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Low physical activity (PA) measured by accelerometers and low heart rate variability (HRV) measured from short-term ECG recordings are associated with worse cognitive function. Wearable long-term ECG monitors are now widely used, and some devices also include an accelerometer. The objective of this study was to evaluate whether PA or HRV measured from long-term ECG monitors was associated with cognitive function among older adults. A total of 1590 ARIC participants had free-living PA and HRV measured over 14 days using the Zio® XT Patch [aged 72–94 years, 58% female, 32% Black]. Cognitive function was measured by cognitive factor scores and adjudicated dementia or mild cognitive impairment (MCI) status. Adjusted linear or multinomial regression models examined whether higher PA or higher HRV was cross-sectionally associated with higher factor scores or lower odds of MCI/dementia. Each 1-unit increase in the total amount of PA was associated with higher global cognition (β = 0.30, 95% CI: 0.16–0.44) and executive function scores (β = 0.38, 95% CI: 0.22–0.53) and lower odds of MCI (OR = 0.38, 95% CI: 0.22–0.67) or dementia (OR = 0.25, 95% CI: 0.08–0.74). HRV (i.e., SDNN and rMSSD) was not associated with cognitive function. More research is needed to define the role of wearable ECG monitors as a tool for digital phenotyping of dementia.

Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants and phenotypes. Here, we examine 2157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2157 proteins follow a bimodal distribution (median r = 0.30). We evaluate protein measure associations with genetic variants, and find approximately 25-30% of the signals on each platform are likely driven by protein-altering variants. We highlight 80 proteins that correlate differently across ancestry groups likely in part due to differing protein-altering variant frequencies by ancestry. Furthermore, adjustment for protein-altering variants with opposite directions of effect by platform improves inter-platform protein measure correlation and results in more concordant genetic and phenotypic associations. Hence, protein-altering variants need to be accounted for across ancestries to facilitate platform-concordant and accurate protein measurement. Affinity-proteomics platforms often yield poorly correlated measurements. Here, the authors show that protein-altering variants drive a portion of inter-platform inconsistency and that accounting for genetic variants can improve concordance of protein measures and phenotypic associations across ancestries.

We previously reported that incident atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. We now aimed to identify predictors of SCD in persons with AF from the Atherosclerosis Risk in Communities (ARIC) study, a community-based cohort study. We included all participants who attended visit 1 (1987-89) and had no prior AF (n = 14,836). Incident AF was identified from study electrocardiograms and hospitalization discharge codes through 2012. SCD was physician-adjudicated. We used cause-specific Cox proportional hazards models, followed by stepwise selection (backwards elimination, removing all variables with p>0.10) to identify predictors of SCD in participants with AF. AF occurred in 2321 (15.6%) participants (age 45-64 years, 58% male, 18% black). Over a median of 3.3 years, SCD occurred in 110 of those with AF (4.7%). Predictors of SCD in AF included higher age, body mass index (BMI), coronary heart disease, hypertension, diabetes, current smoker, left ventricular hypertrophy, increased heart rate, and decreased albumin. Predictors associated only with SCD and not other cardiovascular (CV) death included increased BMI (HR per 5-unit increase, 1.15, 95% CI, 0.97-1.36, p = 0.10), increased heart rate (HR per SD increase, 1.18, 95% CI 0.99-1.41, p = 0.07), and low albumin (HR per SD decrease 1.23, 95% CI 1.02-1.48, p = 0.03). In the ARIC study, predictors of SCD in AF that are not associated with non-sudden CV death included increased BMI, increased heart rate, and low albumin. Further research to confirm these findings in larger community-based cohorts and to elucidate the underlying mechanisms to facilitate prevention is warranted.

Aims/hypothesisThere is controversy regarding the performance of HbA1c in old age. We evaluated the prognostic value of HbA1c and other glycaemic markers (fructosamine, glycated albumin, fasting glucose) with mortality risk in older adults (66–90 years).MethodsThis was a prospective analysis of 5636 participants (31% with diagnosed diabetes, mean age 76, 58% female, 21% black) in the Atherosclerosis Risk in Communities (ARIC) study, baseline 2011–2013. We used Cox regression to examine associations of glycaemic markers (modelled in categories) with mortality risk, stratified by diagnosed diabetes status.ResultsDuring a median of 6 years of follow-up, 983 deaths occurred. Among older adults with diabetes, 30% had low HbA1c (<42 mmol/mol [<6.0%]) and 10% had high HbA1c (≥64 mmol/mol [≥8.0%]); low (HR 1.32 [95% CI 1.04, 1.68]) and high (HR 1.86 [95% CI 1.32, 2.62]) HbA1c were associated with mortality risk vs HbA1c 42–52 mmol/mol (6.0–6.9%) after demographic adjustment. Low fructosamine and glycated albumin were not associated with mortality risk. Both low and high fasting glucose were associated with mortality risk. After further adjustment for lifestyle and clinical risk factors, high HbA1c (HR 1.81 [95% CI 1.28, 2.56]), fructosamine (HR 1.96 [95% CI 1.43–2.69]), glycated albumin (HR 1.81 [95% CI 1.33–2.47]) and fasting glucose (HR 1.81 [95% CI 1.24, 2.66]) were associated with mortality risk. Low HbA1c and fasting glucose were no longer significantly associated with mortality risk. Among participants without diabetes, associations of glycaemic markers with mortality risk were less robust.Conclusions/interpretationElevated HbA1c, fructosamine, glycated albumin and fasting glucose were associated with risk of mortality in older adults with diabetes. Low HbA1c and fasting glucose may be markers of poor prognosis but are possibly confounded by health status. Our findings support the clinical use of HbA1c in older adults with diabetes.

Abstract Background Glycated albumin is of growing interest as an alternative biomarker of glycemia. However, the association of glycated albumin with long-term outcomes in the general population is uncharacterized. We evaluated the associations of glycated albumin and hemoglobin A1c (HbA1c) with mortality in US adults. Methods We conducted a prospective analysis of 12 915 participants in the National Health and Nutrition Examination Survey 1999–2004. We used Cox regression to characterize associations of glycated albumin and HbA1c with all-cause and cardiovascular mortality through 2014. We categorized glycated albumin based on percentiles corresponding to clinical cut-points for HbA1c. No diagnosed diabetes: <5.0% (<12th percentile), 5.0% to 5.6% (12th–82nd percentile, reference), 5.7% to 6.4% (83rd–97th percentile), and ≥6.5% (≥98th percentile). Diagnosed diabetes: <7.0% (<50th percentile), 7.0% to 8.9% (50th–83rd percentile), and ≥9.0% (≥84th percentile). Results Among US adults (mean age 46 years), the prevalence of diagnosed diabetes was 6.8%. Glycated albumin and HbA1c were highly correlated (r = 0.76). Over the median 16.8 years follow-up, there were 2818 deaths (652 cardiovascular). Adults with diagnosed diabetes and glycated albumin ≥84th percentile had the highest risk for all-cause mortality [hazard ratio (HR) 3.96, 95% CI 3.06–5.13] and cardiovascular mortality (HR 6.80, 95% CI 4.20–11.03). HbA1c had associations with all-cause and cardiovascular mortality that were similar to those for glycated albumin. Conclusions Among US adults, increased values of glycated albumin and HbA1c were associated with all-cause and cardiovascular mortality, particularly in persons with diagnosed diabetes. Glycated albumin may be a useful alternative test of glycemia.

Aims/hypothesis Prediabetes (HbA 1c 39–47 mmol/mol [5.7–6.4%] or fasting glucose 5.6–6.9 mmol/l) is associated with elevated risks of microvascular and macrovascular complications. It is unknown to what extent these risks in prediabetes remain after accounting for progression to diabetes. Methods In 10,310 participants from the Atherosclerosis Risk in Communities (ARIC) Study (aged 46–70 years, ~55% women, ~20% Black adults) without diabetes at baseline (1990–1992), we used Cox regression to characterise age- and sex-adjusted associations of prediabetes with ~30 year incidence of complications (composite and separately), including atherosclerotic CVD (ASCVD), heart failure, chronic kidney disease (CKD) and all-cause mortality before and after accounting for intervening incidence of diabetes, modelled as a time-varying variable. We calculated the excess risk of complications in prediabetes remaining after accounting for progression to diabetes. Results Of the 60% of adults with prediabetes at baseline, ~30% progressed to diabetes (median time to diabetes, 7 years). Over the maximum follow-up of ~30 years, there were 7069 events (1937 ASCVD, 2109 heart failure, 3288 CKD and 4785 deaths). Prediabetes was modestly associated with risk of any complication (HR 1.21 [95% CI 1.15, 1.27]) vs normoglycaemia. This association remained significant after accounting for progression to diabetes (HR 1.18 [95% CI 1.12, 1.24]) with 85% (95% CI 75, 94%) of the excess risk of any complication in prediabetes remaining. Results were similar for the individual complications. Conclusions/interpretation Progression to diabetes explained less than one-quarter of the risks of clinical outcomes associated with prediabetes. Prediabetes contributes to the risk of clinical outcomes even without progression to diabetes. Graphical Abstract

ObjectiveTo test cross-sectional associations between urinary concentrations of 2,5-dichlorophenol (2,5-DCP) and 2,4-dichlorophenol (2,4-DCP) with the prevalence of cardiovascular disease (CVD), cancer, lung disease, thyroid problems and liver conditions.MethodsLogistic regression was used to evaluate associations of urinary concentrations of 2,5-DCP and 2,4-DCP with prevalence of various medical conditions among 3617 National Health and Nutrition Examination Survey participants from 2007–2008 and 2009–2010. ORs and 95% CIs for each disease were estimated. All regression models were adjusted for urinary creatinine.ResultsWe observed a monotonically increasing association between quartiles of 2,5-DCP and prevalence of CVD. After adjustment for sociodemographic and lifestyle characteristics, participants with the highest versus lowest quartile of urinary 2,5-DCP had an OR=1.84 (95% CI 1.26 to 2.70) (p linear trend=0.006). The association was similar with further adjustment for established clinical CVD risk factors. Higher 2,5-DCP was also associated with prevalence of all cancers combined (ORQ4 vs Q1=1.50 (95% CI 1.00 to 2.26); p trend=0.05) and, in exploratory analyses, with gynaecological cancers (ORQ4 vs Q1=4.15 (95% CI 1.51 to 11.40; p trend=0.01)). No associations were detected between 2,5-DCP and lung diseases, thyroid problems or liver conditions, nor between 2,4-DCP and prevalent disease.ConclusionIn this nationally representative study, higher urinary 2,5-DCP concentrations were associated with greater prevalence of CVD and all cancers combined. Further examination may be warranted to assess whether chronic exposure to 2,5-DCP is associated with incidence of adverse health outcomes.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biologically inert cleavage product of a peptide formed in response to myocardial wall stress and can be used to screen for subclinical cardiovascular disease in adults. However, associations between NT-proBNP and demographic, lifestyle, and cardiometabolic factors in youth are poorly characterized. Methods and Results: We conducted a cross-sectional analysis of youth ages <20 years old in the nationally representative National Health and Nutrition Examination Survey 1999 to 2004 and measured NT-proBNP in stored serum specimens. We calculated age-and-sex-specific distributions of NT-proBNP and evaluated the associations between NT-proBNP and cardiometabolic risk factors. We found that NT-proBNP was inversely associated with BMI and most cardiometabolic risk factors in the general US population of children and adolescents. The differences in NT-proBNP by age, sex, and race or ethnicity in younger persons mirror those seen in adults. These results suggest that as in adults, levels of NT-proBNP should be interpreted in children and adolescents based on these demographic and clinical factors.

Aims/hypothesis Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. Methods Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. Results Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein–GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p =7.0 × 10 −3 ), while neuropilin-2 was inversely associated (OR 0.44 per SD; p =8.0 × 10 −3 ). Conclusions/interpretation Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets. Graphical abstract