Impact of increased protein intake in older adults: a 12-week double-blind randomised controlled trial.

BACKGROUND: Emerging evidence suggests health-promoting properties of increased protein intake. There is increased interest in plant protein but a dearth of information in relation to its impact on muscle function. The objective of the present work was to examine the impact of intake of different types of proteins on muscle functional parameters including handgrip strength, biomarkers of metabolic health, sleep quality and quality of life in a group of older adults. METHODS: Healthy men and women aged 50 years and older entered a double-blinded, randomised, controlled nutritional intervention study with three parallel arms: high plant protein, high dairy protein and low protein. Participants consumed once daily a ready-to-mix shake (containing 20 g of protein in high protein groups) for 12 weeks. Changes in handgrip and leg strength, body composition, metabolic health, quality of life and sleep quality were analysed by linear mixed models in an intention-to-treat approach. RESULTS: Eligible participants (n = 171) were randomly assigned to the groups (plant: n = 60, dairy: n = 56, low protein: n = 55) and 141 completed the study. Handgrip strength increased after the intervention (Ptime = 0.038), with no significant difference between the groups. There was no significant difference between groups for any other health outcomes. CONCLUSIONS: In a population of older adults, increasing protein intake by 20 g daily for 12 weeks (whether plant-based or dairy-based) did not result in significant differences in muscle function, body composition, metabolic health, sleep quality or quality of life, compared with the low protein group.

Protein intake and its association with sleep quality: results from 3 prospective cohort studies.

BACKGROUND/OBJECTIVES: Sleep quality is a critical factor for daytime functioning and chronic disease risk. We investigated the association between intakes of total protein and protein subtypes and sleep quality in three U.S. cohorts. SUBJECTS/METHODS: In the Nurses' Health Study (NHS), NHS2, and Health Professionals Follow-up study (HPFS), dietary intake was assessed every 4 years using validated food frequency questionnaires. Sleep quality was measured once with the Pittsburgh Sleep Quality Index or adapted versions. With ordinal logistic regression, odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the odds of having better sleep quality versus poorer sleep quality depending on protein intake (%Energy) based on the average of the prior two dietary questionnaires. RESULTS: In 32,212 women from NHS, 51,126 women from NHS2, and 14,796 men from HPFS, total protein intake was not associated with sleep quality. However, the intake of protein from vegetable sources showed no association or a positive association with sleep quality (OR for quartile 4 versus quartile 1 in NHS: 1.12, 1.04-1.20, P-trend < 0.001; NHS2: 1.01, 0.95-1.07, P-trend = 0.90; HPFS: 1.11, 0.99-1.23, P-trend = 0.05), whereas divergent results were observed for animal protein sources. Overall, intakes of processed red meat and poultry were associated with worse sleep quality, whereas no or positive associations were observed for dairy and fish protein. CONCLUSION: Our results suggest that plants as a source of protein may be associated with better sleep quality than animal sources of protein. Further studies are warranted to validate our findings.

Protein intake and its effect on sleep outcomes: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Poor sleep is increasingly seen as an issue of public health concern. In recent years, there has been growing interest in protein as a route to improve sleep outcomes; however, the evidence is limited and inconclusive. OBJECTIVE: To examine, using a systematic review and meta-analysis, the effect of increased protein intake (≥1 g/kg//d, ≥25% of total energy intake, or protein supplementation of ≥10 g/d/) on sleep outcomes in adults. METHODS: On November 30, 2021, 5 electronic databases were searched to identify relevant randomized controlled trials (PubMed, Cochrane, Embase, Web of Science, and CINAHL Plus). Risk of bias was assessed using the Cochrane Risk-of-Bias tool, version 2.0. DATA EXTRACTION: Five sleep outcomes were included in this systematic review (sleep quality [SQ], sleep latency [SL], sleep efficiency [SEff], sleep time [ST], wake episodes, and other sleep outcomes) and 4 in the meta-analysis (SQ, SL, SEff, and ST). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA ANALYSIS: Twelve intervention studies reported on in 10 articles were included. The qualitative analyses showed that increased protein consumption has little influence on sleep outcomes. Only subjective SQ was positively associated with protein consumption in a few studies. Meta-analyses also showed no significant effect of increased protein intake on sleep outcomes (number of studies for SQ, ST, SL, and SEff: 8, 8, 7, and 6, respectively), with very low certainty of evidence. However, results from sensitivity analyses, excluding high-risk studies, suggest a small effect on SQ in favor of high protein intake (mean difference, -4.28; 95%CI, -7.77, -0.79; on a scale from 0 to 100). CONCLUSION: This systematic review and meta-analysis indicate there is no clear relationship between increased protein intake and sleep. However, the strength of the evidence is low and more randomized controlled trials that focus on this specific research question are warranted. Systematic Review Registration: PROSPERO registration no. CRD42020196021.

Obesity, Adiposity, and Risk of Symptomatic Gallstone Disease According to Genetic Susceptibility.

BACKGROUND & AIMS: Adiposity has been consistently associated with gallstone disease risk. We aimed to characterize associations of anthropometric measures (body mass index [BMI], recent weight change, long-term weight change, waist circumference, and waist-to-hip ratio) with symptomatic gallstone disease according to strata of gallstone disease polygenic risk score (PRS). METHODS: We conducted analysis among 34,626 participants with available genome-wide genetic data within 3 large, prospective, U.S. cohorts-the Nurses' Health Study (NHS), Health Professionals Follow-Up Study, and NHS II. We characterized joint associations of PRS and anthropometric measures and tested for interactions on the relative and absolute risk scales. RESULTS: Women in the highest BMI and PRS categories (BMI ≥30 kg/m2 and PRS ≥1 SD above mean) had odds ratio for gallstone disease of 5.55 (95% confidence interval, 5.29 to 5.81) compared with those in the lowest BMI and PRS categories (BMI <25 kg/m2 and PRS <1 SD below the mean). The corresponding odds ratio among men was 1.65 (95% confidence interval, 1.02 to 2.29). Associations for BMI did not vary within strata of PRS on the relative risk scale. On the absolute risk scale, the incidence rate difference between obese and normal-weight individuals was 1086 per 100,000 person-years within the highest PRS category, compared with 666 per 100,000 person-years in the lowest PRS category, with strong evidence for interaction with the ABCG8 locus. CONCLUSIONS: While maintenance of a healthy body weight reduces gallstone disease risk among all individuals, risk reduction is higher among the subset with greater genetic susceptibility to gallstone disease.

Opposing Associations of NT-proBNP With Risks of Diabetes and Diabetes-Related Complications.

OBJECTIVE: Circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) is a classic diagnostic and prognostic marker for heart failure. However, it is inversely associated with diabetes risk. We aimed to investigate relationships of NT-proBNP with risk of diabetes-related complications in initially healthy individuals. RESEARCH DESIGN AND METHODS: We performed a case-cohort study within the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort including a random subcohort (n = 1,294) and incident cases of type 2 diabetes (n = 649) and cardiovascular diseases (n = 478). Incident cases of type 2 diabetes (n = 545) were followed up for microvascular (n = 133) and macrovascular (n = 50) complications. Plasma NT-proBNP was measured at baseline in initially healthy participants. RESULTS: In multivariable models, NT-proBNP was linearly inversely associated with incident type 2 diabetes with a hazard ratio (HR) (95% CI) per doubling in NT-proBNP of 0.91 (0.86, 0.98). The association was only observable in women (0.80 [0.72, 0.90]) compared with men (0.98 [0.91, 1.07]). Among people with incident diabetes, NT-proBNP was positively associated with diabetes complications: overall, 1.31 (1.13, 1.53); microvascular complications, 1.20 (1.01, 1.43); and macrovascular complications, 1.37 (1.03, 1.83). CONCLUSIONS: Although higher NT-proBNP levels are associated with lower diabetes risk, NT-proBNP is a biomarker for vascular complications in people who develop diabetes independent of potential confounders. Thus, NT-proBNP might be informative to monitor risk for diabetes-related microvascular and macrovascular complications, which should be further explored in future prospective studies.

A healthy lifestyle pattern and the risk of symptomatic gallstone disease: results from 2 prospective cohort studies.

BACKGROUND: Symptomatic gallstones cause high financial and disease burden for public health systems. The combined role of diet and other lifestyle factors has not been studied so far. OBJECTIVES: We aimed to investigate the association between an a priori defined healthy lifestyle score (HLS, including healthy diet, moderate alcohol and regular coffee intakes, never smoking, physical activity, and normal weight) and the risk of symptomatic gallstone disease, and to estimate the proportion of cases potentially preventable by lifestyle modification. METHODS: We followed 60,768 women from the Nurses' Health Study (NHS) and 40,744 men from the Health Professionals Follow-up Study (HPFS), both ongoing prospective cohort studies, from baseline (1986) until 2012. Symptomatic gallstone disease was self-reported and validated by review of medical records. The association between the HLS and the risk of symptomatic gallstone disease was investigated using Cox proportional hazards regression. RESULTS: During 1,156,079 and 769,287 person-years of follow-up, respectively, 6946 women and 2513 men reported symptomatic gallstone disease. Comparing 6 with 0 points of the HLS, the multivariable HR of symptomatic gallstone disease was 0.26 (95% CI: 0.15, 0.45) for women, and 0.17 (95% CI: 0.07, 0.43) for men. For individual lifestyle factors, multivariable and mutually adjusted partial population attributable risks (women and men) were 33% and 23% for BMI <25 kg/m2, 10% and 18% for ≥2 cups of coffee per day, 13% and 7% for moderate alcohol intake, 8% and 11% for a high Alternate Healthy Eating Index 2010, 9% and 5% for being physically active, and 1% and 5% for never smoking. The full population attributable risk percentage for all factors combined was 62% and 74%, respectively. CONCLUSIONS: Findings from these large prospective studies indicate that adopting a healthy lifestyle, especially maintaining a healthy weight, can help to prevent a considerable proportion of symptomatic gallstone diseases.

The Role of Protein Intake and its Timing on Body Composition and Muscle Function in Healthy Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Increased protein intake has been suggested to improve gains in muscle mass and strength in adults. Furthermore, the timing of protein intake has been discussed as a margin of opportunity for improved prevention measures. OBJECTIVE: This systematic review investigated the effect of protein supplementation on body composition and muscle function (strength and synthesis) in healthy adults, with an emphasis on the timing of protein intake. METHODS: Randomized controlled trials were identified using PubMed, Web of Science, CINAHL, and Embase, up to March 2019. For meta-analyses, data on lean body mass (LBM), handgrip strength, and leg press strength were pooled by age group (mean age 18-55 or >55 y) and timing of protein intake. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations approach. RESULTS: Data from 65 studies with 2907 participants (1514 men and 1380 women, 13 unknown sex) were included in the review. Twenty-six, 8, and 24 studies were used for meta-analysis on LBM, handgrip strength, and leg press strength, respectively. The protein supplementation was effective in improving (mean difference; 95% CI) LBM in adults (0.62 kg; 0.36, 0.88) and older adults (0.46 kg; 0.23, 0.70), but not handgrip strength (older adults: 0.26 kg; -0.51, 1.04) and leg press strength (adults: 5.80 kg; -0.33, 11.93; older adults: 1.97 kg; -2.78, 6.72). Sensitivity analyses removing studies without exercise training had no impact on the outcomes. Data regarding muscle synthesis were scarce and inconclusive. Subgroup analyses showed no beneficial effect of a specific timing of protein intake on LBM, handgrip strength, and leg press strength. CONCLUSION: Overall, the results support the positive impact of protein supplementation on LBM of adults and older adults, independently of intake timing. Effects on muscle strength and synthesis are less clear and need further investigation. This systematic review was registered on PROSPERO as CRD42019126742.

Diet-quality scores and the risk of symptomatic gallstone disease: a prospective cohort study of male US health professionals.

Objective: To investigate the association between three diet-quality scores corresponding to adherence to healthy dietary patterns [alternate Mediterranean (aMed), Alternate Healthy Eating Index (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH)] and the risk of symptomatic gallstone disease. Methods: The study comprised 43 635 men of the Health Professionals Follow-up Study-an ongoing prospective cohort study of US health professionals. Participants were free of symptomatic gallstone disease and diabetes and provided dietary information every 4 years from 1986 (baseline) until 2012. The aMed, AHEI-2010 and DASH scores were generated and associated with the risk of symptomatic gallstone disease using Cox proportional hazards regression. Results: During 716 904 person-years of follow-up, 2382 incident cases of symptomatic gallstone disease were identified. All three scores were inversely associated with risk of symptomatic gallstone disease after adjustment for potential confounders including age, smoking, physical activity, energy and coffee intake [hazard ratios (HRs) and 95% confidence intervals (CIs)] comparing the highest with the lowest quintiles: aMed: 0.66 (0.57-0.77), AHEI-2010: 0.64 (0.56-0.74) and DASH: 0.66 (0.58-0.76)]. Findings were similar after additional adjustment for body mass index and after inclusion of asymptomatic cases. Associations were stronger when analysis was restricted to cases who had undergone cholecystectomy. Conclusions: In this prospective cohort of male US health professionals, higher adherence to the aMed, AHEI-2010 and DASH diets was associated with lower risk of symptomatic gallstone disease. Dietary recommendations focusing on high-quality diets targeting symptomatic gallstone disease may lower the incidence of this prevalent disease.

Plasma osteoprotegerin, its correlates, and risk of heart failure: a prospective cohort study.

Heart failure (HF) is a disabling condition involving complex vascular, neurohormonal and immune systems' interactions. Osteoprotegerin (OPG), a bone-regulatory cytokine, has been suggested to play a key role in skeletal, vascular, and immune biology, with elevated levels observed in both experimental and clinical HF. In the present study we aimed to identify clinical OPG correlates and investigated whether elevated OPG, as a marker of HF vascular and immune activation, may interact with N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of HF neurohormonal activation, thus synergistically increasing HF risk. We used a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam, comprising 2647 participants including 252 incident HF cases identified during a mean follow-up of 8.2 ± 1.6 years. In both men and women significant positive associations were observed between OPG and age, smoking, prevalent diabetes, C-reactive protein, sex hormone-binding globulin, and additionally prevalent coronary heart disease and uric acid in men only. In women, OPG was furthermore positively related to hypertension and fetuin-A. After multivariable adjustment each doubling of OPG was associated with a 3.01-fold increased HF risk (95 % CI 1.49-6.06) in men. A significant interaction was observed between OPG and NT-proBNP. In men, a combination of high levels of both OPG and NT-proBNP, compared to a combination of low levels, was associated with an approximately fivefold increased HF risk. In women, no associations were observed. These findings suggest that, in men, the activation of different immune, neurohormonal, and vascular pathophysiological pathways may confer increased HF risk.

Higher serum asymmetric dimethylarginine is related to higher risk of heart failure in the EPIC-Potsdam study.

L-Arginine is the substrate of endothelial nitric oxide (NO) synthase forming NO which inherits various biological cardio-protective functions. The dimethylarginines asymmetric (ADMA) and symmetric dimethylarginine (SDMA) can impair the synthesis of NO and are elevated in patients with cardiovascular disease, including heart failure (HF). We investigated the association between dimethylarginines and HF risk in a case-cohort study of the European Prospective Investigation into Cancer and Nutrition (n = 27,548), comprising a random subcohort (n = 2224 including 19 HF cases), and all remaining HF cases (n = 176) that occurred within 8.3 years of follow-up. Serum concentrations of dimethylarginines were measured using liquid chromatography-tandem mass spectrometry. Hazards ratios (HRs) and 95% confidence intervals (CI) were estimated across quartiles and per doubling of ADMA and SDMA concentrations using Cox's proportional hazards regression. After multivariable adjustment, each doubling of ADMA was associated with a 60% higher HF risk (HR [95% CI] 1.60 [1.10-2.31]). Between SDMA and HF risk a U-shaped association was observed (HR [95% CI] for the second, third and fourth quartile compared to the first: 0.52 [0.33-0.82], 0.63 [0.40-0.99], and 0.71 [0.46-1.10], p for nonlinearity <0.01). We provide substantiated evidence for a relationship between ADMA and cardiovascular endpoints. In addition to the established relation between ADMA and myocardial infarction, our findings indicate a positive association between ADMA and HF incidence in persons without apparent myocardial infarction. Targeting the ADMA metabolism might open up new therapeutic perspective for HF prevention and treatment. Further investigations are needed to shed more light on mechanisms involved in the pathogenesis of HF related to elevated ADMA levels.

Gallstones and Risk of Coronary Heart Disease: Prospective Analysis of 270 000 Men and Women From 3 US Cohorts and Meta-Analysis.

OBJECTIVE: Gallstone disease has been related to cardiovascular risk factors; however, whether presence of gallstones predicts coronary heart disease (CHD) is not well established. APPROACH AND RESULTS: We followed up 269 142 participants who were free of cancer and cardiovascular disease at baseline from 3 US cohorts: the Nurses' Health Study (112 520 women; 1980-2010), Nurses' Health Study II (112 919 women; 1989-2011), and the Health Professionals Follow-up Study (43 703 men; 1986-2010) and documented 21 265 incident CHD cases. After adjustment for potential confounders, the hazard ratio for the participants with a history of gallstone disease compared with those without was 1.15 (95% confidence interval, 1.10-1.21) in Nurses' Health Study, 1.33 (95% confidence interval, 1.17-1.51) in Nurses' Health Study II, and 1.11 (95% confidence interval, 1.04-1.20) in Health Professionals Follow-up Study. The associations seemed to be stronger in individuals who were not obese, not diabetic, or were normotensive, compared with their counterparts. We identified 4 published prospective studies by searching PUBMED and EMBASE up to October 2015, coupled with our 3 cohorts, involving 842 553 participants and 51 123 incident CHD cases. The results from meta-analysis revealed that a history of gallstone disease was associated with a 23% (15%-33%) increased CHD risk. CONCLUSION: Our findings support that a history of gallstone disease is associated with increased CHD risk, independently of traditional risk factors.

Gaussian Graphical Models Identify Networks of Dietary Intake in a German Adult Population.

BACKGROUND: Data-reduction methods such as principal component analysis are often used to derive dietary patterns. However, such methods do not assess how foods are consumed in relation to each other. Gaussian graphical models (GGMs) are a set of novel methods that can address this issue. OBJECTIVE: We sought to apply GGMs to derive sex-specific dietary intake networks representing consumption patterns in a German adult population. METHODS: Dietary intake data from 10,780 men and 16,340 women of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort were cross-sectionally analyzed to construct dietary intake networks. Food intake for each participant was estimated using a 148-item food-frequency questionnaire that captured the intake of 49 food groups. GGMs were applied to log-transformed intakes (grams per day) of 49 food groups to construct sex-specific food networks. Semiparametric Gaussian copula graphical models (SGCGMs) were used to confirm GGM results. RESULTS: In men, GGMs identified 1 major dietary network that consisted of intakes of red meat, processed meat, cooked vegetables, sauces, potatoes, cabbage, poultry, legumes, mushrooms, soup, and whole-grain and refined breads. For women, a similar network was identified with the addition of fried potatoes. Other identified networks consisted of dairy products and sweet food groups. SGCGMs yielded results comparable to those of GGMs. CONCLUSIONS: GGMs are a powerful exploratory method that can be used to construct dietary networks representing dietary intake patterns that reveal how foods are consumed in relation to each other. GGMs indicated an apparent major role of red meat intake in a consumption pattern in the studied population. In the future, identified networks might be transformed into pattern scores for investigating their associations with health outcomes.

Presence of gallstones and the risk of cardiovascular diseases: The EPIC-Germany cohort study.

BACKGROUND: Gallstones are common disorders associated with several cardiovascular risk factors. Gallstone formation and atherosclerosis may share key pathways, but studies on putative associations between gallstones and the risk of cardiovascular disease are sparse and non-conclusive. We studied the relationship between gallstones and the risk of subsequent cardiovascular diseases in the German arm of the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: The study comprises 46,468 participants from EPIC-Potsdam and EPIC-Heidelberg aged 35-65 years, free of cardiovascular diseases and diabetes at baseline. Information about the gallstone status at baseline was ascertained via questionnaires. For all incident cases of myocardial infarction and stroke confirmation was obtained from the treating physician. Relative risks were estimated using Cox proportional hazards regression. RESULTS: During eight years of follow-up, 919 participants suffered a stroke or myocardial infarction. After multivariable adjustment for established risk factors, subjects with reported gallstones (n = 4828) had an increased risk of cardiovascular diseases (hazard rate ratio (HR) = 1.24, 95% confidence interval (CI): 1.02, 1.50). In individuals, who underwent a cholecystectomy before baseline a 1.32-fold increase in risk was observed (95%CI: 1.05, 1.65). HRs differed depending on the presence of selected established risk factors (e.g. HR for cardiovascular diseases regarding gallstones in smokers = 1.66, 95%CI: 1.20, 2.30, and non-smokers = 1.09, 95%CI: 0.86, 1.38). CONCLUSIONS: Our results indicate an increased cardiovascular risk for gallstone formers, which cannot be counteracted by gallbladder removal and opens up perspectives for individualized prevention strategies.

Relationship between N-terminal pro-brain natriuretic peptide, obesity and the risk of heart failure in middle-aged German adults.

BACKGROUND: Both high concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and obesity are related to higher heart failure risk. However, inverse relationships between NT-proBNP and obesity have been reported. Therefore, it was investigated whether the association between NT-proBNP and the risk of heart failure differed according to obesity status. METHODS: A case-cohort study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam, comprising a random sub-cohort (non-cases = 1,150, cases = 13, mean age: 50.5±9.0 years) and heart failure cases outside the sub-cohort (n = 197). Weighted Cox proportional hazards regression was used to examine the association between NT-proBNP and heart failure risk during a mean follow-up time of 8 years. Stratified analyses were performed according to obesity status as defined by body mass index (<30 kg/m2 versus ≥30 kg/m2). RESULTS: Overall, NT-proBNP was associated with higher risk of heart failure after multivariable adjustment (hazard ratio (HR) and 95% confidence interval (CI): 2.56 (1.49-4.41) for the top versus bottom tertile of NT-proBNP, ptrend:<0.01). In stratified analyses, the shape of association was linear in non-obese and U-shaped in obese participants: HRs (95%CI) from the first to the third tertile of NT-proBNP for non-obese: reference, 1.72 (0.85-3.49), 2.72 (1.42-5.22), and for obese: 3.29 (1.04-10.40), reference, 3.74 (1.52-9.21). CONCLUSIONS: Although high circulating concentrations of NT-proBNP were positively associated with incident heart failure in the entire sample, the association differed according to obesity status. In obese, an increased risk of heart failure was also observed in those with low NT-proBNP concentrations. If confirmed, this observation warrants further investigation to understand underlying pathophysiological mechanisms.

Plasma fibroblast growth factor 23, parathyroid hormone, 25-hydroxyvitamin D3, and risk of heart failure: a prospective, case-cohort study.

CONTEXT: Bone mineral metabolism may play a role in the development of heart failure (HF). OBJECTIVE: The aim of the study was to investigate the relationships of plasma fibroblast growth factor (FGF) 23, PTH, and 25-hydroxyvitamin D3 [25(OH)D3] with incident congestive HF in a population-based cohort of men and women aged 40-65 and 35-65 years, respectively, at baseline. DESIGN: We conducted a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, including a randomly drawn sample of the total cohort free of HF and all incident HF cases that occurred during a mean follow-up of 8.2 ± 1.6 years. PARTICIPANTS AND SETTING: A total of 221 incident congestive HF cases and 1228 individuals free of HF were included in the study. MAIN OUTCOME MEASURES: Incident congestive HF was measured. RESULTS: In a multivariable model, each doubling of FGF23 [ie, per log (base 2) unit higher FGF23] was associated with a 29% higher HF risk (hazard ratio, 1.29 [95% confidence interval (CI), 1.07-1.56]). After multivariable adjustment, including estimated glomerular filtration rate, PTH was not related to HF risk (hazard ratio per doubling of PTH, 1.21 [95% CI, 0.99-1.48]). However, an interaction was observed between PTH and obesity, suggesting a relationship with HF risk in obese, but not in nonobese individuals. The hazard ratio for HF per doubling of 25(OH)D3 was 1.02 (95% CI, 0.73-1.41). CONCLUSIONS: Our findings provide epidemiological evidence for a positive relationship between FGF23 and risk of HF. The role of PTH in the development of HF remains unclear, in particular in obese individuals, until further confirmation in other studies. 25(OH)D3 was not related to HF.