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Objectives: Studies suggest that endogenous estrogen may be involved in regulating body weight. Dietary lignans can act as estrogen receptor agonists and may be beneficial for weight control. We prospectively examined the association between changes in dietary lignan intake with weight change. Methods: We analyzed data from 124,875 men and women in the Nurses’ Health Study (1986-2010), Nurses’ Health Study II (1991-2011), and the Health Professionals Follow-up Study (1986-2010). We calculated 4-year changes in total lignan intake as well as in four major individual lignans (matairesinol, secoisolariciresinol, pinoresinol, and lariciresinol) using data from a semi-quantitative food frequency questionnaire. Participants reported their height and weight at baseline and updated their current weight every 2 years thereafter, from which we calculated 4-year changes in weight as the primary study outcome. We used multivariable generalized linear regression models to examine the association between 4-year changes in lignan intake with 4-year weight changes over the same period, and these models were adjusted for age, baseline BMI in each period, and relevant lifestyle factors. Results: Each 1-standard deviation (SD) increase in total lignan intake was associated with a 4-year weight change of -0.36 lbs (95% confidence interval [CI] -0.40 to -0.33 lbs; P for trend (Figure) . The observed associations were stronger among certain subgroups, including those with BMI ≥25 kg/m 2 , below-median diet quality, or below-median physical activity level. Conclusions: Increases in dietary lignan intake were associated with less weight gain over the same 4-year period. Our findings support existing dietary recommendations to consume a healthy plant-based diet.

Background: Indolepropionate (IPA), a tryptophan metabolite of human gut microbiota origin, is associated with lower risk of type 2 diabetes (T2D) in humans. The complex interplay among tryptophan intake, the gut microbiome, prebiotics, circulating IPA concentrations, and T2D risk has not been investigated. Objectives: We aimed to identify IPA-producing gut microbiota species and investigate potential diet-microbiota interaction on circulating IPA concentrations. Methods: We included 287 men from the Men’s Lifestyle Validation Study, a sub-study of the Health Professionals Follow-Up Study (HPFS), who provided up to two pairs of fecal samples and two blood samples approximately six months apart. Dietary intake was assessed using 7-day diet records. We identified microbial taxonomic features associated with plasma IPA concentrations using generalized linear regression and calculated a rank-based species score to reflect IPA-producing potential. Associations between plasma concentrations of tryptophan metabolites and T2D risk were examined in 13,032 participants from Nurses’ Health Study (NHS), NHSII, and HPFS. Results: Plasma IPA concentrations were associated with overall gut microbial profiles (permutational analysis of variance test, p=0.001). We identified 17 microbial species, such as Eubacterium eligens, Butyrivibrio crossotus , and Faecalibacterium prausnitzii , whose abundance was significantly associated with increased plasma IPA concentrations (false discovery rate < 0.05). A significant association between higher tryptophan intake and higher IPA concentrations was only observed among men who had higher fiber intake and a higher microbial species score consisting of the 17 species (p-interaction < 0.01). Similar modulation was also observed for major tryptophan food contributors including vegetables (p-interaction < 0.01), red/processed meat (p-interaction = 0.02), egg (p-interaction 0.01), dairy (p-interaction = 0.01), and whole grain (p-interaction < 0.01). Moreover, interactions persisted for all fiber subtypes (soluble/insoluble fiber and pectin). We documented 1,744 incident T2D cases during 218,603 person-years of follow-up. Plasma concentrations of tryptophan and three kynurenine-pathway metabolites (kynurenine, xanthurenate, and quinolinate) were positively associated with T2D risk while an inverse association was found for IPA. Conclusions: Specific microbial species and dietary fiber jointly modulate the associations between tryptophan intake and circulating IPA concentrations. In a subsequent analysis, IPA levels were predictive of lower T2D risk. Our findings suggest that the health effects of dietary tryptophan may depend on both gut microbiome composition and prebiotic consumption.

Introduction: The plant-based portfolio dietary pattern includes recognized cholesterol-lowering foods shown to improve several cardiovascular disease (CVD) risk factors in clinical trials. Epidemiological evidence on the association between longer-term adherence to the portfolio dietary pattern and CVD risk remains more limited. Objective: To examine whether the portfolio dietary pattern is associated with the risk of total CVD, coronary heart disease (CHD, including myocardial infarction and fatal coronary deaths), and stroke. Methods: Participants included 73,925 women in the Nurses’ Health Study (NHS) (1984-2014), 92,354 women in the NHS2 (1991-2017) and 43,970 men from the Health Professionals Follow-up Study (HPFS) (1986-2016) without CVD and cancer at baseline. Diet was assessed using validated food frequency questionnaires at baseline and every four years using a portfolio diet score (PDS) which positively ranks plant protein (soy & pulses), nuts, viscous fiber sources, phytosterols (mg/day) and plant monounsaturated fat sources, and negatively ranks foods high in saturated fat and dietary cholesterol. Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for covariates. Results: During up to 30 years of follow-up, 16,917 incident CVD cases, including 10,666 CHD cases and 6,473 stroke cases, were documented. After multivariable adjustment of lifestyle and other dietary factors, comparing the highest to the lowest quintile, participants with a higher PDS had a lower risk of total CVD (pooled HR: 0.84; 95% CI: 0.80-0.89, P trendP trendP trend=0.001). In addition, a 25-percentile higher PDS was associated with a lower risk of total CVD (pooled HR: 0.91; 95% CI: 0.88-0.93), CHD (pooled HR: 0.89; 95% CI: 0.86-0.92) and stroke (pooled HR: 0.93; 95% CI: 0.89-0.97). Results remained largely consistent across sensitivity and subgroup analyses. Conclusions: Greater adherence to the portfolio dietary pattern was consistently associated with lower risk of CVD, including CHD and stroke, in three large prospective cohorts of U.S. men and women.

Introduction: Thyroid function during pregnancy is pivotal for both maternal and fetal health. Data on environmental determinants of thyroid function in pregnancy are yet limited. We prospectively investigated associations of early pregnancy per- and polyfluoroalkyl substances (PFAS), known environmental endocrine disruptors, with thyroid function longitudinally measured throughout pregnancy. Hypothesis: Early pregnancy PFAS exposure adversely affects thyroid function. Methods: Within the NICHD Fetal Growth Studies-Singleton Cohort, we enrolled 2,802 pregnant women at gestational weeks (gw) 10-14 and measured concentrations of 9 PFAS (NMeFOSAA, PFDA, PFDoDA, PFDS, PFHpA, PFHxS, PFNA, PFOA, PFOS, PFOSA, PFUnDA) in plasma samples collected at enrollment. In a subsample of 321 pregnant women, we determined thyroid markers (fT3, fT4, TSH) at gw 10-14, 15-26, 23-31, 33-39. Associations were assessed with multivariable regressions per standard deviation increase in ln-transformed PFAS (ng/ml), adjusting for age, body mass index, diet, lifestyle and socio-economic factors, and plasma lipids. Results: Plasma PFAS in early pregnancy were associated with markers of thyroid function throughout pregnancy. The associations varied by gestational age. Higher levels of several PFAS were associated with lower TSH and higher fT3 and fT4 levels at gw 10-14. Adjusted beta coefficients [95%CI] with TSH (mIU/L) were: -1.13 [-2.30, 0.05] for PFOS, -3.15 [-4.45, -1.86] for PFDA, -1.75 [-2.95, -0.55] for NMeFOSAA, -1.68 [-3.00, -0.37] for PFNA, -1.29 [-2.62, 0.03] for PFDoDA, -2.07 [-3.30, -0.83] for PFOA, but 1.11 [0.12, 2.09] for PFHxS. Most of these associations were attenuated to non-significant or changed the direction of the association in later pregnancy (for instance, PFOS-TSH association at gw 10-14: -1.13 [-2.30, 0.05], gw 15-26: 0.98 [0.18, 1.78], gw 23-31: 1.31 [0.50, 2.13], PFDA-TSH association at gw 10-14: -3.15 [-4.45, -1.86], at gw 23-31: 1.13 [0.16, 2.11]). Consistent and positive associations across pregnancy were observed for PFOA-fT3 (at gw 10-14: 0.48 [0.05, 0.91], gw 15-26: 0.41 [0.04, 0.78], gw 23-31: 0.42 [0.02, 0.80] pmol/L) and PFHxS-fT4 (at gw 10-14: 0.12 [0.02, 0.21], gw 15-26: 0.67 [0.54, 0.81], gw 23-31: 0.22 [0.12, 0.33], gw 33-39: 0.14 [0.02, 0.26] ng/dL). Conclusions: Plasma levels of selected PFAS congeners in early pregnancy are significantly associated with thyroid markers in pregnancy. The associations varied by gestational timing. These findings indicate a potential environmental impact on thyroid function. In perspective, multiple assessments of PFAS and thyroid markers throughout pregnancy might be necessary and relevant for conducting gestational age-specific interventional trials.

Background: High-quality carbohydrate sources, such as whole grains, have been associated with a lower risk of type 2 diabetes (T2D), whereas low-quality carbohydrate sources, such as refined grains and added sugar, have been associated with a higher T2D risk. However, few studies have considered how replacing dietary carbohydrate with other macronutrients may influence T2D risk. Objective: We examined whether isocaloric substitution of high- or low-quality carbohydrate for fat, protein, and their subtypes is associated with T2D risk. Methods: We included 75,430 women from the Nurses' Health Study (1984-2016), 85,630 women from the Nurses' Health Study II (1991-2017), and 40,261 men from the Health Professionals Follow-Up Study (1986-2016) who were free of T2D, CVD, and cancer at baseline. Dietary data were collected every 2-4 years using a validated, semi-quantitative food frequency questionnaire. High-quality carbohydrate was defined as carbohydrate from whole grains, fruits, vegetables, and legumes. Low-quality carbohydrate was defined as carbohydrate from refined grains, added sugars, and potatoes. We used Cox proportional hazards regression with time-varying covariates to model the substitution of 5% of energy intake from high- and low-quality carbohydrate for isocaloric amounts of fat, protein, and their subtypes [polyunsaturated fat (PUFA), animal and plant monounsaturated fat (MUFA), saturated fat, trans fat, and animal and plant protein]. Cohort-specific estimates were combined using inverse variance-weighted fixed effects meta-analyses. Results: During 4,859,845 years of follow-up, we documented 20,141 incident T2D cases. In multivariable-adjusted meta-analyses, isocaloric substitution of high-quality carbohydrate for total fat [HR (95% CI) 0.94 (0.93, 0.96)], total MUFA [0.95 (0.91, 0.98)], MUFA from animal sources [0.92 (0.88, 0.95)], total protein [0.91 (0.89, 0.94)], or animal protein [0.94 (0.91, 0.97] was associated with a lower T2D risk. On the other hand, the substitution of low-quality carbohydrate for plant MUFA [1.06 (1.02-1.10)] or plant protein [1.06 (1.02-1.11)] was associated with a higher risk of T2D. When we restricted high-quality carbohydrate sources to whole grains, the results were similar or stronger. Additionally, substitution of whole grain carbohydrate for saturated fat [0.87 (0.84, 0.91)], trans fat [0.87 (0.83, 0.92)], PUFA [0.88 (0.84, 0.92)], plant MUFA [0.92 (0.87, 0.96)], or plant protein [0.91 (0.86, 0.97)] was associated with lower T2D risk. Conclusions: The effect of carbohydrate substitution on T2D risk depends not only on the nutrient being substituted but also on the quality of the carbohydrate. Substitution of high-quality carbohydrate, especially carbohydrate from whole grains (i.e. whole wheat bread, oatmeal), for fat or protein, especially animal sources (i.e. beef, poultry), may lower T2D risk.

Background: Consumption of sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) and physical activity are independently associated with type 2 diabetes (T2D) risk; however, it is unknown whether there is an interaction of SSB/ASB intake and physical activity on risk of T2D. Methods: We examined the independent and joint associations between habitual SSB/ASB intake and physical activity with incident T2D risk among 196,101 women and men from the Nurses’ Health Study (NHS, 1980-2016), NHSII (1991-2017), and Health Professional’s Follow-up Study (HPFS, 1986-2016), who were free from chronic diseases at baseline. Cox proportional hazards regressions were used to estimate hazard ratios and 95% confidence intervals (HR; CI), adjusting for demographic and lifestyle T2D risk factors. Results: There were 20,430 incident T2D cases over follow-up of 36, 26, and 30 years in NHS, NHSII, and HPFS, respectively. In multivariable-adjusted models, we confirmed that participants with higher SSBs, ASBs and lower physical activity were independently at higher T2D risk, compared to lower intakes and higher activity levels. In joint analyses for these exposures, participants who did not meet physical activity guidelines and consumed gt 2 servings/day of SSBs had a significantly higher risk of T2D than those who met physical activity guidelines and never/rarely consumed SSBs (1.51; 1.43, 1.60); we observed similar findings for ASBs: 1.29; 1.23, 1.36). Among participants who met physical activity guidelines, those who consumed gt 2 servings/day of SSBs had a HR of 1.23 (1.16, 1.30); the HR for ASBs was 1.07 (1.02, 1.13). Consistent results were observed for women and men. Conclusions: Long-term habitual intake of SSBs or ASBs combined with lower physical activity was associated with higher risk of T2D in three large prospective cohort studies. These findings suggest that even when individuals are physically active, higher consumption of SSBs is associated with a higher risk of T2D. Our results support recommendations and policies to limit the intake of SSB and increase physical activity levels.

Introduction: Ultra-processed foods (UPF) are associated with cardiovascular disease (CVD) in European populations. Evidence is limited from U.S. populations, for specific UPF subgroups, and in the diet quality context. Hypothesis: We hypothesized that U.S. women with higher UPF intake have higher CVD risk and evaluated this association by UPF subgroup and diet quality. Methods: Women from the Nurses' Health Study (NHS; n=75,639; 30-55y) and NHSII (n=90,770; 25-42y) with complete dietary intake data and without CVD/cancer at baseline were prospectively followed (1984-2014 and 1991-2015). Diet, demographics, lifestyle, and medical history were assessed every 2-4y using validated food frequency questionnaires and follow-up questionnaires. NOVA-classified UPF (% of energy) included ten subgroups: bread and cereals; sauces, spreads, and condiments; sweet snacks and desserts; savory snacks; sugar-sweetened beverages; animal-based products; ready-to-eat/heat dishes; yogurt and dairy desserts; hard liquors, and artificially sweetened beverages. The Alternative Healthy Eating Index (AHEI) measured diet quality. Primary outcomes were non-fatal myocardial infarction, fatal coronary heart disease (CHD), and non-fatal/fatal stroke. Multivariable-adjusted Cox regression estimated the associations of cumulatively-averaged UPF and subgroup intake quintiles with CVD risk. Each cohort was analyzed separately, and data were meta-analyzed (fixed effects models). Results: We identified 7,659 CVD cases (CHD=3,889; stroke=3,855) in NHS during 2,002,986 person-years of follow-up, and 1,588 CVD cases (CHD=807; stroke=786) in NHSII during 2,308,569 person-years. Pooled multivariable-adjusted hazard ratios [HRs (95%CIs)] of CVD, CHD, and stroke for the highest quintile of UPF intake ( vs. lowest) were 1.11 (1.04, 1.19; p-trend =0.002), 1.18 (1.08, 1.30; p-trend p-trend =0.37), respectively. Positive associations remained for participants with higher diet quality (AHEI above the sample median): CVD [HR=1.15 (1.05, 1.25; p-trend =0.009)] and CHD [HR=1.24 (1.09, 1.41; p-trend =0.007)]. Values of I 2 were non-significant. For UPF subgroups, intake for the highest quintile of sugar-sweetened beverages and animal-based products was significantly associated with higher risk of CVD, CHD, and stroke. Significant inverse associations were noted for bread and cereals and yogurt and dairy dessert with CVD, CHD, and stroke, for savory snacks with CHD, and for ready-to-eat/heat dishes with stroke. Conclusion: U.S. women with long-term higher total UPF intake had a higher CHD risk, even with a high-quality diet. Sugary drinks and animal-based products were predominant for CVD risk. Some UPF subgroups may contain beneficial components, warranting more nuanced food subgroup analyses. Replication is needed in racially/ethnically-diverse populations.

Background: A healthy lifestyle is associated with a lower risk of premature death. Metabolic pathways of a healthy lifestyle and their association with mortality remain to be understood. This study aimed to identify the metabolomic profile of a healthy lifestyle score and examine its prospective association with all-cause and cause-specific mortality, including death from cardiovascular disease (CVD) and cancer. Methods: The population included 12,146 participants from the Nurses’ Health Study (NHS), NHS II and Health Professionals Follow-Up Study (HPFS)(83% women, 97% white, aged 55±9y). Plasma metabolites were profiled using high-throughput liquid chromatography mass-spectrometry at baseline (NHS:1989-1990; NHSII:1996-1999; HPFS:1993-1995). The healthy lifestyle score was computed by summing the total number of healthy lifestyle factors participants adhered to from validated questionnaires at baseline: healthy diet (Alternative Healthy Eating Index, upper 40%), moderate alcohol intake (women: 5-15 g/d; men: 5-30 g/d), moderate-to-vigorous physical activity (≥30min/d), never smoking and normal BMI (18.5-24.9kg/m 2 ). Deaths were ascertained with death certificates and medical records. The metabolite profile was identified using elastic net regressions with train test validation split (70-30%). Metabolic pathways were determined using Metabolite Set Enrichment Analysis (MSEA). Multivariable-adjusted Cox proportional hazards regressions were used to estimate hazard ratios and 95% confidence intervals (HR[CI]) per unit of score of the healthy lifestyle metabolite profile with mortality risk. Results: The identified profile included 88 metabolites and correlated with the healthy lifestyle score (Pearson r=0.43-0.44; ppb =0.43; p Conclusions: In US adults, we identified a metabolite profile related to a healthy lifestyle largely reflecting lipid metabolism pathways. A higher metabolite score was associated with lower subsequent all-cause mortality risk, specifically from CVD. Findings provide novel insights into potential metabolic pathways underlying the association between a healthy lifestyle and lower premature mortality.

Introduction: The relationship between artificially sweetened beverage (ASB) intake and type 2 diabetes (T2D) risk remains inconclusive. Few studies have evaluated whether circulating metabolites that reflect ASB consumption may unveil potential mechanisms underlying the association between ASB consumption and T2D risk. Hypothesis: We hypothesized that a novel metabolomic profile reflecting habitual ASB consumption would positively associate with incident T2D among US adults. Methods: We quantified 120 plasma metabolites with liquid chromatography-mass spectroscopy in N=3,424 Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-up Study (HPFS) discovery cohort participants, and N=1,870 Framingham Heart Study (FHS) replication cohort participants. Habitual ASB consumption (servings/day; low-calorie cola or other carbonated beverages) was estimated from food frequency questionnaires at the time of blood draw. We used elastic net regression with 10-fold-cross-validation to age- and body mass index- adjusted metabolite levels to identify a metabolite profile associated with higher ASB consumption (ln-transformed). We then derived the continuous ASB metabolomic score as the weighted sum of these metabolites and replicated the analysis in an internal testing set and FHS. Finally, we evaluated the association of quartiles (Q) of the ASB-derived metabolomic score in NHS/NHSII/HPFS and FHS cohorts with incident T2D risk after blood draw (baseline for analysis) using Cox regression models to estimate hazard ratios (HR) and 95% confidence interval (CI), adjusted for demographics, lifestyle, diet, and body mass index at blood draw. Results: The ASB-derived metabolomic profile included 61 metabolites, primarily lipids and amino acids (Pearson correlation coefficients [ r ] between ASB self-reported intake and metabolomic score: r=0.08 [95% CI: 0.05, 0.11; p p =0.001], for discovery and replication, respectively). Mean follow-up was 20 and 16 years from blood draw, including 359 and 241 confirmed incident T2D cases for NHS/NHSII/HPFS and FHS, respectively. Compared with participants in the lowest quartile of the ASB-derived metabolomic profile, higher quartiles were incrementally and significantly at higher T2D risk in NHS/NHSII/HPFS (HR [CI] for Q2, Q3, Q4 vs. Q1: 1.45 [1.04, 2.02], 1.83 [1.33, 2.52], 1.62 [1.18, 2.22], respectively; p-trend =0.003) and FHS (1.76 [1.24, 2.48], 1.82 [1.28, 2.58], 2.45 [1.77, 3.40], respectively; p-trend Conclusions: A robust metabolomic profile of ASB intake was not identified, yet the objective and replicable ASB-derived metabolomic profile was associated with higher incident T2D risk. The identified metabolites may reflect ASB intake, western dietary patterns, underlying metabolic health, and/or T2D-related pathophysiology.

Importance: The Mediterranean diet, and other dietary patterns rich in fruits and vegetables, have been linked to lower risk of frailty in older adults. However, not all plant-based diets are necessarily healthful, and no previous study has evaluated the role of the quality of plant-based dietary patterns in frailty risk. Objective: To assess the association between plant-based diet quality and risk of frailty. Design, setting, and participants: Prospective cohort with 82,234 women aged ≥60y from the Nurses’ Health Study, who were followed from 1990 through 2014. The dates of analysis were April 14 to -June 23, 2021. Exposures: Dietary data were collected every 4-y using a validated semi-quantitative food frequency questionnaire. The plant-based diet quality was assessed with 2 indices (range 18 - 90 points).: a) Healthful Plant-Based Diet Index (hPDI), where healthy plant foods (whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea/coffee) received positive scores, while less healthy plant foods (fruit juices, sweetened beverages, refined grains, potatoes, sweets/desserts) and animal foods received reverse scores; and b) Unhealthful Plant-Based Diet Index (uPDI) where positive scores were given to less healthy plant foods and reverse scores to healthy plant foods and animal foods. Main outcomes: Frailty incidence was assessed every 4 years, being defined as having ≥3 of the following 5 criteria from the FRAIL scale: fatigue, low strength, reduced aerobic capacity, having ≥5 illnesses, and weight loss ≥5%. Methods: Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs), and their 95% confidence interval (CI). Results: We identified 12,910 incident cases of frailty over 1,176,401 person-year follow-up. In the multivariable analysis, the hPDI was inversely associated with the risk of frailty (HR for the highest vs. lowest quintile: 0.69, 95% CI: 0.65-0.73; p-trend Conclusions and relevance: A healthful plant-based diet was associated with lower risk of frailty whereas an unhealthful plant-based diet was associated with higher risk.

Introduction: Multiple healthy eating patterns have been recommended by the Dietary Guidelines for Americans (2015-2020) for the prevention of cardiovascular disease (CVD). However, adherence to these dietary patterns and its relationship with risk of CVD remains unclear among US Hispanic/Latinos. Hypothesis: We aimed to evaluate three healthy eating patterns measured by three dietary quality indices (the Alternate Mediterranean diet (aMED), the Healthy Eating Index (HEI)-2015, and the healthful Plant-based Diet Index (hPDI)), and assessed the hypothesis that higher adherence to healthy eating patterns is associated with lower risk of CVD in US Hispanic/Latinos. Methods: We included 10,766 adult participants representing six Hispanic/Latino backgrounds (Mexican, Puerto Rican, Cuban, Dominican, Central American and South American), free of CVD or cancer at baseline, from the Hispanic Community Health Study/Study of Latinos. Dietary pattern scores were derived using information collected by two 24-hour dietary recalls at baseline (2008-11). The primary outcome was major incident CVD (n=248), comprised of coronary heart disease and stroke, during an average 6-year follow-up period. Relative risks for CVD were estimated using survey Poisson regression after adjustment for demographic, socioeconomic, and behavioral variables and sampling weights. Results: Mean scores of all three dietary quality indices were significantly different across six Hispanic/Latino background groups (all P P P -trend=0.002) for aMED, 0.64 (95% CI 0.39-1.05; P -trend=0.033) for HEI-2015, and 0.56 (95% CI, 0.35-0.88; P -trend=0.009) for hPDI when comparing highest to lowest tertiles in the overall sample. The associations between dietary quality scores and risk of CVD were not different across Hispanic/Latino backgrounds (all P for interaction ≥0.24) or not by US-born status (all P for interaction ≥0.25). Conclusions: Adherence to healthy eating patterns reflected by three diet quality indices varied by Hispanic/Latino background and immigrant generation, and higher compliance to healthy eating patterns was associated with lower risk of CVD risk in the US Hispanic/Latino population.

Introduction: Dietary patterns high in healthy plant foods play an important role in modulating the gut microbiome and promoting cardiometabolic health. Little is known on the diet-gut microbiome relationship in U.S. Hispanics/Latinos, who have a high burden of obesity and diabetes. Hypothesis: Three healthy dietary patterns - the alternate Mediterranean diet (aMED), the Healthy Eating Index (HEI)-2015, and the healthful Plant-based Diet Index (hPDI), will be associated with gut microbiome composition in U.S. Hispanic/Latino adults, and healthy-diet-related species will be related to favorable cardiometabolic traits. Methods: HCHS/SOL is a multi-site community-based cohort. At baseline (2008-11), diet was assessed via two 24-hr recalls. Shotgun sequencing was performed on stool samples collected in 2014-17 (n=2,985). Analysis of Compositions of Microbiomes 2 (ANCOM2) was used to identify associations of dietary pattern scores with gut microbiome species and functions, adjusting for sociodemographic, behavioral, and clinical covariates. Results: Better diet quality according to multiple healthy dietary patterns was associated with higher abundance of species from class Clostridia, including [Eubacterium] eligens , Butyrivibrio crossotus , and Lachnospiraceae bacterium TF01-11 , as well as functions related to fiber fermentation (e.g. pyruvate:ferredoxin oxidoreductase). Poorer diet quality was associated with higher abundance of Acidaminococcus intestini , as well as functions of manganese/iron transport, adhesin protein transport, and nitrate reduction. Healthy diet pattern-enriched Clostridia species were related to more favorable cardiometabolic traits such as lower triglycerides ( Figure 1 ). Conclusions: Healthy dietary patterns in this population are associated with a fiber-fermenting gut microbiome, consistent with previous studies in other racial/ethnic groups. Gut microbiota may be involved in the beneficial effect of higher diet quality on cardiometabolic disease risk.

Background: The relationship between sodium intake and cardiovascular disease (CVD) remains controversial, in part, due to inaccurate assessment of sodium intake. 24-hour urinary excretion over multiple days is considered the optimal method. Methods: We included individual participant data from 6 prospective cohorts among generally healthy adults with sodium and potassium excretion assessed by at least two 24-hour urine collections. Out of 10,709 participants (54% women; mean [SD] age, 51.5 [12.6] years), 571 incident CVD events (including myocardial infarction, coronary revascularization, and stroke) were ascertained during a median follow-up of 8.8 years. We analyzed each cohort using consistent methods and combined the results using random-effects meta-analysis. Results: Median 24-hour urinary sodium excretion (10 th -90 th percentile) was 3,270 (2,099-4,899) mg. Higher sodium excretion, lower potassium excretion and higher sodium-to-potassium ratio were all associated with higher risk of CVD events after controlling for confounding factors (all P values for trend≤0.02); there was no evidence of nonlinearity. The hazard ratio [HR] comparing top with bottom quartiles was 1.67 [95% confidence interval [CI]: 1.21-2.30] for sodium, 0.77 [0.57-1.02] for potassium and 1.72 [1.27-2.32] for sodium-to-potassium ratio. Each 1,000 mg/d increment in sodium excretion was associated with an 18% increase in CVD risk (95%CI: 5%-32%) and each 1,000 mg/d increment in potassium excretion was associated with 18% lower risk (95%CI: 6%-28%). Conclusions: Higher sodium and lower potassium intakes, measured in multiple 24-hour urine samples, were associated with higher risk of CVD in a dose-response manner. These findings support current recommendations to reduce sodium and increase potassium intakes.

Introduction: Atherosclerosis, the main underlying causes of coronary heart disease (CHD) and ischemic stroke, is an inflammatory condition. However, therapeutics targeting inflammation for CHD and stroke are limited, partially due to insufficient evidence for causal inflammatory pathways and druggable targets. Objectives: We aimed to identify causal inflammatory markers for CHD and ischemic stroke, and to characterize the genetic architecture shared between such an inflammatory profile and CHD/stroke. Methods: Pooling multiple databases, we curated the largest genome-wide association summary statistics for 138 markers including 126 inflammatory proteins (C-reactive protein [CRP], N>450k; others such as cytokines, N~3.6k-45k) and 12 blood immune cell types (N>450k) and subsets (N~2.5k); as well as for CHD (N~547k) and stroke (N~521k). We conducted Mendelian randomization (MR) analysis using Causal Analysis Using Summary Effect Estimates and Mode-Based Estimate; and the genome-wide cross-trait meta-analysis using Association analysis based on SubSETs. Results: Of the 138 inflammatory markers, MR analyses identified 3 cellular and 4 protein markers showing significant causal effects for CHD (including white blood cell count, CD8+ T count, interleukin 6, and interleukin 22 receptor subunit alpha 1; FDR FDR APOC1-4 coregulated CHD and 5 causal markers for CHD; lead SNPs showing P FDR FDR P Conclusions: We identified cellular and protein inflammatory markers that potentially have a causal role in the development of CHD and ischemic stroke, based on genetic evidence.

Poor diet quality is strongly associated with elevated risk of cardiovascular disease morbidity and mortality. This scientific statement emphasizes the importance of dietary patterns beyond individual foods or nutrients, underscores the critical role of nutrition early in life, presents elements of heart-healthy dietary patterns, and highlights structural challenges that impede adherence to heart-healthy dietary patterns. Evidence-based dietary pattern guidance to promote cardiometabolic health includes the following: (1) adjust energy intake and expenditure to achieve and maintain a healthy body weight; (2) eat plenty and a variety of fruits and vegetables; (3) choose whole grain foods and products; (4) choose healthy sources of protein (mostly plants; regular intake of fish and seafood; low-fat or fat-free dairy products; and if meat or poultry is desired, choose lean cuts and unprocessed forms); (5) use liquid plant oils rather than tropical oils and partially hydrogenated fats; (6) choose minimally processed foods instead of ultra-processed foods; (7) minimize the intake of beverages and foods with added sugars; (8) choose and prepare foods with little or no salt; (9) if you do not drink alcohol, do not start; if you choose to drink alcohol, limit intake; and (10) adhere to this guidance regardless of where food is prepared or consumed. Challenges that impede adherence to heart-healthy dietary patterns include targeted marketing of unhealthy foods, neighborhood segregation, food and nutrition insecurity, and structural racism. Creating an environment that facilitates, rather than impedes, adherence to heart-healthy dietary patterns among all individuals is a public health imperative.

Background: Plant-based diets have been associated with lower risk of type 2 diabetes mellitus and cardiovascular disease (CVD) and are recommended for both health and environmental benefits. However, the association between changes in plant-based diet quality and mortality remains unclear. Methods: We investigated the associations between 12-year changes (from 1986 to 1998) in plant-based diet quality assessed by 3 plant-based diet indices (score range, 18–90)—an overall plant-based diet index (PDI), a healthful PDI, and an unhealthful PDI—and subsequent total and cause-specific mortality (1998–2014). Participants were 49 407 women in the Nurses’ Health Study (NHS) and 25 907 men in the Health Professionals Follow-Up Study (HPFS) who were free from CVD and cancer in 1998. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Results: We documented 10 686 deaths including 2046 CVD deaths and 3091 cancer deaths in the NHS over 725 316 person-years of follow-up and 6490 deaths including 1872 CVD deaths and 1772 cancer deaths in the HPFS over 371 322 person-years of follow-up. Compared with participants whose indices remained stable, among those with the greatest increases in diet scores (highest quintile), the pooled multivariable-adjusted HRs for total mortality were 0.95 (95% CI, 0.90–1.00) for PDI, 0.90 (95% CI, 0.85–0.95) for healthful PDI, and 1.12 (95% CI, 1.07–1.18) for unhealthful PDI. Among participants with the greatest decrease (lowest quintile), the multivariable-adjusted HRs were 1.09 (95% CI, 1.04–1.15) for PDI, 1.10 (95% CI, 1.05–1.15) for healthful PDI, and 0.93 (95% CI, 0.88–0.98) for unhealthful PDI. For CVD mortality, the risk associated with a 10-point increase in each PDI was 7% lower (95% CI, 1–12%) for PDI, 9% lower (95% CI, 4–14%) for healthful PDI, and 8% higher (95% CI, 2–14%) for unhealthful PDI. There were no consistent associations between changes in plant-based diet indices and cancer mortality. Conclusions: Improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of an unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.

Background: Findings among randomized controlled trials evaluating the effect of red meat on cardiovascular disease risk factors are inconsistent. We provide an updated meta-analysis of randomized controlled trials on red meat and cardiovascular risk factors and determine whether the relationship depends on the composition of the comparison diet, hypothesizing that plant sources would be relatively beneficial. Methods: We conducted a systematic PubMed search of randomized controlled trials published up until July 2017 comparing diets with red meat with diets that replaced red meat with a variety of foods. We stratified comparison diets into high-quality plant protein sources (legumes, soy, nuts); chicken/poultry/fish; fish only; poultry only; mixed animal protein sources (including dairy); carbohydrates (low-quality refined grains and simple sugars, such as white bread, pasta, rice, cookies/biscuits); or usual diet. We performed random-effects meta-analyses comparing differences in changes of blood lipids, apolipoproteins, and blood pressure for all studies combined and stratified by specific comparison diets. Results: Thirty-six studies totaling 1803 participants were included. There were no significant differences between red meat and all comparison diets combined for changes in blood concentrations of total, low-density lipoprotein, or high-density lipoprotein cholesterol, apolipoproteins A1 and B, or blood pressure. Relative to the comparison diets combined, red meat resulted in lesser decreases in triglycerides (weighted mean difference [WMD], 0.065 mmol/L; 95% CI, 0.000–0.129; P for heterogeneity P P =0.003). In comparison with fish, red meat yielded greater decreases in low-density lipoprotein (WMD, –0.173 mmol/L; 95% CI, –0.260 to –0.086; P P =0.004). In comparison with carbohydrates, red meat yielded greater decreases in triglycerides (WMD, –0.181 mmol/L; 95% CI, –0.349 to –0.013). Conclusions: Inconsistencies regarding the effects of red meat on cardiovascular disease risk factors are attributable, in part, to the composition of the comparison diet. Substituting red meat with high-quality plant protein sources, but not with fish or low-quality carbohydrates, leads to more favorable changes in blood lipids and lipoproteins.