Research Project: Diet and Cardiovascular Health

Location: Jean Mayer Human Nutrition Research Center On Aging

2021 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 24-month objectives and the 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 after 6 months, the Western-style compared to the Heart Healthy-type diet-induced dyslipidemia and early-stage atherosclerotic lesions associated with changes in host-microbiome composition and function, predominantly from the phylum Firmicutes and Proteobacteria. The fecal microbiota composition diet by statin and sex interactions were identified and will require additional work to reconcile these findings with the identified dyslipidemia and early-stage atherosclerotic lesions. The results indicate that the differential effects of dietary patterns on cardiometabolic risk factors and atherosclerosis development are, in part, modulated by alterations in the gut microbiome and provide a first step for designing future targeted risk reduction strategies. We are seeking to secure external funding to complete the metabolomic and lipidomic sample analyses. Under Sub-Objective 1.B.1 we observed differential effects of carbohydrate type (simple, refined, and unrefined) on microbial composition and function and fecal concentrations of secondary bile acids associated with favorable relations with selected cardiometabolic risk factors. These included a higher abundance of the butyrate-producing genera Roseburia and lower production of secondary bile acids. Of note, also observed was a high degree of inter-individual differences in gut microbial communities, an important factor to consider for future work designed to determine the effect of dietary interventions on the gut microbiome. Under Sub-Objective 2.A.3 we observed that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have distinct effects on monocyte inflammatory response. Specifically, the effect is broader for DHA than EPA with respect to attenuating pro-inflammatory cytokines. This disparity is potentially mediated by different groups of polyunsaturated fatty acids (PUFA) derivatives, particularly specialized pro-resolving lipid mediators, suggesting a role in the immunomodulatory activities of these fatty acid metabolites and their intermediates. We also worked with Cardiovascular Health Study investigators to determine the relationship between individual non-esterified fatty acids and cardiovascular disease risk. We found in this cohort of older U.S. adults that two diet-derived non-esterified fatty acids, dihomo-gamma-linolenic acid, an unsaturated omega-6 fatty acid, and elaidic acid, a trans fatty acid, were positively associated with coronary heart disease mortality and non-fatal myocardial infarction, respectively, suggesting they could be used as susceptibility biomarkers for these disorders. In the same cohort, we also determined that serum non-esterified conjugated linoleic acid, a trans fatty acid, and palmitoleic acid, a monounsaturated fatty acid of relatively low abundance, were positively associated with carotid artery intima-media thickness and flow-mediated dilation, respectively. Confirmation of the findings would support using these non-esterified fatty acids as modifiable biomarkers for subclinical atherosclerosis.

Accomplishments
1. Taste perception of sweet, salt, sour, bitter and umami linked to health outcomes. Attempts over the past decade to influence U.S. adults to adopt healthier eating patterns associated with a lower risk of developing chronic diseases has resulted in slight improvement. Accumulating evidence suggests that individuals with strong taste perception can detect each of the five basic tastes: sweet, salt, sour, bitter, and umami, have fewer chronic disease risk factors than people with weaker taste perception. Consistent with the trend to use dietary pattern scores to simultaneously account for differences among multiple rather than individual foods, ARS-funded researchers in Boston, Massachusetts, developed taste perception profiles to simultaneously account for differences among multiple tastes rather than individual tastes. Using a data-driven approach, researchers identified six taste profiles based on individuals’ ability to perceive each of the five tastes differentially. In a cohort of older adults with metabolic syndrome, individuals who exhibited the profile represented by low perception for all five tastes, compared with the other profiles, had higher body mass index, body weight, and waist circumference, indicating a higher risk for cardiovascular disease. These data suggest using measures of taste perception on an individual basis may contribute to the refinement of personalized nutrition strategies to increase the effectiveness of dietary modification programs designed to improve diet quality and, ultimately, health outcomes.

Review Publications
Kim, H., Lichtenstein, A.H., Wong, K.E., Appel, L.J., Coresh, J., Rebholz, C.M. 2020. Urine metabolites associated with the Dietary Approaches to Stop Hypertension (DASH) diet: results from the DASH-sodium trial. Molecular Nutrition and Food Research. 65(3):2000695. https://doi.org/10.1002/mnfr.202000695.
Vadiveloo, M., Lichtenstein, A.H., Anderson, C.A., Aspry, K., Foraker, R., Griggs, S., Hayman, L.L., Johnston, E., Stone, N.J., Thorndike, A.N. 2020. Rapid diet assessment screening tools for cardiovascular disease risk reduction across healthcare settings: A scientific statement from the American Heart Association. Circulation: Cardiovascular Quality and Outcomes. 13(9):702-715. https://doi.org/10.1161/HCQ.0000000000000094.
Barzilay, J.I., Buzkova, P., Djousse, L., Ix, J.H., Kizer, J.R., Cauley, J.A., Matthan, N., Lichtenstein, A.H., Mukamal, K.J. 2021. Serum non-esterified fatty acid levels and hip fracture risk: The Cardiovascular Health Study. Osteoporosis International. https://doi.org/10.1007/s00198-021-05897-4.
Schultz, N.S., Chui, K.K., Economos, C.D., Lichtenstein, A.H., Volpe, S.L., Sacheck, J.M. 2020. Impact of physical activity, diet quality and stress on cardiometabolic health in school employees. Preventive Medicine Reports. 20:101243. https://doi.org/10.1016/j.pmedr.2020.101243.
Weaver, C.M., Lichtenstein, A.H., Kris-Etherton, P.M. 2020. Perspective: Guidelines needed for the conduct of human nutrition randomized controlled trials. Advances in Nutrition. 12(1):1-3. https://doi.org/10.1093/advances/nmaa083.
Foti, K., Foraker, R.E., Martyn-Nemeth, P., Anderson, C.A., Cook, N.R., Lichtenstein, A.H., De Ferranti, S.D., Rohm Young, D., Hivert, M., Ross, R., Deedwania, P., Whitsel, L.P., Appel, L.J. 2020. Evidence-based policy making for public health interventions in cardiovascular diseases: formally assessing the feasibility of clinical trials. Circulation: Cardiovascular Quality and Outcomes. 13:e006378. https://doi.org/10.1161/CIRCOUTCOMES.119.006378.
Zhang, X., Liu, Y., Li, S., Lichtenstein, A.H., Chen, S., Na, M., Veldheer, S., Xing, A., Wang, Y., Wu, S., Gao, X. 2021. Alcohol consumption and risk of cardiovascular disease, cancer and mortality: a prospective cohort study. Nutrition Journal. 20:13. https://doi.org/10.1186/s12937-021-00671-y.
Lamon-Fava, S., So, J., Mischoulon, D., Ziegler, T.R., Dunlop, B.W., Kinkead, B., Schettler, P.J., Nierenberg, A.A., Felger, J.C., Rao Maddipati, K., Fava, M., Rapaport, M.H. 2020. Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation. Prostaglandins Leukotrienes and Essential Fatty Acids. https://doi.org/10.1016/j.plefa.2020.102219.