Background A growing body of literature has suggested that obstructive sleep apnea (OSA) and habitual short sleep duration are linked to poor cognitive function. Neuroimaging studies may provide insight into this relation. Objective We tested the hypotheses that OSA and habitual short sleep duration, measured at ages 54-73 years, would be associated with adverse brain morphology at ages 67-89 years. Methods Included in this analysis are 312 ARIC study participants who underwent in-home overnight polysomnography in 1996-1998 and brain MRI scans about 15 years later (2012-2013). Sleep apnea was quantified by the apnea-hypopnea index and categorized as moderate/ severe (≥15.0 events/hour), mild (5.0-14.9 events/hour), or normal (<5.0 events/hour). Habitual sleep duration was categorized, in hours, as <7, 7 to ≥8, 8. MRI outcomes included number of infarcts (total, subcortical, and cortical) and white matter hyperintensity (WMH) and Alzheimer's disease signature region volumes. Multivariable adjusted logistic and linear regression models were used. All models incorporated inverse probability weighting, to adjust for potential selection bias. Results At the time of the sleep study participants were 61.7 (SD: 5.0) years old and 54% female; 19% had moderate/severe sleep apnea. MRI imaging took place 14.8 (SD: 1.0) years later, when participants were 76.5 (SD: 5.2) years old. In multivariable models which accounted for body mass index, neither OSA nor abnormal sleep duration were statistically significantly associated with odds of cerebral infarcts, WMH brain volumes or regional brain volumes. Conclusions In this community-based sample, mid-life OSA and habitually short sleep duration were not associated with later-life cerebral markers of vascular dementia and Alzheimer's disease. However, selection bias may have influenced our results and the modest sample size led to relatively imprecise associations.

(1) Background: Magnesium supplementation may be effective for the prevention of cardiometabolic diseases, but the mechanisms are unclear. Proteomic approaches can assist in identifying the underlying mechanisms. (2) Methods: We collected repeated blood samples from 52 individuals enrolled in a double-blind trial which randomized participants 1:1 to oral magnesium supplementation (400 mg magnesium/day in the form of magnesium oxide) or a matching placebo for 10 weeks. Plasma levels of 91 proteins were measured at baseline with follow-up samples using the Olink Cardiovascular Disease III proximity extension assay panel and were modeled as arbitrary units in a log2 scale. We evaluated the effect of oral magnesium supplementation for changes in protein levels and the baseline association between serum magnesium and protein levels. The Holm procedure was used to adjust for multiple comparisons. (3) Results: Participants were 73% women, 94% white, and had a mean age of 62. Changes in proteins did not significantly differ between the two intervention groups after correction for multiple comparisons. The most statistically significant effects were on myoglobin [difference −0.319 log2 units, 95% confidence interval (CI) (−0.550, −0.088), p = 0.008], tartrate-resistant acid phosphatase type 5 (−0.187, (−0.328, −0.045), p = 0.011), tumor necrosis factor ligand superfamily member 13B (−0.181, (−0.332, −0.031), p = 0.019), ST2 protein (−0.198, (−0.363, −0.032), p = 0.020), and interleukin-1 receptor type 1 (−0.144, (−0.273, −0.015), p = 0.029). Similarly, none of the associations of baseline serum magnesium with protein levels were significant after correction for multiple comparisons. (4) Conclusions: Although we did not identify statistically significant effects of oral magnesium supplementation in this relatively small study, this study demonstrates the value of proteomic approaches for the investigation of mechanisms underlying the beneficial effects of magnesium supplementation. Clinical Trials Registration: ClinicalTrials.gov NCT02837328.

Introduction This study tested the hypotheses that late-midlife obstructive sleep apnea (OSA) and short and long sleep duration are associated with dementia over 15 years of follow-up. Methods A total of 1667 Atherosclerosis Risk in Communities Study participants underwent in-home polysomnography (1996–1998) and were followed for dementia. Dementia was defined by (1) hospitalization diagnosis codes (1996–2012) and (2) a comprehensive neurocognitive examination (2011–2013) with adjudication. Results OSA and sleep duration were not associated with risk of incident dementia. When using adjudicated outcomes, severe OSA (≥30 vs. <5 apnea-hypopnea events/hour) was associated with higher risk of all-cause dementia (risk ratio [95% confidence interval], 2.35 [1.06–5.18]) and Alzheimer's disease dementia (1.66 [1.03–2.68]); associations were attenuated with cardiovascular risk factor adjustment. Sleeping <7 versus 8 to ≤9 hours was associated with higher risk of all-cause dementia (2.00 [1.03–3.86]). Discussion When adjudicated outcome definitions were used, late-midlife OSA and short sleep duration were associated with all-cause and Alzheimer's disease dementia in later life.

Introduction Existing studies predominantly consider the association of late-life lipid levels and subsequent cognitive change. However, midlife rather than late-life risk factors are often most relevant to cognitive health. Methods We quantified the association between measured serum lipids in midlife and subsequent 20-year change in performance on three cognitive tests in 13,997 participants of the Atherosclerosis Risk in Communities study. Results Elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides were associated with greater 20-year decline on a test of executive function, sustained attention, and processing speed. Higher total cholesterol and triglycerides were also associated with greater 20-year decline in memory scores and a measure summarizing performance on all three tests. High-density lipoprotein cholesterol was not associated with cognitive change. Results were materially unchanged in sensitivity analyses addressing informative missingness. Discussion Elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides in midlife were associated with greater 20-year cognitive decline.

Objective: Whether endogenous testosterone concentrations are associated with atrial fibrillation (AF) development is not well established. We assessed the association between plasma total testosterone concentrations and incident AF in a population-based longitudinal study. Study design: Using data from the prospective Atherosclerosis Risk in Communities (ARIC) study, we identified incident AF among 9,282 participants who had plasma total testosterone measured by liquid chromatography tandem mass spectrometry at Visit 4 (1996-1998). Main outcome measures: AF cases were identified by electrocardiograms performed during study visits, hospital records/discharge codes, and death certificates through 2013. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident AF across quartiles of plasma total testosterone, stratified by sex, with multivariable Cox models. Results: The mean age of the participant sample at ARIC Visit 4 was 63 years (range 52-75); 54.5% were women. Mean (SD) plasma total testosterone levels were 537 ng/dL (213) for men and 27.6 ng/dL (34.7) for women. Over a mean of 13.7 years of follow-up, 1664 incident cases of AF were identified. Comparing those in the highest quartile of plasma total testosterone concentration to those in the lowest quartile and after adjustment for potential confounding variables, there was a positive association between plasma total testosterone and incident AF in men (HR 1.33, 95% CI 1.07, 1.66), but no such association in women (HR 0.99, 95% CI 0.80, 1.22). Conclusion: A higher plasma total testosterone concentration was associated with a modestly greater incidence rate of AF in men.

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

We have previously identified associations of 2 circulating secondary bile acids (glycocholenate and glycolithocolate sulfate) with atrial fibrillation (AF) risk in 1,919 blacks in the Atherosclerosis Risk in Communities cohort. We aimed to replicate these findings in an independent sample of 2,003 white and black Atherosclerosis Risk in Communities participants, and performed a new metabolomic analysis in the combined sample of 3,922 participants, followed between 1987 and 2013. Metabolomic profiling was done in baseline serum samples using gas and liquid chromatography mass spectrometry. AF was ascertained from electrocardiograms, hospitalizations, and death certificates. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of AF by 1 standard deviation difference of metabolite levels. Over a mean follow-up of 20 years, 608 participants developed AF. Glycocholenate sulfate was associated with AF in the replication and combined samples (HR 1.10, 95% CI 1.00, 1.21 and HR 1.13, 95% CI 1.04, 1.22, respectively). Glycolithocolate sulfate was not related to AF risk in the replication sample (HR 1.02, 95% CI 0.92, 1.13). An analysis of 245 metabolites in the combined cohort identified 3 additional metabolites associated with AF after multiple-comparison correction: pseudouridine (HR 1.18, 95% CI 1.10, 1.28), uridine (HR 0.86, 95% CI 0.79, 0.93) and acisoga (HR 1.17, 95% CI 1.09, 1.26). In conclusion, we replicated a prospective association among a previously identified secondary bile acid, glycocholenate sulfate, and AF incidence, and identified new metabolites involved in nucleoside and polyamine metabolism as markers of AF risk.

Background Effectiveness data on novel oral anticoagulants (NOACs) versus warfarin for stroke prevention in non-valvular atrial fibrillation (NVAF) by prior warfarin use are limited. Methods We used data from the US MarketScan databases from 2009 to 2012. NVAF patients initiating dabigatran or rivaroxaban were matched with up to 5 warfarin users. Propensity score-adjusted Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for relevant endpoints in NOACs versus warfarin users. Separate analyses were conducted to compare anticoagulant-naïve users of NOACs and those switching from warfarin. Results Among 32,918 dabigatran, 3301 rivaroxaban, and 109,447 warfarin users with NVAF, 225 intracranial bleeds, 1035 ischemic strokes, 958 myocardial infarctions, and 1842 gastrointestinal bleeds were identified. Compared to warfarin users, patients initiating NOACs had similar ischemic stroke rates and lower intracranial bleeding rates, while the gastrointestinal bleeding rate was higher in dabigatran users than warfarin users. Associations of dabigatran with ischemic stroke risk differed between anticoagulant-naïve initiators and patients switching from warfarin; dabigatran was associated with lower ischemic stroke rates in naïve users (HR 0.65, 95% CI 0.52–0.82) but not in switchers (HR 1.20, 95% CI 0.95–1.51), compared to warfarin. Risk of stroke and bleeding was not different between rivaroxaban and warfarin users. Conclusions Real-world effectiveness of NOACs (compared to warfarin) for diverse outcomes was comparable to efficacy reported in published clinical trials. However, harms and benefits of switching from warfarin to dabigatran need to be evaluated.

Objective: To assess the risk of liver injury hospitalisation in patients with atrial fibrillation (AF) after initiation of direct oral anticoagulants (DOACs) or warfarin and to determine predictors of liver injury hospitalisation in this population. Methods: We studied 113 717 patients (mean age 70, 39% women) with AF included in the MarketScan Commercial and Medicare Supplemental databases with a first prescription for oral anticoagulation after 4 November 2011, followed through 31 December 2014. Of these, 56 879 initiated warfarin, 17 286 initiated dabigatran, 30 347 initiated rivaroxaban and 9205 initiated apixaban. Liver injury hospitalisation and comorbidities were identified from healthcare claims. Results: During a median follow-up of 12 months, 960 hospitalisations with liver injury were identified. Rates of liver injury hospitalisation ( per 1000 person-years) by oral anticoagulant were 9.0 (warfarin), 4.0 (dabigatran), 6.6 (rivaroxaban) and 5.6 (apixaban). After multivariable adjustment, liver injury hospitalisation rates were lower in initiators of DOACs compared with warfarin: HR (95% CI) of 0.57 (0.46 to 0.71), 0.88 (0.75 to 1.03) and 0.70 (0.50 to 0.97) for initiators of dabigatran, rivaroxaban, and apixaban, respectively (vs. warfarin). Compared with dabigatran initiators, rivaroxaban initiators had a 56% increased risk of liver injury hospitalisation (HR 1.56, 95% CI 1.22 to 1.99). In addition to type of anticoagulant, prior liver, gallbladder and kidney disease, cancer, anaemia, heart failure and alcoholism significantly predicted liver injury hospitalisation. A predictive model including these variables had adequate discriminative ability (C-statistic 0.67, 95% CI 0.64 to 0.70). Conclusions: Among patients with non-valvular AF, DOACs were associated with lower risk of liver injury hospitalisation compared with warfarin, with dabigatran showing the lowest risk.

Background Patients with atrial fibrillation (AF) experience an increased risk of heart failure (HF). However, data are lacking on current trends in the risk of HF after AF. Objective The purpose of this study was to describe the temporal trends in HF occurrence after AF in a community cohort of patients with incident AF from 2000 to 2013. Methods Cox regression was used to examine the association of year of AF diagnosis with HF and the predictors of developing HF after AF. Results Among 3491 AF patients without prior HF, 750 (21%) developed incident HF over mean follow-up of 3.7 years. Among those with an echocardiogram, 422 (61%) had HF with preserved ejection fraction (HFpEF), and 270 (39%) had HF with reduced ejection fraction (HFrEF). After adjusting for demographics and comorbidities, the risk of developing HF did not change over time (hazard ratio [HR] (95% confidence interval [CI]) per year of AF diagnosis: 1.01 (0.98–1.03) overall; 1.00 (0.98–1.03) for HFpEF; 1.00 (0.96–1.03) for HFrEF). Increasing age, obesity, smoking, diabetes, chronic pulmonary disease, and renal disease were predictors of developing HF. Compared to the Olmsted County, Minnesota, population, a substantial excess risk of developing HF was observed after AF diagnosis [standardized morbidity ratio (95% CI): 9.60 (7.44–12.19), 2.13 (1.56–2.84), and 1.70 (1.34–2.14) at 90 days, 1 year, and 3 years after diagnosis]. Conclusion In the community, HF is a frequent adverse outcome among patients with AF, and HFpEF is more common than HFrEF. The rates of HF after AF have not declined, thus highlighting the importance of continued efforts to improve outcomes in AF.