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:
Dietary fat quality has a significant impact on cardiovascular disease (CVD) risk. Unresolved issues remain regarding the relative effects of stearic acid, a longer chain saturated fatty acid (SFA) relative to palmitic acid, a shorter chain SFA and to palmitic acid’s metabolic product, oleic acid, a monounsaturated fatty acid (MUFA), on CVD risk. To address this issue, we conducted a randomized-controlled crossover trial in 20 mildly hyper-cholesterolemic postmenopausal women to determine the effect of consuming diets in either palmitic (16:0,) stearic (18:0), or oleic (18:1) acids on indicators of systemic inflammation and CVD risk. The experimental diets were formulated using commercially available vegetable oils to facilitate the translational nature of the findings. Plasma levels of 18:1 were similar after participants consumed the 18:0 and 18:1 enriched diet and higher after the 16:0 enriched diet. There was little effect of the diets on mediators of systemic inflammation. In contrast, the diet enriched in 16:0 resulted in a significantly higher T-cell proliferation in response to antibodies against CD3 (T cell receptor) and CD28 (T cell co-receptor) than diets enriched in 18:0 and 18:1. This pattern was not observed in response to stimulation with the T cell mitogen concanavalin A, for which the response was similar regardless of diet phase. Fasting and non-fasting total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) concentrations were significantly lower (~10%) after participants consumed the 18:0 and 18:1 relative to the 16:0 enriched diet. High density lipoprotein-cholesterol (HDL-C) concentrations were significantly higher after participants consumed the 16:0 relative to the 18:0 and 18:1 enriched diet. This resulted in TC/HDL-C ratios that were lowest after participants consumed the 18:1 diet and similar after they consumed the 16:0 and 18:0 diets. Other biochemical measures (glucose homeostasis and blood clotting) were unaffected by the dietary intervention. The plasma fatty acid profile and LDL-C and HDL-C concentrations suggest a proportion of 18:0 may have been converted to 18:1. Although much has been published about the effect of different amounts of dietary carbohydrate (carb) on CVD risk indicators, data on the cardiometabolic effects of different types of carbohydrate (simple, refined and unrefined) are limited. We determined the relative comparability for an isocaloric exchange of unrefined-carb (e.g. whole wheat flour), refined-carb (e.g. white flour) and simple-carb (e.g. high fructose corn syrup), on established and emerging cardiometabolic risk indicators. All foods and beverages (60%E total carb, 15%E protein, 27%E fat, 80mg cholesterol/1000 kcal) were provided to study participants (N=11 men and postmenopausal women, 65 y, BMI 29.8 kg/m2, LDL-C >/=100 mg/dL) for 5 weeks (randomized, single-blind, cross-over design). Body weight was constant. Refined-carb diet resulted in higher fasting serum TC, LDL-C, and non-HDL-C concentrations than simple- and unrefined-carb diets. Dietary carbohydrate type had no significant effect on serum fasting HDL-C, triglycerides, non-esterified fatty acids (NEFA), glucose, insulin, hemoglobin A1c, high-sensitive CRP or IL-6 levels. Carbohydrate type also has no significant effect on non-fasting serum lipid profile or glucose homeostasis. The unrefined-carb diet resulted in significantly higher NEFA concentrations compared to simple- and refined-carb diets. Refined-carb diet resulted in largest mean adipocyte size in comparison to simple- and unrefined-carb diets. However, carbohydrate type had no significant effect on gene expression of macrophage infiltration (CD14 and CD68) and inflammatory markers (serum amyloid-1, adiponectin, leptin, and IL-6) and secretion of adipokines (adiponectin, leptin, and IL-6) in subcutaneous adipose tissue. Cholesterol efflux from monocyte-derived macrophages did not differ among carbohydrate types. Results from this study demonstrate that carbohydrate type alters fasting serum lipids concurrently with changes in adipocyte size. The Ossabaw pig has been established as a model for obesity, metabolic syndrome, atherosclerosis, and non-alcoholic steatohepatitis when fed an extreme diet (high trans-fat and fructose) in caloric excess. To increase the translational nature of this model, we determined if the pigs manifested cardiometabolic risk factors and early stage atherosclerosis when given diets that provided macronutrients in quantities typically consumed by humans and resembled human dietary patterns. Compared were a “Western Diet” with a low PUFA/SFA ratio, high cholesterol, and refined grains to a “Heart Healthy Diet” with a high PUFA/SFA ratio (omega-3 and omega-6 fatty acids), whole grains, fruits/vegetables, and fiber. Also evaluated was the role of atorvastatin (statin) therapy in modulating these effects. Thirty male and female 2-3 month-old Ossabaw pigs were randomized into 4 groups: Western Diet, Western Diet+statin, Heart Healthy Diet, and Heart Healthy Diet+statin). The results indicated that serum fatty acid profiles reflected the predominant fatty acid in the diets. Compared to pigs fed the Western Diet, significantly lower LDL-C, non-HDL-C, HDL-C, triglyceride, hsCRP and alkaline phosphatase levels were observed in pigs fed the Western Diet+statin, Heart Healthy Diet, and Heart Healthy Diet+statin, respectively. No significant effect was observed among groups in glucose, insulin, TNF-alpha, other liver and muscle enzyme levels, and body weight/fat distribution. Histopathological evaluation documented that pigs fed the Heart Healthy Diet and Heart Healthy Diet+statin had intact intima, while pigs fed the Western Diet showed early atherosclerotic changes in the right coronary, left anterior descending (LAD) and left circumflex coronary arteries. These changes ranged from lesions classifiable as Stary type I to type III (Type I: early lesions with adaptive intimal thickening; Type II: fatty streak with foam cells and macrophages; and Type III: pre-arethroma with extracellular lipid droplets). Greater lipid deposition (stained area %) was observed in the aortic arch and thoracic aorta in the Western Diet group compared to the Heart Healthy Diet groups. A lower degree of lesion formation was observed in the LAD and thoracic aorta of the pigs in the Western Diet+statin group compared to the Western Diet group. These data indicate that the Ossabaw pigs manifest a dyslipidemic profile, accompanied by early stage atherosclerosis, similar pathogenesis to humans in response to a Western Diet compared to Heart Healthy Diet. Using archived samples harvested from these pigs we focused on the potential interaction of dietary modification and statin therapy on epicardial adipose tissue (EAT), a visceral adipose tissue depot adjacent to the coronary arteries. EAT is thought to promote the development of coronary artery disease (CAD). Little is known about the effect of diet on the interplay between EAT and CAD. EAT adjacent to the left anterior descending coronary artery was subjected to RNA sequencing and edgeR analysis. Identification of differentially expressed genes was based on a FDR adjusted p<0.1 and absolute log fold change >0.6 (absolute fold change 1.5). Pathway analysis indicated that Interferon Signaling, Th1 Pathway, Bacteria and Virus Pattern Recognition Receptors, iCOS signaling in T Helper Cells, Calcium-induced T Lymphocyte Apoptosis, and UVA-induced MAPK Signaling were activated in pigs fed the Western Diet relative to the Heart Healthy Diet. In the Western Diet fed pigs, upstream regulator analysis predicted the activation inflammatory cytokines TNF-alpha and IL-1ß and regulatory factors and protein receptors involved in interferon mediated signaling through the JAK/STAT1 signaling cascade. Biological processes and functions predicted to be activated in EAT from pigs fed the Western Diet relative to Heart Healthy Diet included inflammatory response, immune cell trafficking and lymphoid tissue development. These data suggest that a Western Diet compared to Heart Healthy Diet induced an inflammatory response in EAT through interferon activation of the JAK/STAT1 signaling cascade in the Ossabaw miniature pig. 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. Our goal was to compare published categorization systems used to differentiate weight maintainers and regainers to identify the approach(es) least discordant with others. We analyzed publicly available data for overweight/obese participants with type 2 diabetes in the intervention group of the Look AHEAD trial who lost >/=3% initial body weight at year 1 and had 3-year follow-up data (n=1,725). When each categorization 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 concordance among the methods. Those labeled maintainers or regainers by >/=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 >/=50% of weight loss maintained categorization was used to define maintainers. We found poor agreement among published weight maintainer/regainer definitions. The >/=50% weight loss maintained cutoff provided the most concordant categorization of maintainers/regainers compared to cluster-assigned categorization.
1. Glycemic index is highly variable and not a reliable dietary guide. The glycemic index (GI) was developed to identify how specific carbohydrate-containing foods influence blood sugar levels and the concept of glycemic load (GL) incorporates both the quality (GI) and quantity of carbohydrate in a meal and was introduced to adjust for serving size. These measurements have not considered how blood sugar levels are affected when carbohydrate-containing foods are eaten in combination with other macronutrients such as fat or protein. ARS-funded researchers in Boston, Massachusetts, found that adding protein significantly decreased measured meal GI and GL, while adding carbohydrate, fat or fiber had little effect on these parameters. These data indicate significant variability in meal GI and GL value determinations results from consuming different food combinations and caution against using glycemic index values for dietary guidance.
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