Ann Christine Skulas-Ray
- Assistant Professor, Nutritional Sciences
- Assistant Professor, Physiological Sciences - GIDP
- Assistant Professor, Immunobiology
- Member of the Graduate Faculty
- Ph.D. Nutrition
- The Pennsylvania State University, University Park, Pennsylvania, United States
- NUTRITION INTERVENTIONS FOR IMPROVING CARDIOVASCULAR DISEASE RISK
- B.S. Biochemistry
- Worcester Polytechnic Institute, Worcester, Massachusetts, United States
- Regulation of Gene Expression by Ajulemic Acid
- University of Arizona, Tucson, Arizona (2015 - Ongoing)
- The Pennsylvania State University, University Park, Pennsylvania (2014 - 2015)
- UMass Medical School (2004 - 2005)
- Member, Graduate Interdisciplinary Program in Physiology
- University of Arizona, Fall 2017
- Member, Center on Aging
- University of Arizona, Spring 2017
inflammation, clinical research, upper-level nutrition
inflammation, health, wellness, supplements, clinical studies, phytochemicals, omega-3, plant bioactives, lipids, fatty acids, triglycerides, cholesterol, blood pressure, cardiovascular, vascular
Nutritional BiologyNSC 408 (Fall 2021)
Nutritional BiologyNSC 408 (Summer I 2021)
Nutritional BiologyNSC 408 (Spring 2021)
Nutrition and DiseaseNSC 610 (Fall 2020)
Nutritional BiologyNSC 408 (Fall 2020)
Nutritional BiologyNSC 408 (Summer I 2020)
Nutritional BiologyNSC 408 (Spring 2020)
Directed RsrchMCB 392 (Fall 2019)
DissertationNSC 920 (Fall 2019)
Introduction to ResearchMCB 795A (Fall 2019)
Honors ThesisNSC 498H (Summer I 2019)
DissertationNSC 920 (Spring 2019)
Honors ThesisNSC 498H (Spring 2019)
Nutritional BiologyNSC 408 (Spring 2019)
Honors Independent StudyNSC 499H (Fall 2018)
Honors ThesisNSC 498H (Fall 2018)
Introduction to ResearchMCB 795A (Fall 2018)
Nutrition and DiseaseNSC 610 (Fall 2018)
Nutritional BiologyNSC 408 (Summer I 2018)
Directed ResearchNSC 392 (Spring 2018)
Nutritional BiologyNSC 408 (Spring 2018)
Nutritional BiologyNSC 408 (Spring 2017)
- Richter, C. K., Skulas-Ray, A. C., & Kris-Etherton, P. M. (2016). Recommended Intake of Fish and Fish Oils Worldwide. In Fish and Fish Oils in Health and Disease(pp 27-47). Academic Press.
- Skulas-Ray, A. C. (2014). Dietary Patterns for the Prevention and Treatment of Cardiovascular Disease. In Clinical Lipidology: A Companion to Braunwald's Heart Disease (2nd ed)(pp 197-209). Philadelphia, PA: Elsevier.
- Skulas-Ray, A. C. (2014). Resolution of Inflammation. In Encyclopedia of Medical Immunology. New York, NY: Springer.
- Skulas-Ray, A. C. (2013). The Role of Diet in the Prevention and Treatment of Cardiovascular Disease. In Nutrition in the Prevention and Treatment of Chronic Disease(pp 541-567). Waltham, MA: Academic Press.
- Cave, C., Hein, N., Smith, L. M., Anderson-Berry, A., Richter, C. K., Bisselou, K. S., Appiah, A. K., Kris-Etherton, P., Skulas-Ray, A. C., Thompson, M., Nordgren, T. M., Hanson, C., & Thoene, M. (2020). Omega-3 Long-Chain Polyunsaturated Fatty Acids Intake by Ethnicity, Income, and Education Level in the United States: NHANES 2003-2014. Nutrients, 12(7).More infoAlthough there are many recognized health benefits for the consumption of omega-3 (n-3) long-chain polyunsaturated fatty acids (LCPUFA), intake in the United States remains below recommended amounts. This analysis was designed to provide an updated assessment of fish and n-3 LCPUFA intake (eicosapentaenoic (EPA), docosahexaenoic acid (DHA), and EPA+DHA) in the United States adult population, based on education, income, and race/ethnicity, using data from the 2003-2014 National Health and Nutrition Examination Survey (NHANES) ( = 44,585). Over this survey period, participants with less education and lower income had significantly lower n-3 LCPUFA intakes and fish intakes ( < 0.001 for all between group comparisons). N-3 LCPUFA intake differed significantly according to ethnicity ( < 0.001), with the highest intake of n-3 LCPUFA and fish in individuals in the "Other" category (including Asian Americans). Supplement use increased EPA + DHA intake, but only 7.4% of individuals consistently took supplements. Overall, n-3 LCPUFA intake in this study population was low, but our findings indicate that individuals with lower educational attainment and income are at even higher risk of lower n-3 LCPUFA and fish intake.
- Kris-Etherton, P. M., Richter, C. K., Bowen, K. J., Skulas-Ray, A. C., Jackson, K. H., Petersen, K. S., & Harris, W. S. (2019). Recent Clinical Trials Shed New Light on the Cardiovascular Benefits of Omega-3 Fatty Acids. Methodist DeBakey cardiovascular journal, 15(3), 171-178.More infoThree recent clinical trials have demonstrated the benefits of marine omega-3 fatty acids on cardiovascular disease end points. In the Vitamin D and Omega-3 Trial (VITAL), 840 mg/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) resulted in a 28% reduced risk for heart attacks, 50% reduced risk for fatal heart attacks, and 17% reduced risk for total coronary heart disease events. In the ASCEND trial (A Study of Cardiovascular Events in Diabetes), cardiovascular disease death was significantly reduced by 19% with 840 mg/d of EPA and DHA. However, the primary composite end points were not significantly reduced in either study. In REDUCE-IT (the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), there was a 25% decrease in the primary end point of major cardiovascular events with 4 g/d EPA (icosapent ethyl) in patients with elevated triglycerides (135-499 mg/dL) who also were taking a statin drug. For clinical practice, we now have compelling evidence of the cardiovascular benefits of omega-3 fatty acids. The findings of REDUCE-IT provide a strong rationale for prescribing icosapent ethyl for patients with hypertriglyceridemia who are on a statin. For primary prevention, the goal is to increase the population intake of omega-3 fatty acids to levels currently recommended, which translates to consuming at least one to two servings of fish/seafood per week. For individuals who prefer taking omega-3 fatty acid supplements, recent findings from clinical trials support the benefits for primary prevention.
- Richter, C. K., Bisselou, K. S., Nordgren, T. M., Smith, L., Appiah, A. K., Hein, N., Anderson-Berry, A., Kris-Etherton, P., Hanson, C., & Skulas-Ray, A. C. (2019). n-3 Docosapentaenoic Acid Intake and Relationship with Plasma Long-Chain n-3 Fatty Acid Concentrations in the United States: NHANES 2003-2014. Lipids, 54(4), 221-230.More infoThe long-chain n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a crucial role in health, but previous National Health and Nutrition Examination Survey (NHANES) analyses have shown that EPA and DHA intake in the United States is far below recommendations (~250-500 mg/day EPA + DHA). Less is known about docosapentaenoic acid (DPA), the metabolic intermediate of EPA and DHA; however, evidence suggests DPA may be an important contributor to long-chain n-3 fatty acid intake and impart unique benefits. We used NHANES 2003-2014 data (n = 45,347) to assess DPA intake and plasma concentrations, as well as the relationship between intake and plasma concentrations of EPA, DPA, and DHA. Mean DPA intake was 22.3 ± 0.8 mg/day from 2013 to 2014, and increased significantly over time (p < 0.001), with the lowest values from 2003 to 2004 (16.2 ± 1.2 mg/day). DPA intake was higher in adults (20-55 years) and seniors (55+ years) compared to younger individuals. In regression analyses, DPA intake was a significant predictor of plasma EPA (β = 138.5; p < 0.001) and DHA (β = 318.9; p < 0.001). Plasma DPA was predicted by EPA and DHA intake (β = 13.15; p = 0.001 and β = 7.4; p = 0.002), but not dietary DPA (p = 0.3). This indicates that DPA intake is not a good marker of plasma DPA status (or vice versa), and further research is needed to understand the factors that affect the interconversion of EPA and DPA. These findings have implications for future long-chain n-3 fatty acids dietary recommendations.
- Skulas-Ray, A. C., Wilson, P. W., Harris, W. S., Brinton, E. A., Kris-Etherton, P. M., Richter, C. K., Jacobson, T. A., Engler, M. B., Miller, M., Robinson, J. G., Blum, C. B., Rodriguez-Leyva, D., de Ferranti, S. D., Welty, F. K., & , A. H. (2019). Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation, 140(12), e673-e691.More infoHypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.
- Thompson, M., Hein, N., Hanson, C., Smith, L. M., Anderson-Berry, A., Richter, C. K., Stessy Bisselou, K., Kusi Appiah, A., Kris-Etherton, P., Skulas-Ray, A. C., & Nordgren, T. M. (2019). Omega-3 Fatty Acid Intake by Age, Gender, and Pregnancy Status in the United States: National Health and Nutrition Examination Survey 2003⁻2014. Nutrients, 11(1).More infoDespite the importance of n-3 fatty acids for health, intakes remain below recommended levels. The objective of this study was to provide an updated assessment of fish and n-3 fatty acid intake (i.e., eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and EPA+DHA) in the United States using the 2003⁻2014 National Health and Nutrition Examination Survey (NHANES) data ( = 45,347)). Over this survey period, toddlers, children, and adolescents (aged 1⁻19) had significantly lower n-3 fatty acid intake ( < 0.001) compared to adults and seniors, which remained significant after adjusting for caloric intake. Females demonstrated lower n-3 fatty acid intake than males ( < 0.001), with adult and senior women having significantly lower intakes compared to men in the same age categories ( < 0.001) after adjustment for energy intake. Women also consumed less fish than men (5.8 versus 6.1 servings/month, < 0.001). The estimated intakes of n-3 fatty acids in pregnant women did not differ from non-pregnant women ( = 0.6 for EPA+DHA), although pregnant women reported consuming less high n-3 fatty acid-containing fish than non-pregnant women (1.8 versus 2.6 servings/month, < 0.001). Our findings indicate that subgroups of the population may be at higher risk of n-3 fatty acid intakes below recommended levels.
- Tindall, A. M., Petersen, K. S., Skulas-Ray, A. C., Richter, C. K., Proctor, D. N., & Kris-Etherton, P. M. (2019). Replacing Saturated Fat With Walnuts or Vegetable Oils Improves Central Blood Pressure and Serum Lipids in Adults at Risk for Cardiovascular Disease: A Randomized Controlled-Feeding Trial. Journal of the American Heart Association, 8(9), e011512.More infoBackground Walnuts have beneficial effects on cardiovascular risk factors, but it is unclear whether these effects are attributable to the fatty acid ( FA ) content, including α-linolenic acid ( ALA ), and/or bioactives. Methods and Results A randomized, controlled, 3-period, crossover, feeding trial was conducted in individuals at risk for cardiovascular disease (n=45). Following a 2-week standard Western diet run-in (12% saturated FAs [ SFA ], 7% polyunsaturated FAs, 12% monounsaturated FAs), participants consumed 3 isocaloric weight-maintenance diets for 6 weeks each: a walnut diet ( WD ; 7% SFA , 16% polyunsaturated FAs, 3% ALA , 9% monounsaturated FAs); a walnut FA -matched diet; and an oleic acid-replaced- ALA diet (7% SFA , 14% polyunsaturated FAs, 0.5% ALA , 12% monounsaturated FAs), which substituted the amount of ALA from walnuts in the WD with oleic acid. This design enabled evaluation of the effects of whole walnuts versus constituent components. The primary end point, central systolic blood pressure, was unchanged, and there were no significant changes in arterial stiffness. There was a treatment effect ( P=0.04) for central diastolic blood pressure; there was a greater change following the WD versus the oleic acid-replaced-ALA diet (-1.78±1.0 versus 0.15±0.7 mm Hg, P=0.04). There were no differences between the WD and the walnut fatty acid-matched diet (-0.22±0.8 mm Hg, P=0.20) or the walnut FA-matched and oleic acid-replaced-ALA diets ( P=0.74). The WD significantly lowered brachial and central mean arterial pressure. All diets lowered total cholesterol, LDL (low-density lipoprotein) cholesterol, HDL (high-density lipoprotein) cholesterol, and non- HDL cholesterol. Conclusions Cardiovascular benefits occurred with all moderate-fat, high-unsaturated-fat diets. As part of a low- SFA diet, the greater improvement in central diastolic blood pressure following the WD versus the oleic acid-replaced-ALA diet indicates benefits of walnuts as a whole-food replacement for SFA . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT02210767.
- Walker, R. E., Jackson, K. H., Tintle, N. L., Shearer, G. C., Bernasconi, A., Masson, S., Latini, R., Heydari, B., Kwong, R. Y., Flock, M., Kris-Etherton, P. M., Hedengran, A., Carney, R. M., Skulas-Ray, A., Gidding, S. S., Dewell, A., Gardner, C. D., Grenon, S. M., Sarter, B., , Newman, J. W., et al. (2019). Predicting the effects of supplemental EPA and DHA on the omega-3 index. The American journal of clinical nutrition, 110(4), 1034-1040.More infoSupplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear.
- Bowen, K. J., Richter, C. K., Skulas-Ray, A. C., Mozaffarian, D., & Kris-Etherton, P. M. (2018). Projected Long-Chain n-3 Fatty Acid Intake Post-Replacement of Vegetables Oils with Stearidonic Acid-Modified Varieties: Results from a National Health and Nutrition Examination Survey 2003-2008 Analysis. Lipids, 53(10), 961-970.More infoEicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake is well below the amount recommended by the 2015-2020 Dietary Guidelines for Americans (0.25 g/day), supporting the need for alternative dietary sources. Stearidonic acid (SDA)-enriched soybeans were bioengineered to endogenously synthesize SDA, which can be readily metabolized to EPA in humans; thus, incorporating the derived SDA-enriched soybean oil into the food supply is a potential strategy to increase EPA. We performed a dietary modeling exercise using National Health and Nutrition Examination Survey 2003-2008 repeat 24-h dietary recall data (n = 24,621) to estimate the potential contribution of SDA-enriched oils to total long-chain n-3 fatty acid intake (defined as EPA + DHA + EPA-equivalents) following two hypothetical scenarios: (1) replacement of regular soybean oil with SDA soybean oil and (2) replacement of four common vegetable oils (corn, canola, cottonseed, and soybean) with respective SDA-modified varieties. Estimated median daily intakes increased from 0.11 to 0.16 g/day post-replacement of regular soybean oil with SDA-modified soybean oil, and to 0.21 g/day post-replacement of four oils with SDA-modified oil; the corresponding mean intakes were 0.17, 0.27, and 0.44 g/day, respectively. The percent of the population who met the 0.25 g/day recommendation increased from at least 10% to at least 30% and 40% in scenarios 1 and 2, respectively. Additional strategies are needed to ensure the majority of the US population achieve EPA and DHA recommendations, and should be assessed using methods designed to estimate the distribution of usual intake of these episodically consumed nutrients.
- Norris, P. C., Skulas-Ray, A. C., Riley, I., Richter, C. K., Kris-Etherton, P. M., Jensen, G. L., Serhan, C. N., & Maddipati, K. R. (2018). Identification of specialized pro-resolving mediator clusters from healthy adults after intravenous low-dose endotoxin and omega-3 supplementation: a methodological validation. Scientific reports, 8(1), 18050.More infoSpecialized pro-resolving mediator(s) (SPMs) are produced from the endogenous ω-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and accelerate resolution of acute inflammation. We identified specific clusters of SPM in human plasma and serum using LC-MS/MS based lipid mediator (LM) metabololipidomics in two separate laboratories for inter-laboratory validation. The human plasma cluster consisted of resolvin (Rv)E1, RvD1, lipoxin (LX)B, 18-HEPE, and 17-HDHA, and the human serum cluster consisted of RvE1, RvD1, AT-LXA, 18-HEPE, and 17-HDHA. Human plasma and serum SPM clusters were increased after ω-3 supplementation (triglyceride dietary supplements or prescription ethyl esters) and low dose intravenous lipopolysaccharide (LPS) challenge. These results were corroborated by parallel determinations with the same coded samples in a second, separate laboratory using essentially identical metabololipidomic operational parameters. In these healthy subjects, two ω-3 supplementation protocols (Study A and Study B) temporally increased the SPM cluster throughout the endotoxin-challenge time course. Study A and Study B were randomized and Study B also had a crossover design with placebo and endotoxin challenge. Endotoxin challenge temporally regulated lipid mediator production in human serum, where pro-inflammatory eicosanoid (prostaglandins and thromboxane) concentrations peaked by 8 hours post-endotoxin and SPMs such as resolvins and lipoxins initially decreased by 2 h and were then elevated at 24 hours. In healthy adults given ω-3 supplementation, the plasma concentration of the SPM cluster (RvE1, RvD1, LXB, 18-HEPE, and 17-HDHA) peaked at two hours post endotoxin challenge. These results from two separate laboratories with the same samples provide evidence for temporal production of specific pro-resolving mediators with ω-3 supplementation that together support the role of SPM in vivo in inflammation-resolution in humans.
- Richter, C. K., Bowen, K. J., Mozaffarian, D., Kris-Etherton, P. M., & Skulas-Ray, A. C. (2017). Total Long-Chain n-3 Fatty Acid Intake and Food Sources in the United States Compared to Recommended Intakes: NHANES 2003-2008. Lipids, 52(11), 917-927.More infoThe American Heart Association recommends consuming fish (particularly oily fish) at least two times per week, which would provide ≈ 0.5 g/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) for cardiovascular disease risk reduction. Previous analyses indicate that this recommendation is not being met; however, few studies have assessed different ethnicities, subpopulations requiring additional n-3 fatty acid intake (i.e., children and pregnant and/or lactating women), or deciles of intake. Data from the National Health and Nutrition Examination Survey 2003-2008 was used to assess n-3 fatty acid intake from foods and supplements in the US population, according to age, sex, and ethnicity. A unique "EPA equivalents" factor, which accounts for potential conversion of shorter-chain n-3 fatty acids, was used to calculate total long-chain n-3 fatty acid intake. Data are reported for 24,621 individuals. More than 90% consumed less than the recommended 0.5 g/day from food sources (median = 0.11 g/day; mean = 0.17 g/day). Among the top 15% of n-3 fatty acid consumers, fish was the largest dietary contributor (71.2%). Intake was highest in men aged 20 years or more, and lowest in children and women who are or may become pregnant and/or are lactating. Among ethnicities, intake was lowest in Mexican-Americans. Only 6.2% of the total population reported n-3 fatty acid supplement use, and this did not alter median daily intake. Additional strategies are needed to increase awareness of health benefits (particularly among Mexican-Americans and women of childbearing age) and promote consumption of oily fish or alternative dietary sources to meet current recommendations.
- Richter, C. K., Skulas-Ray, A. C., Fleming, J. A., Link, C. J., Mukherjea, R., Krul, E. S., & Kris-Etherton, P. M. (2017). Effects of isoflavone-containing soya protein on ex vivo cholesterol efflux, vascular function and blood markers of CVD risk in adults with moderately elevated blood pressure: a dose-response randomised controlled trial. The British journal of nutrition, 117(10), 1403-1413.More infoEmerging CVD risk factors (e.g. HDL function and central haemodynamics) may account for residual CVD risk experienced by individuals who meet LDL-cholesterol and blood pressure (BP) targets. Recent evidence suggests that these emerging risk factors can be modified by polyphenol-rich interventions such as soya, but additional research is needed. This study was designed to investigate the effects of an isoflavone-containing soya protein isolate (delivering 25 and 50 g/d soya protein) on HDL function (i.e. ex vivo cholesterol efflux), macrovascular function and blood markers of CVD risk. Middle-aged adults (n 20; mean age=51·6 (sem 6·6) years) with moderately elevated brachial BP (mean systolic BP=129 (sem 9) mmHg; mean diastolic BP=82·5 (sem 8·4) mmHg) consumed 0 (control), 25 and 50 g/d soya protein in a randomised cross-over design. Soya and control powders were consumed for 6 weeks each with a 2-week compliance break between treatment periods. Blood samples and vascular function measures were obtained at baseline and following each supplementation period. Supplementation with 50 g/d soya protein significantly reduced brachial diastolic BP (-2·3 mmHg) compared with 25 g/d soya protein (Tukey-adjusted P=0·03) but not the control. Soya supplementation did not improve ex vivo cholesterol efflux, macrovascular function or other blood markers of CVD risk compared with the carbohydrate-matched control. Additional research is needed to clarify whether effects on these CVD risk factors depend on the relative health of participants and/or equol producing capacity.
- Richter, C. K., Skulas-Ray, A. C., Gaugler, T. L., Lambert, J. D., Proctor, D. N., & Kris-Etherton, P. M. (2016). Incorporating freeze-dried strawberry powder into a high-fat meal does not alter postprandial vascular function or blood markers of cardiovascular disease risk: a randomized controlled trial. The American journal of clinical nutrition.More infoPostprandial dysmetabolism-an exaggerated spike in triglycerides, glucose, and insulin-increases cardiovascular disease risk by inducing oxidative stress, inflammation, and endothelial dysfunction. Polyphenol-rich foods may blunt these effects when they are incorporated into a high-fat, calorie-dense meal. Strawberries are a rich source of polyphenols, but there is little research on their postprandial effects.
- Kim, J., Moore, D. J., Maurer, D. G., Kim-Shapiro, D. B., Basu, S., Flanagan, M. P., Skulas-Ray, A. C., Kris-Etherton, P., & Proctor, D. N. (2015). Acute dietary nitrate supplementation does not augment submaximal forearm exercise hyperemia in healthy young men. Applied physiology, nutrition, and metabolism = Physiologie appliquée, nutrition et métabolisme, 40(2), 122-8.More infoDespite the popularity of dietary nitrate supplementation and the growing evidence base of its potential ergogenic and vascular health benefits, there is no direct information about its effects on exercising limb blood flow in humans. We hypothesized that acute dietary nitrate supplementation from beetroot juice would augment the increases in forearm blood flow, as well as the progressive dilation of the brachial artery, during graded handgrip exercise in healthy young men. In a randomized, double-blind, placebo-controlled crossover study, 12 young (22 ± 2 years) healthy men consumed a beetroot juice (140 mL Beet-It Sport, James White Juice Company) that provided 12.9 mmol (0.8 g) of nitrate or placebo (nitrate-depleted Beet-It Sport) on 2 study visits. At 3 h postconsumption, brachial artery diameter, flow, and blood velocity were measured (Doppler ultrasound) at rest and during 6 exercise intensities. Nitrate supplementation raised plasma nitrate (19.5-fold) and nitrite (1.6-fold) concentrations, and lowered resting arterial pulse wave velocity (PWV) versus placebo (all p < 0.05), indicating absorption, conversion, and a biological effect of this supplement. The supplement-associated lowering of PWV was also negatively correlated with plasma nitrite (r = -0.72, p = 0.0127). Despite these systemic effects, nitrate supplementation had no effect on brachial artery diameter, flow, or shear rates at rest (all p ≥ 0.28) or during any exercise workload (all p ≥ 0.18). These findings suggest that acute dietary nitrate supplementation favorably modifies arterial PWV, but does not augment blood flow or brachial artery vasodilation during nonfatiguing forearm exercise in healthy young men.
- McCrea, C. E., West, S. G., Kris-Etherton, P. M., Lambert, J. D., Gaugler, T. L., Teeter, D. L., Sauder, K. A., Gu, Y., Glisan, S. L., & Skulas-Ray, A. C. (2015). Effects of culinary spices and psychological stress on postprandial lipemia and lipase activity: results of a randomized crossover study and in vitro experiments. Journal of translational medicine, 13, 7.More infoData suggest that culinary spices are a potent, low-calorie modality for improving physiological responses to high fat meals. In a pilot study (N = 6 healthy adults), we showed that a meal containing a high antioxidant spice blend attenuated postprandial lipemia by 30% compared to a low spice meal. Our goal was to confirm this effect in a larger sample and to consider the influence of acute psychological stress on fat metabolism. Further, we used in vitro methods to evaluate the inhibitory effect of spices on digestive enzymes.
- Richter, C. K., Skulas-Ray, A. C., Champagne, C. M., & Kris-Etherton, P. M. (2015). Plant Protein and Animal Proteins: Do They Differentially Affect Cardiovascular Disease Risk?. Advances in nutrition (Bethesda, Md.), 6(6), 712-28.More infoProteins from plant-based compared with animal-based food sources may have different effects on cardiovascular disease (CVD) risk factors. Numerous epidemiologic and intervention studies have evaluated their respective health benefits; however, it is difficult to isolate the role of plant or animal protein on CVD risk. This review evaluates the current evidence from observational and intervention studies, focusing on the specific protein-providing foods and populations studied. Dietary protein is derived from many food sources, and each provides a different composite of nonprotein compounds that can also affect CVD risk factors. Increasing the consumption of protein-rich foods also typically results in lower intakes of other nutrients, which may simultaneously influence outcomes. Given these complexities, blanket statements about plant or animal protein may be too general, and greater consideration of the specific protein food sources and the background diet is required. The potential mechanisms responsible for any specific effects of plant and animal protein are similarly multifaceted and include the amino acid content of particular foods, contributions from other nonprotein compounds provided concomitantly by the whole food, and interactions with the gut microbiome. Evidence to date is inconclusive, and additional studies are needed to further advance our understanding of the complexity of plant protein vs. animal protein comparisons. Nonetheless, current evidence supports the idea that CVD risk can be reduced by a dietary pattern that provides more plant sources of protein compared with the typical American diet and also includes animal-based protein foods that are unprocessed and low in saturated fat.
- Skulas-Ray, A. C. (2015). Omega-3 fatty acids and inflammation: a perspective on the challenges of evaluating efficacy in clinical research. Prostaglandins & other lipid mediators, 116-117, 104-11.More infoChronic inflammation is a common underpinning of many diseases. There is a strong pre-clinical evidence base demonstrating the efficacy of omega-3 fatty acids for ameliorating inflammation and thereby reducing disease burden. Clinically, C-reactive protein (CRP) serves as both a reliable marker for monitoring inflammation and a modifiable endpoint for studies of anti-inflammatory pharmaceuticals. However, clinical omega-3 fatty acid supplementation trials have not replicated pre-clinical findings in terms of consistent CRP reductions. Methodological differences present numerous challenges in translating pre-clinical evidence to clinical results. It is crucial that future clinical nutrition research clearly distinguish between the reversal of established inflammation and preventing the development of inflammation. Future clinical studies evaluating the ability of omega-3 fatty acids to attenuate an excessive inflammatory response, may be advanced by employing new statistical approaches and utilizing models of induced inflammation, such as low-dose human endotoxemia.
- Skulas-Ray, A. C., Alaupovic, P., Kris-Etherton, P. M., & West, S. G. (2015). Dose-response effects of marine omega-3 fatty acids on apolipoproteins, apolipoprotein-defined lipoprotein subclasses, and Lp-PLA2 in individuals with moderate hypertriglyceridemia. Journal of clinical lipidology, 9(3), 360-7.More infoApolipoprotein (apo) distribution and lipoprotein (Lp)-associated markers of inflammation, such as lipoprotein-associated phospholipase A2 (Lp-PLA2), influence the atherogenicity of circulating lipids and lipoproteins. Little evidence exists regarding the dose-response effects of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on apos, apo-defined Lps, and Lp-PLA2.
- Skulas-Ray, A. C., Flock, M. R., Richter, C. K., Harris, W. S., West, S. G., & Kris-Etherton, P. M. (2015). Red Blood Cell Docosapentaenoic Acid (DPA n-3) is Inversely Associated with Triglycerides and C-reactive Protein (CRP) in Healthy Adults and Dose-Dependently Increases Following n-3 Fatty Acid Supplementation. Nutrients, 7(8), 6390-404.More infoThe role of the long-chain omega-3 (n-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in lipid metabolism and inflammation has been extensively studied; however, little is known about the relationship between docosapentaenoic acid (DPA, 22:5 n-3) and inflammation and triglycerides (TG). We evaluated whether n-3 DPA content of red blood cells (RBC) was associated with markers of inflammation (interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and C-reactive protein (CRP) and fasting TG prior to n-3 supplementation in two studies (Study 1: n = 115, aged 20-44 years, body mass index (BMI) 20-30 kg/m2, TG = 34-176 mg/dL; Study 2: n = 28, aged 22-65 years, BMI 24-37 kg/m2, TG = 141-339 mg/dL). We also characterized the dose-response effects of n-3 fatty acid supplementation on RBC n-3 DPA after five months of supplementation with fish oil (Study 1: 0, 300, 600, 900, and 1800 mg/day EPA + DHA) and eight weeks of prescription n-3 ethyl esters (Study 2: 0, 850, and 3400 mg/day EPA + DHA). In Study 1, RBC n-3 DPA was inversely correlated with CRP (R2 = 36%, p < 0.001) and with fasting TG (r = -0.30, p = 0.001). The latter finding was replicated in Study 2 (r = -0.33, p = 0.04). In both studies, n-3 supplementation significantly increased RBC n-3 DPA dose-dependently. Relative increases were greater for Study 1, with increases of 29%-61% vs. 14%-26% for Study 2. The associations between RBC n-3 DPA, CRP, and fasting TG may have important implications for the prevention of atherosclerosis and chronic inflammatory diseases and warrant further study.
- Flock, M. R., Skulas-Ray, A. C., Harris, W. S., Gaugler, T. L., Fleming, J. A., & Kris-Etherton, P. M. (2014). Effects of supplemental long-chain omega-3 fatty acids and erythrocyte membrane fatty acid content on circulating inflammatory markers in a randomized controlled trial of healthy adults. Prostaglandins, leukotrienes, and essential fatty acids, 91(4), 161-8.More infoThe long-chain omega-3 polyunsaturated (n-3 PUFA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), may have anti-inflammatory effects. We evaluated the dose-response effect of EPA+DHA supplementation on circulating TNF-α, IL-6, and CRP and explored associations between red blood cell (RBC) membrane PUFA content and TNF-α, IL-6, and CRP. Young adults with low fish intake (n=116) received one of five doses (0, 300, 600, 900, or 1,800 mg/d EPA+DHA) for 5 months. There were no significant effects of supplemental EPA+DHA on IL-6 or CRP; however, there was a marginal treatment effect for TNF-α (p
- Richter, C. K., Skulas-Ray, A. C., & Kris-Etherton, P. M. (2014). Recent findings of studies on the Mediterranean diet: what are the implications for current dietary recommendations?. Endocrinology and metabolism clinics of North America, 43(4), 963-80.More infoThere is evidence from epidemiologic studies and clinical trials demonstrating that the Mediterranean dietary pattern reduces the risk of many chronic diseases, including cardiovascular disease (CVD), and the attendant risk factors. A Mediterranean-style diet reflects most food and nutrient goals in current dietary guidelines. Minor modifications to reduce sodium and saturated fat intake can be made to further meet recommendations. Including the Mediterranean diet in the list of recommended evidence-based dietary patterns offers an additional strategy for improving dietary habits, which may help individuals achieve better long-term adherence to dietary guidelines and sustain optimal reductions in CVD risk.
- West, S. G., McIntyre, M. D., Piotrowski, M. J., Poupin, N., Miller, D. L., Preston, A. G., Wagner, P., Groves, L. F., & Skulas-Ray, A. C. (2014). Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults. The British journal of nutrition, 111(4), 653-61.More infoThe consumption of cocoa and dark chocolate is associated with a lower risk of CVD, and improvements in endothelial function may mediate this relationship. Less is known about the effects of cocoa/chocolate on the augmentation index (AI), a measure of vascular stiffness and vascular tone in the peripheral arterioles. We enrolled thirty middle-aged, overweight adults in a randomised, placebo-controlled, 4-week, cross-over study. During the active treatment (cocoa) period, the participants consumed 37 g/d of dark chocolate and a sugar-free cocoa beverage (total cocoa = 22 g/d, total flavanols (TF) = 814 mg/d). Colour-matched controls included a low-flavanol chocolate bar and a cocoa-free beverage with no added sugar (TF = 3 mg/d). Treatments were matched for total fat, saturated fat, carbohydrates and protein. The cocoa treatment significantly increased the basal diameter and peak diameter of the brachial artery by 6% (+2 mm) and basal blood flow volume by 22%. Substantial decreases in the AI, a measure of arterial stiffness, were observed in only women. Flow-mediated dilation and the reactive hyperaemia index remained unchanged. The consumption of cocoa had no effect on fasting blood measures, while the control treatment increased fasting insulin concentration and insulin resistance (P= 0·01). Fasting blood pressure (BP) remained unchanged, although the acute consumption of cocoa increased resting BP by 4 mmHg. In summary, the high-flavanol cocoa and dark chocolate treatment was associated with enhanced vasodilation in both conduit and resistance arteries and was accompanied by significant reductions in arterial stiffness in women.
- Blumberg, J. B., Camesano, T. A., Cassidy, A., Kris-Etherton, P., Howell, A., Manach, C., Ostertag, L. M., Sies, H., Skulas-Ray, A., & Vita, J. A. (2013). Cranberries and their bioactive constituents in human health. Advances in nutrition (Bethesda, Md.), 4(6), 618-32.More infoRecent observational and clinical studies have raised interest in the potential health effects of cranberry consumption, an association that appears to be due to the phytochemical content of this fruit. The profile of cranberry bioactives is distinct from that of other berry fruit, being rich in A-type proanthocyanidins (PACs) in contrast to the B-type PACs present in most other fruit. Basic research has suggested a number of potential mechanisms of action of cranberry bioactives, although further molecular studies are necessary. Human studies on the health effects of cranberry products have focused principally on urinary tract and cardiovascular health, with some attention also directed to oral health and gastrointestinal epithelia. Evidence suggesting that cranberries may decrease the recurrence of urinary tract infections is important because a nutritional approach to this condition could lower the use of antibiotic treatment and the consequent development of resistance to these drugs. There is encouraging, but limited, evidence of a cardioprotective effect of cranberries mediated via actions on antioxidant capacity and lipoprotein profiles. The mixed outcomes from clinical studies with cranberry products could result from interventions testing a variety of products, often uncharacterized in their composition of bioactives, using different doses and regimens, as well as the absence of a biomarker for compliance to the protocol. Daily consumption of a variety of fruit is necessary to achieve a healthy dietary pattern, meet recommendations for micronutrient intake, and promote the intake of a diversity of phytochemicals. Berry fruit, including cranberries, represent a rich source of phenolic bioactives that may contribute to human health.
- Flock, M. R., Skulas-Ray, A. C., Harris, W. S., Etherton, T. D., Fleming, J. A., & Kris-Etherton, P. M. (2013). Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. Journal of the American Heart Association, 2(6), e000513.More infoThe erythrocyte membrane content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which constitutes the omega-3 index (O3I), predicts cardiovascular disease mortality. The amount of EPA+DHA needed to achieve a target O3I is poorly defined, as are the determinants of the O3I response to a change in EPA+DHA intake. The objective of this study was to develop a predictive model of the O3I response to EPA+DHA supplementation in healthy adults, specifically identifying factors that determine the response.
- Sauder, K. A., Skulas-Ray, A. C., Campbell, T. S., Johnson, J. A., Kris-Etherton, P. M., & West, S. G. (2013). Effects of omega-3 fatty acid supplementation on heart rate variability at rest and during acute stress in adults with moderate hypertriglyceridemia. Psychosomatic medicine, 75(4), 382-9.More infoThis study examined the dose-dependent effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on heart rate variability (HRV) at rest and during standard laboratory stress tasks. We also investigated whether EPA + DHA supplementation was associated with changes in mood state.
- McCrea, C. E., Skulas-Ray, A. C., Chow, M., & West, S. G. (2012). Test-retest reliability of pulse amplitude tonometry measures of vascular endothelial function: implications for clinical trial design. Vascular medicine (London, England).More infoEndothelial dysfunction is an important outcome for assessing vascular health in intervention studies. However, reliability of the standard non-invasive method (flow-mediated dilation) is a significant challenge for clinical applications and multicenter trials. We evaluated the repeatability of pulse amplitude tonometry (PAT) to measure change in pulse wave amplitude during reactive hyperemia (Itamar Medical Ltd, Caesarea, Israel). Twenty healthy adults completed two PAT tests (mean interval = 19.5 days) under standardized conditions. PAT-derived measures of endothelial function (reactive hyperemia index, RHI) and arterial stiffness (augmentation index, AI) showed strong repeatability (intra-class correlations = 0.74 and 0.83, respectively). To guide future research, we also analyzed sample size requirements for a range of effect sizes. A crossover design powered at 0.90 requires 28 participants to detect a 15% change in RHI. Our study is the first to show that PAT measurements are repeatable in adults over an interval greater than 1 week.
- Sauder, K. A., Johnston, E. R., Skulas-Ray, A. C., Campbell, T. S., & West, S. G. (2012). Effect of meal content on heart rate variability and cardiovascular reactivity to mental stress. Psychophysiology, 49(4), 470-7.More infoLittle is known about transient effects of foods and nutrients on reactivity to mental stress. In a randomized crossover study of healthy adults (n=20), we measured heart rate variability (respiratory sinus arrhythmia), blood pressure, and other hemodynamic variables after three test meals varying in type and amount of fat. Measurements were collected at rest and during speech and cold pressor tasks. There were significant postmeal changes in resting diastolic blood pressure (-4%), cardiac output (+18%), total peripheral resistance (-17%), and interleukin-6 (-27%). Heart rate variability and hemodynamic reactivity to stress was not affected by meal content. We recommend that future studies control for time since last meal and continue to examine effects of meal content on heart rate variability.
- Skulas-Ray, A. C., Kris-Etherton, P. M., Harris, W. S., & West, S. G. (2012). Effects of marine-derived omega-3 fatty acids on systemic hemodynamics at rest and during stress: a dose-response study. Annals of behavioral medicine : a publication of the Society of Behavioral Medicine, 44(3), 301-8.More infoOmega-3 fatty acids reduced heart rate (HR) and blood pressure (BP) in some studies, but dose-response studies are rare, and little is known about underlying mechanisms.
- Skulas-Ray, A. C., Kris-Etherton, P. M., Harris, W. S., Vanden Heuvel, J. P., Wagner, P. R., & West, S. G. (2011). Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. The American journal of clinical nutrition, 93(2), 243-52.More infoEicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to reduce cardiovascular mortality at a dose of ≈1 g/d. Studies using higher doses have shown evidence of reduced inflammation and improved endothelial function. Few studies have compared these doses.
- Skulas-Ray, A. C., Kris-Etherton, P. M., Teeter, D. L., Chen, C. O., Vanden Heuvel, J. P., & West, S. G. (2011). A high antioxidant spice blend attenuates postprandial insulin and triglyceride responses and increases some plasma measures of antioxidant activity in healthy, overweight men. The Journal of nutrition, 141(8), 1451-7.More infoThere is much interest in the potential of dietary antioxidants to attenuate in vivo oxidative stress, but little characterization of the time course of plasma effects exists. Culinary spices have demonstrated potent in vitro antioxidant properties. The objective of this study was to examine whether adding 14 g of a high antioxidant spice blend to a 5060-kJ (1200 kcal) meal exerted significant postprandial effects on markers of plasma antioxidant status and metabolism. Healthy overweight men (n = 6) consumed a control and spiced meal in a randomized crossover design with 1 wk between testing sessions. Blood was sampled prior to the meal and at 30-min intervals for 3.5 h (total of 8 samples). Mixed linear models demonstrated a treatment × time interaction (P < 0.05) for insulin and TG, corresponding with 21 and 31% reductions in postprandial levels with the spiced meal, respectively. Adding spices to the meal significantly increased the ferric reducing antioxidant power, such that postprandial increases following the spiced meal were 2-fold greater than after the control meal (P = 0.009). The hydrophilic oxygen radical absorbance capacity (ORAC) of plasma also was increased by spices (P = 0.02). There were no treatment differences in glucose, total thiols, lipophilic ORAC, or total ORAC. The incorporation of spices into the diet may help normalize postprandial insulin and TG and enhance antioxidant defenses.
- Zurier, R. B., Sun, Y., George, K. L., Stebulis, J. A., Rossetti, R. G., Skulas, A., Judge, E., & Serhan, C. N. (2009). Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A4. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 23(5), 1503-9.More infoAjulemic acid (AjA), a synthetic nonpsychoactive cannabinoid, and lipoxin A(4) (LXA(4)), an eicosanoid formed from sequential actions of 5- and 15-lipoxygenases (LOX), facilitate resolution of inflammation. The purpose of this study was to determine whether the ability of AjA to limit the progress of inflammation might relate to an increase in LXA(4), a known anti-inflammatory and proresolving mediator. Addition of AjA (0-30 microM) in vitro to human blood and synovial cells increased production of LXA(4) (ELISA) 2- to 5-fold. Administration of AjA to mice with peritonitis resulted in a 25-75% reduction of cells invading the peritoneum, and a 7-fold increase in LXA(4) identified by mass spectrometry. Blockade of 12/15 LOX, which leads to LXA(4) synthesis via 15-HETE production, reduced (>90%) the ability of AjA to enhance production of LXA(4) in vitro. These results suggest that AjA and other agents that increase endogenous compounds that facilitate resolution of inflammation may be useful for conditions characterized by inflammation and tissue injury.
- Parker, J., Atez, F., Rossetti, R. G., Skulas, A., Patel, R., & Zurier, R. B. (2008). Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Rheumatology international, 28(7), 631-5.More infoInterleukin-6 (IL-6) is a multifunctional cytokine which contributes to inflammation and tissue injury in several diseases. Thus, inhibition of IL-6 production may be a useful strategy for treatment of patients with diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A synthetic nonpsychoactive cannabinoid, ajulemic acid (AjA), prevents joint damage in experimental arthritis. Results of experiments presented here indicate that addition of AjA (3-30 microM) to human monocyte derived macrophages in vitro reduces steady state levels of IL-6 mRNA and the subsequent secretion of IL-6 from LPS stimulated cells. Although AjA binds to and activates PPARgamma, its anti IL-6 effects are PPARgamma independent. These studies provide evidence to support the view that AjA may prove to be an effective, safe antiinflammatory agent.
- Skulas-Ray, A. C., West, S. G., Davidson, M. H., & Kris-Etherton, P. M. (2008). Omega-3 fatty acid concentrates in the treatment of moderate hypertriglyceridemia. Expert opinion on pharmacotherapy, 9(7), 1237-48.More infoModerate hypertriglyceridemia is fairly common, and elevated triglycerides are a risk factor for coronary heart disease. The omega-3 fatty acids EPA and DHA have been shown to lower triglycerides in many clinical studies. Prescription omega-3 fatty acid concentrates (P-OM3) are indicated for use in people with very high triglycerides (> 500 mg/dl). Current guidelines recommend that triglycerides should be less < 150 mg/dl.
- Skulas-Ray, A. C., Glickenstein, D. A., Silva Torres, G. E., Mayer, C., Thomson, C. A., Rojo-Wissar, D. M., & Haynes, P. L. (2019, June). Longer Sleep Duration Precedes Greater Water Intake at Breakfast. In Sleep, 42, A72.
- Skulas-Ray, A. C. (2018, March). 18-HEPE is Increased in Plasma of Healthyt Adults after Intravenous Low-Dose Endotoxin Challenge and n-3 Fatty Acid Supplementation. The 17th International Winter Eicosanoid Conference. Baltimore, MD.More infoInvited Talk
- Skulas-Ray, A. C. (2018, May). Docosapentaenoic acid (DPA) intake in the United States and relationship to plasma n-3 fatty acid concentrations: NHANES 2003-2014. The 13th Congress of the International Society for the Study of Fatty Acids and Lipids. Las Vegas, Nevada: Eicosanoid Research Foundation.