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BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D(3) would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D(3) (2000 IU per day), n–3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D(3), as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. CONCLUSIONS: Vitamin D(3) supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.)

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 %.

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.

Sudden cardiac death from arrhythmia is a major cause of mortality worldwide. In this study, we developed a novel deep learning (DL) approach that blends neural networks and survival analysis to predict patient-specific survival curves from contrast-enhanced cardiac magnetic resonance images and clinical covariates for patients with ischemic heart disease. The DL-predicted survival curves offer accurate predictions at times up to 10 years and allow for estimation of uncertainty in predictions. The performance of this learning architecture was evaluated on multi-center internal validation data and tested on an independent test set, achieving concordance indexes of 0.83 and 0.74 and 10-year integrated Brier scores of 0.12 and 0.14. We demonstrate that our DL approach, with only raw cardiac images as input, outperforms standard survival models constructed using clinical covariates. This technology has the potential to transform clinical decision-making by offering accurate and generalizable predictions of patient-specific survival probabilities of arrhythmic death over time.

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.

The VITAL study was a nationwide, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of vitamin DTo investigate the effects of vitamin DSerum levels of four inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6, interleukin-10, and tumor necrosis factor-α) were measured in a total of 2713 samples from those 1054 VITAL/CCI participants (aged 64.9 ± 6.5 years, 49% female, 84% white, and 9% black) at baseline, year 2, and year 4 follow-up visits.In multiple-adjusted models, vitamin DVitamin D

A familial predisposition to sudden and/or arrhythmic death (SAD) in the setting of coronary artery disease (CAD) exists; however, the genetic basis is poorly understood.The purpose of this study was to determine whether a genome-wide polygenic score for coronary artery disease (GPSA previously validated GPSOver a median follow-up of 8.0 years, participants in the top GPSAmong CAD patients without severe systolic dysfunction, high GPS

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations ( 20 nmol/L, 3% of controls) or high concentrations (100- 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

BACKGROUND: Circulating branched-chain amino acids (BCAAs—isoleucine, leucine, and valine) are strongly associated with higher risk of incident type 2 diabetes (T2D); however, determinants of elevated fasting BCAA concentrations are largely unknown. OBJECTIVES: We aimed to characterize the modifiable lifestyle factors related to plasma BCAAs. METHODS: We performed a cross-sectional analysis among n = 18,897 women (mean ± SD age: 54.9 ± 7.2 y) in the Women's Health Study, free of T2D and cardiovascular disease at baseline blood draw. Lifestyle factors, weight, and height were self-reported via questionnaire, including smoking status, alcohol, leisure-time physical activity (LTPA), diet quality scores [2010 Alternative Healthy Eating Index (without alcohol) (aHEI); alternate Mediterranean Diet (aMED)], and dietary sources of BCAAs. Plasma BCAAs were quantified via NMR spectroscopy. We calculated multivariable-adjusted percentage mean differences (95% CIs) and P values for linear trend of BCAAs stratified by categoric lifestyle factors. We estimated R(2) from univariate cubic spline regression models to estimate the variability in BCAAs explained. RESULTS: Compared with women with BMI (in kg/m(2))

Context It is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting. Objective The objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk. Design VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT including 25 871 adults, randomly assigned November 2011 to March 2014 and treated for 5.3 years (median). Setting This is a nationwide study. Participants Men 50 years or older and women 55 years or older (mean age, 67.1 years) without cancer or cardiovascular disease at baseline participated in this study. Interventions Interventions included vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (1 g/day) or respective placebos in a 2 × 2 factorial design. Main Outcome Measures Main outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit. Results Baseline serum total 25-hydroxyvitamin D (25[OH]D) level was 77 nmol/L; characteristics were well-balanced between groups. Numbers of participants with 2 or more falls were similar between active and placebo groups (9.8% vs 9.4%). Over 5 years, there were no differences in the proportion having 2 or more falls (odds ratio [OR] = 0.97; 95% CI, 0.90-1.05, P = .50), falls resulting in a doctor visit (OR = 1.03; 95% CI, 0.94-1.13, P = .46), or resulting in a hospital visit (OR = 1.04; 95% CI, 0.90-1.19, P = .61) between groups. Results did not differ between those with baseline 25(OH)D less than 50 vs 50 nmol/L or greater or other cut points. Conclusion Daily supplemental vitamin D3 vs placebo did not decrease fall risk in generally healthy adults not selected for vitamin D insufficiency. This large RCT does not indicate that supplemental vitamin D should be used for primary prevention of falls in the US population.

BACKGROUND: Elevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease. OBJECTIVES: The purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD). METHODS: In a prospective case-cohort study within the Women’s Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. RESULTS: The risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR](Q4): 3.05 [95% confidence interval (CI): 1.46 to 6.39]; ptrend = 0.002; PAD HR(Q4): 2.58 [95% CI: 1.18 to 5.63]; p(trend) = 0.019), whereas sdLDL-C was significantly associated with MI alone (HR(Q4): 3.71 [95% CI: 1.59 to 8.63]; p(trend) < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B

BACKGROUND: Elevated postprandial triglycerides reflect a pro-atherogenic milieu, but underlying mechanisms are unclear. OBJECTIVE: We examined differences between fasting and nonfasting profiles of directly measured lipoprotein size and subfractions to assess if postprandial triglycerides reflected increases in very low density and intermediate density lipoproteins (VLDL and IDL) and remnants, or small dense lipid depleted LDL particles (sdLDL). METHODS: We conducted a cross-sectional analysis of 15,397 participants (10,135 fasting; 5262 nonfasting [0.05). CONCLUSIONS: Directly measured particle and cholesterol concentrations of VLDL, not sdLDL, were higher nonfasting and may partly contribute to the pro-atherogenicity of postprandial hypertriglyceridemia. These differences, although statistically significant, were small and may not fully explain the increased risk of postprandial hypertriglyceridemia. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique identifier: NCT01169259.

Background The relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method. Methods We included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis. Results Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94). Conclusions Higher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).

ImportanceWomen have a lower incidence of atrial fibrillation (AF) compared with men in several studies, but it is unclear whether this sex difference is independent of sex differences in prevalent cardiovascular disease (CVD), body size, and other risk factors.ObjectiveTo examine sex differences in AF incidence and whether AF risk factors differ by sex in a contemporary cohort of men and women without prevalent CVD.Design, Setting, and ParticipantsThis was a prospective cohort analysis within the Vitamin D and Omega-3 Trial (VITAL) Rhythm Study, a randomized trial that examined the effect of vitamin D and ω-3 fatty acid supplementation on incident AF among men 50 years or older and women 55 years or older without a prior history of prevalent AF, CVD, or cancer at baseline. Data were analyzed from September 29, 2020, to June 29, 2021.ExposuresSex, height, weight, body mass index (BMI), body surface area (BSA), and other AF risk factors at study enrollment.Main Outcomes and MeasuresIncident AF confirmed by medical record review.ResultsA total of 25 119 individuals (mean [SD] age, 67.0 [7.1] years; 12 757 women [51%]) were included in this study. Over a median (IQR) follow-up of 5.3 (5.1-5.7) years, 900 confirmed incident AF events occurred among 12 362 men (495 events, 4.0%) and 12 757 women (405 events, 3.2%). After adjustment for age and treatment assignment, women were at lower risk for incident AF than men (hazard ratio [HR], 0.68; 95% CI, 0.59-0.77; P P P = .001), height and weight (HR 1.49, 95% CI, 1.21-1.82; P P = .009) were substituted for BMI in the multivariate model. In stratified models, risk factor associations with incident AF were similar for women and men.Conclusions and RelevanceIn this cohort study, findings suggest that after controlling for height and/or body size, women without CVD at baseline were at higher risk for AF than men, suggesting that sex differences in body size account for much of the protective association between female sex and AF. These data underscore the importance of AF prevention in women.

Purpose of Review The scientific consensus on which global health organizations base public health policies is that high sodium intake increases blood pressure (BP) in a linear fashion contributing to cardiovascular disease (CVD). A moderate reduction in sodium intake to 2000 mg per day helps ensure that BP remains at a healthy level to reduce the burden of CVD. Recent Findings Yet, since as long ago as 1988, and more recently in eight articles published in the European Heart Journal in 2020 and 2021, some researchers have propagated a myth that reducing sodium does not consistently reduce CVD but rather that lower sodium might increase the risk of CVD. These claims are not well-founded and support some food and beverage industry’s vested interests in the use of excessive amounts of salt to preserve food, enhance taste, and increase thirst. Nevertheless, some researchers, often with funding from the food industry, continue to publish such claims without addressing the numerous objections. This article analyzes the eight articles as a case study, summarizes misleading claims, their objections, and it offers possible reasons for such claims. Summary Our study calls upon journal editors to ensure that unfounded claims about sodium intake be rigorously challenged by independent reviewers before publication; to avoid editorial writers who have been co-authors with the subject paper’s authors; to require statements of conflict of interest; and to ensure that their pages are used only by those who seek to advance knowledge by engaging in the scientific method and its collegial pursuit. The public interest in the prevention and treatment of disease requires no less.

Falls and decreased physical function increase markedly with age and result in injury, hospitalization, and premature death. Emerging studies show potential benefits of supplemental cocoa extract on physical performance, including grip strength and walking speed in older adults. However, there are no large, long-term randomized controlled trials of effects of supplemental cocoa extract on falls, muscle performance, and/or fall-related injuries.The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a double-blind, placebo-controlled, 2 × 2 factorial trial investigating effects of supplementation with cocoa extract (500 mg/d, including 80 mg (-)-epicatechin) and/or a multivitamin on prevention of cardiovascular disease and cancer in 21,442 women (≥65 years) and men (≥60 years).Effects on Falls and Physical Performance is an ancillary study to COSMOS that will clarify effects of cocoa extract and/or multivitamin supplementation on falls, physical performance, and incident fracture outcomes in older adults. Injurious fall(s) resulting in healthcare utilization and recurrent falls were regularly assessed by follow-up questionnaires in the overall cohort. Incident fractures were also assessed by annual questionnaires. Circumstances surrounding falls and any fall-related injuries will be confirmed by medical record review. Effects of the interventions on 2-year changes in physical performance measures (grip strength, walking speed, and the Short Physical Performance Battery) will be tested in a clinic sub-cohort (n = 603).Results from this ancillary study will determine whether supplemental cocoa extract slows age-related declines in physical performance and decrease injurious and recurrent falls and fall-related injuries and fractures that are major public health problems in older adults.

ImportanceIn the Vitamin D and Omega-3 Trial (VITAL), the effects of randomized vitamin D supplementation (cholecalciferol), 2000 IU/d, reduced the risk of several health outcomes among participants with normal, but not elevated, body weights. It was unclear whether weight had any association with the outcomes of the supplementation.ObjectiveTo investigate whether baseline body mass index (BMI) modifies vitamin D metabolism and response to supplementation.Design, Setting, and ParticipantsVITAL is a completed randomized, double-blind, placebo-controlled trial for the primary prevention of cancer and cardiovascular disease. In the present cohort study, an analysis was conducted in a subset of VITAL participants who provided a blood sample at baseline and a subset with a repeated sample at 2 years’ follow-up. VITAL was conducted from July 1, 2010, to November 10, 2018; data analysis for the present study was conducted from August 1, 2021, to November 9, 2021.InterventionsTreatment outcomes of vitamin D, 2000 IU/d, supplementation vs placebo associated with clinical and novel vitamin D–related biomarkers by BMI category adjusted for other factors associated with vitamin D status.Main Outcomes and MeasuresMultivariable-adjusted means (SE) or 95% CIs of vitamin D–related serum biomarkers at baseline and follow-up: total 25-hydroxyvitamin D (25-OHD), 25-OHD3, free vitamin D (FVD), bioavailable vitamin D (BioD), vitamin D–binding protein (VDBP), albumin, parathyroid hormone (PTH), and calcium, and log-transformed as needed.ResultsA total of 16 515 participants (mean [SD] age, 67.7 [7.0] years; 8371 women [50.7%]; 12420 non-Hispanic White [76.9%]) were analyzed at baseline, including 2742 with a follow-up blood sample. Before randomization, serum total 25-OHD levels were incrementally lower at higher BMI categories (adjusted mean [SE]: underweight, 32.3 [0.7] ng/mL; normal weight, 32.3 [0.1] ng/mL; overweight, 30.5 [0.1] ng/mL; obesity class I, 29.0 [0.2] ng/mL; and obesity class II, 28.0 [0.2] ng/mL; P P P Conclusions and RelevanceIn this randomized cohort study, vitamin D supplementation increased serum vitamin D–related biomarkers, with a blunted response observed for participants with overweight or obesity at baseline. These longitudinal findings suggest that BMI may be associated with modified response to vitamin D supplementation and may in part explain the observed diminished outcomes of supplementation for various health outcomes among individuals with higher BMI.

ImportanceStatin-associated muscle symptoms (SAMS) are common and may lead to discontinuation of indicated statin therapy. Observational studies suggest that vitamin D therapy is associated with reduced statin intolerance, but no randomized studies have been reported.ObjectiveTo test whether vitamin D supplementation was associated with prevention of SAMS and a reduction of statin discontinuation.Design, Setting, and ParticipantsMen 50 years or older and women 55 years or older, free of cancer and cardiovascular disease, were enrolled in a randomized, placebo-controlled, double-blind clinical trial of vitamin D supplementation. Participants who initiated statin therapy after randomization were surveyed in early 2016. The data were analyzed in early 2022.InterventionsDaily cholecalciferol (2000 international units) or placebo with assessment of statin prescriptions during follow-up.Main Outcomes and MeasuresMuscle pain or discomfort lasting several days (primary outcome) and discontinuation of a statin due to SAMS (secondary outcome).ResultsStatins were initiated by 1033 vitamin D–assigned participants and 1050 placebo-assigned participants; mean (SD) age was 66.8 (6.2) years and 49% were women. Over 4.8 years of follow-up, SAMS were reported by 317 participants (31%) assigned vitamin D and 325 assigned placebo (31%). The adjusted odds ratio (OR) was 0.97 (95% CI, 0.80-1.18; P = .78). Statins were discontinued by 137 participants (13%) assigned to vitamin D and 133 assigned to placebo (13%) with an adjusted OR of 1.04 (95% CI, 0.80-1.35; P = .78). These results were consistent across pretreatment 25-hydroxy vitamin D levels (interaction P value = .83). Among participants with levels less than 20 ng/mL, SAMS were reported by 28 of 85 vitamin D–assigned participants (33%) and 33 of 95 placebo-assigned participants (35%). For those with levels less than 30 ng/ml, SAMS were reported by 88 of 330 vitamin–D assigned participants (27%) and 96 of 323 of placebo-assigned participants (30%).Conclusions and RelevanceVitamin D supplementation did not prevent SAMS or reduce statin discontinuation. These results were consistent across pretreatment 25-hydroxy vitamin D levels.Trial RegistrationClinicalTrials.gov Identifier: NCT01169259

BACKGROUND Observational studies suggest vitamin D and marine ω-3 fatty acid (n-3 FA) supplements are associated with lower systemic inflammation. However, past trials have been inconsistent. METHODS The randomized, double-blind, placebo-controlled VITamin D and OmegA-3 TriaL (VITAL) tested vitamin D (2000 IU/day) and/or n-3 FA (1 g/day) supplementation in a 2 × 2 factorial design among women ≥55 and men ≥50 years of age. We assessed changes in interleukin (IL)-6, tumor necrosis factor receptor 2 (TNFR2), and high-sensitivity C-reactive protein (hsCRP) concentrations from baseline to 1 year among participants randomized to vitamin D + n-3 FA (392), vitamin D (392), n-3 FA (392), or placebo only (385). Geometric means and percent changes were compared, adjusting for baseline factors. RESULTS Baseline characteristics were well balanced. In the active arms, 25-OH vitamin D rose 39% and n-3 FA rose 55% vs minimal change in placebo arms. Neither supplement reduced biomarkers at 1 year. Vitamin D resulted in 8.2% higher IL-6 (95% CI, 1.5%–15.3%; adjusted P = 0.02), but TNFR2 and hsCRP did not. Among 784 receiving vitamin D, hsCRP increased 35.7% (7.8%–70.9%) in those with low ( CONCLUSIONS In this large sample from a population-based randomized controlled trial, neither vitamin D nor n-3 FA supplementation over 1 year decreased these biomarkers of inflammation. ClinicalTrials.gov Identifier NCT01169259; NCT01351805

Objectives To determine associations between geographic region and late-life depression (LLD) severity, item-level symptom burden, and treatment; to evaluate whether racial/ethnic disparities in LLD, previously observed in the overall sample, vary by region. Methods We included 25,502 VITAL (Vitamin D and Omega-3 Trial) participants and administered the Patient Health Questionnaire-8 for depressive symptoms; participants also reported medication and/or counseling care for depression. Multivariable regression analyses were performed. Results Despite overall lower LLD severity and item-level symptom burden in the Midwest vs. Northeast, higher LLD severity and item-level burden were observed among minorities, especially Black and Hispanic adults, compared to non-Hispanic whites in this region. Racial/ethnic disparities in item-level symptoms (e.g., anhedonia, sadness, psychomotor changes) varied by region. There were no significant differences in depression care by region; furthermore, regional variation was not observed in racial disparities in care: e.g., among those with clinician/physician-diagnosed depression, Blacks vs. non-Hispanic whites had >50% lower odds of treatment in all regions. Conclusion LLD varied by geographic region. Furthermore, magnitudes of racial/ethnic disparities in LLD severity and item-level symptom burden, but not depression care, differed by region.

Introduction: Few post-MI or CHD patients fulfill guideline-based criteria for ICD implantation; however, limited data exist regarding the proportion and predictors of patients who subsequently undergo ICD implantation during long term follow-up. Methods: PREDETERMINE [NCT01114269] is an ongoing, prospective, multicenter cohort of adults with CHD and mild-moderate left ventricular dysfunction (LVEF=35-50%) and/or history of MI not meeting guideline criteria for primary prevention ICD at inclusion based on LVEF and NYHA. ICD implantation events/indications were captured. Multivariable Cox regression was used to estimate the hazard ratios for the outcome of ICD implantation using demographic, clinical, ECG, and biomarker parameters as prespecified covariates. Results: In 5738 patients (mean age=64.4, 76.2% male, mean LVEF=52.1%), 293 ICD implantations (5.1%) occurred over a median follow-up of 7.3 years. Of these, 217 were for primary prevention, 65 for secondary prevention, and 11 for unclear indications. In age-adjusted models, patients who received an ICD differed according to several clinical, ECG, and biomarker parameters [Table]. After multivariable adjustment, male sex, HTN, prior CABG, contiguous Q waves on ECG, QRS duration > 110 ms, and NT-proBNP levels were directly associated with ICD implantation, while age, LVEF and CRP were negatively associated [Table]. In multivariable models, ICD implantation was associated with a trend towards reduced mortality (HR=0.80; 95% HR, 0.62-1.03, P=0.08). Conclusion: In this long-term prospective cohort of CHD patients without ICD indications at baseline, 5% of the population underwent ICD implantation, which was associated with a trend toward reduced mortality. Several clinical factors were independently associated with ICD implant and may assist in the identification of subgroups of CHD patients at risk for worsening LV dysfunction and/or sustained ventricular arrhythmias.

Introduction: Insulin resistance is central to the development of type 2 diabetes (T2D). Association between specific biomarkers of glucose-insulin homeostasis and T2D have been inconsistent. Whether vitamin D or omega-3 fatty acids (n-3 FA) can modify these associations is also unclear. Hypothesis: We hypothesized that higher insulin, C-peptide, insulin resistance score (IRS), and HbA1c are each associated with higher T2D risk, and that these associations would be attenuated among participants who received vitamin D or n-3 FA. Methods: VITAL Diabetes (NCT01633177) was a pre-specified ancillary 2x2 factorial study in the VITAL RCT to assess whether vitamin D (cholecalciferol, 2000 IU/d) or n-3 FA (EPA + DHA, 1 g/d) could prevent T2D. Subjects without baseline reported T2D and with HbA1c Results: Mean age of participants was 66 years, approximately 45% were female, and 16% were African American. Each of the glucose-insulin homeostasis biomarkers was associated with T2D risk ( Table 1 ), aOR (95% CI) per SD increment, insulin: 1.46 (1.10, 1.94), C-peptide: 1.72 (1.28, 2.31), IRS: 1.59 (1.26, 2.01), and HbA1c: 80.43 (25.90, 249.77). Biomarker associations did not differ by randomized treatment ( P interaction >0.05). Conclusions: In VITAL Diabetes, insulin, C-peptide, IRS, and HbA1c were each associated with an increased risk of T2D, independent of other risk factors. Randomization to either vitamin D or n-3 FA did not modify these associations.

Introduction: Dysglycemia and insulin resistance increase cardiovascular disease (CVD) risk. Associations between specific glucose-insulin biomarkers and CVD have been inconsistent. Hypothesis: We hypothesized that higher insulin, C-peptide, insulin resistance score (IRS), and HbA1c are associated with incident CVD and coronary heart disease (CHD) events and that both vitamin D and omega-3 fatty acids (n-3 FA) would improve these biomarkers and attenuate their risks with CVD. Methods: VITAL (NCT01169259) was a 2x2 factorial design RCT testing vitamin D (cholecalciferol, 2000 IU/d) and n-3 FA (EPA+DHA, 1 g/d) for the primary prevention of CVD. Incident CVD cases [non-fatal myocardial infarction (MI), non-fatal stroke, or CV death] were matched 1:1 on age and sex to healthy controls (n=715 CVD pairs including 423 CHD [MI, revascularization, CHD death] pairs). Conditional logistic regression adjusting for demographics, CV risk factors, and randomized treatment was used to assess the adjusted odds ratio (aOR) and 95% CI between baseline levels of insulin, C-peptide, IRS (Insulinх0.0265+C-peptideх0.00511+Creatinineх-3.2641), and HbA1c with risk of CVD and CHD events. In control participants, we examined the randomized effects of vitamin D or n-3 FA on changes in these biomarkers at 1- or 2-years follow-up. Results: Mean age of participants was 71 years, approximately 42% were female, and 12% were African American. Baseline insulin, C-peptide, and IRS were not associated with CVD ( Figure 1 ). HbA1c was associated with CVD risk, aOR (95% CI) per SD increment, 1.17 (1.01, 1.38). Of the 4 biomarkers, only IRS was associated with CHD risk, aOR (95% CI): 1.22 (1.01, 1.46). Randomization to vitamin D or n-3 FA did not modify levels of these biomarkers or their associations. Conclusions: HbA1c was significantly associated with CVD risk, whereas IRS was associated with CHD risk. Neither vitamin D nor n-3 FA appreciably modified these biomarker levels or their risk associations.

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: To better understand the cardioprotective mechanisms of regular physical activity (PA), we examined its association with plasma bioactive lipids (BAL) and prospective cardiovascular disease (CVD) events and evaluated the extent to which BMI might mediate this association. Hypothesis: 1) Higher PA associates with a bioactive lipid profile related to lower CVD risk; 2) BMI mediates the PA-BAL and BAL-CVD associations. Methods: Using linear models (adjusted for age, sex, race, smoking, LDL, and total cholesterol), self-reported PA was examined with BAL assayed by an untargeted metabolomics platform in VITAL (N=1032) with validation in JUPITER (N=589). After performing mediation analysis through BMI (same adjustments), we evaluated both BMI-mediated and non-mediated PA-BAL associations with incident CVD using similarly adjusted conditional logistic regression in two nested CVD case-control studies: VITAL-CVD (770 pairs, followed by mediation analysis) and JUPITER-CVD (415 case-control pairs - validation) Results: We detected 237 significant PA-BAL associations in VITAL with replication in JUPITER (FDRvice-versa . Conclusion: We identified a signature of 22 PA-related BAL, which were also associated with incident CVD in two independent case-control studies. Although BMI-mediated associations were predominant, non-mediated effects were also detected, implying that more than one pathway may play a role in the PA-CVD relationship.