1a. Objectives (from AD-416):
LAB NAME: Cardiovascular Nutrition 1. Determine the effect of diets differing in fat and carbohydrate type on cardiometabolic risk indicators, lipoprotein and fatty acid metabolism, response to lipid modifying therapy, and gene-nutrient interactions, using human, animal and in vitro models. 1.1 – Relative effects of palmitate (16:0), stearate (18:0) and oleate (18:1) on cardiometabolic risk factors, fatty acid kinetics and lipoprotein-mediated in vitro endothelial cell inflammatory response. 1.2 – Relative effects of simple, refined and unrefined carbohydrate on cardiometabolic risk factors, macrophage cholesterol homeostasis, subcutaneous adipose tissue macrophage infiltration/inflammatory gene expression, and intestinal microbiome. 1.3 – Synergistic effects of a ‘heart healthy’ diet and statin therapy on atherosclerosis using a porcine model. 1.4 – Common and differential effects of eicosapentaenoic acid and docosahexaenoic acid on lipid metabolism and systemic inflammation. 2. Determine the relationship between food preferences, consumption patterns and dietary acculturation, and cardiovascular health using population-based datasets. 2.1 – Impact of acculturation status on dietary patterns and health outcomes in Chinese Americans. 3. Identify novel biomarkers for food and nutrient intake related to dietary patterns and cardiovascular health. 3.1 – Effect of a comprehensive 12 month approach to family weight management on biomarkers of dietary intake and cardiometabolic risk factors in child-mothers/female guardian pairs. 3.2 – Novel nutrient biomarkers to predict risk of heart failure.
1b. Approach (from AD-416):
LAB NAME: Cardiovascular Nutrition In the next 5 years the Cardiovascular Nutrition Laboratory (CNL) will investigate the effects of diets differing in fat type and carbohydrate type on cardiometabolic risk factors, fatty acid metabolism, response to lipid modifying therapy, and gene-nutrient interactions using human, animal and in vitro models. This will be accomplished by assessing the relative effects of palmitate, stearate and oleate on cardiometabolic risk factors, fatty acid kinetics and in vitro endothelial cell inflammatory response to lipoprotein particles; relative effects of simple-carbohydrate, refined-carbohydrate and unrefined-carbohydrate on cardiometabolic risk factors, macrophage cholesterol homeostasis, and intestinal microbiome; synergistic effects of an atherogenic or ‘ heart healthy’ diet with/without statin therapy on atherosclerosis development using a porcine model; and relative effects of eicosapentaenoic and docosahexaenoic acids on systemic inflammation and lipid metabolism. The CNL will determine the relationship between food preferences, consumption patterns and dietary acculturation, and cardiovascular health using population-based datasets by assessing the impact of acculturation status on dietary patterns and health outcomes. In addition, the CNL will identify and adjudicate novel biomarkers for food and nutrient intake and merge them with established biomarkers thereof, and assess potential relationships with family-wide CVD risk and weight management, and heart failure risk.
3. Progress Report:
CARDIOVASCULAR LAB: Global glycemic index (GI) and glycemic load (GL) values, the overall glycemic response to an eating pattern, are used to identify diet/disease relationships. Conclusions derived from this approach to relate dietary habits to health outcomes are only useful if GI and GL values of individual foods are consistent among individuals and are unaffected by the absolute amount of food consumed or macronutrients eaten in tandem. Our hypothesis was that increasing amounts of macronutrients (carbohydrate, protein, fat) and fiber added to the “gold” standard challenge of 50g available carbohydrate from white bread will alter the GI and GL values. The trial included 4 studies, during which subjects (n=20-22, 50% female, 50-80y, BMI 25-30kg/m2, free from chronic disease and having fasting glucose levels less than or equal to 125mg/dL) received the “gold” standard food challenge plus different amounts of an additional macronutrient in a random order. Studies 1-3 consisted of 4 food challenges, containing white bread (50g available carbohydrate + 500mL water) alone or with additional carbohydrate (12.5g, 25g, 50g), protein (12.5g, 25g, 50g) and fat (5.6g, 11.1g, 22.2g) from Rice Chex breakfast cereal (General Mills), tuna and unsalted butter, respectively. Study 4 consisted of 3 food challenges, containing white bread alone or with additional fiber (4.8g, 9.6g) from Cheerios (General Mills). Arterialized venous blood was sampled at 0, 15, 30, 45, 60, 90 and 120 minutes, and GI and GL values were calculated using the recommended incremental area under the curve method. Addition of 12.5g, 25g and 50g of carbohydrate to white bread significantly increased glucose area under the curve, GI values and GL values; while addition of protein (50g) to white bread significantly decreased glucose area under the curve, GI values and GL values. Addition of fat or fiber to the white bread challenge had no significant effect on any measure. These data indicate that variability in postprandial GI and GL values is introduced when carbohydrate containing foods are consumed in different amounts or in combination with protein. These conclusions raise a concern with regard to whether GI and GL values from individual foods should be used to calculate global GI and GL scores from dietary intake data. Current recommendations for the prevention and treatment of cardiovascular disease are to focus on lifestyle modifications to improve risk factors prior to initiating drug therapy. However, if lifestyle modifications do not result in adequate improvement in cardiovascular disease risk factors, pharmacotherapy is recommended. The most common form of pharmacotherapy is statins, a class of drugs that inhibits endogenous cholesterol biosynthesis. With this in mind we initiated a study to determine the effect of dietary modification with and without statin (atorvastatin) therapy in the Ossabaw miniature pig, an experimental model previously demonstrated to develop diet induced atherosclerotic lesions. In response to an atherogenic diet (high in saturated fat/cholesterol and refined grains), compared to a heart healthy diet (high in unsaturated fat, whole grain, fruits/vegetables and fiber), the pigs had significantly higher plasma total cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride concentrations, and developed early stage lesions in the aorta and coronary arteries. Atorvastatin therapy mediated this response. We are now moving to the second phase of this project, to determine the metabolomic and lipidomic profile of the plasma, left anterior descending coronary artery, liver, visceral adipose tissue, and epicardial adipose tissue as well as composition of bile from pigs fed an atherogenic or heart healthy diet with or without statin therapy. Our hypotheses are that diet (atherogenic versus heart healthy), with and without statin therapy, will result in unique metabolomic profiles that provide novel biomarkers and mechanistic insight into the interplay between diet and/or drug therapy and early stage atherosclerotic lesion formation, and modify plasma and tissue specific lipidomic profiles and lipid mediators that will be associated with differences in inflammation markers, cardiometabolic risk factors, tissue transcriptomics, early stage atherosclerosis progression and bile acid composition. The Action for Health in Diabetes (Look AHEAD) trial was designed to reduce the risk of heart disease in individuals with diabetes. The approach used was to encourage weight loss through reduced caloric intake and increased physical activity. The success rate was highly variable. Of concern, after successful weight loss during the first year of intensive lifestyle modification, many subjects regained the weight. To sustain a lower heart disease risk in individuals with diabetes, it is critical to develop methods that will distinguish weight loss “maintainers” from “regainers” so that approaches can be developed, a priori, to support attaining and sustaining cardiometabolic health. To accomplish this goal we compared published categorization systems used to differentiate weight “maintainers” and “regainers” to identify the approach least discordant with others. Analyzed was Publicly available data for overweight/obese participants with type 2 diabetes in the intervention group of the Look AHEAD trial who lost greater than or equal to 3% initial body weight at year 1 and had 3-year follow-up data. Kappa coefficients were calculated to determine agreement among 12 weight “maintainer”/”regainer” categorization systems identified from peer reviewed literature. When each categorization system was compared to all others, 62/66 comparisons showed poor agreement and 4/66 comparisons showed substantial agreement. Hierarchical clustering assigned participants to 2 distinct groups representing the concordance among the methods. Those who were labeled as “maintainers” or “regainers” by greater than or equal to 7/12 methods clustered together and were given a “maintainer”/”regainer” assignment. When each method was compared to the cluster-assigned categorization, 3/12 showed substantial agreement and 8/12 showed poor agreement. Nearly perfect concordance was reached when the greater than or equal to 50% of weight loss maintained categorization was used to define maintainers. This cutoff appears to be the most appropriate categorization of “maintainers”/”regainers” and will be used to assess the relationship of “maintainers”/”regainers” and cardiovascular risk factors.
1. An omega-3 fatty acid rich in seafood has differential effects on pro-inflammatory cytokines. Seafood, rich in omega-3 fatty acids, is an important component of a heart-healthy diet. However, more recent data has questioned the efficacy of omega-3 fatty acids and seafood in reducing cardiovascular disease risk. Some of the inconsistency in the reports could be attributed to the complex role of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), on inflammatory factors called cytokines. Tufts University researchers at USDA in Boston, Massachusetts, have found that DHA did not have a consistent effect on pro-inflammatory cytokines. In cultured macrophages it reduced interleukin 6, but not tumor necrosis factor alpha or mRNA expression. These results explain some of the inconsistent data reported for the effect of omega-3 fatty acids and cardiovascular disease and support the continued recommendation to include seafood in a heart-healthy diet.
2. A family-based intervention to improve body mass index Z-score in children improves cardiometabolic risk factors. Overweight and obesity in children increases their risk of developing cardiovascular disease later in life. Tufts University researchers at USDA in Boston, Massachusetts, in collaboration with researchers at Einstein Medical School in New York City, New York, initiated a 12-month randomized controlled trial to decrease excess body weight gain, referred to as body mass index Z-score, in high risk children aged 7-12 years. The control intervention consisted of quarterly pediatrician consultations to address the American Academy of Pediatrics obesity recommendations. The experimental intervention included quarterly pediatrician consultations with the addition of a structured family-based behavioral change program consisting of eight skill-building core sessions and monthly post-core support sessions taught by a multidisciplinary staff. During the 12-month intervention period, children in both the control and experimental interventions significantly improved their body mass index Z-score. Compared to the control intervention, the experimental intervention resulted in greater decreases in total cholesterol, low-density lipoprotein cholesterol, and a measure of liver function. These data provide support for the benefit of early intervention to improve risk factors associated with the development of cardiovascular disease later in life.
3. Estimating the reliability of glycemic index values and potential sources of methodological and biological variability limit the utility of glycemic index values in formulating dietary guidance. The utility of glycemic index (GI) values for chronic disease risk management remains controversial. While absolute GI value determinations for individual foods have been shown to vary in individuals with diabetes, there is a dearth of data on the reliability of GI value determinations and potential sources of variability among healthy adults. Tufts University researchers at USDA in Boston, Massachusetts, found that the mean GI value for white bread, the standard food to which others are compared, was 62 ± 15 calculated using the recommended method. However, the average variation of this value was 20% among different tests conducted in the same individual and 25% among tests conducted among different individuals. Increasing the number of participants, repeating the tests of both the reference food and the other foods, and increasing the length between blood draws did not lessen the amount of variation. Among the biological factors assessed HbA1c values, a marker of long term glucose control, contributed the most variability among individuals. These findings indicate there was substantial variability in individual responses to GI value determinations, demonstrating that it is not a good tool for guiding food choices.
4. Metabolically healthy overweight/obese women have healthier diets and engage in more physical activity than metabolically unhealthy overweight/obese women. To better understand the differences between metabolically healthy overweight/obese and metabolically unhealthy overweight/obese individuals and identify potential determinants thereof, Tufts University researchers at USDA in Boston, Massachusetts, in collaboration with researchers at the University of Massachusetts Boston, Massachusetts, compared dietary data and objective measures of physical activity between the two groups. Compared to metabolically unhealthy overweight/obese women, metabolically healthy overweight/obese women spent significantly fewer minutes per day in sedentary behavior, significantly more minutes per day in light physical activity, and had significantly higher daily metabolic equivalent, a measure of physical exertion. Metabolically healthy overweight/obese had better diet quality as indicated by significantly higher fiber intake and number of servings of vegetables; and a lower intake of saturated fat, monounsaturated fat, trans fats and dairy servings, compared to metabolically unhealthy overweight/obese. These data show that metabolically unhealthy overweight/obese individuals can improve their risk factors by improving their diet and modestly increasing their level of physical activity.
5. Significant Activities that Support Special Target Populations:
Nie, S., Zhang, J., Martinez-Zaguilan, R., Sennoune, S., Hossen, M., Lichtenstein, A.H., Cao, J., Meyerrose, G.E., Paone, R., Soontrapa, S., Fan, Z., Wang, S. 2015. Detection of atherosclerotic lesions and intimal macrophages using CD36-targeted nanovesicles. Journal of Controlled Release. 220(A):61-70. doi: 10.1016/j.jconrel.2015.10.004.
Millen, B.E., Abrams, S., Adams-Campbell, L., Anderson, C.A., Brenna, J., Campbell, W., Clinton, S., Hu, F., Nelson, M., Neuhouser, M.L., Perez-Escamilla, R., Siega-Riz, A., Story, M., Lichtestein, A.H. 2016. The 2015 Dietary Guidelines Advisory Committee scientific report: development and major conclusions. Advances in Nutrition. 7(3):438-444. doi: 10.3945/an.116.012120.
Bigornia, S.J., Lichtenstein, A.H., Harris, W.S., Tucker, K.L. 2016. Associations of erythrocyte fatty acid patterns with insulin resistance. American Journal of Clinical Nutrition. 103(3):902-909. doi: 10.3945/ajcn.115.123604.
Folta, S.C., Seguin, R.A., Chui, K., Clark, V., Corbin, M.A., Goldberg, J.P., Heidkamp-Young, E., Lichtenstein, A.H., Wiker, N., Nelson, M.E. 2015. National dissemination of StrongWomen – Healthy Hearts: A community-based program to reduce risk of cardiovascular disease among midlife and older women. American Journal of Public Health. 105(12):2578-2585.
Gunsalus, K.T., Tornberg-Belanger, S.N., Matthan, N., Lichtenstein, A.H., Kumamoto, C.A. 2015. Manipulation of host diet to reduce gastrointestinal colonization by the opportunistic pathogen Candida albicans. mSphere. 1(1). pii:e00020-15. doi:10.1128/mSphere.00020-15.
Tsunoda, F., Lamon-Fava, S., Asztalos, B.F., Iyer, L.K., Richardson, K., Schaefer, E.J. 2015. Effects of oral eicosapentaenoic acid versus docosahexaenoic acid on human peripheral blood mononuclear cell gene expression. Atherosclerosis. 241(2):400-408.
Appel, L.J., Lichtenstein, A.H., Callahan, E.A., Sinaiko, A., Van Horn, L., Whitsel, L. 2015. Reducing sodium intake in children: a public health investment. The Journal of Clinical Hypertension. 17(9):657-662.
Lichtenstein, A.H. 2015. Fatty acids - trans fatty acids. In: Caballero, B., Finglas, P., and Toldrá, F., editors. The Encyclopedia of Food and Health, vol. 2. Oxford, England: Academic Press. pp. 645-648.
Camhi, S.M., Crouter, S.E., Hayman, L.L., Must, A., Lichtenstein, A.H. 2015. Lifestyle behaviors in metabolically healthy and unhealthy overweight and obese women. PLoS One. 10(9):e0138548. doi: 10.1371/journal.pone.0138548.