Development of a Multibiomarker Panel of Healthy Eating Index in United States Adults: A Machine Learning Approach.

BACKGROUND: Dietary and nutritional biomarkers are objective dietary assessment tools that will enable a more accurate and precise determination of diet-disease relations. However, the lack of established biomarker panels for dietary patterns is concerning, as dietary patterns continue to be the focus of dietary guidelines. OBJECTIVES: We aimed to develop and validate a panel of objective biomarkers that reflects the Healthy Eating Index (HEI) by applying machine learning approaches to the National Health and Nutrition Examination Survey data. METHODS: Cross-sectional population-based data (eligible criteria: age ≥20 y, not pregnant, no reported supplement use of dedicated vitamin A, D, E, or fish oils; n = 3481) from the 2003 to 2004 cycle of the NHANES were used to develop 2 multibiomarker panels of the HEI, 1 with (primary panel) and 1 without (secondary panel) plasma FAs. Up to 46 blood-based dietary and nutritional biomarkers (24 FAs, 11 carotenoids, and 11 vitamins) were included for variable selection using the least absolute shrinkage and selection operator controlling for age, sex, ethnicity, and education. The explanatory impact of selected biomarker panels was assessed by comparing the regression models with and without the selected biomarkers. In addition, 5 comparative machine learning models were constructed to validate the biomarker selection. RESULTS: The primary multibiomarker panel (8 FAs, 5 carotenoids, and 5 vitamins) significantly improved the explained variability of the HEI (adjusted R2 increased from 0.056 to 0.245). The secondary multibiomarker panel (8 vitamins and 10 carotenoids) had lesser predictive capabilities (adjusted R2 increased from 0.048 to 0.189). CONCLUSIONS: Two multibiomarker panels were developed and validated to reflect a healthy dietary pattern consistent with the HEI. Future research should seek to test these multibiomarker panels in randomly assigned trials and identify whether they have broad application in healthy dietary pattern assessment.

Early Life Determinants of Vascular Structure in Fetuses, Infants, Children, and Adolescents: A Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the association between early life exposures during the first 1000 days (conception to age 24 months) and aortic intima-media thickness (aIMT), an early indicator of cardiovascular disease (CVD) risk, in youths. STUDY DESIGN: The MEDLINE, Embase, Scopus, CINAHL, and Allied and Complementary Medicine databases were searched from inception to July 2021. Eligibility criteria included observational controlled studies in youths aged <20 years with risk factors/exposures during the first 1000 days and aIMT measurements (unadjusted mean ± SD). Outcome data were pooled using a random-effects meta-analysis. Meta-regression was used to investigate confounders. RESULTS: A total of 8657 articles were identified, of which 34 were included in our meta-analysis. The age of participants ranged from 22.9 weeks gestation in utero to 10.9 years. In the meta-analysis (n = 1220 cases, n = 1997 controls), the following factors were associated with greater aIMT: small for gestational age (SGA) status (14 studies, mean difference, 0.082 mm; 95% CI, 0.051-0.112; P < .001; I2 = 97%), intrauterine growth restriction (6 studies; mean difference, 0.198 mm, 95% CI, 0.088-0.309; P < .001; I2 = 97%), preeclampsia (2 studies; mean difference, 0.038 mm; 95% CI, 0.024-0.051; P < .001; I2 = 38%), and large for gestational age (LGA) status (3 studies; mean difference, 0.089 mm; 95% CI, 0.043-0.0136; P < .001; I2 = 93%). In meta-regression, older age (P < .001), higher prevalence of maternal smoking (P = .04), and SGA (P < .001) were associated with greater difference in aIMT in preterm participants compared with controls. Limitations included the high heterogeneity present in most meta-analyses and the scope of our meta-regression. CONCLUSIONS: Adverse early life exposures are associated with greater aIMT in youths, consistent with an increased risk for CVD later in life. Further research is needed to determine whether intervention and preventive strategies deliver clinical benefits to improve future cardiovascular health.

Epigenetic Aging in Early Life: Role of Maternal and Early Childhood Nutrition.

PURPOSE OF REVIEW: Early life presents a pivotal period during which nutritional exposures are more likely to cause epigenetic modifications, which may impact an individual's health during adulthood. This article reviews the current evidence regarding maternal and early childhood nutritional exposures and their role in epigenetic aging. RECENT FINDINGS: Maternal and early life consumption of diets higher in fiber, antioxidants, polyphenols, B vitamins, vitamin D, and ω-3 fatty acids is associated with slower epigenetic aging. Conversely, diets higher in glycemic load, fat, saturated fat, and ω-6 fatty acids demonstrate a positive association with epigenetic aging. Maternal and early life nutrition directly and indirectly influences epigenetic aging via changes in one-carbon metabolism, cardiometabolic health, and the microbiome. Clinical trials are warranted to determine the specific foods, dietary patterns, and dietary supplements that will normalize or lower epigenetic aging across the life course.

Maternal dietary fatty acid composition and newborn epigenetic aging-a geometric framework approach.

BACKGROUND: Maternal nutrition is associated with epigenetic and cardiometabolic risk factors in offspring. Research in humans has primarily focused on assessing the impact of individual nutrients. OBJECTIVES: We sought to assess the collective impact of maternal dietary MUFAs, PUFAs, and SFAs on epigenetic aging and cardiometabolic risk markers in healthy newborn infants using a geometric framework approach. METHODS: Body fatness (n = 162), aortic intima-media thickness (aIMT; n = 131), heart rate variability (n = 118), and epigenetic age acceleration (n = 124) were assessed in newborn infants. Maternal dietary intake was cross-sectionally assessed in the immediate postpartum period via a validated 80-item self-administered FFQ. Generalized additive models were used to explore interactive associations of nutrient intake, with results visualized as response surfaces. RESULTS: After adjustment for total energy intake, maternal age, gestational age, and sex there was a 3-way interactive association of MUFAs, PUFAs, and SFAs (P = 0.001) with newborn epigenetic aging. This suggests that the nature of each fat class association depends upon one another. Response surfaces revealed MUFAs were positively associated with newborn epigenetic age acceleration only at proportionately lower intakes of SFAs or PUFAs. We also demonstrate a potential beneficial association of omega-3 (n-3) PUFAs with newborn epigenetic age acceleration (P = 0.008). There was no significant association of fat class with newborn aIMT, heart rate variability, or body fatness. CONCLUSIONS: In this study, we demonstrated an association between maternal dietary fat class composition and epigenetic aging in newborns. Future research should consider other characteristics such as the source of maternal dietary fatty acids.

Medium-Chain Triglyceride Oil and Blood Lipids: A Systematic Review and Meta-Analysis of Randomized Trials.

BACKGROUND: Dietary saturated fat raises total cholesterol and LDL cholesterol levels. It is unclear whether these effects differ by the fatty acid chain lengths of saturated fats; particularly, it is unclear whether medium-chain fatty acids increase lipid levels. OBJECTIVES: We conducted a systematic review to determine the effects of medium-chain triglyceride (MCT) oil, consisting almost exclusively of medium-chain fatty acids (6:0-10:0), on blood lipids. METHODS: We searched Medline and Embase through March 2020 for randomized trials with a minimum 2-week intervention period that compared MCT oil with another fat or oil. Outcomes were total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. Included studies were restricted to adults above 18 years of age. Studies conducted in populations receiving enteral or parenteral nutrition were excluded. Data were pooled using a random-effects meta-analysis. RESULTS: Seven articles were included in the meta-analysis; LDL cholesterol and HDL cholesterol were reported in 6 studies. MCT oil intake did not affect total cholesterol (0.04 mmol/L; 95% CI, -0.11 to 0.20; I2 = 33.6%), LDL cholesterol (0.02 mmol/L; 95% CI, -0.13 to 0.17; I2 = 28.7%), or HDL cholesterol (-0.01 mmol/L; 95% CI, -0.10 to 0.09; I2 = 74.1%) levels, but did increase triglycerides (0.14 mmol/L; 95% CI, 0.01-0.27; I2 = 42.8%). Subgroup analyses showed that the effects of MCT oil on total cholesterol and LDL cholesterol differed based on the fatty acid profile of the control oil (Pinteraction = 0.003 and 0.008, respectively), with MCT oil increasing total cholesterol and LDL cholesterol when compared to a comparator consisting predominantly of unsaturated fatty acids, and with some evidence for reductions when compared to longer-chain SFAs. CONCLUSIONS: MCT oil does not affect total cholesterol, LDL cholesterol, or HDL cholesterol levels, but does cause a small increase in triglycerides.

Epigenetic aging in newborns: role of maternal diet.

BACKGROUND: Epigenetic aging is associated with higher risk of cardiovascular disease, cancer, and all-cause mortality and may be a mechanistic link between early-life exposures, such as maternal dietary characteristics during pregnancy, and risk of adult disease. OBJECTIVES: We sought to determine the early-life risk factors for newborn epigenetic aging, specifically maternal dietary macronutrient intake, and whether epigenetic aging is associated with cardiovascular health markers in the newborn. METHODS: Epigenetic age acceleration of 169 newborns was measured from saliva using the Horvath age calculator. Maternal diet during pregnancy was assessed using food-frequency questionnaires. RESULTS: Newborns with positive age acceleration were more likely to be female and have greater body fatness. Maternal intakes of saturated fat [6.2 wk epigenetic age acceleration (95% CI: 1.0, 11.3) per 5% of energy; P = 0.02] and monounsaturated fat [12.4 wk (95% CI: 4.2, 20.5) per 5% of energy; P = 0.003] were associated with higher epigenetic age acceleration in the newborn. The strongest association of individual fatty acids were for palmitoleic acid (25.3 wk; 95% CI: 11.4, 39.2; P = 0.0004), oleic acid (2.2 wk; 95% CI: 0.8, 3.6; P = 0.002), and palmitic acid (2.9 wk; 95% CI: 1.0, 4.9; P = 0.004) per 1% of energy intake. Vitamin D supplementation was associated with lower epigenetic age acceleration (-8.1 wk; 95% CI: -14.5, -1.7; P = 0.01). Epigenetic age acceleration was associated with aortic intima-media thickness in preterm infants [1.0 µm (95% CI: 0.2, 1.8) per week of epigenetic age acceleration; P = 0.01], but not among those born at term (P = 0.78). Epigenetic age acceleration was not associated with heart rate variability in either preterm or term born infants (both P > 0.2). CONCLUSIONS: This study provides evidence of maternal dietary characteristics that are associated with epigenetic aging in the offspring. Prospective intervention studies are required to determine whether such associations are causal.

ω-3 Fatty Acids, Impaired Fetal Growth, and Cardiovascular Risk: Nutrition as Precision Medicine.

Precision medicine refers to treatment or prevention strategies in a group of individuals identified by their phenotype or genotype. Dietary components or patterns may play an important role in precision medicine. There is emerging evidence to support a role for n-3 (ω-3) fatty acids in lowering blood pressure and reducing the extent of subclinical atherosclerosis in people born with impaired fetal growth, a group at increased risk of coronary artery disease partly due to an increased risk of hypertensive disorders. The evidence linking n-3 fatty acid intake with less atherosclerosis and lower blood pressure in people with impaired fetal growth has been derived from studies in young children, adolescents, and adults and has included dietary assessments by questionnaires and circulating biomarkers. Furthermore, results appear to be similar for shorter chain n-3 fatty acids from plant sources and long-chain n-3 fatty acids from marine sources. The general framework used to develop this evidence, consisting of hypothesis-driven analyses from observational studies and post hoc analyses of a randomized clinical trial, before a priori testing as a primary outcome in randomized trials, is presented and proposed as a potential model for the identification and development of dietary precision medicine strategies.

Marine Omega-3 Fatty Acids, Complications of Pregnancy and Maternal Risk Factors for Offspring Cardio-Metabolic Disease.

Marine omega-3 polyunsaturated fatty acids (n-3 PUFA) are important nutrients during periods of rapid growth and development in utero and infancy. Maternal health and risk factors play a crucial role in birth outcomes and subsequently offspring cardio-metabolic health. Evidence from observational studies and randomized trials have suggested a potential association of maternal intake of marine n-3 PUFAs during pregnancy with pregnancy and birth outcomes. However, there is inconsistency in the literature on whether marine n-3 PUFA supplementation during pregnancy can prevent maternal complications of pregnancy. This narrative literature review summarizes recent evidence on observational and clinical trials of marine n-3 PUFA intake on maternal risk factors and effects on offspring cardio-metabolic health. The current evidence generally does not support a role of maternal n-3 PUFA supplementation in altering the incidence of gestational diabetes, pregnancy-induced hypertension, or pre-eclampsia. It may be that benefits from marine n-3 PUFA supplementation are more pronounced in high-risk populations, such as women with a history of complications of pregnancy, or women with low marine n-3 PUFA intake. Discrepancies between studies may be related to differences in study design, dosage, fatty acid interplay, and length of treatment. Further prospective double-blind studies are needed to clarify the impact of long-chain marine n-3 PUFAs on risk factors for cardio-metabolic disease in the offspring.

Association between Micronutrients Intake/Status and Carotid Intima Media Thickness: A Systematic Review.

BACKGROUND: Carotid intima media thickness (IMT) is a noninvasive marker of the extent and severity of subclinical atherosclerosis. Micronutrient intake may affect atherosclerosis and play a major role in the development of cardiovascular diseases (CVDs). OBJECTIVE: The primary aim of this review was to synthesize the evidence regarding the association between carotid IMT and selected micronutrients. METHOD: The authors searched PubMed, Cochrane, and EMBASE databases from inception to June 2016 for selected micronutrients, CVD, carotid IMT, and antioxidants. Thirty-five original studies met the inclusion criteria and were reviewed following preferred reporting items for systematic review and meta-analysis guidelines. RESULTS: Although not all studies found consistent results, the weight of the evidence suggests that high intakes and/or circulatory levels of magnesium, as well as vitamin D and the vitamin B group, may be associated with lower carotid IMT or reduced progression of carotid IMT. The majority of studies did not find any significant association between vitamin E and C and carotid IMT. Less evidence was available for associations of retinol, zinc, and iron with carotid IMT. CONCLUSIONS: In general, the current evidence concerning micronutrient intake and carotid IMT is largely inconclusive. Pragmatic clinical trials are required to determine whether dietary or supplemental intake of specific micronutrients alters carotid IMT, which is a surrogate measure of cardiovascular risk.

From the α to the ω-3: Breaking the link between impaired fetal growth and adult cardiovascular disease.

Atherosclerotic vascular disease is an important cause of premature morbidity and mortality. An extensive body of epidemiologic data links impaired fetal growth, evidenced by reductions in birth weight, with a higher risk for cardiovascular disease in adulthood. This association appears to be at least partially independent of established cardiovascular risk factors, such as hypertension and type 2 diabetes. There is currently no clinically established strategy to prevent cardiovascular events secondary to being born with poor fetal growth. This review summarizes recent evidence that suggests that ω-3 polyunsaturated fatty acids may be beneficial for this indication; in particular being associated with more marked reductions in blood pressure and subclinical atherosclerosis in people who were born with poor fetal growth, than in those with healthy birth weight. Possible mechanisms, and the evidence base required to support the implementation of dietary guidelines specific to people born with impaired fetal growth are also described.

High intake of dietary long-chain ω-3 fatty acids is associated with lower blood pressure in children born with low birth weight: NHANES 2003-2008.

Reduced fetal growth is associated with increased systolic blood pressure. Recently, we found an inverse association between serum ω-3 fatty acids and systolic blood pressure in young adults born with impaired fetal growth. We investigated the associations of dietary intake in childhood of the long-chain ω-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid with blood pressure parameters in children born with reduced birth weight. We analyzed data from 3457 children aged 8 to 15 years participating in the continuous National Health and Nutrition Examination Survey 2003-2004, 2005-2006, and 2007-2008. Dietary intake was assessed by two 24-hour dietary recalls, birth weight by questionnaire, and blood pressure was measured. Systolic blood pressure was 1.1 mm Hg higher in those with reduced (<10th centile) compared with normal birth weight (≥ 10th centile), consistent with previous findings, although not statistically significant (P=0.40); however, pulse pressure was significantly higher in these children (3.4 mm Hg). In the 354 participants with reduced birth weight, when compared with children with the lowest tertile of intake, those who had the highest tertile of dietary eicosapentaenoic acid and docosahexaenoic acid intake had significantly lower systolic blood pressure (-4.9 mm Hg [95% confidence interval, -9.7 to -0.1]) and pulse pressure (-7.7 mm Hg [95% confidence interval, -15.0 to -0.4]). High-dietary intakes of eicosapentaenoic acid and docosahexaenoic acid are associated with lower systolic blood pressure and pulse pressure in children born with reduced birth weight. These data are consistent with the hypothesis that long-chain ω-3 fatty acids reduce blood pressure in those with impaired fetal growth.

Fetal growth, omega-3 (n-3) fatty acids, and progression of subclinical atherosclerosis: preventing fetal origins of disease? The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Impaired fetal growth is independently associated with an increased risk of cardiovascular events in adulthood. Prevention strategies that can be implemented during adulthood have not been identified. OBJECTIVE: The objective was to determine whether habitual omega-3 (n-3) fatty acid intake is associated with the rate of increase of carotid intima-media thickness during adulthood in individuals with impaired fetal growth. DESIGN: This was a population-based, prospective cohort study of 1573 adults in Finland. Carotid intima-media thickness was assessed in 2001 (at ages 24-39 y) and in 2007. Participants were categorized as having had impaired fetal growth (term birth with birth weight <10th percentile for sex or preterm birth with birth weight <25th percentile for gestational age and sex; n = 193) or normal fetal growth (all other participants; n = 1380). Omega-3 fatty acid intake was assessed by using a food-frequency questionnaire and on the basis of serum fatty acid concentrations. RESULTS: In multivariable models, the 6-y progression of carotid intima-media thickness was inversely associated with dietary omega-3 fatty acids in those with impaired fetal growth (P = 0.04). Similarly, serum omega-3 fatty acid concentrations were inversely associated with the 6-y progression of carotid intima-media thickness in those with impaired fetal growth (P = 0.04) but were not noted in those with normal fetal growth (P = 0.94 and P = 0.26, respectively). CONCLUSION: Dietary intake of omega-3 fatty acids is associated with a slower rate of increase in carotid intima-media thickness in those with impaired fetal growth.

Impaired fetal growth and arterial wall thickening: a randomized trial of ω-3 supplementation.

OBJECTIVES: Impaired fetal growth is an independent cardiovascular risk factor and is associated with arterial wall thickening in children. No preventive strategy has been identified. We sought to determine whether dietary ω-3 fatty acid supplementation during early childhood prevents the association between impaired fetal growth and carotid arterial wall thickening. METHODS: The Childhood Asthma Prevention Study was a randomized, controlled single-blind trial in 616 children born at term, recruited antenatally from maternity hospitals in Sydney. Participants were randomized to either a 500-mg-daily fish oil supplement and canola-based margarines and cooking oil (ω-3 group), or a 500-mg-daily sunflower oil supplement and ω-6 fatty acid-rich margarines and cooking oil (control group), from the start of bottle-feeding or 6 months of age until 5 years of age. Carotid intima-media thickness (IMT), a noninvasive measure of subclinical atherosclerosis, was the primary endpoint of a cardiovascular substudy (CardioCAPS) at age 8 years. We examined the association of fetal growth with carotid IMT in children with birth weight <90th percentile (ω-3 group [n = 187], control group [n = 176]). RESULTS: In the control group, fetal growth was inversely associated with carotid IMT, but this was prevented in the ω-3 group (difference between groups of 0.041 mm [95% confidence interval 0.006, 0.075] per kg birth weight, adjusted for gestational age and gender, P(heterogeneity) = .02). CONCLUSIONS: The inverse association of fetal growth with arterial wall thickness in childhood can be prevented by dietary ω-3 fatty acid supplementation over the first 5 years of life.

Effect of altering dietary n-6:n-3 PUFA ratio on cardiovascular risk measures in patients treated with statins: a pilot study.

Increasing dietary n-3 PUFA decreases the risk of CHD. Since n-6 PUFA compete with n-3 PUFA for common metabolic enzymes, the n-6:n-3 ratio intake rather than the n-3 PUFA intake levels per se may be critical. We aimed to examine whether altering the n-6:n-3 ratio affects cardiovascular risk factors in hypercholesterolaemic patients on lipid management with statins. Adhering to a randomised, crossover study design, patients on statins (n 11) were placed on one of two dietary interventions (Diet high-ratio (HR) - n-6:n-3 = 30:1 or Diet low-ratio (LR) - n-6:n-3 = 1·7:1) for 4 weeks followed after an 8-week washout period by the alternate diet. Foods enriched with n-3 or n-6 PUFA were delivered to each patient, who were given clear guidance on consumption expectations for the study. Measures of lipid profile, blood pressure and vascular function were determined. Diet LR significantly reduced body weight, LDL-cholesterol, high-sensitivity C-reactive protein, blood pressure and the apoA-1:apoB ratio. While Diet HR trended towards a similar cardioprotective profile, most of the parameters examined did not reach statistical significance. A direct comparison between diets demonstrated no significant superiority of Diet LR over Diet HR. These results suggest that a dietary intervention focused on n-6 and n-3 fatty acids may improve cardiovascular risk factors in patients over and above standard lipid management, but there is no significant advantage of a low n-6:n-3 ratio diet when compared to a high-ratio diet.