Changes in fruit and vegetable consumption in relation to changes in sleep characteristics over a 3-month period among young adults

OBJECTIVE: To evaluate whether increases in fruit and vegetable (FV) consumption were associated with concomitant changes in insomnia symptoms, sleep duration, and quality. DESIGN: Secondary longitudinal analysis of a randomized trial, baseline to 3 months. SETTING: Integrated health care systems in Detroit, Michigan and Danville, Pennsylvania. PARTICIPANTS: About 1165 young adults who were low consumers of FV (/day) at baseline. INTERVENTION: Online 3-arm program designed to increase FV consumption. MEASUREMENTS: We categorized FV changes into 4 categories: no change or decrease, 1 serving increase, 2 serving increase, and 3 or more serving increase. We then compared the changes in chronic insomnia classification (yes or no), sleep duration, quality, and time to fall asleep (all self-reported) across the FV change categories. Analyses were both overall and stratified by gender, adjusting for potential confounders (depression, physical activity, education, children, and study site). RESULTS: Average age ± SD was 26 ± 2.8 years (71% women). At 3-month follow-up, participants on average increased FV intake by 1.2 ± 1.4 servings. Women who increased FV intake by 3+ servings showed improvements in insomnia symptoms (2-fold higher odds of improvement; 95% CI 1.1 to 3.6), sleep quality (0.2-point higher sleep quality score; 95% CI -0.01, 0.3), and time to fall asleep (4.2 minutes; 95% CI -8, 0) compared to women who did not change or decreased their FV intake. Associations were not as apparent among men. CONCLUSION: Young women with low consumption of FV may experience improvements in insomnia-related sleep difficulties by increasing their consumption of FV

VALIDATION OF POLYGENIC SCORE FOR BETA-BLOCKER SURVIVAL BENEFIT IN HEART FAILURE USING THE UNITED KINGDOM BIOBANK

Background: A novel polygenic response predictor (PRP) for beta blocker (BB) survival benefit in heart failure (HF) was recently described which separated European ancestry BB responders from non-responders using a score derived from 44 genetic loci. We tested whether this would replicate in the United Kingdom Biobank (UKB) dataset. Methods: UKB data pull identified patients with a HF diagnosis, genetic data and prescription data. Ejection fraction (EF) data was not available. BB exposure was quantified using BB dose and prescription frequency. The PRP was calculated using the genetic loci, weights, and cutoff value from the original description. Cox models were constructed of time to all-cause mortality adjusted for clinical risk (MAGGIC score), BB propensity score, BB exposure and BB exposure*PRP interaction. Results: Among 7502 HF patients included, 34% were women, 54% had coronary disease, 33% atrial fibrillation, 51% baseline BB usage, and 22% (n=1651) were PRP-predicted responders. Patients in the PRP responder group had strong survival benefit associated with BB exposure (HR=0.55, p=0.016), while PRP non-responders showed little BB effect (HR=0.92, p=0.466) and this difference was significant (p-interaction =0.051). Survival curves by PRP group and dichotomized BB exposure (high vs. low) are shown in the figure. Conclusion: The polygenic BB response predictor replicated in HF patients from the UKB regardless of EF. This innovative genomic medicine tool requires testing in a clinical trial

Genetics of heart rate in heart failure patients (GenHRate)

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction \u3c 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant hits (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 x 10(-8)). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts

Genetics of heart rate in heart failure patients (GenHRate)

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction \u3c 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant hits (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 x 10(-8)). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts

Plasma Proteomic Profile Predicts Survival in Heart Failure With Reduced Ejection Fraction

BACKGROUND: It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score (PRS) for survival in patients with HFrEF (HFrEF-PRS). Methods: Patients meeting Framingham criteria for HF with EF\u3c50% were enrolled (n=1017) and plasma underwent SOMAscan® profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and N-Terminal pro-B-Type Natriuretic Peptide (NTproBNP), then was tested in the validation cohort. Risk stratification improvement was evaluated by C-statistic, integrated discrimination index (IDI), continuous net reclassification index (NRI), and median improvement in risk score (MIRS) for 1-year and 3-year mortality. Results: Participants\u27 mean age was 68 years, 48% identified as African American, 35% were female and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio (HR) =2.27 [95% Confidence interval (95%CI) 1.84-2.82], p=6.3x10(-14)), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles (p=2.2x10(-6)), and it remained significant after adjustment for clinical score and NTproBNP (HR=1.37, 95%CI 1.05-1.79, p=0.021). The HFrEF-PRS improved metrics of risk stratification (C-statistic change=0.009, p=0.612; IDI=0.041, p=0.010; NRI=0.391, p=0.078; MIRS=0.039, p=0.016) and associated with cardiovascular death and HF phenotypes (e.g. 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF. Conclusions: A plasma multi-protein score improved risk stratification in HFrEF patients and identified novel candidates

Race and beta-blocker survival benefit in patients with heart failure: an investigation of self-reported race and proportion of African genetic ancestry

BACKGROUND: It remains unclear whether beta-blockade is similarly effective in black patients with heart failure and reduced ejection fraction as in white patients, but self-reported race is a complex social construct with both biological and environmental components. The objective of this study was to compare the reduction in mortality associated with beta-blocker exposure in heart failure and reduced ejection fraction patients by both self-reported race and by proportion African genetic ancestry. METHODS AND RESULTS: Insured patients with heart failure and reduced ejection fraction (n=1122) were included in a prospective registry at Henry Ford Health System. This included 575 self-reported blacks (129 deaths, 22%) and 547 self-reported whites (126 deaths, 23%) followed for a median 3.0 years. Beta-blocker exposure (BBexp) was calculated from pharmacy claims, and the proportion of African genetic ancestry was determined from genome-wide array data. Time-dependent Cox proportional hazards regression was used to separately test the association of BBexp with all-cause mortality by self-reported race or by proportion of African genetic ancestry. Both sets of models were evaluated unadjusted and then adjusted for baseline risk factors and beta-blocker propensity score. BBexp effect estimates were protective and of similar magnitude both by self-reported race and by African genetic ancestry (adjusted hazard ratio=0.56 in blacks and adjusted hazard ratio=0.48 in whites). The tests for interactions with BBexp for both self-reported race and for African genetic ancestry were not statistically significant in any model (P\u3e0.1 for all). CONCLUSIONS: Among black and white patients with heart failure and reduced ejection fraction, reduction in all-cause mortality associated with BBexp was similar, regardless of self-reported race or proportion African genetic ancestry

Sleep Duration and Quality in Relation to Fruit and Vegetable Intake of US Young Adults: a Secondary Analysis

BACKGROUND: Sleep is gaining recognition as a determinant of diet, yet this relationship remains understudied among young adults. We sought to examine how sleep duration and quality were related to fruit and vegetable (FV) intake within a diverse sample of young adults. METHODS: Participants (n = 1444) ages 21-30 (69% women, 15% African American, 35% full or part time in college) consuming \u3c 5 servings/day of FV (eligibility criteria) completed a baseline survey to enroll in a randomized online FV intervention. Sleep questions included duration, perceived sleep quality, time to fall asleep, and insomnia symptoms. Overall and gender-stratified linear regression models compared average daily FV intake and sleep characteristics, adjusting for confounders. RESULTS: One-third (32%) of the participants reported \u3c 7 h of sleep per night, and 36% noted insomnia symptoms ≥ 3 times per week. Women, a BMI \u3e 30, African American race/ethnicity, less education, unemployment, higher depression, and stress were related to suboptimal sleep. Bivariate analyses showed that better sleep was associated with higher FV intake. After accounting for confounders, men with better sleep quality and shorter time to fall asleep had higher intakes of FV (1.12 serving/day difference in highest versus lowest quality [95% CI 0.48, 1.75] and a 0.52 serving/day higher intake difference for shortest versus longest fall asleep time [95% CI 0.90, 0.15], respectively). CONCLUSION: Sleep was highly prevalent in a diverse sample of community-based young adults and may contribute to lower FV intake among men. These associations highlight young adulthood as an important period for promoting healthy sleep habits

Serum miRNAs as potential biomarkers for early prediction of type 1 diabetes

Background The incidence of type 1 diabetes (T1D), a T cell-mediated beta cell destructive autoimmune disease, has been increasing about 3-4% annually for several decades. Individuals at risk for T1D are diagnosed at a late stage when the possibility for disease prevention is absent. Autoantibodies (AA) to islet antigens such as islet antigen (IA)-2, IA-2b, and glutamate decarboxylase (GAD65) appear earlier before T1D onset and are used for early T1D prediction. However, the appearance of islet AA marks a relatively late stage of the autoimmune process and therefore is not suitable for early disease intervention. More importantly AA lack causal relationship with the pathogenesis of T1D. Therefore, there is an urgent need for better (increased specificity/sensitivity) and earlier (predating autoantibodies) markers for the prediction of AA development. MicroRNAs (miRNAs) have emerged as an important regulatory factors in pancreatic β-cell development, homeostasis, function, and in a variety of immune cell development, differentiation and function. Our recent study showed that miRNAs regulate T1D development and serum miRNAs are potential biomarkers for T1D progression in mouse models. Our objective here is to identify specific serum miRNA biomarkers for earlier and better prediction of individuals at risk for T1D in human. Method We performed serum miRNA expressions profiles in 35 AA positive (IAA and ICA) non-T1D subjects and 40 AA negative relative subjects from the Diabetes Prevention Trial-Type 1 (DPT-1) cohort, using the TaqMan low-density arrays. miRNAs with changed expression level were further confirmed by a single TaqMan RT-PCR. Result 9 miRNAs (miR-146a, miR-561 and miR-548a-3p, miR-184 and miR-200a) were down-regulated and 2 miRNAs (miR-30c and miR-487a) are up-regulated in the serum of AA+ non-T1D subjects compared to that from AA- subjects (two-sample t-test P\u3c0.05). In addition, a cluster of five miRNAs (miR-146a, miR-197, miR-193b, miR-574-3p, and miR-561) was identified to clearly separate AA+ subjects from AA- subjects with higher sensitivity and specificity ( LASSO logistic regression). miRNA target and pathway prediction analyses revealed that some of these miRNAs are related to immune function and beta-cell homeostasis and potentially involved in autoimmune processes. Conclusion We have identified distinct serum miRNA expressions profiles in AA+ subjects compared to AA- subjects. These serum miRNAs could serve as potential biomarkers for early prediction of autoimmune processes in individuals at risk for T1D, which need to be further confirmed in the future studies

Plasma proteomic profile predicts survival in heart failure with reduced ejection fraction

Background: Whether the plasma proteome can predict the course of heart failure (HF) and has incremental value to established predictors is uncertain. Methods: Patients meeting Framingham HF criteria with history of reduced ejection fraction (n=1017) were prospectively enrolled in a registry and donated fasting blood samples. Plasma underwent analysis on the SOMAscan proteomic discovery platform, quantifying 4789 proteins using standard assay and quality controls. Patients were randomly divided into derivation (n=681) and validation (n=336) cohorts. We derived a proteomic risk score (PRS) in the derivation cohort using Lasso-penalized Cox regression and then tested it in the validation cohort. Both models were adjusted for an establish HF clinical risk score (MAGGIC) and NTproBNP. We assessed risk stratification improvement in the validation cohort by comparing models with and without PRS using the model C statistic, continuous net reclassification index (NRI), integrated discrimination index (IDI), and the median improvement in risk score (MIRS). Results: Overall 47.5% of patients were African American, 35.2% were female, mean ejection fraction was 34.8%, and average age was 67.9 years. After median follow-up of 3.6 years, there were 296 deaths (194 in derivation and 102 in validation). Optimized modeling defined a 32 protein PRS (hazard ratio [HR] 2.33, p\u3c2.00E-16) which was also statistically significant when tested in the validation cohort (PRS HR=1.19, p=4.87E-02) and showed some improvement in risk stratification (Table). Conclusion: A plasma multi-protein predictive score can improve risk stratification in HF patients on top of a validated clinical score and NT-proBNP. Additional investigation is warranted to define mechanisms underlying individual proteins and explore proteomic clinical applications

Difficult-to-control blood pressure in non-diabetic hypertensive subjects is associated with upregulated gene expression of inflammatory pathways

Introduction: Hypertension (HTN) causes cardiovascular disease. Despite this, many patients do not achieve blood pressure (BP) control. We hypothesized that non-diabetic hypertensive subjects with difficult-to-control BP will activate predictive signaling pathways. Methods: We collected demographics and 24-h and first-morning urine collections from 61 subjects enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). A validated instrument was administered to asses sugar sweetened beverage intake and converted to grams fructose per day. The BP-Difficult (BPD) group had SBP \u3e140 mmHg or \u3e120 mmHg for intensive group subjects, or BP at goal for the trial group and more than the median number of agents in each group in study as a whole. The BP Easy group (BPE) comprised the remainder of subjects. Mean BP from two visits before SPRINT termination established the study BP. Gene expression from transcriptomic sequencing of cellular RNAs of first-morning urine were assessed for differential expression (DE) genes (\u3e1.5-fold change; P\u3c0.01) by the Wilcoxon Rank-Sum test and pathway analysis. 354erd Results: Recoverable RNA from 51 subjects was present in 33 BPD and 18 BPE subjects. In the BPD group, 338 genes were upregulated and 3 downregulated; pathway analysis identified interferon, phosphoinositide 3-kinase, B cell receptor, and inducible nitric oxide synthase signaling as key upregulated pathways (P\u3c0.05). Most upregulated genes were components of pro-inflammatory pathways: interferon (IFNAR1), interleukin-2 and -4 (IL2RG, IL4R), tumor necrosis factor receptor (TNFRSF1B), and infiltrating B lymphocytes (PIK3AP1). BPD subjects with low 24-h urine sodium (\u3c200 mmol) and fructose intake (\u3c40 g/day) had 59 DE genes: 57 upregulated and 2 downregulated. Significant pathways included STAT3 and Cdc42 signaling pathways (P\u3c0.05), and IL2RG, MAPK14, TGFB1, and IFNAR1 were components of these pathways. Conclusions: Urinary cells from a difficult-to-control BP SPRINT cohort demonstrated molecular signatures associated with specific pro-inflammatory pathways and immune mediators