Research Project: Diet and Cardiovascular Health

Location: Jean Mayer Human Nutrition Research Center On Aging

2022 Annual Report

Objectives
Objective 1: Determine the effect of food components and their metabolites, dietary patterns, and lipid-modifying therapies on cardiometabolic risk factors and lipoprotein, sterol, bile acid, and fatty acid metabolism in humans, and using animal, and in vitro models. Sub-objective 1.A: Elucidate the relationship between dietary patterns, with and without statin therapy, on atherosclerotic lesion development and concomitant tissue-specific inflammation using the Ossabaw pig as an experimental model. Sub-objective 1.B: Compare the effects of an isocaloric exchange of simple-carbohydrate (carb), refined-carb, and unrefined-carb on (i) plasma cardiovascular risk factors, (ii) targeted metabolomic and lipidomic markers, and (iii) gut microbiome signatures in humans. Objective 2: Identify novel biomarkers of food intake (e.g., metabolomic, lipidomic, proteomic, and microbiome) and relate them to cardiovascular health. Sub-objective 2.A: Determine the differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation, relative to placebo, on (i) plasma measures of cardiovascular risk, and (ii) biomarkers of inflammation and inflammatory cell gene expression in subjects with elevated inflammatory status. Sub-objective 2.B: Evaluate the effects of very long chain omega-3 ('-3) fatty acid supplementation (1.86 g EPA and 1.5 g DHA daily) on the composition and functionality of high density lipoprotein (HDL) subpopulations, and the influence thereof on coronary artery atherosclerotic plaque burden in individuals with stable coronary artery disease on statins.

Approach
Cardiovascular disease continues to be the leading cause of death and disability in the United States. The risk of developing cardiovascular disease increases with age. Preventive measures, especially dietary modification, are more efficacious and cost effective than treatment. However, some dietary recommendations, particularly related to carbohydrate and fat type, are enmeshed in controversy. This controversy undermines public confidence in dietary guidance, thereby impeding efforts to improve the overall quality of the American diet. To address this conundrum, in the next 5 years, the Cardiovascular Nutrition Laboratory will determine the effect of food components and their metabolites, dietary patterns, and lipid-modifying therapies on cardiometabolic risk factors and lipoprotein, sterol, bile acid, and fatty acid metabolism in humans, and using animal and in vitro models. We will accomplish this by determining the effect of dietary modification on cardiovascular health by elucidating the relationships among diet, tissue specific inflammation and atherosclerosis progression using the Ossabaw pig model; investigating the effect of carbohydrate type on cardiovascular disease risk factors and the gut microbiome by conducting human intervention trials; and assessing the relationship among very long chain omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid), inflammation and coronary artery atherosclerotic plaque progression using in vitro and in vivo approaches. More specifically, we will elucidate the relationship between dietary patterns, with and without statin therapy, on atherosclerotic lesion development and concomitant tissue-specific inflammation in the Ossabaw pig, and compare the effects of an isocaloric exchange of simple-carbohydrate, refined-carbohydrate, and unrefined-carbohydrate on cardiovascular risk factors, targeted metabolomic and lipidomic markers, and gut microbiome signatures in humans. We will assess potential complementary and/or synergistic effects between dietary modification and pharmacotherapy intended to reduce cardiovascular disease risk. Additionally, the Cardiovascular Nutrition Laboratory will identify novel biomarkers of food intake (e.g., metabolomic, lipidomic, proteomic, and microbiome) and relate them to cardiovascular health by determining the differential effects of very long chain omega-3 acid supplementation on plasma measures of cardiovascular risk and biomarkers of inflammation and inflammatory cell gene expression in individuals with elevated inflammatory status, and evaluating the effects of very long chain omega-3 fatty acid supplementation on the composition and functionality of high density lipoprotein subpopulations, and the influence thereof on coronary artery atherosclerotic plaque burden in individuals with stable coronary artery disease treated with statins. We will use these data to better understand the relationship between diet and cardiovascular health. The results of the proposed work will help facilitate updating and refining the Dietary Guidelines for Americans intended to support healthy aging.

Progress Report
Reported is the progress on our 36-month objectives and their sub-objectives all of which fall under National Program 107 Action Plan Component 3 – Scientific Basis for Dietary Guidance, Problem Statement 3A: Improve the Scientific Basis for Updating National Dietary Standards and Guidelines. Under Objective A.I.3, in collaboration with ARS Beltsville investigators, we used 16S rRNA gene sequencing to assess the effect of gut fecal microbial composition and from those data inferred metabolic function in Ossabaw pigs fed either a Heart Healthy-type or Western-type diet with or without statin therapy. We found gut microbiome genus alpha diversity was transiently reduced one month after feeding Western-type diet or Heart Healthy-type diet with no significant change at the end of the feeding period, 7 months. Gut microbiome bacterial communities were clustered and separated by diet as early as one-month post-intervention. A repeated measures multivariate analysis of Amplicon Sequence Variants identified enrichment in several families within order Bacteroidales (Prevotellaceae, Paludibacteriaceae, Bacteroidaceae), Selenomonadales (Veillonellaceae, Acidaminococcaceae), Clostridiales (Lachnospiraceae, Family XIII, Ruminococcaceae) in addition to Coriobacteriales (Coriobacteriaceae, Eggerthellaceae) in Western-type diet compared to Heart Healthy-type diet fed pigs. Western-type diet-induced dyslipidemia and early atherogenic lesion formation were positively associated with Amplicon Sequence Variants within Ruminococcaceae and Lachnospiraceae families with a statin-induced inverse association dependent on sex and diet. Predicted metagenomic functional content indicated differences in metabolic pathway abundances with less fermentative metabolic pathways and higher inflammation in pigs fed the Western-type diet compared to Heart Healthy-type diet. These results suggest that the differential effects of dietary patterns on cardiometabolic risk factors and atherosclerosis development are modulated, in part, by alterations in the gut microbiome and such knowledge may lead to the development of targeted risk reduction strategies. Under Sub-Objective 1.B.1; we compared the effects of an isocaloric exchange of simple-carbohydrate(carb), refined-carb, and unrefined-carb on (i) plasma cardiovascular risk factors, (ii) targeted metabolomic and lipidomic markers, and (iii) gut microbiome signatures in humans, we observed differential effects of carbohydrate type (simple, refined, and unrefined) on microbial composition and function, and fecal concentrations of secondary bile acids, that were associated with favorable relations with selected cardiometabolic risk factors. A secondary analysis was conducted to determine if circulating metabolites induced by consuming diets enriched in the different types of dietary carbohydrate is a viable option to characterize intake. Total plasma metabolites (>2,500) were measured. Of those, 829 were identified. Due to the large number of identified metabolites, based on prior work, a conservation variable importance in projection score of 1.7 was used as a cut off value, resulting in 60 metabolites. Of those, 37% were lipid, 20% were amino acid, 17% were xenobiotic, 13% were phospholipid and 13% were carbohydrate, carboxylic acids, ketone body and vitamin related. The data suggest that phenylethylamine, cysteine, betaine, pipecolic acid and 3-methylhistidine are biomarkers for unrefined carbohydrate compared to simple carbohydrate and refined carbohydrate intake. Pathway enrichment analysis revealed that mitochondria beta-oxidation of short chain saturated fatty acids, beta-oxidation of very long chain fatty acids and fatty acid biosynthesis were significantly activated in when participants consumed the simple carbohydrate diet, compared to refined carbohydrate and unrefined carbohydrate diets.

Accomplishments
1. Taste perception influences food choices. Public health attempts to encourage the U.S. population to adopt healthier eating patterns have resulted in few improvements in recent decades. Emerging data suggests individuals’ taste perception – the ability to detect sweet, salt, sour, bitter and umami – could be an important determinant of food choices. To determine the impact of all five 5 tastes on food choices, ARS-funded researchers in Boston, Massachusetts, developed taste perception profiles and examined their association with self-reported dietary patterns. They found that groups with different taste perception profiles reported dietary patterns differing in many characteristics. These data support the role of taste perception as an influencer of food choices. Increased awareness of this factor may enhance development of personalized nutrition guidance to improve compliance with current chronic disease risk reduction guidance that will ultimately improve long term health outcomes.

Review Publications
Kris-Etherton, P., Petersen, K., Despres, J., Anderson, C.A., Deedwania, P., Furie, K.L., Lear, S., Lichtenstein, A.H., Lobelo, F., Morris, P., Sacks, F.M., Ma, J. 2021. Strategies for promotion of a healthy lifestyle in clinical settings: Pillars of ideal cardiovascular health: A science advisory from the American Heart Association. Circulation. 144(24):e495-e514. https://doi.org/10.1161/CIR.0000000000001018.
Kim, H., Lichtenstein, A.H., White, K., Wong, K.E., Miller III, E.R., Coresh, J., Appel, L.J., Rebholz, C.M. 2022. Plasma metabolites associated with a protein-rich dietary pattern: Results from the OmniHeart trial. Molecular Nutrition and Food Research. https://doi.org/10.1002/mnfr.202100890.
Gervis, J., Fernandez-Carrion, R., Chui, K.K., Ma, J., Coltell, O., Sorli, J.V., Asensio, E.M., Ortega-Azorin, C., Perez-Fidalgo, J., Portoles, O., Lichtenstein, A.H., Corella, D. 2021. Associations between taste perception profiles and empirically derived dietary patterns: an exploratory analysis among older adults with metabolic syndrome. Nutrients. 14(1):142. https://doi.org/10.3390/nu14010142.
Huang, N.K., Matthan, N., Matuszek, G.H., Lichtenstein, A.H. 2022. Plasma metabolite profiles following consumption of animal protein and soybean-based diet in hypercholesterolemic postmenopausal women. Metabolites. 12(3):209. https://doi.org/10.3390/metabo12030209.
Tanprasertsuk, J., Scott, T.M., Barbey, A.K., Barger, K., Wang, X., Johnson, M., Poon, L.W., Vishwanathan, R., Matthan, N., Lichtenstein, A.H., Ferland, G., Johnson, E.J. 2021. Carotenoid-rich brain nutrient pattern is positively correlated with higher cognition and lower depression in the oldest old with no dementia. Frontiers in Nutrition. 8:704691. https://doi.org/10.3389/fnut.2021.704691.
Pellegrini, C.N., Buzkova, P., Lichtenstein, A.H., Matthan, N.R., Ix, J.H., Siscovick, D.S., Heckbert, S.R., Tracy, R.P., Mukamal, K.J., Djousse, L., Kizer, J.R. 2021. Individual non-esterified fatty acids and incident atrial fibrillation late in life. Heart. 107(22):1805-1812. https://doi.org/10.1136/heartjnl-2020-317929.
Huang, N.K., Buzkova, P., Matthan, N., Djousse, L., Kizer, J.R., Mukamal, K., Polak, J.F., Lichtenstein, A.H. 2021. Serum non-esterified fatty acids, carotid artery intima-media thickness and flow-mediated dilation in older adults: The Cardiovascular Health Study (CHS). Nutrients. 13(9):3052. https://doi.org/10.3390/nu13093052.
So, J., Wu, D., Lichtenstein, A.H., Tai, A.K., Matthan, N.R., Rao Maddipati, K., Lamon-Fava, S. 2020. EPA and DHA differentially modulate monocyte inflammatory response in subjects with chronic inflammation in part via plasma specialized pro-resolving lipid mediators: A randomized, double-blind, crossover study. Atherosclerosis. 316:90-98. https://doi.org/10.1016/j.atherosclerosis.2020.11.018.
Chang, W., So, J., Lamon-Fava, S. 2021. Differential and shared effects of eicosapentaenoic acid and docosahexaenoic acid on serum metabolome in subjects with chronic inflammation. Scientific Reports. 11:16324. https://doi.org/10.1038/s41598-021-95590-7.
Lichtenstein, A.H., Appel, L.J., Vadiveloo, M., Hu, F.B., Kris-Etherton, P.M., Rebholz, C.M., Sacks, F.M., Thorndike, A.M., Van Horn, L., Wylie-Rosett, J. 2021. 2021 Dietary guidance to improve cardiovascular health: A scientific statement from the American Heart Association. Circulation. 144(23):e472-e487. https://doi.org/10.1161/CIR.0000000000001031.
Reboussin, D.M., Kris-Etherton, P.M., Lichtenstein, A.H., Li, Z., Sabate, J., Matthan, N., Petersen, K.S., Rajaram, S., Vitolins, M.Z., Ford, N. 2021. The design and rationale of a multi-center randomized clinical trial comparing one avocado per day to usual diet: The Habitual Diet and Avocado Trial (HAT). Contemporary Clinical Trials. 110: 106565. https://doi.org/10.1016/j.cct.2021.106565.
Garvey, M.E., Shi, L., Lichtenstein, A.H., Must, A., Hayman, L.L., Crouter, S.E., Camhi, S.M. 2022. Associations of bone mineral density with lean mass, fat mass, and physical activity in young overweight and obese women - A feasibility study. International Journal of Exercise Science. 15(7):585-598.
Ginsberg, H.N., Packard, C., Chapman, M.J., Boren, J., Aguilar-Salinas, C.A., Averna, M., Ference, B.A., Gaudet, D., Hegele, R.A., Kersten, S., Lewis, G.F., Lichtenstein, A.H., Moulin, P., Nordestgaard, B.G., Remeley, A.T., Staels, B., Stroes, E.S., Taskinen, M., Tokgozoglu, L.S., Tybjaerg-Hansen, A., Stock, J.K., Catapano, A.L. 2021. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. European Heart Journal. 42(47):4791-4806. https://doi.org/10.1093/eurheartj/ehab551.
Matthan, N., Barger, K., Wylie-Rosett, J., Xue, X., Groisman-Perelstein, A.E., Diamantis, P.M., Ginsberg, M., Mossavar-Rahmani, Y., Lichtenstein, A.H. 2021. Spillover effects of a family-based childhood weight management intervention on parental nutrient biomarkers and cardiometabolic risk factors. Current Developments in Nutrition. 6(2):nzab152. https://doi.org/10.1093/cdn/nzab152.
Schwager, J.L., Nevitt, M.C., Torner, J., Lewis, C.E., Matthan, N.R., Wang, N., Sun, X., Lichtenstein, A.H., Felson, D. 2020. Association of serum low-density lipoprotein, high-density lipoprotein, and total cholesterol with development of knee osteoarthritis. Arthritis Care and Research. 74(2):274-280. https://doi.org/10.1002/acr.24455.