A randomized, double blind, cross-over, placebo-controlled clinical trial to assess the effects of Candesartan on the insulin sensitivity on non diabetic, non hypertense subjects with dysglyce mia and abdominal obesity. "ARAMIA"

BACKGROUND: The raising prevalence of type-2 diabetes mellitus and obesity has been recognized as a major problem for public health, affecting both developed and developing countries. Impaired fasting plasma glucose has been previously associated with endothelial dysfunction, higher levels of inflammatory markers and increased risk of developing insulin resistance and cardiovascular events. Besides life-style changes, the blockade of the renin-angiotensin system has been proposed as a useful alternative intervention to improve insulin resistance and decrease the number of new type-2 diabetes cases. The aim of this clinical trial is to study the effect of the treatment with Candesartan, an angiotensin II receptor antagonist, on the insulin resistance, the plasma levels of adipoquines, oxidative stress and prothrombotic markers, in a group of non diabetic, non hypertensive, dysglycemic and obese subjects. METHODS AND DESIGN: A randomized, double blind, cross-over, placebo-controlled, clinical trial was designed to assess the effects of Candesartan (up to 32 mg/day during 6 months) on the Homeostasis Model Assessment (HOMA) index, lipid profile, protrombotic state, oxidative stress and plasma levels of inflammatory markers. The participants will be recruited in the "Fundación Cardiovascular de Colombia". Subjects who fullfil selection criteria will receive permanent educational, nutritional and exercise support during their participation in the study. After a 15 days-run-in period with placebo and life-style recommendations, the patients who have a treatment compliance equal or greater than 80% will be randomlly assigned to one of the treatment groups. Group A will receive Candesartan during 6 months and placebo during 6 months. Group B will receive placebo during the first 6 months, and then, Candesartan during the last 6 months. Control visits will be programed monthly and all parameters of interest will be evaluated every 6 months. HYPOTHESIS: Treatment with Candesartan, could improve the HOMA index, the response to the oral glucose tolerance test and reduce the plasma levels of adipoquines, oxidative stress and prothrombotic markers, in non diabetic, non hypertense subjects with dysglycemia and abdominal obesity, recruited from a population at high risk of developing insulin resistance. These effects are independent of the changes in arterial blood pressure. Trial registration: NCT0031920

Desarrollo de la fuerza muscular en niños como estrategia para disminuir el riesgo de enfermedad cardiometabólica

Los factores de riesgo para las enfermedades cardiometabólicas (ECM) como la obesidad, la resistencia a la insulina y el síndrome metabólico tienen su inicio en la infancia. Existe evidencia de que la adiposidad infantil se relaciona con factores de riesgo para presentar enfermedad cardiovascular en la vida adulta, principalmente en la población hispana, en la cual se ha observado mayor vulnerabilidad para desarrollar enfermedades crónicas no transmisibles. Las altas tasas de morbimortalidad secundaria a enfermedades cardiovasculares en países de medianos y bajos ingresos económicos como Colombia, demanda profundizar en el estudio de los mecanismos que relacionan las bases biológicas y epigenéticas de la programación fetal y el riesgo de presentar ECM. Nosotros hemos publicado evidencias de que nuestra población tiene una alta sensibilidad para presentar inflamación de bajo grado y resistencia a la insulina a menores niveles de adiposidad visceral, asociada a una menor fuerza de empuñadura, la cual es un marcador del contenido de masa muscular. Proponemos que mejorar la condición física, sobre todo la capacidad aeróbica y la fuerza muscular, es una intervención efectiva para disminuir el riesgo de desarrollar enfermedad cardiovascular en niños y adolescentes colombianos, al disminuir la masa grasa, los marcadores de inflamación crónica de bajo grado y mejorar la cantidad y calidad de la masa muscular. Abstract Risk factors for cardiometabolic diseases such as obesity, insulin resistance, and metabolic syndrome arise during childhood. There is evidence that adiposity in children is associated with risk factors for cardiovascular disease later in life, particularly among the Hispanic population, where vulnerability for the development of chronic non-communicable diseases is greater. The high mortality and morbidity rates of cardiovascular disease in middle-and low-income countries such as Colombia, makes it necessary to delve deeper into the mechanisms related to the biological and epigenetic basis of fetal programming, and the risk to develop cardiometabolic diseases. Based in our published studies, we have evidence that our population is highly prone to having chronic low- grade inflammation and insulin resistance at lower levels of visceral adiposity, associated with a weaker handgrip, a muscle mass marker. Therefore, we propose that improving physical condition, more particularly aerobic capacity and muscle strength, is an effective intervention to decrease the risk of cardiovascular disease in Colombian children and adolescents, through a decrease in the fat mass, chronic low- grade inflammation markers, and an improvement in both the quality and amount of muscle mass

Papel de las adaptaciones epigenéticas en el riesgo de enfermedades cardiovasculares en la población latinoamericana

Las enfermedades cardio-metabólicas (obesidad, diabetes mellitus tipo 2, infarto agudo de miocardio y accidente cerebro-vascular) son al momento el problema de salud pública más relevante en Colombia. La rápida urbanización experimentada por el país en los últimos 50 años, así como los cambios en los hábitos nutricionales y en la actividad física asociada a la urbanización han determinado que en el proceso de adaptación biológica de la población colombiana a este rápido proceso medioambiental, se sobre expresen por vía epigenética, substancias pro inflamatorias y aquellas que llevan a resistencia a la insulina, mecanismo que confiere una mayor susceptibilidad para que nuestra población desarrolle las enfermedades cardio-metabólicas. Este proceso es especialmente grave en los niños escolares de nuestras ciudades. De frente a esta situación, en el presente artículo revisamos una serie de evidencias que nos llevan a proponer que el ejercicio, especialmente el de fuerza puede, vía epigenética, determinar un mayor desarrollo de masa muscular y la expresión de sustancias producidas en el músculo que tienen propiedades anti inflamatorias y que mejoran la sensibilidad a la insulina, por lo cual se contraponen al estado de resistencia a la insulina y a la inflamación de bajo grado, producto de la obesidad especialmente abdominal

Consenso latinoamericano de hipertensión en pacientes con diabetes tipo 2 y síndrome metabólico

El presente documento ha sido preparado por un grupo de expertos, miembros de las sociedades de cardiología, endocrinología, medicina interna, nefrología y diabetes de los países de América Latina, para que sirva de guía a los médicos que cuidan a pacientes con diabetes, hipertensión y enfermedades concomitantes o complicaciones de ambas condiciones. Aunque el concepto de síndrome metabólico actualmente es discutido, la alta prevalencia en América Latina del conjunto de alteraciones metabólicas que lo conforman sugiere que el síndrome metabólico es una entidad nosografías útil en el contexto de la medicina atinoamericana. Por lo tanto, en el presente documento se presta especial atención a este síndrome con el fin de alertar a los médicos de una particular población de alto riesgo, en la que por lo general se subestimada y no se trata en forma optima los factores de riego que constituyen el síndrome metabólico. Las presentes recomendaciones son el resultado de las presentaciones y los debates en los paneles de discusión durante una reunión de 2 días celebrada en Bucaramanga en octubre de 2012.Todos los participantes han aprobado las conclusiones finales. Los autores reconocen que la publicación y difusión de las guías no serán suficientes para alcanzar los cambios recomendados, tanto en las estrategias diagnósticas como terapéuticas, por lo que se ha programado intervenciones que permitan identificar las barreras del conocimiento, de las actitudes y de comportamiento, lo que permitirá tanto a los médicos como a los pacientes una adecuada adherencia a las recomendaciones de las guías

Evaluation of the effects of the Colombian blueberry (Vaccinium meridionale Swartz) on markers of high-density lipoprotein (HDL) function, inflammation and oxidative stress in women with metabolic syndrome

ABSTRACT: Introduction: Metabolic syndrome (MetS) is defined by the National Cholesterol Education Program- Adult Panel Treatment III (NCEP-ATPIII) as the presence of three or more cardiovascular risk factors (CVRF). Around one quarter of the world population have this syndrome that increases twice the risk of developing cardiovascular diseases (CVD) in the next 5 to 10 years, the leading cause of mortality in the world. The consumption of fruit and vegetables have been associated with lower risk of MetS. This benefit has been attributed to several bioactive components such as phytochemicals with antioxidant properties and modulation of cellular signaling pathways. Fruits of the gender Vaccinium are rich in phytochemicals with predominance of polyphenols, especially anthocyanins, which exhibit a high antioxidant capacity. Human intervention studies with Vaccinium have demonstrated beneficial effects on reducing traditional CVRF, inflammation and oxidative stress markers and to improve antioxidant capacity and HDL function. In Colombia grows the specie Vaccinium meridionale Swartz, also called agraz, with demonstrated high antioxidant capacity. However, fruit consumption in Colombia is insufficient, there is not agroindustrial development of Vaccinium crops in Colombia and the information about the effects of chronic consumption of agraz on inflammation, oxidative stress and antioxidant markers in people at high risk of CVD is very limited. General objective: To evaluate the effects of agraz (V. meridionale Swartz) on markers of high-density lipoprotein function, inflammation and oxidative stress in women with MetS. Methodology: Forty women (25–60 years) from Medellín-Colombia with MetS according to NCEP-ATPIII criteria were included in this double-blind and crossover study. Volunteers were assigned to consume daily a dose of 200 mL of reconstituted freeze dried agraz (equivalent to the total phenols present in 200 g of fresh agraz fruits) or placebo (without polyphenols) beverage over 4 weeks. After a 4-week washout period, they consumed the alternate treatment for additional 4 weeks. During the whole study, participants were asked to maintain their habitual physical activity and diet, except for the consumption of polyphenol-rich foods. Antropometrics [height, weight and waist circumference (WC)] and blood pressure were measured. Blood samples were obtained after a 12h overnight fasting to determine lipid profile and glucose at the beginning and end of each intervention period. In addition, the following markers were measured in samples obtained at the end of placebo and agraz periods: serum high-density lipoprotein (HDL) function markers (apolipoprotein-A1; paraoxonase 1 (PON1) activity; cholesterol efflux capacity), oxidative stress markers (serum myeloperoxidase -MPO) and advanced oxidation protein products -AOPP, and urinary F2-isoprostanes and 8-hydroxy 2 deoxyguanosine -8-OHDG), inflammatory markers (serum cytokines/chemokines and high sensitivity C-reactive protein (hs-CRP) levels, and the activation of nuclear factor-kB in peripheral blood mononuclear cells), endogenous antioxidant enzyme activity [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)], and serum total antioxidant capacity (TAC) determined by different methods [ABTS 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid); FRAP (ferric reducing ability of plasma) and ORAC (Oxygen Radical Absorbance Capacity)]. For the statistical analysis, after evaluating the data distribution, repeated measures ANOVA or Friedman test were used in the analysis of variables with baseline measures. Paired samples t-test or Wilcoxon test were used to evaluate the association between the end of each intervention period. In addition, we analyzed the women separated into two groups [obese and overweight, according to body mass index (BMI)] to evaluate the differential response of agraz consumption. Furthermore, the results were analyzed according to blood antioxidant response after agraz intake. Mann- Whitney U test or Student’s t-test were used to evaluate the associations between the independent groups. Finally, changes after agraz consumption (agraz minus placebo period) were calculated and the correlation between changes were determined with Pearson´s or Spearman´s correlation coefficient. All analyses were done using SPSS version 21 for Windows (SPSS, IBM Corporation, 2012). Differences with a value of p<0.05 were considered significant. Results. Forty women (47.2 ± 9.4 years old) with MetS finished the study with an adherence above 90%. No differences in macronutrient intake and physical activity were observed during the whole study. We already published the effects of agraz on anthropometric, blood pressure and blood lipid profile and glucose, in this population. In the whole group, there were not significant differences in HDL function, inflammation, oxidative stress and antioxidant markers, after comparing the end of both intervention periods (placebo versus agraz) (p > 0.05). Regarding HDL function, interestingly, only after agraz period there were significant positive correlations between PON1 activities and cholesterol efflux. Additionally, there were significant inverse correlations between changes in inflammatory markers and HDL function markers and positive correlations with oxidative markers. When analyzing the effects of agraz consumption on inflammation in women according to BMI classification, we found significantly reductions in hs-CRP levels in overweight women compared to obese women (p=0.028). Further, regarding oxidative stress effects, there was a significant reduction in urinary 8-OHdG levels in obese women after agraz consumption compared to placebo (p=0.031). Women who increased SOD activity after agraz consumption, compared to placebo, significantly reduced oxidative stress markers like 8-OHdG (p=0.022) and F2-isoprostane (p=0.034). Likewise, those women who increased GPx activity after agraz intake, significantly reductions in total cholesterol (p=0.023) and low-density lipoprotein cholesterol (LDL-c) (p= 0.022) levels. Finally, the increase in serum TAC (determined by ABTS) after 4 weeks of agraz consumption, was significantly associated with reduction in waist circumference. Conclusion: the chronic consumption of agraz over 4 weeks in a daily dose of 200mL (total phenols equivalent to 200g of fresh fruit) in 40 women with MetS did not significant improved HDL function, inflammation and antioxidant markers in the whole group. However, agraz consumption demonstrated to have a differential effect between obese and overweight women, with better anti-inflammatory effect in overweight women. Possibly, obese women have a more inflammatory state that requires a more drastic dietary intervention in this specific population. Interestingly, the effect on OxS markers was better in obese women. In addition, the group of women who increase these antioxidant parameters significantly improved CVRF such as reduction in lipid and DNA oxidation, total cholesterol, LDL-c and waist circumference. We demonstrated differential responses to agraz consumption in this population, which could suggest there is an individual variability influencing the beneficial effects of this fruit

Markers of iron status and cardiometabolic disease risk: an exploration of the association based on cross-sectional and prospective studies in multiple populations

The aim of this thesis is to contribute to the understanding of iron metabolism, as a factor associated with cardiometabolic risk, by undertaking secondary data analyses. The objectives were to identify gaps in existing knowledge in terms of populations studied and alternative iron markers, and to attempt to fill the gaps with additional analyses and interpretation. Serum ferritin was the most widely available measure of iron status but the role of serum transferrin and soluble transferrin receptor (sTfR) levels was considered where available. I have taken a life-course approach with analyses in childhood and adulthood, and have included both intermediate factors such as the metabolic syndrome (MetS), and disease diagnoses of diabetes and cardiovascular disease as outcomes. Chapter one presents a review of empirical research literature on the relationship between iron metabolism and cardiometabolic risk, concepts surrounding iron markers and the study outcomes. This chapter also describes the gaps in understanding the iron-cardiometabolic risk relationship, which are subsequently explored in chapters two to six. Chapter two explores the link between serum ferritin and transferrin and MetS in cross-sectional and prospective studies of 725 Spanish children and 567 Chilean adolescents. I found associations between both ends of the ferritin distribution and MetS or glucose metabolism markers in different paediatric populations. For instance, whereas in the Spanish children there was a decrease of 0.02 SD units in the change of MetS score over time for every SD unit increase in ferritin, in the Chilean male adolescents being in the highest tertile of ferritin (v. the lowest) was associated with an increase of 0.25 SD units of MetS score. Furthermore, sustained high ferritin levels at various time points and gradual increase of ferritin during childhood were associated with higher MetS score in adolescence. The third chapter describes the association between serum ferritin status and MetS in adults in two cross-sectional studies of Scottish populations (2,047 individuals from Shetland Islands and 8,563 subjects from the Scottish Health Surveys (SHeS) 1995- 1998). I also examined the overall association between ferritin, MetS and each MetS component in adults, by conducting a meta-analysis and investigating potential relevant sources of heterogeneity for the association. Interestingly, ferritin levels were positively associated with MetS in the Scottish populations, but the association was not independent of the effect of covariates, mainly body mass index (BMI) and transaminase levels [Men Odds ratio (OR) 95% confidence interval (CI) 1.43(0.83- 2.46); Postmenopausal women OR (95%CI) 1.09(0.62-1.90); Premenopausal women OR (95%CI) 1.02(0.42-2.46), P>0.05]. The meta-analysis supported this finding by describing hepatic injury markers and BMI as the major attenuating factors of the ferritin-MetS association. Chapter four investigates the association between sTfR or ferritin, and MetS in 725 Croatian adults in a cross-sectional study. There was no evidence of an association between sTfR and MetS [Men OR (95%CI) 1.35(0.90-2.02); Postmenopausal women OR (95%CI) 0.73(0.47-1.15); Premenopausal women OR (95%CI) 0.87(0.66-1.17), P>0.05]. In contrast serum ferritin, was positively and independently associated with MetS in men and postmenopausal women (P<0.05) [Men OR (95%CI) 1.78(1.31- 2.42); Postmenopausal women OR (95%CI) 1.71(1.12-2.62); Premenopausal women OR (95%CI) 1.24(0.85-1.80)]. These contrasting results suggest that different iron markers reflect different physiological processes other than iron metabolism. Chapter five evaluates the longitudinal association between serum ferritin and several cardiometabolic disease outcomes (CMDs) in the nationally representative SHeS 1995 and 1998 (n = 6,497). I found an independent positive longitudinal association between ferritin and cerebrovascular disease (CEVD), which was strengthened by using higher cut-points for increased ferritin [higher v. lowest sextile fully adjusted Hazard ratio(HR) 95%CI 2.08 (1.09-3.94), P=0.024], and a not significant association with coronary heart disease (CHD) after adjustment for covariates. My analyses confirmed the widely established association with type 2 diabetes (T2D) [whole sample fully adjusted HR 95% CI 1.59(1.10-2.34), P=0.006], even with serum ferritin within the normal range. The above set of observations confirm ferritin as biomarker mainly related to the development of T2D and identifies the need to investigate the association between ferritin and CEVD in other populations. Chapter six investigates whether ferritin is associated with risk for cardiovascular complications among people with T2D using cross-sectional study designs in two populations with differing baseline cardiovascular risk (Spanish study SIDIAP n=38,617) and (Edinburgh Type 2 Diabetes Study (ET2DS) n= 821) with additional analysis of follow-up data for ET2DS. Interestingly, ferritin levels were negatively associated with prevalence of cardiovascular disease, mainly CHD, in people with T2D in both studies [ET2DS OR (95%CI): 0.80(0.67-0.96), P=0.020; SIDIAP study: 0.85(0.83-0.88), P<0.001). Ferritin was also negatively associated with incident cardiovascular disease in ET2DS: HR 95% CI: 0.39(0.16-0.93), P=0.035. Therefore, the association between iron status and CMD risk in people with T2D appears to differ from that in general populations in which a positive association has been more commonly described. In conclusion, serum ferritin is associated with cardiometabolic risk in different ways in a variety of populations. Inconsistent associations for other iron markers suggest that iron biomarkers reflect factors other than iron homeostasis that influence cardiometabolic risk. The association between iron markers and MetS appears to differ between populations. This thesis illustrates the complex relationship between iron metabolism markers, MetS and CMD, and identifies the need for further research on the topic in order to extend knowledge about pathophysiology and the potential for measures of iron status as biomarkers for CMD