Ada Cuevas

Diet and Endothelial Function

Endothelial dysfunction is one of the earliest events in atherogenesis. A consequence of endothelial damage is a lower availability of nitric oxide (NO), the most potent endogenous vasodilator. NO inhibits platelet aggregation, smooth muscle cell proliferation and adhesion of monocytes to endothelial cells. Endothelial dysfunction is present in patients with cardiovascular disease and/or coronary risk factors, such as hypertension, dyslipidemia, diabetes, smoking or hyperhomocysteinemia. At present, soluble markers and high resolution ultrasound of the brachial artery, have provided simple tools for the study of endothelial function and the effects of several interventions. It has been demonstrated that dietary factors may induce significant changes on vascular reactivity. Nutrients, such as fish oil, antioxidants, L-arginine, folic acid and soy protein have shown an improvement in endothelial function that can mediate, at least partially, the cardioprotective effects of these substances. Attention has been focused on dietary patterns in populations with lower prevalence of cardiovascular disease. There is some evidence suggesting that Mediterranean diet characterized by high consumption of vegetables, fish, olive oil and moderate wine consumption may have a positive effect on endothelial function. These results give us evidence on the significant role of diet on endothelial function and its impact on the pathogenesis of atherosclerosis.

Wine, Diet, Antioxidant Defenses, and Oxidative Damage

Abstract: Oxidative stress is a central mechanism for the pathogenesis of ischemic heart disease and atherogenesis, for cancer and other chronic diseases in general, and it also plays a major role in the aging process. Dietary antioxidants constitute a large group of compounds that differ in mechanism of action, bioavailability and side effects. A systematic analysis of the role of the various antioxidants in chronic diseases is hampered by the difficulty of employing death or clinical events as end points in intervention studies. Therefore, valid markers for oxidative stress, which show dose response and are sensitive to changes in dietary supply of antioxidants, are potentially of great value when trying to establish healthy dietary patterns, or when one component, like red wine, is evaluated specifically. To evaluate potential oxidative stress markers we have studied the effect of different diets plus wine supplementation on antioxidant defenses and oxidative damage. In three experimental series, four groups of young male university students, one of older men and other of older women, 20‐24 volunteers each, received Mediterranean or occidental (high‐fat) diets alone or supplemented with red wine, white wine, or fruits and vegetables. Measurements included, leukocyte DNA 8‐OH‐deoxyguanosine (8OHdG), plasma 7β‐hydroxycholesterol, TBARS and well‐characterized antioxidants, and plasma and urine polyphenol antioxidants. In all experimental groups that received red wine, consumption resulted in marked decrease in 8OHdG. The changes observed in 8OHdG correlate positively with the other markers of oxidative damage, and shows a clear inverse correlation with the plasma level of well established antioxidants and with measurements of total antioxidant capacity. Urinary total polyphenol content as well as the sum of some specific plasma species also correlate inversely with 8OHdG. In conclusion, the results identify 8OHdG as a very promising general marker of oxidative stress in nutrition intervention studies in humans, and red wine shows a remarkable protective effect.

Cardiovascular Risk Factors in Vegetarians: Normalization of Hyperhomocysteinemia with Vitamin B12 and Reduction of Platelet Aggregation with n-3 Fatty Acids

Hyperhomocysteinemia in association with vitamin B12 deficiency, and increased platelet aggregation, probably due to dietary lack of n-3 fatty acids, constitute cardiovascular risk factors frequently observed in vegetarians. We tested if administration of vitamin B12 normalizes the concentration of total plasma homocysteine, and if intake of eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) fatty acids modulates platelet function in a population of lactoovovegetarians. One week after a single intramuscular injection of cyanocobalamin (10000 μg) in 18 individuals, serum vitamin B12 increased from 149±63 pg/mL to 532±204 pg/mL (p<0.0001) and total tHcy dropped from 12.4±4.7 to 7.9±3.1 μmol/L (p<0.0001). Ten of fourteen of these vegetarians completed an 8-week supplementation with 700 mg/day of each eicosapentaenoic and docosahexaenoic acids. Increased incorporation of these fatty acids into plasma lipids was observed in all of them, together with a significant reduction in maximum percentage or slope of platelet aggregation with all the agonists tested (ADP, epinephrin, collagen, arachidonic acid). No significant change in bleeding time was observed after n-3 fatty acid trial. Supplementation with vitamin B12 and n-3 fatty acids corrects hyperhomocysteinemia and reduces platelet reactivity to agonists in vegetarians. Whether this supplementation improves the already reduced cardiovascular morbidity and mortality associated with vegetarian diet has yet to be demonstrated.

Mechanisms of long-term weight regain in patients undergoing sleeve gastrectomy

OBJECTIVES Weight regain after bariatric surgery may be associated with behavioral, metabolic, or mechanical factors alone or in combination. The aim of this study was to investigate which factors are related to weight regain in the long-term after sleeve gastrectomy (SG). METHODS A retrospective case-control study with 40 patients undergoing SG (32 women, 8 men; age 42.9 ± 10.7 y; preoperative body mass index 35 ± 2.8 kg/m(2)), was performed. Patients were grouped according percentile->50% (cases) or <50% (controls)-of weight regain (%WR cutoff: 25% of weight loss). Weight history, anthropometry, glucose, insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), thyroid-stimulating hormone, resting energy expenditure, body composition, dietary survey, psychological test, and physical activity were recorded. Residual gastric capacity was estimated using a radiologic method. RESULTS (MEDIAN [P25-P75]): The evaluation was conducted 38.5 mo (34-41 mo) after SG. Percent weight regain ranged from 2.7% to 129.2% (25.4% [13-37.1]). Patients in the higher %WR group had a greater residual gastric volume (252.7 ± 108.4 versus 148.5 ± 25.3; P < 0.05) and the estimated volume was significantly correlated with %WR (r = 0.673; P = 0.023). Significantly higher body mass index (P = 0.001), resting energy expenditure (P = 0.04), fasting insulin (P = 0.01), and HOMA-IR (P = 0.02) were observed in the higher %WR group. A higher fat intake and a trend toward higher total energy intake were observed in the group with greater %WR. Clinical or borderline levels of anxiety were more frequently observed in the higher %WR group (70% versus 30%; P = 0.01). CONCLUSIONS Results from the present study demonstrated that the most important factor associated with long-term weight regain after SG was residual gastric volume. Additional prospective studies with larger numbers of patients are necessary to confirm our results.

Trends in Obesity and Diabetes Prevalence in a Chilean Urban Population: 1993–2001

BACKGROUND In recent years, the Chilean population has suffered significant lifestyle changes associated with the rapid socioeconomic development of the country. These changes can induce a significant increase in the prevalence of some chronic diseases, such as obesity, dyslipidemia, and diabetes mellitus. We aimed to assess diabetes mellitus, obesity, and hypercholesterolemia trends in a Chilean urban population followed between 1993 and 2001. METHODS A total of 1584 adults, living in Santiago, the capital of Chile, were randomly enrolled in a cross-sectional epidemiologic study in 1993. The same population was re-evaluated in 2001, recruiting 964 individuals from the original sample. Prevalences of diabetes mellitus, obesity, and hypercholesterolemia were determined according to standard criteria. We tested the significance of the differences between the observed prevalence of diabetes mellitus, obesity, and hypercholesterolemia in the 964 subjects evaluated in 2001 compared with the expected prevalence according to population aging based in data from 1993. FINDINGS In 1993, 3.8% of the sample population had diabetes mellitus, 21.8% had obesity, and 37.3 % exhibited hypercholesterolemia. In 2001, the observed prevalence of diabetes mellitus, obesity, and hypercholesterolemia was 10.1%, 32%, and 58%, respectively. The latter percentages were significantly higher than the expected prevalence according to the aging of the population (6.5% for diabetes mellitus, 27.7% for obesity, and 47.7 for hypercholesteromia). INTERPRETATION Our findings indicate that Chilean population has suffered an accelerated increase in the prevalence of diabetes mellitus, obesity, and hypercholesterolemia, due to the ongoing epidemiological transition that will lead to an enormous public health burden in the near future.

A Latin American Perspective on the New ACC/AHA Clinical Guidelines for Managing Atherosclerotic Cardiovascular Disease

Atherosclerotic heart disease and stroke are leading causes of disability and death worldwide, affecting not only developed countries, but also low- and middle-income regions. Different strategies for handling dyslipidemia as a critical pathogenic risk factor for atherosclerosis have been proposed. However, these recommendations are not applied at all in many countries or even in whole regions of the world. Recently, new US guidelines on risk assessment, lifestyle changes, and high blood cholesterol level treatment to manage atherosclerotic disease were released. In this article, we analyze these new guidelines and discuss their potential applications in preventive cardiovascular medicine in Latin America.

A Failed Pregnancy Stress Test: A New and Under-Recognized Cardiovascular Risk Factor

Cardiovascular diseases (CVD) are the world’s leading cause of morbidity and mortality in women. However, most of the studies about physiologic factors, preventive strategies, and therapeutic interventions have been conducted mainly in men. Consequently, in the past few years, there has been a decline in the prevalence of CVD in men but not in women. One of the reasons for this difference could be gender-based disparity in cardiovascular care; women have been under-evaluated and under-treated for cardiovascular prevention. In addition, in the past decade, important information regarding specific female conditions, such as body composition, use of sex hormones, and long-term consequences of complications during the pregnancy, suggested that they may affect the onset, clinical course, and prognosis of CVD. Pregnancy is a state where significant physiologic adaptation occurs; from the cardiovascular point of view, these changes include an increase in blood volume, a decrease in total vascular resistance, and a small increase in heart rate and stroke volume maintaining a stable mean arterial pressure. In addition to those cardiovascular changes, pregnancy exhibits a relative insulin resistance and up-regulation of proinflammatory cytokines such as interleukin-6 and blood clotting factors. The magnitude of these changes has led some authors to consider pregnancy as a “maternal stress test,” in which some women do not tolerate the associated hemodynamic and metabolic changes and develop complications such as recurrent pregnancy loss, stillbirth, premature labor, gestational diabetes, or preeclampsia. Epidemiologic studies provide evidence that women with the above-mentioned complications of pregnancy are at increased risk for CVD later in life. The results of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort in Heidelberg showed that women who experience spontaneous pregnancy loss/stillbirth are at higher risk of myocardial infarction later in life, independent of the other known factors of CVD. Women who had recurrent pregnancy loss had a hazard ratio (HR) for myocardial infarction of 8.9 (95% CI, 3.18–24.9). In the same cohort, patients who had a stillbirth exhibited a myocardial infarction HR of 2.32 (95% CI, 1.19–4.5). For preterm labor, the CVD risk was increased by 2.0 (95% CI, 1.22–3.47). In addition, several studies have shown that hypertensive pregnancies are at greater risk of CVD (including cardiac, cerebrovascular, and peripheral arterial disease). Population-based studies link preeclampsia to an increased risk of later chronic hypertension (relative risk, 1.3– 8.0) and cardiovascular morbidity/mortality (relative risk, 1.3– 3.07) compared with normotensive pregnancy. Gestational diabetes mellitus (GDM) has also been associated with a greater risk of cardiovascular events, but the direct link between GDM and CVD has not been as clear as for hypertension. Nevertheless, women with previous GDM exhibit higher values of endothelial dysfunction, higher C-reactive protein levels, and higher levels of inflammatory markers, as well as a strong association with intimal media thickness, all of which are conditions that increase the risk for CVD. It has been shown that a high proportion of women with GDM will develop type 2 diabetes within 2–5 years, which in turn will increase the woman’s risk for CVD. These results highlight the importance of early identification and A. M. Cuevas (*) Department of Clinical Nutrition and Metabolism, Clinica Las Condes, Santiago, Chile e-mail: acuevas@clc.cl

Expression of MYD88 in Adipose Tissue of Obese People: Is There Some Role in the Development of Metabolic Syndrome?

BACKGROUND The mechanism leading to the development of metabolic complications in obese individuals is not fully understood. Thus, the objective of this study was to examine differences in insulin resistance, inflammation, cytokine and adipokine levels, and expression of selected genes across obese individuals with different number of metabolic syndrome (MetS) components. METHODS Forty obese individuals who underwent bariatric surgery, divided in three groups based on the number of components of MetS, in addition to abdominal obesity (0, 1, and 2-3 additional components), were studied. Levels of inflammatory proteins, insulin resistance, cytokines, adipokines, and gene expression in subcutaneous (SAT) and visceral adipose tissue (VAT) were compared. RESULTS There was a significantly higher expression of MYD88 in SAT among those with more components of MetS (P = 0.008). In SAT, but not in VAT, MYD88 expression was significantly correlated with toll-like receptor 4 expression (r = 0.7, P < 0.05). Expression of adipsin in SAT was also associated with the presence of more components of MetS, but with borderline statistical significance (P = 0.05). There were no significant differences in insulin resistance, inflammation, and cytokine and adipokine levels by the number of components of MetS. CONCLUSIONS Our study suggests that MYD88 expression in SAT of obese subjects could be associated with the development of components of MetS.

Eficacia y seguridad de una dieta muy baja en calorías en un grupo de mujeres chilenas con sobrepeso u obesidad

Background: Very low calorie diets (VLCDs) have been used to induce a rapid decrease in total body weight. Aim: To evaluate the efficacy and safety of a VLCD in a group of overweight and obese Chilean women. Material and Methods: Thirty women with a body mass index (BMI) > 27 kg/m2 were enrolled to a 4 weeks intervention with a VLCD (using liquid meal replacement). Anthropometric and metabolic parameters were evaluated at baseline and at the end of the intervention. Results: Twenty five women (83%) completed the total intervention period. Average weight loss was 5.7 ± 1.5 kg (-6.9% of the initial weight) corresponding to a 34.7 ± 13.4% of the excess of weight. Significant improvements in triglycerides, total cholesterol and LDL cholesterol (Low Density Lipoproteins) were observed. Insulin resistance determined by Homeostasis model assessment (HOMA), decreased significantly from 3.3 ± 1.8 to 2.0 ± 0.9 (p = 0.003). No serious adverse events were reported. Conclusions: Short term use of VLCDs is safe and effective to induce rapid weight loss in Chilean women.

Nuevos fármacos para el tratamiento de la hipercolesterolemia

Statins are the preferred treatment for hypercholesterolemia and several studies have demonstrated their long-term safety and efficacy in reducing cardiovascular morbidity and mortality. However, in some cases of severe hypercholesterolemia such as homozygous and heterozygous familial hypercholesterolemia or statin intolerant patients, statins can be less efficient. In recent years, new lipid-lowering agents with novel mechanisms of action have been developed to reduce LDL-cholesterol in patients with severe hypercholesterolemia, associated or not to conventional lipid-lowering therapy. These therapies include microsomal transfer protein inhibitor (Lomitapide), antisense oligonucleotide to Apo B100 (Mipomersen) and monoclonal antibodies against Proprotein convertase subtilisin/kexin type 9 (PCSK9). Different studies have shown the great effectiveness of these new therapies. Short-term studies confirmed their adequate security profile, especially in patients with homozygous familiar hypercholesterolemia or severe hypercholesterolemia. Some of these agents have been also tested in statin-intolerant patients. However, long-term studies are needed to evaluate their safety, effectiveness and impact on cardiovascular risk reduction.