1 ± 18.3 mL/min/1.73 m², P=0.909). We found a significant positive association between eGFR and HDL-c levels (r=0.3371; P=0.0145) for WMS men. The MS components showed no significant differences in RTP for different interquartile ranges, except for diastolic blood pressure (DBP) in women, where there was a significant variation among the quartiles evaluated (P=0.0009). Conclusion: the prevalence of MS was similar in the different quartiles in both sexes, in relation to time post TX. There was no significant difference in eGFR in patients WMS and WoMS, in both sexes. Concluding that the MS did not vary in relation to time post transplant.

Obesity, Cardiovascular Risk Factors, and Weight Loss in a Population of Adult Mexican Americans

The study of obesity has evolved into one of the most important public health issues in the United States (U.S.), particularly in Hispanic populations. Mexican Americans, the largest Hispanic ethnic subgroup in the U.S., have been significantly impacted by obesity and related cardiovascular diseases. Mexican Americans living in the Lower Rio Grande Valley (the Valley) in the Texas-Mexico border are one of the most disadvantaged and hard-to-reach minority groups. Demographic factors, socioeconomic status, acculturation, and physical activity behavior have been found to be important predictors of health, although research findings are mixed when establishing predictors of obesity in this population. Furthermore, while obesity has long been linked to cardiovascular disease (CVD) risk factors such as hypertension, type 2 diabetes, and dyslipidemia; information on the relationships between obesity and these CVD risk factors have been mostly from non-minority population groups. Overall, research has been mixed in establishing the association between obesity and related CVD risk factors in this population calling attention to the need for further research. Nevertheless, identifying predictors of success for weight loss in this population will be important if health disparities are to be addressed. The overall objective of the findings presented in this dissertation was to attain a more informed profile of obesity and CVD risk factors in this population. In particular, we examined predictors of obesity, measures of obesity and association with cardiovascular disease risk factors in a sample of 975 Mexican Americans participating in a health promotion program in the Valley region. Findings suggest acculturation factors to be one of the most important predictors of obesity in this population. Results also point to the need of identifying other possible risk factors for predicting CVD risk. Finally, initial body mass index is an important predictor of weight loss in this population group. Thus, indicating that this population is not only amenable to change, but that improvements in weight loss are feasible. This finding strengthens the relevance of prevention programs such as Beyond Sabor for Mexican populations at risk, in particular, food bank recipients.

Irregularidade do ciclo menstrual no Menacme como marcador para fatores de risco cardiovasculares na pós-menopausa

A associação entre fatores de risco cardiovascular (FRCV) na pósmenopausa e o antecedente de irregularidade menstrual no menacme foi avaliado em estudo caso-controle envolvendo 414 mulheres na pósmenopausa com idade de 60,4 ± 5,5 anos e IMC de 25,3 ± 4,7 kg/m2. As variáveis consideradas foram: caracterização do ciclo menstrual entre 20 e 35 anos (independente) e relato atual sobre ocorrência de hipertensão arterial, dislipidemia, diabetes mellitus e doença arterial coronariana (dependentes). Utilizou-se o teste qui-quadrado e modelos de regressão logística, ajustados para outras variáveis implicadas no risco para doenças CV, com nível de significância 5%. Observou-se que mulheres que relataram irregularidade menstrual prévia estiveram associadas com risco aumentado para ocorrência de algum FRCV [odds ratio ajustado (OR)= 2,14; IC-95%= 1,02–4,48], quando comparadas àquelas com ciclos regulares. Análise estratificada demonstrou as seguintes associações significativas com o antecedente de irregularidade menstrual: hipertensão arterial (OR= 2,4; 95% IC= 1,39–5,41), hipercolesterolemia (OR= 2,32; 95% IC= 1,17–4,59), hipertrigliceridemia (OR= 2,09; 95% IC= 1,10–4,33) e angioplastia coronariana (OR= 6,82; 95% IC= 1,44–32,18). Os dados sugerem que o antecedente de irregularidade menstrual, indicativo da ocorrência da síndrome dos ovários policísticos na idade reprodutiva, pode estar relacionado com aumento do risco para doenças CV na pós-menopausa __________________________________________________ABSTRACT Menstrual Cycle Irregularity as a Marker of Cardiovascular Risk Factors at Postmenopausal Years.To evaluate the association between cardiovascular risk factors (CVRF)during postmenopausal years and previous menstrual irregularity during reproductive years, we performed a case-control study in 414 postmenopausal women (mean age 60.4 ± 5.5 years; BMI 25.3 ± 4.7 kg/m2). The variables assessed were: menstrual cycle characteristics at age 20–35y (independent) and records of arterial hypertension, dyslipidemia, diabetes mellitus, and coronary heart disease (dependent). Statistical analysis used the chi-square test and logistic regression, adjusting for potential confounders for cardiovascular risk, with significance set at 5%. Women reporting previous menstrual irregularity were associated with increased risk for some CVRF [adjusted odds ratio (OR) 2.14; CI-95%= 1.02–4.48], when compared with those reporting regular menstrual cycles. Stratified analysis demonstrated significant associations of previous menstrual irregularity with: arterial hypertension [OR= 2.74; CI-95%= 1.39–5.41), hypercholesterolemia (OR= 2.32; CI-95%= 1.17–4.59), hypertriglyceridemia (OR= 2.09; CI-95%=1.10–4.33), and coronary angioplasty (OR= 6.82; CI-95%= 1.44–32.18). These data suggest that a prior history of menstrual irregularity, as indicative of polycystic ovary syndrome, may be related to increased risk for CVD during postmenopausal years

Obésité abdominale et autres déterminants du risque cardiométabolique dans deux populations urbaines noires apparentées : Port-au-Prince (Haïti) et Cotonou (Bénin)

L’obésité est un problème de santé publique reconnu. Dans la dernière décennie l’obésité abdominale (OA) a été considérée comme une maladie métabolique qui contribue davantage au risque de diabète et de maladies cardiovasculaires que l’obésité générale définie par l’indice de masse corporelle. Toutefois, dans les populations d’origine africaine, la relation entre l’OA et les autres biomarqueurs de risque cardiométabolique (RCM) demeure obscure à cause du manque d’études chez ces populations et de l’absence de valeurs-seuils spécifiques pour juger d’une OA. Cette étude visait à comparer la prévalence des biomarqueurs de RCM (OA, hypertension artérielle, hyperglycémie, dyslipidémie, résistance à l'insuline et inflammation pré-clinique) chez les Béninois de Cotonou et les Haïtiens de Port-au-Prince (PAP), à étudier l’association de l’OA avec les autres biomarqueurs de RCM, à documenter le rôle du niveau socio-économique (NSE) et du mode de vie dans cette association et à ’identifier les indicateurs anthropométriques de l’OA -tour de taille (TT) et le ratio TT/hauteur (TT/H)- et les seuils qui prédisent le mieux le RCM à Cotonou et à PAP. Il s’est agi d’une analyse de données transversales chez 452 adultes (52 % hommes) apparemment en bonne santé, âgés de 25 à 60 ans, avec 200 sujets vivant à Cotonou (Bénin) et 252 sujets à PAP (Haïti). Les biomarqueurs de RCM considérés étaient : le syndrome métabolique (SMet) d’après les critères harmonisés de 2009 et ses composantes individuelles - une OA à partir d’un TT ≥ 94cm chez les hommes et ≥ 80cm chez les femmes, une hypertension, une dyslipidémie et une hyperglycémie; la résistance à l’insuline définie chez l’ensemble des sujets de l’étude à partir du 75e centile de l’Homeostasis Model Assessment (HOMA-IR); un ratio d’athérogénicité élevé (Cholestérol sérique total/HDL-Cholestérol); et l’inflammation pré-clinique mesurée à partir d’un niveau de protéine C-réactive ultrasensible (PCRus) entre 3 et 10 mg/l. Le ratio TT/H était aussi considéré pour définir l’OA à partir d’un seuil de 0,5. Les données sur les habitudes alimentaires, la consommation d’alcool, le tabagisme, les caractéristiques sociodémographiques et les conditions socio-économiques incluant le niveau d’éducation et un proxy du revenu (basé sur l’analyse par composante principale des biens et des possessions) ont été recueillies au moyen d’un questionnaire. Sur la base de données de fréquence de consommation d’aliments occidentaux, urbains et traditionnels, des schémas alimentaires des sujets de chaque ville ont été identifiés par analyse typologique. La validité et les valeurs-seuils de TT et du ratio TT/H prédictives du RCM ont été définies à partir des courbes ROC (Receiver Operating Characteristics). Le SMet était présent chez 21,5 % et 16,1 % des participants, respectivement à Cotonou et à PAP. La prévalence d’OA était élevée à Cotonou (52,5 %) qu’à PAP (36%), avec une prévalence plus élevée chez les femmes que chez les hommes. Le profil lipidique sérique était plus athérogène à PAP avec 89,3 % d’HDL-c bas à PAP contre 79,7 % à Cotonou et un ratio CT/HDL-c élevé de 73,4 % à PAP contre 42 % à Cotonou. Les valeurs-seuils spécifiques de TT et du TT/H étaient respectivement 94 cm et 0,59 chez les femmes et 80 cm et 0,50 chez les hommes. Les analyses multivariées de l’OA avec les biomarqueurs de RCM les plus fortement prévalents dans ces deux populations montraient que l’OA était associée à un risque accru de résistance à l’insuline, d’athérogénicité et de tension artérielle élevée et ceci, indépendamment des facteurs socio-économiques et du mode de vie. Deux schémas alimentaires ont émergé, transitionnel et traditionnel, dans chaque ville, mais ceux-ci ne se révélaient pas associés aux biomarqueurs de RCM bien qu’ils soient en lien avec les variables socio-économiques. La présente étude confirme la présence de plusieurs biomarqueurs de RCM chez des sujets apparemment sains. En outre, l’OA est un élément clé du RCM dans ces deux populations. Les seuils actuels de TT devraient être reconsidérés éventuellement à la lumière d’études de plus grande envergure, afin de mieux définir l’OA chez les Noirs africains ou d’origine africaine, ce qui permettra une surveillance épidémiologique plus adéquate des biomarqueurs de RCM.

Régulation épigénétique de la défense antioxydante et de l'Angiopoietin-like 2 dans le contexte du vieillissement et des maladies cardiovasculaires

Suite à l’exposition à des facteurs de risque incluant la malnutrition, la dyslipidémie, la sédentarité et les désordres métaboliques, les maladies cardiovasculaires (MCV) sont caractérisées par un état pro-oxydant et pro-inflammatoire, et une dérégulation de l’expression de divers facteurs responsables de l’homéostasie de l’environnement rédox et inflammatoire. L’implication d’enzymes antioxydantes telles que les superoxyde dismutases (SOD) et les glutathion peroxydases (Gpx), ainsi que la contribution de médiateurs pro-inflammatoires tels que l’angiopoietin-like 2 (Angptl2) ont été rapportées dans le cadre des MCV. Toutefois, les mécanismes moléculaires sensibles aux facteurs de risque et menant au développement des MCV sont peu connus. L’épigénétique est un mécanisme de régulation de l’expression génique sensible aux stimuli extracellulaires et pourrait donc contribuer au développement des MCV. La méthylation de l’ADN est un des mécanismes épigénétiques pouvant varier tant de manière gène-spécifique qu’à l’échelle génomique, et la conséquence de tels changements sur l’expression des gènes ciblés dépend du site de méthylation. Puisqu’il a été démontré que des variations au niveau de la méthylation de l’ADN peuvent être associées à divers contextes pathologiques incluant les MCV, le but de nos travaux était d’étudier le lien entre la méthylation de gènes antioxydants et pro-inflammatoires avec leurs répercussions fonctionnelles biologiques en présence de facteurs de risques associés aux MCV, tels que le vieillissement, la dyslipidémie et la sédentarité. Dans la première étude, nous avons observé que dans l’artère fémorale de souris vieillissantes, la méthylation au niveau du promoteur du gène Sod2, codant pour l’enzyme antioxydante superoxyde dismutase de type 2 (SOD2 ou MnSOD), diminue avec l’âge. Ceci serait associé à l’induction de l’expression de MnSOD, renforçant ainsi la défense antioxydante endogène. Le vieillissement étant associé à une accumulation de la production de radicaux libres, nous avons étudié la vasodilatation dépendante de l’endothélium qui est sensible au stress oxydant. Nous avons observé que la capacité vasodilatatrice globale a été maintenue chez les souris âgées, aux dépens d’une diminution des facteurs hyperpolarisants dérivés de l’endothélium (EDHF) et d’une contribution accentuée de la voie du monoxyde d’azote (NO). Nous avons ensuite utilisé deux approches visant à réduire les niveaux de stress oxydant in vivo, soit la supplémentation avec un antioxydant, la catéchine, et l’exposition chronique à de l’exercice physique volontaire. Ces interventions ont permis de prévenir à la fois les changements au niveau de la fonction endothéliale et de l’hypométhylation de Sod2. Cette première étude démontre donc la sensibilité de la méthylation de l’ADN à l’environnement rédox. Dans la deuxième étude, nous avons démontré une régulation de l’expression de l’enzyme antioxydante glutathion peroxydase 1 (Gpx1) en lien avec la méthylation de son gène codant, Gpx1, dans un contexte de dyslipidémie sévère. Nos résultats démontrent que dans le muscle squelettique de souris transgéniques sévèrement dyslipidémiques (LDLr-/-; hApoB+/+), Gpx1 est hyperméthylé, ce qui diminue l’expression de Gpx1 et affaiblit la défense antioxydante endogène. Chez ces souris, l’exercice physique chronique a permis d’augmenter l’expression de Gpx1 en lien avec une hypométhylation transitoire de son gène. Cette étude démontre que le stress oxydant associé à la dyslipidémie sévère altère les mécanismes de défense antioxydante, en partie via un mécanisme épigénétique. De plus, on observe également que l’exercice physique permet de renverser ces effets et peut induire des changements épigénétiques, mais de manière transitoire. La troisième étude avait pour but d’étudier la régulation de l’Angptl2, une protéine circulante pro-inflammatoire, dans le contexte des MCV. Nous avons observé que chez des patients coronariens, la concentration circulante d’Angptl2 est significativement plus élevée que chez des sujets sains et ce, en lien avec une hypométhylation de son gène, ANGPTL2, mesurée dans les leucocytes circulants. Nous sommes les premiers à démontrer qu’en réponse à l’environnement pro-inflammatoire associé à une MCV, l’expression de l’Angptl2 est stimulée par un mécanisme épigénétique. Nos études ont permis d’identifier des nouvelles régions régulatrices différentiellement méthylées situées dans les gènes impliqués dans la défense antioxydante, soit Sod2 en lien avec le vieillissement et Gpx1 en lien avec la dyslipidémie et l’exercice. Nous avons également démontré un mécanisme de régulation de l’Angptl2 dépendant de la méthylation d’ANGPTL2 et ce, pour la première fois dans un contexte de MCV. Ces observations illustrent la nature dynamique de la régulation épigénétique par la méthylation de l’ADN en réponse aux stimuli environnementaux. Nos études contribuent ainsi à la compréhension et l’identification de mécanismes moléculaires impliqués dans le développement du phénotype pathologique suite à l’exposition aux facteurs de risque, ce qui ouvre la voie à de nouvelles approches thérapeutiques.