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Related Perspective from Physical Activity and Survival in Postmenopausal Women with Breast Cancer: Results from the Women's Health Initiative

Statins are highly effective medications that reduce risk of atherosclerotic cardiovascular disease, but are very commonly discontinued by patients because of muscle symptoms. The risk factors for statin-associated muscle symptoms (SAMS) are not well understood, so in this study we examined the predictors of SAMS in a well-studied cohort of patients in the VITAL trial. We found that female sex and younger age (50-64 years) were significant, independent predictors of higher rates of SAMS.

Purpose of Review Clonal hematopoiesis of indeterminate potential (CHIP) has been identified as a novel cardiovascular risk factor. Here we review the relationship of lifestyle and environmental risk factors predisposing to somatic mutations and CHIP and provide an overview on age-related cardiovascular outcomes. Recent Findings CHIP has been associated with accelerated atherosclerosis and cardiovascular disease in both epidemiological and experimental studies. The most commonly mutated candidate driver genes are DNMT3A, TET2, JAK2, and ASXL1. The underlying mechanisms appear predominantly related to inflammatory pathways. Although age is the dominant risk factor for developing CHIP, emerging evidence suggests that other factors such as smoking, obesity/type 2 diabetes, or an unhealthy diet play a role in the occurrence of somatic mutations. Summary Evidence suggests a strong link between vascular risk factors, somatic hematopoietic mutations, and age-related cardiovascular disease. Further studies on CHIP biology are required to identify targeted interventions for risk reduction in patients with CHIP and inform the utility of screening strategies.

Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested.We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults.We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns.Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Background Recommended systolic blood pressure targets often do not consider the relationship of low diastolic blood pressure (DBP) levels with cardiovascular disease (CVD) and all-cause mortality risk, which is especially relevant for older people with concurrent comorbidities. We examined the relationship of DBP levels to CVD and all-cause mortality in older women in the Women’s Health Initiative Long Life Study (WHI-LLS). Methods The study sample included 7,875 women (mean age: 79 years) who underwent a blood pressure measurement at an in-person home visit conducted in 2012–2013. CVD and all-cause mortality were centrally adjudicated. Hazard ratios (HRs) were obtained from adjusted Cox proportional hazards models. Results After 5 years follow-up, all-cause mortality occurred in 18.4% of women. Compared with a DBP of 80 mm Hg, the fully adjusted HR for mortality was 1.33 (95% confidence interval [CI]: 1.04–1.71) for a DBP of 50 mm Hg and 1.67 (95% CI: 1.29–2.16) for a DBP of 100 mm Hg. The HRs for CVD were 1.14 (95% CI: 0.78–1.67) for a DBP of 50 mm Hg and HR 1.50 (95% CI: 1.03–2.17) for a DBP of 100 mm Hg. The nadir DBP associated with lowest mortality risk was 72 mm Hg overall. Conclusions In older women, consideration should be given to the potential adverse effects of low and high DBP. Low DBP may serve as a risk marker. DBP target levels between 68 and 75 mm Hg may avoid higher mortality risk.

Background and Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease–related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes ( DNMT3A , TET2 , and ASXL1 ) with any stroke, ischemic stroke, and hemorrhagic stroke. Results: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03–1.27]; P =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01–1.51]; P =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. Conclusions: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

To investigate the prospective associations between red meat consumption and all-cause and cardiovascular diseases (CVD) mortality, and to assess the modification effects of lifestyle and genetic risk factors.180,642 individuals free of CVD or cancer were enrolled from 2006 to 2010 and followed up to 2018 in the UK Biobank. Information on demographics, lifestyles, and medical history was collected through a baseline touchscreen questionnaire. The information on diet was collected through a single touchscreen food-frequency questionnaire. A total of ten single-nucleotide polymorphisms were used to calculate the genetic risk score (GRS) of trimethylamine N-oxide (TMAO), a gut microbiota metabolite from red meat. Adjusted Cox proportional hazard regression models were used to assess the association of red meat consumption with mortality.We documented 3596 deaths [655 CVD deaths, 285 coronary heart disease (CHD) deaths, and 149 stroke deaths] during median 8.6 years of follow-up. Compared with the lowest red meat intake ( 1.5 times/week), the highest red meat intake (≥ 3.0 times/week) was associated with a 20%, 53%, and 101% elevated risk for CVD, CHD, and stroke mortality (P for trend = 0.04, 0.007, and 0.02, respectively), but not all-cause mortality. We found that the associations between red meat intake and mortality were not modified by dietary and lifestyle factors, as well as TMAO GRS. In addition, substitution analyses showed that a decrease in red meat consumption and an increase in the consumption of poultry or cereal was significantly associated with 9%-16% lower CVD or CHD mortality risk.Our results indicated that red meat consumption was associated with higher risks of CVD, CHD, and stroke mortality, and the associations were not modified by lifestyle and genetic risk factors. Replacing red meat by poultry or cereal was related to lower risks of CVD and CHD mortality.

Background Higher physical activity levels are associated with lower breast cancer-specific mortality. In addition, the metabolic syndrome is associated with higher breast cancer-specific mortality. Whether the physical activity association with breast cancer mortality is modified by number of metabolic syndrome components (cardiometabolic risk factors) in postmenopausal women with early-stage breast cancer remains unknown. Methods Cardiovascular risk factors included high waist circumference, hypertension, high cholesterol, and diabetes. Breast cancers were verified by medical record review. Mortality finding were enhanced by serial National Death Index queries. Cox proportional hazards regression models were used to estimate associations between baseline physical activity and subsequent breast cancer-specific and overall mortality following breast cancer diagnosis in Women’s Health Initiative participants. These associations were examined after stratifying by cardiometabolic risk factor group. Results Among 161,308 Women’s Health Initiative (WHI) participants, 8543 breast cancers occurred after 9.5 years (median) follow-up in women, additionally with information on cardiometabolic risk factors and physical activity at entry. In multi-variable analyses, as measured from cancer diagnosis, higher physical activity levels were associated with lower all-cause mortality risk (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.78–0.95, trend P P = 0.09). The physical activity and all-cause mortality association was not significantly modified by cardiometabolic risk factor number. Conclusions Among women with early-stage breast cancer, although higher antecedent physical activity was associated with lower risk of all-cause mortality, the association did not differ by cardiometabolic risk factor number.

OBJECTIVE: Oral postmenopausal hormone therapy (HT) has been shown to be associated with venous thromboembolism (VTE), but whether this association is modified by VTE-associated genetic susceptibility is unknown. We examined interactions between oral HT use and a genetic risk score (GRS) of VTE. METHOD: Eligible women were postmenopausal women who had data on oral HT use, VTE incidence between 1990 and 2012, and genetic data in the Nurses’ Health Study. We built a GRS aggregating 16 VTE-related genetic variants. We used Cox regression to estimate associations of HT use with incident VTE and assessed interactions between HT use and VTE GRS. We also estimated incidence of VTE between age 50 and 79 years for groups of women defined by HT use and VTE GRS. RESULTS: We identified 432 incident VTE cases. Current HT users were at higher risk of VTE than never users (HR: 1.9, 95% CI: 1.5–2.6), with slightly higher risk for estrogen plus progestin HT than estrogen only (HR: 2.4 versus 1.9). The GRS was associated with VTE risk (HR comparing 4(th) quartile to 1(st): 2.0, 95% CI: 1.2–3.4). We did not observe significant multiplicative interactions between HT use and GRS. The estimated VTE risk difference (per 10,000 person-years) comparing 50-year-old current HT users to never users was 22.5 for women in the highest GRS quartile and 9.8 for women in the lowest GRS quartile. CONCLUSION: The VTE GRS might inform clinical guidance regarding the balance of risks and benefits of HT use, especially among younger women.

OBJECTIVE: To evaluate the association between parity and breastfeeding and anti-Müllerian hormone levels (AMH) and change in AMH levels over time. Furthermore, we examined whether AMH levels mediate the relation of parity and breastfeeding with age at menopause. STUDY DESIGN: Observational, prospective cohort study. MAIN OUTCOME MEASURES: AMH levels were assessed in a subset of premenopausal participants in the Nurses’ Health Study II, including 1619 women who provided a blood sample in 1996–1999 and an additional 800 women who provided a second premenopausal sample in 2010–2012. RESULTS: In multivariable linear regression models adjusted for parity, body mass index, smoking, and other factors, mean log AMH levels in 1996–99 were 39% higher in women reporting ≥25 months of total breastfeeding vs.

PDF - 68KB, Association of height with risk of colorectal cancer by level of potential effect modifiers. HR4s are adjusted for covariates in footnote 1 in Table 3.

Contains more detailed information on the individual cohorts contributing to the study and their genotyping results; Supplemental Tables 1 and 2

PDF - 69KB, Association of height with risk of melanoma cancer by level of potential effect modifiers. HR4s are adjusted for covariates in footnote 6 in Table 3.

Percentage of Participants Enrolled in the Women's Health Initiative Dietary Modification Trial Who Were Alive and Not Withdrawn on March 31, 2005 Who Consented to Extended Follow-up (n=45560 )

PDF - 22KB, Legends for supplementary figures 1-5.

PDF - 68KB, Association of height with risk of breast cancer by level of potential effect modifiers. HR4s are adjusted for covariates in footnote 3 in Table 3.

To evaluate the effect of vitamin D(3) supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86–1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D(3) group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78–0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91–1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D(3) therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D(3) supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D(3) did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D(3) administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Background: Prospective studies in Western and Asian populations suggest that height is a risk factor for various cancers. However, few studies have explored potential confounding or effect modification of the association by other factors.Methods: We examined the association between height measured at enrollment in 144,701 women participating in the Women's Health Initiative and risk of all cancers combined and cancer at 19 specific sites. Over a median follow-up of 12.0 years, 20,928 incident cancers were identified. We used Cox proportional hazards models to estimate HR and 95% confidence intervals (CI) per 10 cm increase in height, with adjustment for established risk factors. We also examined potential effect modification of the association with all cancer and specific cancers.Results: Height was significantly positively associated with risk of all cancers (HR = 1.13; 95% CI, 1.11–1.16), as well as with cancers of the thyroid, rectum, kidney, endometrium, colorectum, colon, ovary, and breast, and with multiple myeloma and melanoma (range of HRs: 1.13 for breast cancer to 1.29 for multiple myeloma and thyroid cancer). These associations were generally insensitive to adjustment for confounders, and there was little evidence of effect modification.Conclusions: This study confirms the positive association of height with risk of all cancers and a substantial number of cancer sites.Impact: Identification of single-nucleotide polymorphisms associated both with height and with increased cancer risk may help elucidate the association. Cancer Epidemiol Biomarkers Prev; 22(8); 1353–63. ©2013 AACR.

Supplementary Fig. 1. Longitudinal plots of mean (95% CI) percentage of energy as fat during follow-up and the extension period, stratified by quartiles of percentage energy as fat at baseline. Estimates of mean (95% CI) for percentage of energy from fat were based on 24-hour dietary recall.

Background: The Women's Health Initiative (WHI) low-fat (20% kcal) dietary modification (DM) trial (1993–2005) demonstrated a nonsignificant reduction in breast cancer, a nominally significant reduction in ovarian cancer, and no effect on other cancers (mean 8.3 years intervention). Consent to nonintervention follow-up was 83% (n = 37,858). This analysis was designed to assess postintervention cancer risk in women randomized to the low-fat diet (40%) versus usual diet comparison (60%).Methods: Randomized, controlled low-fat diet intervention for prevention of breast and colorectal cancers conducted in 48,835 postmenopausal U.S. women, ages 50 to 79 years at 40 U.S. sites. Outcomes included total invasive cancer, breast cancer, and colorectal cancer, and cancer-specific and overall mortality.Results: There were no intervention effects on invasive breast or colorectal cancer, other cancers, or cancer-specific or overall mortality during the postintervention period or the combined intervention and follow-up periods. For invasive breast cancer, the hazard ratios (HR) and 95% confidence interval (CI) were 0.92 (0.84–1.01) during intervention, 1.08 (0.94–1.24) during the postintervention period, and 0.97 (0.89–1.05) during cumulative follow-up. A reduced risk for estrogen receptor positive/progesterone receptor–negative tumors was demonstrated during follow-up. In women with higher baseline fat intake (quartile), point estimates of breast cancer risk were HR, 0.76 (95% CI, 0.62–0.92) during intervention versus HR, 1.11 (95% CI, 0.84–1.4) during postintervention follow-up (Pdiff = 0.03).Conclusions: Dietary fat intake increased postintervention in intervention women; no long-term reduction in cancer risk or mortality was shown in the WHI DM trial.Impact: Dietary advisement to reduce fat for cancer prevention after menopause generally was not supported by the WHI DM trial. Cancer Epidemiol Biomarkers Prev; 23(12); 2924–35. ©2014 AACR.

Background: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D.Methods: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS).Results: We did not observe a statistically significant association between the 25(OH)D-associated SNPs and colorectal cancer marginally, conditionally, or as a GRS, or for colon or rectal cancer separately.Conclusions: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of colorectal cancer. Additional work is warranted to investigate the complex relationship between 25(OH)D and colorectal cancer risk.Impact: There was no association observed between genetic markers of circulating 25(OH)D and colorectal cancer. These genetic markers account for a small proportion of the variance in 25(OH)D. Cancer Epidemiol Biomarkers Prev; 22(11); 2037–46. ©2013 AACR.

Supplementary Table 1. Number of pancreatic cancer cases by cohort with available plasma leptin levels and genotyped SNPs at LEPR Supplementary Table 2. Characteristics of controls from five prospective cohorts Supplementary Table 3. Partial Spearman correlation coefficients between plasma leptin and covariates among controls Supplementary Table 4. Odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer according to quintiles of plasma leptin in sensitivity analyses excluding diabetics and short time intervals from blood collection to cancer diagnosis Supplementary Table 5. Multivariate-adjusted ORs (95% CI) for pancreatic cancer by plasma leptin, among subgroups* Supplementary Table 6. Association between SNPs at the LEPR gene and risk of pancreatic cancer among men Supplementary Table 7. Genomic and functional support for rs10493380 and correlated (r2 {greater than or equal to} 0.6) surrogate variants in HaploReg and Regulome DB Supplementary Table 8. Association between single nucleotide polymorphisms at the LEPR gene and plasma leptin among controls Supplementary Figure 1. Association results, recombination hotspots and linkage disequilibrium for single nucleotide polymorphisms at the LEPR gene region among women.

Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case–control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27–7.16; Ptrend = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (Ptrend = 0.21). Results were similar across cohorts (Pheterogeneity = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18–2.02; multiple hypothesis-corrected P = 0.03). No SNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasma leptin were associated with an elevated risk of pancreatic cancer among men, but not among women. Cancer Res; 76(24); 7160–7. ©2016 AACR.

Supplementary Table 2. Effects of Randomization Assignment to Dietary Modification Intervention vs. Comparison on Clinical Outcomes Before and After Termination of the Intervention in the Women's Health Initiative Dietary Modification Trial

PDF - 67KB, Association of height with risk of lung cancer in ever smokers by level of potential effect modifiers. HR4s are adjusted for covariates in footnote 6 in Table 3.

PDF file - 64K, Breast cancer risk OR(95% CI) for 1 year change in estrogen metabolites (EM) among women randomized to active treatment in the WHI Hormone Trials, with cases stratified by median follow-up time

Background and AimsThe microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain ofEscherichia coliharboring thepksisland that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown.MethodsSBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival.ResultsIn total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5×10-28). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1×10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6×10-6) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was theAPC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3×10-80). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88- positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage.ConclusionSBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.

Introduction: Integrating multiple metabolomics signatures related to coronary heart disease (CHD) into a metabolomic risk score (MRS) may contribute to improving the risk prediction beyond traditional risk factors, although applications of the MRS remain underdetermined, especially in people at usual risk. Hypothesis: We analyzed associations of plasma metabolites with the risk of CHD to develop MRS for predicting risk of incident CHD by incorporating comprehensive metabolic pathways among women at usual risk from the Nurses’ Health Study (NHS). We also tested whether changes in CHD-related plasma metabolites were associated with significant reductions in atherosclerotic cardiovascular disease (ASCVD) risk scores among participants in the POUNDS Lost trial. Methods: Untargeted metabolomics profiling was performed to measure plasma metabolites at baseline in a prospective nested case-control of 762 incident cases of CHD (fatal CHD and nonfatal myocardial infarction) and 762 matched controls identified over 10-14 years of follow-up time in NHS. An MRS of CHD risk was created based on metabolites that were selected through conditional logistic regression with the elastic net procedure. The POUNDS Lost trial included adults with overweight/obesity who consumed weight-loss diets with different macronutrient intakes. We measured untargeted plasma metabolomics signatures at baseline, 6 months, and 2 years to calculate changes in response to the dietary interventions. The primary outcome in the POUNDS Lost trial was the reduction of 10-year ASCVD risk scores calculated by the validated pooled cohort equations. Results: Various plasma metabolites (such as gut-microbiota-related and others in the pathways of ceramides, phospholipids, and polyamine metabolism) were associated with the risk of incident CHD ( P FDR Conclusions: Comprehensive metabolomic scores were strongly related to the risk of incident CHD among women without prior CHD. Dietary interventions may modify the unfavorable relations between CHD-risk-related metabolites and ASCVD risk. Further studies in other populations are warranted to validate the performance of MRS in predicting ASCVD events.

Introduction: Recent evidence suggests that intake of ultra-processed foods (UPF) is related to unfavorable cardio-metabolic risk profiles among generally healthy populations. However, evidence on the relationship between UPF intake and cardiovascular disease (CVD) among patients with type 2 diabetes (T2D) is lacking. Hypothesis: We assessed the hypothesis that higher intake of dietary UPF is associated with higher risks of CVD among individuals with T2D. Methods: We prospectively followed 13,272 men and women participating in the Health Professionals Follow-Up Study (HPFS) and Nurses’ Health Study (NHS) with T2D at baseline and during follow-up (HPFS: 1986-2018; NHS: 1980-2014). Diet was repeatedly assessed using validated food frequency questionnaires every 2-4 years. UPF were categorized according to the Nova classification. CVD was defined as fatal and non-fatal coronary heart disease (CHD) (including nonfatal myocardial infarction, coronary artery bypass graft surgery, and coronary angioplasty and stent) and fatal and non-fatal stroke. Associations of UPF consumption with risks of CVD were assessed using Cox regression. Results: During 165,761 person-years of follow-up, 1,826 total CHD and 529 total stroke were identified and confirmed. After adjusting for demographics, lifestyle, medical history, dietary factors, and diabetes medication use, higher total intake of UPF was associated with higher risk of CHD. The multivariable-adjusted HRs (95% CIs) were 1.20 (1.02, 1.43) ( P trend = 0.03) when comparing the highest and lowest quintiles (Q5 vs. Q1) or 1.03 (1.01, 1.04) for each 1 serving/day increment of UPF. No association between UPF intake and risk of stroke was observed (Q5 vs. Q1: 0.92 (0.67, 1.24)). These results were consistent across subgroups in analyses stratified by age, sex, BMI, diet quality, physical activity, smoking, diabetes medication use, or diabetes duration. In addition, compared with participants who had a stable or decreased consumption of UPF (≤0 change in UPF) from pre- to post-diabetes diagnosis, participants who increased consumption of UPF (>0 increment of UPF intake) after diabetes diagnosis had a 15% (1%, 31%) higher risk of CHD. Conclusions: Among participants with T2D, higher dietary UPF consumption was associated with a higher risk of CHD, but not stroke. These results provide further support for the current recommendations to limit UPF consumption for the prevention of CHD among patients with diabetes.

Introduction: There is limited evidence on the association between long-term consumption of ultra-processed foods (UPF) and the risk of type 2 diabetes (T2D), among the U.S population. The overall strength of this association has also not been established. Hypothesis: Higher intake of UPF is associated with a higher risk of T2D in U.S. adults. The pooled risk estimates from published literature reinforce the positive relationship between the UPF intakes and T2D. Methods: We first assessed this relationship among 71,871 women from the Nurses’ Health Study (NHS, 1984-2016), 87,918 women from NHSII (1991-2017), and 38,847 men from the Health Professionals Follow-up Study (HPFS, 1986-2016) who were all free of T2D at baseline. Diet was assessed using food frequency questionnaires, every 2-4 years. UPF were categorized according to the Nova classification. Information on incident cases of T2D was obtained through follow-up questionnaires every 2 years. The association between UPF intake and incident T2D was examined using Cox proportional hazards models. Second, after conducting a systematic review of prospective cohort studies, risk estimates from all included cohorts were pooled in a random-effects, dose-response, meta-analysis to assess nonlinearity of the association between total UPF intake and T2D risk. Finally, the strength of the meta-evidence was assessed using NutriGrade. Results: During 5,187,678 person-years of follow-up across the three cohorts, 19,503 T2D cases were documented. The pooled multivariable-adjusted hazard ratios (HRs) for T2D between the extreme quintiles of total UPF intake (% of grams/day), was 1.36 (95% confidence interval (CI): 1.29, 1.44; P trend 2 =23.1%; P heterogeneity =0.25). Per NutriGrade, the evidence supporting the positive relationship between total UPF intake and T2D was of high quality. Conclusions: High quality evidence shows that total UPF consumption is associated with higher risk of T2D, although not all individual foods classified as ultra-processed were associated with a higher risk in these U.S. cohorts.

OBJECTIVE We examined the relationship between ultra-processed food (UPF) intake and type 2 diabetes (T2D) risk among 3 large U.S. cohorts, conducted a meta-analysis of prospective cohort studies, and assessed meta-evidence quality. RESEARCH DESIGN AND METHODS We included 71,871 women from the Nurses’ Health Study, 87,918 women from the Nurses’ Health Study II, and 38,847 men from the Health Professional Follow-Up Study. Diet was assessed using food frequency questionnaires and UPF was categorized per the NOVA classification. Associations of total and subgroups of UPF with T2D were assessed using Cox proportional hazards models. We subsequently conducted a meta-analysis of prospective cohort studies on total UPF and T2D risk, and assessed meta-evidence quality using the NutriGrade scoring system. RESULTS Among the U.S. cohorts (5,187,678 person-years; n = 19,503 T2D cases), the hazard ratio for T2D comparing extreme quintiles of total UPF intake (percentage of grams per day) was 1.46 (95% CI 1.39–1.54). Among subgroups, refined breads; sauces, spreads, and condiments; artificially and sugar-sweetened beverages; animal-based products; and ready-to-eat mixed dishes were associated with higher T2D risk. Cereals; dark and whole-grain breads; packaged sweet and savory snacks; fruit-based products; and yogurt and dairy-based desserts were associated with lower T2D risk. In the meta-analysis (n = 415,554 participants; n = 21,932 T2D cases), each 10% increment in total UPF was associated with a 12% (95% CI 10%–13%) higher risk. Per NutriGrade, high-quality evidence supports this relationship. CONCLUSION High-quality meta-evidence shows that total UPF consumption is associated with higher T2D risk. However, some UPF subgroups were associated with lower risk in the U.S. cohorts.

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: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in elevated risks for coronary heart disease (CHD) and death, but its association with incident type 2 diabetes (T2D) is unknown. Hypothesis: We hypothesized that CHIP is associated with elevated risk of incident T2D. Methods: CHIP was derived from whole genome sequencing of blood DNA in NHLBI Trans-omics for Precision Medicine (TOPMed) cohorts. We analyzed 17,637 participants without prior T2D, cardiovascular disease, or cancer at blood draw, with prospective follow-up for incident T2D. We evaluated baseline prevalence of CHIP vs. no CHIP with incident T2D risk using Cox regression. We also investigated CHIP variants previously related to CHD: DNMT3A , TET2 , ASXL1 , JAK2 , and TP53 . We estimated multivariable-adjusted hazard ratios and 95% confidence intervals (HR [CI]) adjusted for age, sex, body mass index, smoking, alcohol, and education. We combined cohort estimates via fixed effects meta-analysis. Results: On average, participants were age 63.4 years (SD=11.5) and 76% female. Prevalence of CHIP was 6.0% (1,055) at baseline. There were 2,467 incident T2D cases over mean=9.8 years follow-up. Compared to those without a mutation, having CHIP was associated with a 23% higher T2D risk, both overall (combined HR=1.23; 95% CI=1.04, 1.45), and among those with CHD-related CHIP mutations (87% of total CHIP): HR=1.23 (1.03, 1.46). Although those with CHIP mutations of TET2 (HR=1.48; 1.05, 2.08) and ASXL1 (HR=1.76; 1.03, 2.99) had larger elevations in T2D risk, and DNMT3A was suggestive of increased T2D risk (HR=1.15; 0.93, 1.43), statistical power was limited for JAK2 and TP53 mutation analyses. Conclusions: CHIP was associated with higher incidence of T2D. CHIP mutations located on loci previously implicated in aging and CHD were also related to T2D, suggesting shared pathology of atherosclerosis and T2D.

Backgrounds: Cocoa and cocoa flavonoids may exert health benefits including improving insulin sensitivity and lowering type 2 diabetes (T2D) risk. Previous studies have reported inverse associations between chocolate consumption and T2D risk, although it is largely unknown regarding whether the associations differ between dark chocolate and milk chocolate. The objective of this study is to prospectively examine the associations between the consumption of dark chocolate, milk chocolate, and total chocolate, and the risk of T2D, in three large cohort studies with repeat dietary measurements over 10 years of follow-up. Methods: Data from three prospective cohorts in the United States were used, including Nurses’ Health Study (2006-2020), Nurses’ Health Study II (2007-2019), and Health Professionals Follow-Up Study (2006-2020). Dark and milk chocolate consumption information was assessed at baseline and updated every 4 years through a validated food frequency questionnaire. Chocolate consumption was categorized into 4 groups: never or Results: After adjusting for lifestyle and dietary risk factors for diabetes, compared to participants who never or rarely eat chocolate, those who consumed any chocolate ≥5 servings/week had a 22% (95% CI: 10% to 32%; p for trend = 0.0003) lower rate of T2D. For dark chocolate, those who consumed ≥5 servings/week had a non-significant 16% (95% CI: -2% to 31%; p for trend = 0.005) lower rate of T2D than those who never or rarely eat dark chocolate. The associations between milk chocolate intake and T2D risk are largely null. Spline regression shows an L-shaped non-linear dose-response relationship between total chocolate intake and the risk of T2D (p=0.02 for curvature). The risk reduction plateaus when the total chocolate intake is higher than 5 servings/week. There is a linear dose-response association between dark chocolate intake with the risk of T2D (p=0.006 for linearity). Conclusion: Higher consumption of total chocolate and especially dark chocolate was significantly associated with a lower risk of type 2 diabetes. These findings support the potential cardiometabolic benefits of consuming chocolates that are rich in flavonoids.

Objective: Randomized controlled trials (RCTs) provide opportunities to estimate the causal effects of interventions on disease risk; however, large-scale, long-term RCTs of diet for the prevention of major chronic disease endpoints are sparse. We sought to summarize RCTs comparing the effectiveness of dietary interventions for the primary prevention of clinical cardiovascular disease (CVD) events and type 2 diabetes (T2D) in adults. Methods: We conducted a systematic review and meta-analysis (PROSPERO #CRD42021283728) of RCTs exclusively with dietary interventions with outcomes of incident primary CVD events and/or T2D among adults. We searched MEDLINE and other databases and references. Eligible interventions included those providing instruction, education, and/or provisions to modify intakes of nutrients, foods, or overall dietary patterns. We excluded meal replacement products, dietary supplements, interventions with concomitant comprehensive lifestyle programs, exercise regimens, etc., trials in secondary prevention populations, and trials assessing risk factor or biomarker changes only, rather than clinical events. Two investigators performed screening and data extraction in parallel. We conducted a random effects meta-analysis to estimate the pooled effectiveness of dietary interventions compared with usual diet or low-fat control groups for CVD and T2D outcomes, separately. Results: Among the 5365 citations generated in our searches, we identified 4 eligible RCTs, representing 56,721 participants with mean ages ranging from 44.7 to 67.9 years. Mean intervention duration was 2.3 to 8.1 years, resulting in 3,151 CVD events and 3,603 T2D cases. Compared with the control diets, the various healthy dietary patterns were related to a combined 7% (relative risk [RR] = 0.93, confidence interval [CI] = 0.87-1.00) lower CVD risk and 8% (RR = 0.92, CI = 0.86-0.98) lower T2D risk. Conclusion: Despite major morbidity and mortality from CVD and T2D, there have been few large, population-based, long-term RCTs assessing the exclusive effectiveness of dietary modification for the primary prevention of clinical CVD events or T2D. Results, however, indicate that various healthy diets may be modestly effective for primary prevention.

Introduction: Recent evidence suggests that dietary proteins modulate the microbial composition and metabolite production to influence host physiology. Gut-microbiota-related metabolites, such as trimethylamine N-oxide (TMAO) and its precursors, phenylacetylglutamine (PAGln) and p-tolyl (cresol) sulfate, have been recently implicated as atherogenic metabolites derived from the microbial metabolism of protein foods (such as red meat) and amino acids. Hypothesis: We tested a hypothesis that combined effects of atherogenic gut microbiota-related metabolites may be strongly related to the risk of incident coronary heart disease (CHD) among women. Methods: We conducted a prospective nested case-control study of 762 incident cases of CHD (fatal CHD and nonfatal myocardial infarction) and 762 matched controls identified over 10-14 years of follow-up. Plasma metabolites (TMAO, N,N,N-trimethyllysine, PAGln, and p-tolyl (cresol) sulfate) were measured at baseline. We regressed the CHD outcome against metabolites using conditional logistic regression and then calculated an atherogenic microbial metabolite score (AMMS) of CHD by summing the β effects of metabolites. Results: Every 1 SD increment of AMMS was associated with a matching factor-adjusted RR of 1.28 (95% CI: 1.15, 1.44) and a multivariable-adjusted RR of 1.26 (1.12, 1.42) for CHD controlling for demographic, dietary, and lifestyle factors, postmenopausal hormone use, and body mass index. Dose-response analysis showed a linear relation between AMMS and the risk of CHD ( P Fig ). Conclusions: Atherogenic gut microbiota-related metabolite scores were significantly associated with risk of incident CHD among women without prior CHD.

Background: The effect of omega-3 (n-3) treatment on cardiovascular disease (CVD) outcomes in randomized controlled trials remains inconsistent. We hypothesize that the downstream products of n-3 metabolism, including bioactive lipids (BALs), have a heterogeneous relationship with CVD, which may provide insight into response heterogeneity. Methods: Using state of the art LC-MS, we assayed the plasma bioactive lipidome (>10K BALs) across 3,512 individuals at baseline and Y1 or -2, in the VITAL substudies (CVD case control N=1540; CTSC subcohort N=1054; 45% women, median age 70, 20% non-white) and JUPITER CVD case control (N=918) (NCT01169259, NCT00239681). Linear regression revealed BALs that change consistently with n-3 treatment (n3BALs) (discovery in VITAL controls, validation in an independent VITAL CTSC substudy, cumulative FDR .05). n3BALs that are also associated with CVD in VITAL CVD were identified using adjusted conditional logistic regression (p Results: 354 BALs changed in response to randomized n-3 vs placebo. Baseline levels of 8 of these BALs were significantly associated with incident CVD (Figure, panels A, B). When combined into the multivariable BAL score, 5 were inversely and 3 positively associated with the CVD risk. The BAL score was significantly associated with CVD with fully adjusted HR/SD of 1.32, 95%CI [1.12 - 1.55] in external study, Figure panel C. N-3 therapy, statin therapy and baseline fish intake were associated with weak Y1 or -2 reduction in BAL score. Conclusions: Downstream BALs are altered in response to n-3 treatment and associate with both decreased as well as increased risk of CVD. BAL response to n-3 treatment may explain clinical heterogeneity associated with fish oil supplementation and may be utilized for selection of more specific treatment.

Background: Average life expectancy has increased substantially in recent decades in most developed countries; however, a sizable proportion of the increased life expectancy is spent in suboptimal health. Hypothesis: We investigated whether levels of cardiovascular health (CVH), estimated by the American Heart Association’s newly released Life’s Essential 8 (LE8) metrics, was associated with life expectancy free of major chronic disease including cardiovascular disease (CVD), diabetes, cancer, and dementia, in UK adults. Methods: This study included 136,599 adults in the UK Biobank who were initially free of CVD, diabetes, cancer, and dementia and had complete data on LE8 metrics. Eight components were used to create the LE8 score, including diet, physical activity, tobacco/nicotine exposure, sleep, body mass index, non-high-density-lipoprotein cholesterol, blood glucose and blood pressure. Multistate life tables were applied to calculate the total life expectancy and years lived with and without diseases (CVD, diabetes, cancer, and dementia) according to adherence to the levels of CVH (poor, intermediate and ideal) in men and women. Results: Compared to those with poor CVH (referent), men and women with ideal CVH had an average 5.2 (95 % CI, 3.6 to 6.8) and 6.3 (95% CI, 4.9 to 7.9) more years of total life expectancy at age 50, respectively. The percentage of life expectancy free of chronic diseases out of total life expectancy was 75.9% for men and 83.4% for women who had ideal CVH, compared to 64.9% and 69.4%, respectively, for those with poor CVH. Moreover, we found that disparities in disease-free years related to low socioeconomic status were substantially narrowed by adhering to ideal CVH in both men and women. Conclusions: Adherence to ideal CVH, evaluated with the LE8 metrics, is associated with markedly extended life expectancy and more years lived free of major chronic diseases, as well as narrowing of socioeconomic health inequalities, in both men and women.

Background: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a recently completed randomized, double-blind, placebo-controlled, 2x2 factorial trial of a multivitamin and cocoa extract supplement (containing 500 mg/d flavanols) in 21,442 older adults. In view of favorable effects of multivitamins on cognition and promising signals for cardiovascular risk reduction with cocoa extract, we conducted a pilot study to explore whether these interventions affected gut microbial composition and function. Methods: We conducted deep shotgun metagenomic sequencing in 30 COSMOS participants using fecal samples collected at baseline and year 2. We performed taxonomic profiling using MetaPhlAn2 and functional profiling using HUMAnN2. After proper quality filtering, we analyzed effects of both interventions on 2-year changes in microbial features, adjusting for age, sex, and body mass index. Results: Cocoa extract supplementation significantly altered the overall gut microbial taxonomic compositions from baseline to year 2, and explained 5.5% of the variance in the 2-year changes in relative abundance of all microbial species ( P =0.008). We further found that randomized cocoa extract supplementation altered the relative abundance of a few microbial species, including those previously linked to anti-inflammatory and cardiometabolic benefits (e.g., Akkermansia muciniphila , nominal P de novo biosynthesis, FDR=0.03, and 28 other pathways with nominal P P Summary: Our pilot study suggests that cocoa extract and multivitamin supplementation in COSMOS may alter the gut microbiome and influence pathways relevant to health, emphasizing the need for larger studies that allow for more detailed investigations.

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: The potential health effects of dietary glutamine and glutamate have been studied in healthy populations, but evidence among individuals with type 2 diabetes (T2D) who have altered macronutrient metabolism and elevated cardiovascular disease (CVD) risk is limited. Objectives: We aimed to examine dietary glutamine and glutamate in relation to subsequent risk of CVD, including coronary heart disease and stroke, and all-cause and cause-specific mortality among individuals with T2D. Methods: We prospectively followed 15,040 men and women with T2D at baseline or diagnosed during follow-up (Nurses' Health Study: 1980-2014, Health Professionals Follow-Up Study: 1986-2018). Diet was repeatedly assessed using validated food frequency questionnaires every 2-4 years since baseline. Associations of energy-adjusted glutamine and glutamate intake, as well as their ratio, with CVD risk and mortality were assessed using Cox proportional hazards models with adjustments for demographics, dietary and lifestyle factors, and medical history. Results: During 196,955 and 225,371person-years of follow-up in participants with T2D, there were 2,927 incident CVD cases and 4,898 deaths, respectively. Higher intake of glutamine was associated with lower risk of incident CVD, total mortality and CVD mortality: comparing extreme quintiles, the HRs (95%CIs) were 0.88 (0.77, 0.99), 0.85 (0.77, 0.94), and 0.82 (0.69, 0.98), respectively (all P trend P trend Conclusions: In patients with T2D, dietary glutamine and glutamate demonstrated divergent associations with CVD incidence and mortality, and higher dietary glutamine-to-glutamate ratio was significantly associated with lower CVD incidence and mortality. These data suggest a potential critical role of these two amino acids in the etiology of cardiometabolic diseases and early deaths also among adults with T2D.

Introduction: Adverse pregnancy outcomes (APOs) have been linked with maternal mortality, higher risk of metabolic and cardiovascular diseases, and adverse neonatal outcomes. The World Health Organization recommends the adoption of a healthy lifestyle (maintaining a normal BMI, not smoking, regular exercise, healthy diet, avoiding harmful alcohol intake, and multivitamin supplementation) before conception to improve pregnancy health. However, the combined effect of these lifestyle factors on reducing APOs is unknown. Hypothesis: Adherence to healthy lifestyle prior to pregnancy may be associated with a lower risk of subsequent development of APOs. Methods: We followed 15,509 women without chronic diseases (27,135 pregnancies) and participating in an ongoing cohort in the United States, the Nurses’ Health Study II. Healthy lifestyle factors preceding pregnancy were prospectively assessed every 2 to 4 years from 1991 to 2009, using validated measures. Reproductive history was self-reported in 2001 and 2009. A composite outcome of APOs included miscarriage, ectopic pregnancy, gestational diabetes, gestational hypertension, preeclampsia, preterm birth, stillbirth, and low birth weight ( Results: The mean (SD) maternal age was 35.1 (4.2) years. Nearly one in three pregnancies (N=9,702, 35.8%) were complicated with an APO. All healthy lifestyle factors, except alcohol consumption, were independently associated with APOs after mutual adjustment for each other. The combination of 6 low-risk factors (BMI=18.5-24.9 kg/m 2 , non-smoking, ≥150 minutes/week of moderate to vigorous physical activity, healthy eating (top 40% of Dietary Approaches to Stop Hypertension score), low-to-moderate alcohol intake (P trend2 but did not differ by parity. If the relationships were causal, 10% of APOs in the study population could have been prevented by the adoption of all 6 healthy lifestyle factors (population attributable risk=10%, 95% CI=6%-14%). Conclusions: Our findings suggest that pre-conception healthy lifestyle is associated with a substantially lower risk of APOs and could be an effective intervention for the prevention of APOs and their downstream long-term maternal and offspring health consequences.

Introduction: Hypothalamic amenorrhea (HA) is a neuroendocrine disorder characterized by ovulatory dysfunction, anovulation, and infertility, which can be prolonged for months to years. Menstrual cycle irregularity and amenorrhea identify individuals with higher CVD risk, but existing evidence has not examined HA separately from polycystic ovary syndrome (PCOS). It remains unknown whether HA is associated with CVD events across the lifecourse. Hypothesis: We hypothesized that the HA phenotype (oligo/amenorrhea without PCOS traits) would identify individuals at increased risk for CVD. Methods: Nurses’ Health Study II participants with available information on menstrual cycle characteristics who were premenopausal and free of CVD at baseline comprised the analytic sample (n=83,281). Menstrual cycle regularity was retrospectively reported for ages 18-22y on the baseline questionnaire in 1989 while the 1993 biennial questionnaire captured current menstrual cycle regularity (at ages 29-49y); PCOS traits (severe acne, hirsutism) were additionally ascertained in 1993. Participants were followed for confirmed incident CVD (MI, stroke, and fatal CHD) from 1993 through 2017. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the relationship between HA and CVD, adjusted for age, race/ethnicity, parental education, parental history of CVD Results: Thirteen percent of participants (n=11,071) ever had HA: 8.5% of participants (n=7,081) had HA at ages 18-22y while 6.5% (n=5,428) had HA at ages 29-46y. Persistent HA (HA at both 18-22y and 29-46 y) was identified in 1.7% of participants (n=1,438). CVD events occurred in 253 individuals who ever had HA (HA at either 18-22y or 29-46y) and 1,228 individuals without the HA phenotype. Individuals who ever had HA had a 20% higher rate of CVD (CI: 1.05-1.38). HA phenotype at ages 18-22y was not associated with CVD risk (HR=1.14; CI: 0.96-1.35) while HA phenotype at ages 29-46y was associated with a 30% higher rate of CVD (CI: 1.10-1.54) compared to individuals without HA phenotype. Individuals with persistent HA across both age ranges had a 69% higher rate of CVD (CI: 1.24-2.28). Underlying associations were strongest between ever HA and stroke (HR=1.25; CI: 1.03-1.51) and between persistent HA and CHD (HR=1.90; CI: 1.27-2.86), although case counts were small. Conclusions: HA phenotype in mid-adulthood identified individuals at increased risk of CVD compared to those without HA. As there are multiple HA subtypes, defined by varying combinations of psychosocial stress, anxiety, physical activity and weight loss, future studies should examine which HA subtypes are associated with CVD risk.

OBJECTIVE The present study aims to prospectively examine the association between post-diagnosis low carbohydrate diet (LCD) patterns and mortality among individuals with type 2 diabetes (T2D). RSEARCH DESIGN AND METHODS Among participants with incident diabetes identified in the Nurses’ Health Study and Health Professionals Follow-Up Study, an overall total low carbohydrate diet score (TLCDS) was calculated based on the percentage of energy as total carbohydrates. In addition, vegetable (VLCDS), animal (ALCDS), healthy (HLCDS), and unhealthy LCDS (ULCDS) were further derived that emphasized different sources and quality of macronutrients. Multivariable-adjusted Cox model were used to assess the association between the LCDS and mortality. RESULTS Among 10,101 incident T2D cases contributing 139,407 person-years during follow-up, we documented 4,595 deaths of which 1,389 cases were attributed to cardiovascular disease (CVD) and 881 to cancer. The pooled multivariable-adjusted hazard ratios (HRs, 95% CIs) of total mortality per 10 points increment of post-diagnosis LCDS were 0.87 (0.82,0.92) for TLCDS, 0.76 (0.71,0.82) for VLCDS, and 0.78 (0.73,0.84) for HLCDS. Both VLCDS and HLCDS were also associated with significantly lower CVD and cancer mortality. Each 10 points increase of TLCDS, VLCDS, and HLCDS from pre-diagnosis to post-diagnosis period was associated with 12% (7%, 17%), 25% (19%, 30%), and 25% (19%, 30%) lower total mortality, respectively. No significant associations were observed for ALCDS and ULCDS. CONCLUSIONS Among people with T2D, greater adherence to LCD patterns that emphasize high quality sources of macronutrients was significantly associated with lower total, cardiovascular, and cancer mortality.