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Background: Gestational diabetes mellitus (GDM) is associated with increased long-term risk of cardiovascular disease but the cardiovascular structural and functional changes that contribute to risk are not well understood. Objectives: The purpose of this study was to determine whether GDM is associated with adverse cardiac remodeling and endothelial dysfunction a decade after delivery, independent of type 2 diabetes. Methods: Women with deliveries between 2008 and 2009 were initially selected from a prospective clinical cohort. Pregnancy history was chart abstracted and a follow-up study visit was conducted at 8 to 10 years postpartum. Cardiac structure and function were assessed with echocardiography. Endothelial function was measured with peripheral arterial tonometry and glycocalyx analysis. Results: Among 254 women assessed at an average age of 38 years, 53 (21%) had prior GDM. At follow-up, women with GDM had more incident prediabetes or diabetes (58% vs 20% without GDM), more impairment in peripheral arterial tonometry (reactive hyperemia 1.58 vs 1.95; P = 0.01) and reduced perfusion, a marker of glycocalyx assessment (red blood cell filling 0.70 ± 0.04 vs 0.72 ± 0.05; P

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Background It is unclear how metabolic syndrome (MetS) and diabetes affect Gal‐3 (galectin 3) levels and the resulting implications for heart failure (HF) risk. We assessed relationships of MetS and diabetes with Gal‐3, and their joint associations with incident HF. Methods and Results We included 8445 participants without HF (mean age, 63 years; 59% men; 16% Black race) at ARIC (Atherosclerosis Risk in Communities) study visit 4 (1996–1999). We categorized participants as having MetS only, MetS with diabetes, or neither, and by quartiles of MetS severity Z score. We assessed cross‐sectional associations of metabolic risk categories with high Gal‐3 level (≥75th percentile) using logistic regression. We used Cox regression to evaluate combined associations of metabolic risk categories and Gal‐3 quartiles with HF. In cross‐sectional analyses, compared with no MetS and no diabetes, MetS only (odds ratio [OR], 1.24 [95% CI, 1.10–1.41]) and MetS with diabetes (OR, 1.59 [95% CI, 1.32–1.92]) were associated with elevated Gal‐3. Over a median follow‐up of 20.5 years, there were 1749 HF events. Compared with individuals with neither diabetes nor MetS and with Gal‐3 in the lowest quartile, the combination of MetS with diabetes and Gal‐3 ≥75th percentile was associated with a 4‐fold higher HF risk (hazard ratio, 4.35 [95% CI, 3.30–5.73]). Gal‐3 provided HF prognostic information above and beyond MetS, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), high‐sensitivity cardiac troponin T, and CRP (C‐reactive protein) (ΔC statistic for models with versus without Gal‐3: 0.003; P=0.004). Conclusions MetS and diabetes are associated with elevated Gal‐3. The HF risk significantly increased with the combination of greater metabolic risk and higher Gal‐3.

Objective: High sensitivity cardiac troponin (hs-cTn) may be useful to monitor residual risk in secondary prevention. Our objective was to study the correlations and comparative associations with mortality of four hs-cTn assays in US adults with known cardiovascular disease (CVD). Methods: We studied 1,211 adults with a history of CVD who participated in the National Health and Nutrition Examination Survey (NHANES) 1999–2004. Using stored samples, we measured hs-cTnT (Roche) and three hs-cTnI assays (Abbott, Siemens, and Ortho). Outcomes were all-cause and CVD mortality, with follow-up through December 31, 2019. Results: Mean age was 64 years, 48 % were female, and 80 % identified as non-Hispanic White. Pearson's correlation coefficients between hs-cTn assays ranged from 0.67 to 0.85. There were 848 deaths (365 from CVD). Among adults with a history of prior non-fatal CVD, each hs-cTn assay (log-transformed, per 1-SD) was independently associated with CVD death (HRs ranging from 1.55 to 2.16 per 1-SD, all p-values

Abstract Background Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients. Methods We searched PubMed and Embase for publications that used ‘simple subclassification’ approaches using simple categorisation of clinical characteristics, or ‘complex subclassification’ approaches which used machine learning or ‘omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches. Results Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes. Conclusion Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.

OBJECTIVES/GOALS: Chronic kidney disease (CKD) affects nearly 40% of adults with diabetes. Our objective is to assess trends in risk factor control and use of 2022 ADA and KDIGO guideline-recommended medications. METHODS/STUDY POPULATION: Using data from 1988 to 2020 from the National Health and Nutrition Examination Survey, we will examine trends in sociodemographic risk factors and glycemic, blood pressure, and lipid control among adults with CKD and diabetes. Glycemic control will be defined as a hemoglobin A1c (HbA1c)

Objective: N-terminal pro-brain-type natriuretic peptide (NT-proBNP) is a marker of cardiac wall stress and is a predictor of cardiovascular disease. Higher diet quality is associated with lower risk of cardiovascular disease. The association between diet quality and subclinical cardiovascular disease assessed by NT-proBNP is uncharacterized. We investigated the associations between diet quality, using Healthy Eating Index-2015 (HEI-2015), and NT-proBNP from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Methods: We included 9,782 adults from NHANES 1999-2004 without self-reported cardiovascular disease. The HEI-2015 ranges from 0 to 100, with higher scores indicating better diet quality. The HEI-2015 was categorized into sex-specific quintiles. Regression models were used to quantify associations between the overall HEI-2015 score and its 13 components with log-transformed NT-proBNP. The beta coefficients were converted to percent differences. Results: Among 9,782 participants, mean age was 45 years, 48% were men, and 72% were non-Hispanic White adults. After adjusting for sociodemographic characteristics, lifestyle factors, and medical history, those in the highest vs. lowest HEI-2015 quintile had an 8.5% (95% CI: -14.6% to -2.0%) lower NT-proBNP level. There was a dose-response association between HEI-2015 and NT-proBNP (P value for trend = 0.01). Each 1-unit higher in sodium and added sugars score indicating lower intake was associated with lower NT-proBNP by 7.7% (95% CI: -12.8% to -2.2%) and 6.5% (95% CI: -12.0% to -0.7%), respectively. Conclusion: Higher diet quality, especially lower intakes of sodium and added sugars, was associated with lower serum levels of NT-proBNP.

Background: The presence and interpretation of racial and ethnic differences in circulating N-terminal pro-brain-type natriuretic peptide (NT-proBNP), a diagnostic biomarker for heart failure, are controversial. Objective: To examine racial and ethnic differences in NT-proBNP levels among the general US adult population. Methods: We performed a cross-sectional analysis of data from the 1999–2004 National Health and Nutrition Examination Survey (NHANES). We included 4717 non-Hispanic White, 1675 non-Hispanic Black, and 2148 Mexican American adults aged 20 years or older without a history of cardiovascular disease. We examined the associations of race and ethnicity with NT-proBNP using linear and logistic regression models in the overall population and in a younger, ‘healthy’ subsample. Results: The mean age was 45 years. Median NT-proBNP levels were significantly lower among Black (29.3 pg/mL) and Mexican American adults (28.3.4 pg/mL) compared to White adults (49.1pg/mL, P-values

Abstract Objective Newer antidiabetic medications such as sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) and glucagon‐like peptide 1 receptor agonists (GLP1RA) result in weight loss in clinical trials. However, the real‐world effectiveness remains unclear. The magnitude of weight change associated with antidiabetic medication using real‐world data was examined. Methods Patients with diabetes who initiated SGLT2i (n = 906), GLP1RA (n = 782), dipeptidyl peptidase‐4 inhibitors (DPP4i, n = 1881), or sulfonylureas (n = 3255) in Geisinger Health System were identified. Outcomes were percent weight change per year and time to 5% weight loss. Propensity scores were used to account for differences across groups. Results The mean ± SD age of patients was 57.5 ± 14.1 years, 3381 (49.5%) were female, and 6450 (94.5%) had body mass index ≥25 kg/m2. Compared with sulfonylureas, newer antidiabetic medications were associated with significant weight loss (−3.2% [95% confidence interval: −3.8%, −2.6%] per year for SGLT2i; −2.9% [−3.6%, −2.3%] per year for GLP1RA; and −1.7% [−2.1%, −1.3%] per year for DPP4i). SGLT2i and GLP1RA were also associated with significant weight loss compared with DPP4i. Among patients with overweight or obesity, SGLT2i and GLP1RA users were more likely to achieve 5% weight loss compared with sulfonylureas and DPP4i. Conclusions In real‐world practice, SGLT2i and GLP1RA were associated with significant weight loss compared with sulfonylureas and DPP4i. These results may further motivate uptake of SGLT2i and GLP1RA, especially among patients who were overweight or had obesity.

Background NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) is strongly associated with mortality in patients with heart failure. Prior studies, primarily in middle‐aged and older populations, have suggested that NT‐proBNP has prognostic value in ambulatory adults. Methods and Results We conducted a prospective cohort analysis of adults, aged ≥20 years, in the nationally representative 1999 to 2004 National Health and Nutrition Examination Survey, to characterize the association of NT‐proBNP with mortality in the general US adult population overall and by age, race and ethnicity, and body mass index. We used Cox regression to characterize associations of NT‐proBNP with all‐cause and cardiovascular disease (CVD) mortality through 2019, adjusting for demographics and cardiovascular risk factors. We included 10 645 individuals (mean age, 45.7 years; 50.8% women; 72.8% White adults; 8.5% with a self‐reported history of CVD). There were 3155 deaths (1009 CVD‐related) over a median 17.3 years of follow‐up. Among individuals without prior CVD, elevated NT‐proBNP (≥75th percentile [81.5 pg/mL] versus 0.05). Conclusions In a representative sample of the US adult population, NT‐proBNP was an important independent risk factor for all‐cause and CVD mortality. NT‐proBNP may be useful for monitoring risk in the general adult population.

Background We characterized the burden and prognostic value of subclinical cardiovascular disease (CVD) assessed by cardiac biomarkers among adults with and without diabetes in the general US population. Methods and Results We measured hs‐cTnT (high‐sensitivity cardiac troponin T) and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) in stored serum samples from the 1999 to 2004 National Health and Nutrition Examination Survey. Among US adults without a history of CVD (n=10 304), we estimated the prevalence of elevated hs‐cTnT (≥14 ng/L) and NT‐proBNP (≥125 pg/mL) in those with and without diabetes. We examined the associations between elevated hs‐cTnT and NT‐proBNP with all‐cause and CVD mortality after adjustment for demographics and traditional CVD risk factors. The crude prevalence of subclinical CVD (elevated hs‐cTnT or NT‐proBNP) was ≈2 times higher in adults with (versus without) diabetes (33.4% versus 16.1%). After age adjustment, elevated hs‐cTnT, but not elevated NT‐proBNP, was more common in those with diabetes, overall and across age, sex, race and ethnicity, and weight status. The prevalence of elevated hs‐cTnT was significantly higher in those with longer diabetes duration and worse glycemic control. In persons with diabetes, elevated hs‐cTnT and NT‐proBNP were independently associated with all‐cause mortality (adjusted hazard ratio [HR], 1.77 [95% CI, 1.33–2.34] and HR, 1.78 [95% CI, 1.26–2.51]) and CVD mortality (adjusted HR, 1.54 [95% CI, 0.83–2.85] and HR, 2.46 [95% CI, 1.31–4.60]). Conclusions Subclinical CVD affects ≈1 in 3 US adults with diabetes and confers substantial risk for mortality. Routine testing of cardiac biomarkers may be useful for assessing and monitoring risk in persons with diabetes.

BackgroundRegular clinical assessment is critical to optimize lower extremity wound healing. However, family and work obligations, socioeconomic, transportation, and time barriers often limit patient follow-up. We assessed the feasibility of a novel, patient-centered, remote wound management system (Healthy.io Minuteful for Wound Digital Management System) for the surveillance of lower extremity wounds.MethodsWe enrolled 25 patients from our outpatient multidisciplinary limb preservation clinic with a diabetic foot ulcer, who had undergone revascularization and podiatric interventions prior to enrollment. Patients and their caregivers were instructed on how to use the digital management system and asked to perform one at-home wound scan per week for a total of 8 weeks using a smartphone application. We collected prospective data on patient engagement, smartphone app useability, and patient satisfaction.ResultsTwenty-five patients (mean age 65.5 ± 13.7 years, 60.0% male, 52.0% Black) were enrolled over 3 months. Mean baseline wound area was 18.0 ± 15.2 cm2, 24.0% of patients were recovering from osteomyelitis, and post-surgical WiFi stage was 1 in 24.0%, 2 in 40.0%, 3 in 28.0%, and 4 in 8.00% of patients. We provided a smartphone to 28.0% of patients who did not have access to one that was compatible with the technology. Wound scans were obtained by patients (40.0%) and caregivers (60.0%). Overall, 179 wound scans were submitted through the app. The mean number of wound scans acquired per patient was 0.72 ± 0.63 per week, for a total mean of 5.80 ± 5.30 scans over the course of 8 weeks. Use of the digital wound management system triggered an early change in wound management for 36.0% of patients. Patient satisfaction was high; 94.0% of patients reported the system was useful.ConclusionThe Healthy.io Minuteful for Wound Digital Management System is a feasible means of remote wound monitoring for use by patients and/or their caregivers.

This study of 23,000 non-diabetic individuals highlights loci associated with fasting glucose and fasting insulin in diverse cohorts with whole genome sequence data.

Objective: To investigate longitudinal changes in the blood concentration of fibroblast growth factor 23 (FGF23) from midlife to late life and their major predictors in the general population. Patients and Methods: In 14,444 participants of the Atherosclerosis Risk in Communities Study, we analyzed the association of 31,095 measurements of serum intact FGF23 with age using data from 3 visits (visit 2 [N=13,460; mean age, 57 years]; visit 3 [N=12,323; mean age, 60 years]; and visit 5 [N=6122; mean age, 76 years]) and a linear mixed-effects model. Among 5804 participants who had FGF23 measurements at both visits 3 and 5, we explored predictors of FGF23 change from midlife to late life using linear regression models. Prespecified risk factors were estimated glomerular filtration rate, body mass index, ever smoking, ever drinker, diabetes, hypertension, history of cardiovascular disease, total cholesterol, and high-density lipoprotein cholesterol. Results: Median FGF23 concentrations were 41.9 pg/mL (interquartile interval [IQI], 33.9 to 51.8 pg/mL) at visit 2, 38.3 pg/mL (IQI, 30.6 to 48.3 pg/mL) at visit 3, and 55.0 pg/mL (IQI, 44.4 to 70.3 pg/mL) at visit 5. A linear mixed-effects model showed that the association of FGF23 with age was nonlinear, with a slight decline or no change in age 45-60 years and a monotonic increase in age greater than or equal to 65 years (FGF23, +10 to 15 pg/mL per 10 years of age). In a multivariable linear regression model, significantly greater increases in FGF23 were noted, with midlife estimated glomerular filtration rate less than 60 mL/min per 1.73 m2 vs more than or equal to 60 mL/min per 1.73 m2 (ΔFGF23, +4.4 pg/mL [95% CI, 0.9 to 8.0]), diabetes vs no diabetes (ΔFGF23, +6.2 pg/mL [95% CI, 4.1 to 8.3]), and hypertension vs no hypertension (ΔFGF23, +4.1 pg/mL [95% CI, 2.7 to 5.4]). Conclusion: FGF23 did not show any major changes in midlife but increased linearly in late life. Reduced kidney function, diabetes, and hypertension were robustly associated with a greater increase in FGF23. Further investigations are needed to understand the potential mechanisms linking these conditions to an increase in FGF23 concentrations.

Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.

Background GDF15 (growth differentiation factor 15) is a potent predictor of bleeding in people with cardiovascular disease. However, whether GDF15 is associated with bleeding in individuals without a history of cardiovascular disease is unknown. Methods and Results The study population was from the ARIC (Atherosclerosis Risk in Communities) study. We studied the association of GDF15 with hospitalized bleeding events among 9205 participants (1993–1995) without prior bleeding and cardiovascular disease (mean age 60 years, 57% women, 21% Black). Plasma levels of GDF15 were measured in relative fluorescence units using DNA‐based aptamer technology. Bleeding was ascertained using discharge codes. We examined hazard ratios (HRs) of incident bleeding using Cox models and risk prediction with the addition of GDF15 to clinical predictors of bleeding. There were 1328 hospitalizations with bleeding during a median follow‐up of 22.5 years. The majority (76.5%) were because of gastrointestinal bleeding. The absolute incidence rate of bleeding per 1000 person‐years was 11.64 in the highest quartile of GDF15 versus 5.22 in the lowest quartile. The highest versus lowest quartile of GDF15 demonstrated an adjusted HR of 2.00 (95% CI, 1.69–2.35) for total bleeding. The findings were consistent when we examined bleeding as the primary discharge diagnosis. The addition of GDF15 to clinical predictors of bleeding improved the C‐statistic by 0.006 (0.002–0.011) from 0.684 to 0.690, P=0.008. Conclusions Higher levels of GDF15 were associated with bleeding events and improved the risk prediction beyond clinical predictors in individuals without cardiovascular disease.

The benefits of plant-based diets may depend on the type of plant. To determine the associations of healthy and unhealthy plant-based diet types on risk of hospitalization with respiratory infections or any infection, we used dietary intake data reported in a food frequency questionnaire from the Atherosclerosis Risk in Communities Study to calculate a plant-based diet index (PDI), a healthy PDI (HPDI), and an unhealthy PDI (UPDI). Cox regression was used to calculate hazard ratios for the associations of the three plant-based diet indices with the risk of hospitalization with respiratory infections and any infection-related hospitalization. Comparing the highest to lowest quintiles, HPDI was associated with a lower risk of hospitalization with respiratory infections (HR 0.86, 95% CI: 0.75, 0.99), and a lower risk of hospitalization with any infections (HR 0.87, 95% CI: 0.78, 0.97). The PDI was associated with a lower risk of hospitalization with any infections (HR 0.86, 95% CI: 0.76, 0.96). Significant associations were not observed with the UPDI. Adults with a high PDI and HPDI had a lower risk of hospitalization with any infections, whereas adults with a high HPDI had lower risk of hospitalizations with respiratory infections.

Abstract Peripheral neuropathy is associated with substantial morbidity, but risk factors other than diabetes are largely uncharacterized. The aim of this study was to describe the prevalence and risk factors for peripheral neuropathy in adults with and without diabetes from two different population-based studies in the US. We performed a cross-sectional analysis of 5200 black and white participants from NHANES (1999–2004, age 40–85 years) and 3362 black and white participants from the ARIC Study (2016–2017, age 70–89 years) who underwent monofilament testing for peripheral neuropathy using a shared protocol. We used logistic regression to quantify age, sex, and race-adjusted risk factor associations for peripheral neuropathy among middle-aged (40–69 years) and older (≥ 70 years) adults. The age, sex, and race-adjusted prevalence of peripheral neuropathy (decreased sensation on monofilament testing) was 10.4% for middle-aged adults in NHANES, 26.8% for older adults in NHANES, and 39.2% for older adults in ARIC. Diabetes was an important risk factor, but more strongly associated with peripheral neuropathy in middle-aged (OR ~ 5 for long-standing diabetes) compared to older adults (ORs ~ 1.5–2). Male sex (ORs ~ 2), black race (ORs ~ 1.3–1.5), and greater height (ORs ~ 1.5–3) were robust risk factors for peripheral neuropathy. Other risk factors included body mass index, education, and peripheral artery disease. The burden of peripheral neuropathy defined by abnormal monofilament testing among older adults is substantial, even among adults without diabetes. Studies are needed to understand the etiology and prognosis of peripheral neuropathy in the absence of diabetes.

Background The contribution of atrial cardiopathy to dementia risk is uncharacterized. We aimed to evaluate the association of atrial cardiopathy with incident dementia and potential mediation by atrial fibrillation (AF) and stroke. Methods and Results We conducted a prospective cohort analysis of participants in the ARIC (Atherosclerosis Risk in Communities) study attending visit 5 (2011–2013). We used Cox regression to determine the association between atrial cardiopathy and risk of dementia. Structural equation modeling methods were used to determine potential mediation by AF and/or stroke. Atrial cardiopathy was defined if ≥1 of the following at visit 5: P‐wave terminal force >5000 mV·ms in ECG lead V1, NT‐proBNP (N‐terminal pro–brain natriuretic peptide) >250 pg/mL or left atrial volume index ≥34 mL/m2 by transthoracic echocardiography. We repeated our analysis necessitating ≥2 markers to define atrial cardiopathy. The prevalence of atrial cardiopathy was 34% in the 5078 participants (mean age 75 years, 59% female, 21% Black adults), with 763 participants developing dementia. Atrial cardiopathy was significantly associated with dementia (adjusted HR, 1.35 [95% CI, 1.16–1.58]), with strengthening of the effect estimate when necessitating ≥2 biomarkers (adjusted HR, 1.54 [95% CI, 1.25–1.89]). There was an increased risk of dementia among those with atrial cardiopathy when excluding those with AF (adjusted HR, 1.31 [95% CI, 1.12–1.55]) or stroke (adjusted HR, 1.28 [95% CI, 1.09–1.52]). The proportion of the effect mediated by AF was 4% (P=0.005), and 9% was mediated by stroke (P=0.048). Conclusions Atrial cardiopathy was significantly associated with an increased risk of dementia, with only a small percent mediation of the effect by AF or stroke.

Summary: Background: The Endocrine Society Clinical Practice Guidelines recommend the avoidance of medications that may cause weight gain (i.e., obesogenic medications) in individuals with overweight or obesity. Obesity disproportionately affects people with lower socioeconomic status (SES); however, it is unknown whether the use of obesogenic medications differs by SES. Methods: We included adults with overweight or obesity and used prescription medications from 2009-2018 of the US National Health and Nutrition Examination Survey. We examined the associations between a composite measure of SES and use of obesogenic medications and anti-obesity medications. The composite SES included

Background Laboratory data suggest obesity is linked to myocardial inflammation and fibrosis, but clinical data are limited. We aimed to examine the association of obesity with galectin‐3, a biomarker of cardiac inflammation and fibrosis, and the related implications for heart failure (HF) risk. Methods and Results We evaluated 8687 participants (mean age 63 years; 21% Black) at ARIC (Atherosclerosis Risk in Communities) Visit 4 (1996–1998) who were free of heart disease. We used adjusted logistic regression to estimate the association of body mass index (BMI) categories with elevated galectin‐3 (≥75th sex‐specific percentile) overall and across demographic subgroups, with tests for interaction. We used Cox proportional hazards models to assess the combined associations of galectin‐3 and BMI with incident HF (through December 31, 2019). Higher BMI was associated with higher odds of elevated galectin‐3 (odds ratio [OR], 2.32; 95% CI, 1.88–2.86) for severe obesity ([BMI ≥35 kg/m2] versus normal weight [BMI 18.5‐4‐fold higher risk of HF (HR, 4.19; 95% CI, 2.98–5.88) than those with normal weight and galectin‐3

Type 2 diabetes (T2D) is associated with reduced gut microbiome diversity, although the cause is unclear. Metabolites generated by gut microbes also appear to be causative factors in T2D. We therefore searched for serum metabolites predictive of gut microbiome diversity in 1018 females from TwinsUK with concurrent metabolomic profiling and microbiome composition. We generated a Microbial Metabolites Diversity (MMD) score of six circulating metabolites that explained over 18% of the variance in microbiome alpha diversity. Moreover, the MMD score was associated with a significantly lower odds of prevalent (OR[95%CI] = 0.22[0.07;0.70], P = .01) and incident T2D (HR[95%CI] = 0.31[0.11,0.90], P = .03). We replicated our results in 1522 individuals from the ARIC study (prevalent T2D: OR[95%CI] = 0.79[0.64,0.96], P = .02, incident T2D: HR[95%CI] = 0.87[0.79,0.95], P = .003). The MMD score mediated 28%[15%,94%] of the total effect of gut microbiome on T2D after adjusting for confounders. Metabolites predicting higher microbiome diversity included 3-phenylpropionate(hydrocinnamate), indolepropionate, cinnamoylglycine and 5-alpha-pregnan-3beta,20 alpha-diol monosulfate(2) of which indolepropionate and phenylpropionate have already been linked to lower incidence of T2D. Metabolites correlating with lower microbial diversity included glutarate and imidazole propionate, of which the latter has been implicated in insulin resistance. Our results suggest that the effect of gut microbiome diversity on T2D is largely mediated by microbial metabolites, which might be modifiable by diet.

Background Whether cardiac structure and function abnormalities associated with dysglycemia are sufficient to explain the increased risk of death or heart failure (HF) remains unclear. Methods and Results We analyzed 6059 participants (mean age, 75±5 years; 58% women; and 22% Black individuals) who attended the ARIC (Atherosclerosis Risk in Communities) study visit 5 examination (2011–2013). Participants were categorized as no diabetes, pre‐diabetes, and diabetes (on the basis of medical history and glycated hemoglobin values). We assessed whether diabetes modified the association between echocardiographic measures of cardiac structure and function and the composite of all‐cause death or HF hospitalization and then estimated the extent to which the increased risk of the composite outcome associated with diabetes was explained by cardiac structure and function. Diabetes was prevalent in 33.5% of the subjects. Death or HF occurred in 1111 (18%) at a rate of 3.6 per 100 person‐years. Both measures of cardiac structure and function and diabetes status were significantly associated with worse prognosis after accounting for clinical confounders. While diabetes was consistently associated with a higher risk of events, it did not significantly modify the association between cardiac abnormalities and the risk of death or HF, except for subjects with higher left atrial volume who showed higher relative risk of events (P for interaction

Background and Purpose Liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyl transpeptidase [GGT]) are glutamate-regulatory enzymes, and higher glutamate levels correlated with worse prognosis of patients with neurotrauma. However, less is known about the association between liver enzymes and incidence of stroke. We evaluated the association between serum levels of AST, ALT, and GGT and incidence of stroke in the Atherosclerosis Risk in Communities (ARIC) study cohort from 1990 to 1992 through December 31, 2016. Methods We included 12,588 ARIC participants without prevalent stroke and with data on liver enzymes ALT, AST, and GGT at baseline. We used multivariable Cox regression models to examine the associations between liver enzymes levels at baseline and stroke risk (overall, ischemic stroke, and intracerebral hemorrhage [ICH]) through December 31, 2016, adjusting for potential confounders. Results During a median follow-up time of 24.2 years, we observed 1,012 incident strokes (922ischemic strokes and 90 ICH). In age, sex, and race-center adjusted models, the hazard ratios (HRs; 95% confidence intervals [CIs]) for the highest compared to lowest GGT quartile were 1.94 (95% CI, 1.64 to 2.30) for all incident stroke and 2.01 (95% CI, 1.68 to 2.41) for ischemic stroke, with the results supporting a dose-response association (P for linear trend

Abstract Background Insulin resistance may contribute to aortic stiffening that leads to end-organ damage. We examined the cross-sectional association and prospective association of insulin resistance and aortic stiffness in older adults without diabetes. Methods We analyzed 2571 men and women at Visit 5 (in 2011–2013), and 2350 men and women at repeat examinations from baseline at Visit 1 (in 1987–1989) to Visit 5 (in 2011–2013). Linear regression was used to estimate the difference in aortic stiffness per standard unit of HOMA-IR, TG/HDL-C, and TyG at Visit 5. Linear mixed effects were used to assess if high, as opposed to non-high, aortic stiffness (> 75th percentile) was preceded by a faster annual rate of change in log-HOMA-IR, log-TG/HDL-C, and log-TyG from Visit 1 to Visit 5. Results The mean age of participants was 75 years, 37% (n = 957) were men, and 17% (n = 433) were African American. At Visit 5, higher HOMA-IR, higher TG/HDL-C, and higher TyG were associated with higher aortic stiffness (16 cm/s per SD (95% CI 6, 27), 29 cm/s per SD (95% CI 18, 40), and 32 cm/s per SD (95% CI 22, 42), respectively). From Visit 1 to Visit 5, high aortic stiffness, compared to non-high aortic stiffness, was not preceded by a faster annual rate of change in log-HOMA-IR from baseline to 9 years (0.030 (95% CI 0.024, 0.035) vs. 0.025 (95% CI 0.021, 0.028); p = 0.15) or 9 years onward (0.011 (95% CI 0.007, 0.015) vs. 0.011 (95% CI 0.009, 0.013); p = 0.31); in log-TG/HDL-C from baseline to 9 years (0.019 (95% CI 0.015, 0.024) vs. 0.024 (95% CI 0.022, 0.026); p = 0.06) or 9 years onward (− 0.007 (95% CI − 0.010, − 0.005) vs. − 0.009 (95% CI − 0.010, − 0.007); p = 0.08); or in log-TyG from baseline to 9 years (0.002 (95% CI 0.002, 0.003) vs. 0.003 (95% CI 0.003, 0.003); p = 0.03) or 9 years onward (0 (95% CI 0, 0) vs. 0 (95% CI 0, 0); p = 0.08). Conclusions Among older adults without diabetes, insulin resistance was associated with aortic stiffness, but the putative role of insulin resistance in aortic stiffness over the life course requires further study.

Background: Fibroblast growth factor 23 (FGF-23) regulates phosphorus and is associated with cardiovascular disease (CVD), particularly in patients with chronic kidney disease. However, data are limited regarding its contribution to different CVD subtypes across wide age ranges in the general population. Methods: Using data from ARIC, we evaluated the associations of FGF-23 with heart failure (HF), coronary heart disease (CHD), stroke, and composite CVD (any CVD event) in 12,039 participants at mid-life (visit 3 [1993–1995], mean age 60.0 [SD 5.7] years) and 5608 of the same participants at late-life (visit 5 [2011−2013], 75.5 [5.1] years). Results: During a median of 9.0 years from visit 3 and 6.9 years from visit 5, we observed 1636 and 1137 composite CVD events, respectively. Higher FGF-23 at visit 5, but not necessarily at visit 3, was significantly associated with the risk of CVD independently of potential confounders including kidney function (adjusted HRs for top vs. bottom quartile, 1.56 [95% CI, 1.30–1.87] at visit 5 and 1.10 [95% CI, 0.95–1.27] at visit 3, p-for-difference

Background Ankle‐brachial index (ABI) is used to identify lower‐extremity peripheral artery disease (PAD). However, its association with severe ischemic leg outcomes (eg, amputation) has not been investigated in the general population. Methods and Results Among 13 735 ARIC (Atherosclerosis Risk in Communities) study participants without clinical manifestations of PAD (mean age, 54 [SD, 5.8] years; 44.4% men; and 73.6% White) at baseline (1987–1989), we quantified the prospective association between ABI and subsequent severe ischemic leg outcomes, critical limb ischemia (PAD with rest pain or tissue loss) and ischemic leg amputation (PAD requiring amputation) according to discharge diagnosis. Over a median follow‐up of ≈28 years, there were 221 and 129 events of critical limb ischemia and ischemic leg amputation, respectively. After adjusting for demographics, ABI ≤0.90 versus 1.11 to 1.20 had a ≈4‐fold higher risk of critical limb ischemia and ischemic leg amputation (hazard ratios, 3.85 [95% CI, 2.09–7.11] and 4.39 [95% CI, 2.08–9.27]). The magnitude of the association was modestly attenuated after multivariable adjustment (hazard ratios, 2.44 [95% CI, 1.29–4.61] and 2.72 [95% CI, 1.25–5.91], respectively). ABI 0.91 to 1.00 and 1.01 to 1.10 were also associated with these severe leg outcomes, with hazard ratios ranging from 1.7 to 2.0 after accounting for potential clinical and demographic confounders. The associations were largely consistent across various subgroups. Conclusions In a middle‐aged community‐based cohort, lower ABI was independently and robustly associated with increased risk of severe ischemic leg outcomes. Our results further support ABI ≤0.90 as a threshold diagnosing PAD and also suggest the importance of recognizing the prognostic value of ABI 0.91 to 1.10 for limb prognosis.

Rationale & Objective: Retinopathy and chronic kidney disease (CKD) are typically considered microvascular complications of diabetes, and cardiovascular and cerebrovascular diseases are considered macrovascular complications; however, all may share common pathological mechanisms. This study quantified the association of retinopathy with risk of kidney disease and compared with the association with cardiovascular disease in persons with diabetes. Study Design: Retrospective cohort study. Setting & Participants: 1,759 participants in the ARIC study who had diabetes at visit 4 and underwent retinal examination at visit 3. Exposure: Retinopathy. Outcome: Prevalent CKD (estimated glomerular filtration rate [eGFR] 30 mg/g), incident CKD, incident end-stage kidney disease (ESKD), incident coronary heart disease (CHD), and incident stroke. Analytical Approach: The cross-sectional association of retinopathy with prevalent CKD and albuminuria was assessed by logistic regression. The associations between retinopathy, incident CKD, incident ESKD, incident CHD, and incident stroke were examined using Cox proportional hazards models. Seemingly unrelated regression was used to compare the strength of association between retinopathy and outcomes. Results: During the median follow-up period of 14.2 years, 723 participants developed CKD, and there were 109 ESKD events, 399 CHD events, and 196 stroke events. Compared with the participants without retinopathy, participants with retinopathy were more likely to have reduced eGFR (OR, 1.56 [95% CI, 1.09-2.23]) and UACR > 30 mg/g (OR, 1.61 [95% CI, 1.24-2.10]). Retinopathy was associated with risk of incident CKD (HR, 1.22 [95% CI, 1.02-1.46]), ESKD (HR, 1.69 [95% CI, 1.11-2.58]), CHD (HR, 1.46 [95% CI, 1.15-1.84]), and stroke (HR, 1.43 [95% CI, 1.03-1.97]). A stronger relationship was found between retinopathy and CHD when compared with retinopathy and CKD (P = 0.03); all other associations were similar. Limitations: Retinal examination and kidney measurements were taken at different visits. Conclusions: The presence of retinopathy was associated with higher prevalence of kidney disease and higher risk of incident CKD, ESKD, and CHD. These results may suggest that a similar mechanism underlies the development of retinopathy and other adverse outcomes in diabetes.

Background and Objectives: Bipolar Affective Disorder is the sixth leading cause of disability-adjusted life years in individuals aged 15-44 years. Among the patients with Bipolar Disorder, about 60% are at least partially non-adherent to medications. This study attempted to study attitude towards drug adherence in inpatients with bipolar affective disorder. Materials and Methods: Consecutive patients, between 18 to 60 years of age, diagnosed with Bipolar Affective Disorder, undergoing inpatient treatment over a two-month period, were recruited. Their attitude towards drug adherence was assessed using a 30-item version of the Drug Attitude Inventory (DAI). Results: Subjects in this study had good medication adherence (DAI= 3.12± 7.09), indicating these patients tended to report favourable views towards their psychiatric medications. Conclusion: Assessment of attitude towards non-adherence in this population showed good medication adherence and a positive response to treatment.

Background Current strategies for cardiovascular disease (CVD) risk assessment focus on 10‐year or longer timeframes. Shorter‐term CVD risk is also clinically relevant, particularly for high‐risk occupations, but is under‐investigated. Methods and Results We pooled data from participants in the ARIC (Atherosclerosis Risk in Communities study), MESA (Multi‐Ethnic Study of Atherosclerosis), and DHS (Dallas Heart Study), free from CVD at baseline (N=16 581). Measurements included N‐terminal pro‐B‐type natriuretic peptide (>100 pg/mL prospectively defined as abnormal); high‐sensitivity cardiac troponin T (abnormal >5 ng/L); high‐sensitivity C‐reactive protein (abnormal >3 mg/L); left ventricular hypertrophy by ECG (abnormal if present); carotid intima‐media thickness, and plaque (abnormal >75th percentile for age and sex or presence of plaque); and coronary artery calcium (abnormal >10 Agatston U). Each abnormal test result except left ventricular hypertrophy by ECG was independently associated with increased 3‐year risk of global CVD (myocardial infarction, stroke, coronary revascularization, incident heart failure, or atrial fibrillation), even after adjustment for traditional CVD risk factors and the other test results. When a simple integer score counting the number of abnormal tests was used, 3‐year multivariable‐adjusted global CVD risk was increased among participants with integer scores of 1, 2, 3, and 4, by ≈2‐, 3‐, 4.5‐ and 8‐fold, respectively, when compared with those with a score of 0. Qualitatively similar results were obtained for atherosclerotic CVD (fatal or non‐fatal myocardial infarction or stroke). Conclusions A strategy incorporating multiple biomarkers and atherosclerosis imaging improved assessment of 3‐year global and atherosclerotic CVD risk compared with a standard approach using traditional risk factors.

Background Circulating galectin‐3 levels provide prognostic information in patients with established heart failure (HF), but the associations between galectin‐3 levels and other incident cardiovascular events in asymptomatic individuals at midlife and when remeasured ≈15 years later are largely uncharacterized. Methods and Results Using multivariable Cox proportional hazards models, we identified associations between plasma galectin‐3 levels (hazard ratio [HR] per 1 SD increase in natural log galectin‐3) and incident coronary heart disease, ischemic stroke, HF hospitalization, and total mortality in ARIC (Atherosclerosis Risk in Communities) participants free of cardiovascular disease at ARIC visit 4 (1996–1998; n=9247) and at ARIC visit 5 (2011–2013; n=4829). Higher galectin‐3 level at visit 4 (median age 62) was independently associated with incident coronary heart disease (adjusted HR, 1.30; 95% CI, 1.06–1.60), ischemic stroke (HR, 1.42; 95% CI, 1.01–2.00), HF (HR, 1.44; 95% CI, 1.17–1.76), and mortality (HR, 1.56; 95% CI, 1.35–1.80). At visit 5 (median age, 74), higher galectin‐3 level was associated with incident HF (HR, 1.93; 95% CI, 1.15–3.24) and total mortality (HR, 1.70; 95% CI, 1.15–2.52), but not coronary heart disease or stoke. Individuals with the greatest increase in galectin‐3 levels from visit 4 to visit 5 were also at increased risk of incident HF and total mortality. Conclusions In a large, biracial community‐based cohort, galectin‐3 measured at midlife and older age was associated with increased risk of cardiovascular events. An increase in galectin‐3 levels over this period was also associated with increased risk.

Background Greater physical activity (PA) is associated with lower heart failure (HF) risk. However, it is unclear whether this inverse association exists across all subgroups at high risk for HF, particularly among those with preexisting atherosclerotic cardiovascular disease. Methods and Results We followed 13 810 ARIC (Atherosclerosis Risk in Communities) study participants (mean age 55 years, 54% women, 26% black) without HF at baseline (visit 1; 1987–1989). PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines: recommended, intermediate, or poor. We constructed Cox models to estimate associations between PA categories and incident HF within each high‐risk subgroup at baseline, with tests for interaction. We performed additional analyses modeling incident coronary heart disease as a time‐varying covariate. Over a median of 26 years of follow‐up, there were 2994 HF events. Compared with poor PA, recommended PA was associated with lower HF risk among participants with hypertension, obesity, diabetes mellitus, and metabolic syndrome (all P

Background hs‐cTnT (high‐sensitivity cardiac troponin T), but not NT‐proBNP (N‐terminal pro–B natriuretic peptide), has been shown to predict bleeding in patients with atrial fibrillation. Whether these biomarkers are independently associated with bleeding in the general population is unknown. Methods and Results We used Cox proportional hazards models to examine the association of hs‐cTnT and NT‐proBNP with incident bleeding (defined by International Classification of Diseases, Ninth Revision [ICD‐9] codes) among 9550 middle‐aged men and women without a history of cardiovascular disease or bleeding. There were 847 hospitalizations with bleeding (92% from gastrointestinal bleeding) during a median follow‐up of 9.0 years. Serum levels of hs‐cTnT were associated with bleeding in a graded fashion, with a hazard ratio of 1.28 (95% CI, 1.06–1.59) for 6 to

Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

Background Whether physical activity is a determinant of peripheral artery disease (PAD) remains unclear. We therefore assessed the association of physical activity (amount and intensity) with subsequent risk of hospitalization with PAD and its severe form, critical limb ischemia, in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results We included 12 513 participants free of cardiovascular disease at baseline (1987–1989), with a mean age of 53.9 years, 55.3% women, and 25.0% black. Physical activity was assessed using a modified Baecke questionnaire and categorized into poor (no moderate [3 to

Abstract Background Ethnic minority populations in the United States (US) are disproportionately affected by cardiovascular disease (CVD) risk factors, including hypertension, overweight/obesity, and diabetes. The size and diversity of ethnic minority immigrant populations in the US have increased substantially over the past three decades. However, most studies on immigrants in the US are limited to Asians and Hispanics; only a few have examined the prevalence of CVD risk factors across diverse immigrant populations. The prevalence of diagnosed hypertension, overweight/obesity, and diagnosed diabetes was examined and contrasted among a socioeconomically diverse sample of immigrants. It was hypothesized that considerable variability would exist in the prevalence of hypertension, overweight and diabetes. Methods A cross-sectional analysis of the 2010–2016 National Health Interview Survey (NHIS) was conducted among 41,717 immigrants born in Europe, South America, Mexico/Central America/Caribbean, Russia, Africa, Middle East, Indian subcontinent, Asia and Southeast Asia. The outcomes were the prevalence of diagnosed hypertension, overweight/obesity, and diagnosed diabetes. Results The highest multivariable adjusted prevalence of diagnosed hypertension was observed in Russian (24.2%) and Southeast Asian immigrants (23.5%). Immigrants from Mexico/Central America/Caribbean and the Indian subcontinent had the highest prevalence of overweight/obesity (71.5 and 73.4%, respectively) and diagnosed diabetes (9.6 and 10.1%, respectively). Compared to European immigrants, immigrants from Mexico/Central America/Caribbean and the Indian subcontinent respectively had higher prevalence of overweight/obesity (Prevalence Ratio (PR): 1.19[95% CI, 1.13–1.24]) and (PR: 1.22[95% CI, 1.14–1.29]), and diabetes (PR: 1.70[95% CI, 1.42–2.03]) and (PR: 1.78[95% CI, 1.36–2.32]). African immigrants and Middle Eastern immigrants had a higher prevalence of diabetes (PR: 1.41[95% CI, 1.01–1.96]) and PR: 1.57(95% CI: 1.09–2.25), respectively, than European immigrants —without a corresponding higher prevalence of overweight/obesity. Conclusions Immigrants from Mexico/Central America/Caribbean and the Indian subcontinent bore the highest burden of overweight/obesity and diabetes while those from Southeast Asia and Russia bore the highest burden of hypertension.