Research Project: Diet and Cardiovascular Health

Location: Jean Mayer Human Nutrition Research Center On Aging

2020 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
Progress was made on all our 12-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, we completed the histopathology and immunohistochemistry of the blood vessel samples. This resulted in the observation that the Ossabaw pigs manifested a dyslipidemic and inflammatory profile accompanied by early-stage atherosclerosis when fed a Western-type diet compared with a heart healthy-type diet. Manifestations included higher concentrations of low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, HDL cholesterol, high-sensitivity C-reactive protein, tumor necrosis factor a, alkaline phosphatase, and alanine aminotransferase compared with pigs fed the heart healthy-type diet. In addition, the Western-type diet compared to the heart healthy-type diet resulted in a greater degree of atheromatous changes (macrophage infiltration, foam cells, fatty streaks) and lesion incidence. These responses were moderately reduced by statin therapy. Collectively, these data demonstrated that the Ossabaw pig represents a good translational model to examine mechanistic pathways of whole food–based dietary patterns on cardiometabolic health. With regard to Objective 1.A.2, working with collaborators at the Beltsville, Maryland, ARS and samples from this same pig study, using pathway analysis we found that in epicardial fat (type of fat overlaying the coronary artery thought to exacerbate atherosclerosis) there was an up-regulation of interferon signaling in response to both the Western-type diet and statin therapy. However, the expression signature of the interferon related differentially expressed genes in the epicardial fat did not add value to the histological assessment of atherosclerosis in the underlying coronary artery with respect to predicting response to dietary modification or statin therapy. These results suggest this interferon-mediated immune response was not associated with the presence of atherosclerosis. Under Sub-objective 1.B.1, we found that after participants consumed a standardized diet enriched in refined-carbohydrate, compared to simple- or unrefined-carbohydrate, they had larger mean abdominal subcutaneous adipocyte area and higher fasting serum LDL- and non HDL-cholesterol concentrations, but in contrast to our original hypothesis these diets had little effect on other cardiometabolic risk indicators. The findings raise the intriguing possibility that refined carbohydrate may have unique effects on cardiometabolic risk indicators distinct from simple- or unrefined-carbohydrate enriched diets. Under Objective 2.A.1, we found that supplementation with high-doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglyceride and raised LDL-C concentrations, which appeared to be mediated by cholesteryl ester transfer protein and lipoprotein lipase activities. Regarding Sub-objective 2.A.2 we found that EPA and DHA differently modulate the balance between pro- and anti-inflammatory cytokines in serum and blood monocytes in participants specifically recruited to have low-grade chronic inflammation. While DHA inhibited a broader range of pro- and anti-inflammatory cytokines, EPA preserved the anti-inflammatory interleukin-10 expression. For Sub-objective 2.B.1 we determined that EPA supplementation lowered lipoprotein- phospholipase A2 (PLA2) without adversely affecting LDL-C concentrations. Consistent with prior reports, Docosahexaenoic acid (DHA) supplementation decreased postprandial triglyceride concentrations, but raised LDL-C concentrations. With regard to HDL-induced cholesterol efflux, capacity was significantly correlated with the lipid-binding capacity of its major apolipoprotein, apoA-I.

Accomplishments

Review Publications
Niisuke, K., Horvath, K.V., Asztalos, B.F. 2018. Where next with HDL assays? Current Opinion in Lipidology. 29(4):293-298. https://doi.org/10.1097/MOL.0000000000000529.
Asztalos, B.F., Niisuke, K., Horvath, K.V. 2019. High-density lipoprotein: our elusive friend. Current Opinion in Lipidology. 30(4):314-319. https://doi.org/10.1097/MOL.0000000000000612.
Lichtenstein, A.H. 2019. Dietary fat and cardiovascular disease: ebb and flow over the last half century. Advances in Nutrition. 10(Suppl_4):S332-S339. https://doi.org/10.1093/advances/nmz024.
Ma, J., Rebholz, C.M., Braun, K.V., Reynolds, L.M., Aslibekyan, S., Xia, R., Biligowda, N.G., Huan, T., Liu, C., Mendelson, M.M., Joehanes, R., Hu, E.A., Vitolins, M.Z., Wood, A.C., Lohman, K., Ochoa-Rosales, C., Van Meurs, J., Uitterlinden, A., Liu, Y., Elhadad, M.A., Heier, M., Waldenberger, M., Peters, A., Colcino, E., Whitsel, E.A., Baldassari, A., Gharib, S.A., Sotoodehnia, N., Brody, J.A., Sitlani, C.M., Tanaka, T., Hill, W.D., Corley, J., Deary, I.J., Zhang, Y., Schottker, B., Brenner, H., Walker, M.E., Ye, S., Nguyen, S., Pankow, J., Demerath, E.W., Zheng, Y., Hou, L., Liang, L., Lichtenstein, A.H., Hu, F.B., Fornage, M., Voortman, T., Levy, D. 2020. Whole blood DNA methylation signatures of diet are associated with cardiovascular disease risk factors and all-cause mortality. Circulation: Genomic and Precision Medicine. https://doi.org/10.1161/CIRCGEN.119.002766.
Huang, N.K., Matthan, N.R., Galluccio, J.M., Shi, P., Lichtenstein, A.H., Mozaffarian, D. 2020. Supplementation with seabuckthorn oil augmented in 16:1n-7t increases serum trans-palmitoleic acid in metabolically healthy adults: a randomized crossover dose-escalation study. Journal of Nutrition. https://doi.org/10.1093/jn/nxaa060.
Coltell, O., Sorli, J.V., Asensio, E.M., Fernandez-Carrion, R., Barragan, R., Ortega-Azorin, C., Estruch, R., Gonzalez, J.I., Salas-Salvado, J., Lamon-Fava, S., Lichtenstein, A.H., Corella, D. 2019. Association between taste perception and adiposity in overweight or obese older subjects with metabolic syndrome and identification of novel taste-related genes. American Journal of Clinical Nutrition. 109(6):1709-1723. https://doi.org/10.1093/ajcn/nqz038.
Matthan, N.R., Wylie-Rosett, J., Xue, X., Gao, Q., Groisman-Perelstein, A.E., Diamantis, P.M., Ginsberg, M., Mossavar-Rahmani, Y., Barger, K., Lichtenstein, A.H. 2019. Effect of a family-based intervention on nutrient biomarkers, desaturase enzyme activities and cardiometabolic risk factors in overweight and obese children. Current Developments in Nutrition. 4(1). https://doi.org/10.1093/cdn/nzz138.
Rogriguez-Morato, J., Jayawardene, S., Dolnikowski, G., Galluccio, J., Lichtenstein, A.H., Matthan, N.R. 2020. Simplified method for the measurement of plasma alkylresorcinols: biomarker of whole grain intake. Rapid Communications in Mass Spectrometry. 34:e8805. https://doi.org/10.1002/rcm.8805.
Rebholz, C.M., Kim, H., Ma, J., Jacques, P.F., Levy, D., Lichtenstein, A.H. 2019. Diet indices reflecting changes to Dietary Guidelines for Americans from 1990 to 2015 are more strongly associated with risk of coronary heart disease. Current Developments in Nutrition. https://doi.org/10.1093/cdn/nzz123.
Lichtenstein, A.H. 2019. Optimal nutrition guidance for older adults. In: Rippe, J., editor. Lifestyle Medicine, 3rd edition. Boca Raton, FL: Taylor & Francis Group. p.125-134.
Wu, S., An, S., Li, W., Lichtenstein, A.H., Gao, J., Kris-Etherton, P.M., Wu, Y., Jin, C., Huang, S., Hu, F., Gao, X. 2019. Association of trajectory of cardiovascular health score and incident cardiovascular disease. JAMA Network Open. 2(5):e194758. https://doi.org/10.1001/jamanetworkopen.2019.4758.
Schultz, N.S., Chui, K., Economos, C.D., Lichtenstein, A.H., Volpe, S.L., Sacheck, J.M. 2019. A qualitative investigation of factors that influence school employee health behaviors: implications for wellness programming. Journal of School Health. 89(11):890-898. https://doi.org/10.1111/josh.12831.
Lichtenstein, A.H., Berger, S., Huggins, G.S., McCaffery, J.M., Jacques, P.F. 2019. Change in cardiometabolic risk factors associated with magnitude of weight regain 3 years after a 1-year intensive lifestyle intervention in type 2 diabetes mellitus: the Look AHEAD trial. Journal of the American Heart Association. 8(20). https://doi.org/10.1161/JAHA.118.010951.
Chung, S.T., Cravalho, C.K., Meyers, A.G., Courville, A.B., Yang, S., Matthan, N.R., Mabundo, L., Sampson, M.L., Ouwerkerk, R., Gharib, A.M., Lichtenstein, A.H., Remaley, A.T., Sumner, A.E. 2019. The triglyceride paradox is related to lipoprotein size, visceral adiposity and stearoyl-CoA desaturase activity in black vs. white women. Circulation Research. 126(1):94-108. https://doi.org/10.1161/CIRCRESAHA.119.315701.