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Objectives The aim of the study was to compare the predictions of five popular cardiovascular disease ( CVD) risk prediction models, namely the Data Collection on Adverse Events of Anti- HIV Drugs ( D: A: D) model, the Framingham Heart Study ( FHS) coronary heart disease ( FHS-CHD) and general CVD ( FHS-CVD) models, the American Heart Association ( AHA) atherosclerotic cardiovascular disease risk score ( ASCVD) model and the Systematic Coronary Risk Evaluation for the Netherlands ( SCORE-NL) model. Methods A cross-sectional design was used to compare the cumulative CVD risk predictions of the models. Furthermore, the predictions of the general CVD models were compared with those of the HIV-specific D: A: D model using three categories (< 10%, 10-20% and > 20%) to categorize the risk and to determine the degree to which patients were categorized similarly or in a higher/lower category. Results A total of 997 HIV-infected patients were included in the study: 81% were male and they had a median age of 46 [interquartile range ( IQR) 40-52] years, a known duration of HIV infection of 6.8 ( IQR 3.7-10.9) years, and a median time on ART of 6.4 ( IQR 3.0-11.5) years. The D: A: D, ASCVD and SCORE-NL models gave a lower cumulative CVD risk, compared with that of the FHS-CVD and FHS-CHD models. Comparing the general CVD models with the D: A: D model, the FHS-CVD and FHS-CHD models only classified 65% and 79% of patients, respectively, in the same category as did the D: A: D model. However, for the ASCVD and SCORE-NL models, this percentage was 89% and 87%, respectively. Furthermore, FHS-CVD and FHS-CHD attributed a higher CVD risk to 33% and 16% of patients, respectively, while this percentage was < 6% for ASCVD and SCORE-NL. Conclusions When using FHS-CVD and FHS-CHD, a higher overall CVD risk was attributed to the HIV-infected patients than when using the D: A: D, ASCVD and SCORE-NL models. This could have consequences regarding overtreatment, drug-related adverse events and drug−drug interactions. [ABSTRACT FROM AUTHOR]

Objective: Elevated plasma interleukin-18 (IL-18) has been linked to onset of diabetes mellitus (DM) and its complications. However, so far this association has been shown only in predominantly white populations. We examined IL-18 levels and their association with incident DM in a racially heterogeneous population.Research Design and Methods: In a nested case-cohort design representing a 9-year follow-up of 9,740 middle-aged, initially healthy, nondiabetic white and African American participants of the Atherosclerosis Risk in Communities Study, we selected and measured analytes on race-stratified (50% white, 50% African American) random samples of both cases of incident diabetes (n = 548) and eligible members of the full cohort (n = 536). RESULTS Baseline IL-18 levels were significantly higher in white participants compared with African American participants (P < 0.001). Although white participants in the fourth (versus first) quartile of IL-18 levels had a significant hazard ratio (HR) for developing DM (HR: 2.1, 95% CI: 1.3-3.4), after adjustment for age, sex, and study center, no difference was seen among African Americans (HR: 1.0, 95% CI: 0.6-1.7). Unlike those in African Americans, IL-18 levels in whites had a significant correlation with age (P < 0.01); anthropometric characteristics such as waist circumference (P < 0.001), height (P = 0.04), waist-to-hip ratio (P < 0.001), and BMI (P < 0.01); and total (P < 0.001) and high-molecular-weight (P < 0.001) adiponectin.Conclusions: There are racial differences in levels of IL-18 and the association of IL-18 with risk factors and incident type 2 DM. In addition, there seems to be a complex interplay of inflammation and adiposity in the development of DM. [ABSTRACT FROM AUTHOR]

Objective: To compare the associations of nontraditional (fructosamine, glycated albumin, 1,5-anhydroglucitol [1,5-AG]) and standard (fasting glucose, HbA(1c)) glycemic markers with common microvascular conditions associated with diabetes mellitus.Research Design and Methods: We conducted a cross-sectional study of 1,600 participants (227 with a history of diabetes and 1,323 without) from the Atherosclerosis Risk in Communities (ARIC) Study, a community-based population. We conducted logistic regression analyses of the associations of diabetes-specific tertiles of fructosamine, glycated albumin, 1/(1,5-AG), fasting glucose, and HbA(1c) with prevalence of chronic kidney disease, albuminuria, and retinopathy after adjustment for demographic, clinical, and lifestyle variables.Results: We observed significant positive trends in the associations of each marker with albuminuria and retinopathy, even after accounting for demographic, clinical, and lifestyle factors (all P trends <0.05). The associations with chronic kidney disease were similar in direction but were only significant for higher glycated albumin (P trend = 0.005), fructosamine (P trend = 0.003), and HbA(1c) (P trend = 0.005) values. After further adjustment for HbA(1c), glycated albumin and fructosamine remained significantly or borderline significantly associated with the microvascular outcomes.Conclusions: In cross-sectional analyses, two serum markers of glycemia-glycated albumin and fructosamine-are as, or more strongly, associated with microvascular conditions as HbA(1c). These markers may be useful in settings where whole blood is not available. Whether they might complement or outperform HbA(1c) in terms of long-term predictive value requires further investigation. [ABSTRACT FROM AUTHOR]

Objective: We examined whether a 1-year intensive lifestyle intervention (ILI) for weight loss reduced elevated high-sensitivity C-reactive protein (hs-CRP) levels in obese individuals with diabetes and identified metabolic and fitness predictors of hs-CRP change.Research Design and Methods: Look AHEAD (Action for Health in Diabetes) is an ongoing multicenter clinical trial examining the effects of weight loss achieved through ILI on cardiovascular events and overall mortality in obese/overweight adults with type 2 diabetes. We report on 1,759 Look AHEAD participants who had hs-CRP and fitness data at baseline and 1 year. Subjects were randomly assigned to ILI or to usual care (diabetes support and education [DSE]). ILI involved frequent counseling to increase moderate-intensity exercise to 175 min/week, reduce caloric and saturated fat intake, and change macronutrient composition to improve glycemic control.Results: ILI reduced median hs-CRP by 43.6% from baseline to 1 year, compared with a 16.7% reduction with DSE (P<0.001). ILI decreased weight (8.8%), A1C (0.7%), and triglycerides (17%) and increased fitness (19%) and HDL cholesterol (7.5%) (P<0.0001 vs. changes with DSE). Changes in adiposity and glucose control with ILI remained independent predictors of hs-CRP change at 1 year (P<0.0001 for each) after adjustment for demographics, smoking, cardiovascular history, statin and thiazolidinedione use, and changes in fitness and lipid control. Neither statin nor insulin therapy modified the association between ILI and hs-CRP.Conclusions: A 1-year lifestyle intervention for weight loss in obese individuals with diabetes was associated with substantial reductions in hs-CRP. Improved glycemic control and reduced adiposity had comparable effects on hs-CRP change. [ABSTRACT FROM AUTHOR]

A history of intimate partner violence (IPV) is linked to cardiovascular disorders among women. Static autonomic nervous system (ANS) imbalance may result from chronic stress associated with exposure to IPV. Autonomic nervous system imbalance is associated with an excessive proinflammatory response that may increase the risk for inflammatory diseases, including atherosclerosis. To better understand the process from IPV to poorer health outcomes in women diagnosed with acute coronary syndrome (ACS) we developed and tested a biobehavioral model of the psychological and biological pathway from IPV to chronic illness. We hypothesized that among women hospitalized for ACS, those who reported sexual abuse, with or without physical abuse, would have greater alterations in their serum levels of neuroendocrine markers, proinflammatory cytokines, and cell adhesion molecules and a chemotactic cytokine, at time of hospitalization for ACS, and 3 and 6 months later, than do women with physical abuse only. Participants were 45 women, primarily African American, admitted to a county hospital with a diagnosis of ACS. We evaluated 11 biomarkers and found a moderate group effect size for vascular cell adhesion molecule-1. All others had a small effect size. [ABSTRACT FROM AUTHOR]

The authors performed a case-cohort study nested within the Atherosclerosis Risk in Communities (ARIC) Study to determine the association between plasma ferritin level and risk of type 2 diabetes mellitus. Persons with incident cases of type 2 diabetes diagnosed over an average follow-up period of 7.9 years (n = 599) were compared with a random sample of the cohort (n = 690). After adjustment for age, gender, menopausal status, ethnicity, center, smoking, and alcohol intake, the hazard ratio for diabetes, comparing the fifth quintile of ferritin with the first quintile, was 1.74 (95% confidence interval: 1.14, 2.65; p-trend < 0.001). After further adjustment for body mass index and components of the metabolic syndrome, the hazard ratio was 0.81 (95% confidence interval: 0.49, 1.34; p-trend = 0.87). From a causal perspective, there are two alternative interpretations of these findings. Elevated iron stores, reflected in elevated plasma ferritin levels, may induce baseline metabolic abnormalities that ultimately result in diabetes. Alternatively, elevated ferritin may be just one of several metabolic abnormalities related to the underlying process that ultimately results in diabetes, rather than a causal factor for diabetes. Longitudinal studies with repeated measurements of glucose and iron metabolism parameters are needed to establish the role of iron stores and plasma ferritin in diabetes development. [ABSTRACT FROM AUTHOR]

Objective: Dipeptidyl peptidase IV (DPP-IV) is not only important in beta-cell function but also has proinflammatory actions. We aimed to investigate whether it could act as a link between low-grade chronic inflammation and diabetes.Research Design and Methods: Using a case-cohort design, we followed 546 middle-aged individuals who developed diabetes and 538 who did not over approximately 9 years within the Atherosclerosis Risk in Communities study.Results: In weighted analyses, the correlation between DPP-IV levels and anthropometric, inflammatory, or metabolic variables was minimal (Spearman correlations <0.11). Those who developed diabetes had mean DPP-IV values similar to those who did not (P = 0.18). Individuals in the highest quartile of DPP-IV were not at greater risk of diabetes (hazard ratio 0.88 [95% CI 0.62-1.24]) in Cox proportional hazards models adjusting for age, sex, race, study center, and multiple additional diabetes risk factors.Conclusions: Fasting DPP-IV levels do not appear to predict incident diabetes. [ABSTRACT FROM AUTHOR]

Objective: To examine usual marine omega-3 fatty acid (mO-3FA) intake in individuals with diabetes; its association with adiposity, lipid, and glucose control; and its changes with behavioral lifestyle intervention for weight loss.Research Design and Methods: Cross-sectional and 1-year longitudinal analyses were performed on 2,397 Look AHEAD (Action for Health in Diabetes) participants. Look AHEAD is a cardiovascular outcome trial evaluating the effects of intensive lifestyle intervention for weight loss in overweight/obese subjects with type 2 diabetes.Results: Baseline mO-3FA intake was 162 +/- 138 mg/day. It was inversely associated with triglycerides (beta = -0.41, P < 0.001) and weakly with HDL (beta = 4.14, P = 0.050), after multiple covariate adjustment. One-year mO-3FA and fried/sandwich fish intake decreased with intensive lifestyle intervention (P < 0.001).Conclusions: mO-3FA intake in Look AHEAD participants was low but associated favorably with lipids. These results encourage investigation on the potential benefits of increasing mO-3FA intake in lifestyle interventions for weight loss in individuals with diabetes. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study is to describe the proportion of "JUPITER-eligible" (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) individuals and clinical outcomes of individuals based on high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C) strata in the ARIC (Atherosclerosis Risk in Communities) study.Background: Questions remain after the JUPITER study, including whether the observed cardiovascular disease (CVD) event rates would persist with time and how these event rates would compare with other populations (lower hs-CRP and/or higher LDL-C levels).Methods: After stratification into 4 groups based on LDL-C and hs-CRP levels, with cutoffs at 130 mg/dl and 2.0 mg/l, respectively, incident CVD events were examined (mean follow-up, 6.9 years) and compared.Results: Of 8,907 age-eligible participants, 18.2% (n = 1,621) were JUPITER-eligible (hs-CRP > or = 2.0 mg/l, LDL-C <130 mg/dl) and had an absolute CVD risk of approximately 10.9% over a mean follow-up of 6.9 years (1.57% per year). If JUPITER hazard ratios were applied to this group, the number needed to treat to prevent 1 CVD event would be estimated at 38 over 5 years and 26 over 6.9 years.Conclusions: ARIC participants with elevated hs-CRP and low LDL-C had a CVD event rate of 1.57% per year over 6.9 years, similar to the CVD event rate noted in the JUPITER study placebo group (1.36% per year over 1.9 years). The association of hs-CRP > or = 2.0 mg/l with increased CVD risk and mortality regardless of LDL-C provides us a simple method of using age and hs-CRP level for identifying higher risk individuals. (Atherosclerosis Risk in Communities study; NCT00005131). [ABSTRACT FROM AUTHOR]

Background: High-density lipoprotein (HDL) modulates the blood-brain barrier and cerebrovascular integrity, likely influencing the risk of Alzheimer's disease (AD), neurodegeneration, and cognitive decline., Objective: This study aims to identify HDL protein cargo associated with brain amyloid deposition and brain volume in regions vulnerable to AD pathology in older adults., Methods: HDL was separated from the plasma of 65 non-demented participants of the Atherosclerosis Risk in Communities (ARIC) study using a fast protein liquid chromatography method. HDL cargo proteins were measured using a label-free, untargeted proteomic method based on mass spectrometry and data-independent acquisition. Linear regression with multiple imputations assessed the associations between each HDL cargo protein (log2-transformed) and brain amyloid deposition or temporal-parietal meta-ROI volume, adjusting for covariates., Results: The mean (SD) age of the participants was 76.3 (5.4) years old, 53.8% (35/65) female, 30.8% (20/65) black, and 28.1% (18/64, 1 missing) APOE4 carriers. We found few HDL cargo proteins associated with brain amyloid deposition and considerably more HDL cargo proteins associated with temporal-parietal meta-ROI volume. Two HDL cargo proteins mostly associated with temporoparietal meta-ROI volume were fibrinogen B (FGB) and plasminogen (PLG). A doubling of FGB in HDL was associated with a greater temporoparietal meta-ROI volume of 1638 mm 3 (95% CI [688, 2589]). In comparison, a doubling of PLG in HDL was associated with a lower temporoparietal meta-ROI of 2025 mm 3 (95% CI [-3669, -1034])., Conclusions: This study suggests that HDL cargo proteins associated with temporal-parietal meta-ROI volume are involved in complement and coagulation pathways., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Varicose veins are common in older adults and are associated with adverse clinical outcomes such as deep venous thrombosis. Established risk factors for varicose veins include female sex, height, and obesity, but other risk factors are relatively uncharacterized., Methods: This was a prospective cohort analysis of 6241 participants aged 66-70 years from the Atherosclerosis Risk in Communities (ARIC) Study. Incident varicose veins were defined as two outpatient encounters (at least a week apart) or inpatient diagnoses through 2018 with ICD 9 code 454 or ICD 10 code I83. Participants with a history of clinically-recognized varicose veins at baseline were excluded. Cox regression was used to evaluate established (e.g., female, height, body mass index) and potential demographic and clinical risk factors., Results: During a median follow-up of 13 years, 349 (6%) of participants developed clinically-recognized varicose veins. Consistent with prior research, female sex, taller height, and higher body mass index were associated with varicose veins. After accounting for these, White race, prevalent heart failure, loop diuretic use, higher cardiac troponin T, and higher natriuretic peptide were independently associated with incident varicose veins., Conclusions: In this community-based cohort study of older adults, known and newly identified risk factors, including cardiac function and heart failure, were independently associated with incidence of clinically-recognized varicose veins. The potential usefulness of cardiac biomarkers for prevention and screening of varicose veins requires further investigations., Competing Interests: Conflict of interest No financial disclosures have been reported by the authors of this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Higher circulating concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) are associated with left ventricular remodeling and with incident heart failure. The associations of these cardiac biomarkers with changes in cardiac structure and function over time are uncharacterized., Methods: Among 2006 participants in the ARIC prospective cohort study (Atherosclerosis Risk in Communities) who were free of overt cardiovascular disease and underwent echocardiography at study visits 5 (2011- 2013) and 7 (2018-2019), we assessed the associations of NT-proBNP, hs-cTnT, and hs-cTnI concentrations at visit 5 with changes in left ventricular structure and function between visits 5 and 7 (≈7-year change) using multivariable linear regression with the biomarkers modeled as restricted cubic splines. Models were adjusted for age, sex, race, body mass index, smoking, diabetes, hypertension, and renal function at visit 5; blood pressure and heart rate at both visits; and the baseline value of the echocardiographic parameter of interest., Results: Mean±SD age was 74±4 years at visit 5; 61% were women; and 23% were Black adults. Median (25th-75th percentile) concentrations at visit 5 of NT-proBNP, hs-cTnT, and hs-cTnI were 87 ng/L (50-157 ng/L), 9 ng/L (6-12 ng/L), and 2.6 ng/L (1.9-3.9 ng/L). In adjusted models, elevated baseline concentrations of NT-proBNP and hs-cTnI were significantly associated with 7-year decline in left ventricular systolic function (ejection fraction, longitudinal and circumferential strain) and worsening diastolic indices. In contrast, elevated baseline concentrations of hs-cTnT were not significantly associated with 7-year changes in cardiac structure, systolic function, or diastolic function (all P >0.05)., Conclusions: Higher concentrations of NT-proBNP and hs-cTnI, but not hs-cTnT, were associated with greater declines in left ventricular function over ≈7 years in late life independently of traditional cardiovascular risk factors., Competing Interests: Dr Myhre has consulted for Amarin, AmGen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Novartis, Novo Nordisk, Pharmacosmos, Roche Diagnostics, Sanofi, Us2.ai, and Vifor. Dr Ballantyne has been a consultant for Abbott Diagnostics and Roche Diagnostics. Dr Shah has received research support from Novartis and consulting fees from Philips Ultrasound and Janssen. The other authors report no conflicts.

Objective: Mandatory folic acid fortification of enriched grains has reduced neural tube defect prevalence in several countries. We examined salt as an additional vehicle for folic acid fortification. The primary objective was to examine the change in serum folate concentration after 1 month of consumption of fortified iodised salt with folic acid (FISFA) among women of reproductive age. The secondary objectives were to examine (1) the feasibility of implementing FISFA intervention and (2) the acceptability of FISFA., Design: We conducted a pre–post intervention study (January–April 2023). Participants received a FISFA saltshaker with the study salt (1 g of sodium chloride salt fortified with 100 mcg of folic acid) to use instead of regular table salt for 1 month. Serum folate was measured using the Elecsys Folate-III immunoassay method at baseline and 1-month endpoint. Change in serum folate was assessed using a two-tailed Wilcoxon signed rank test for paired samples., Setting: Metropolitan city, Southern USA., Participants: Non-pregnant, 18–40-year-old women who lived alone/with a partner., Results: Thirty-two eligible women consented to participate, including eleven non-Hispanic-White, eleven non-Hispanic-Black and ten Hispanic. Post-intervention, there was a significant increase in median serum folate concentration of 1·40 nmol/l (IQR 0·74–2·05; P < 0·001) from 24·08 nmol/l to 25·96 nmol/l in an analytical sample of n 29. An increase was seen in 28/29 (93 %) participants. Feasibility: 100 % study consent and compliance. FISFA acceptability: 25 d average use; 1·28 g average daily intake; 96·7 % and 90 % reported taste and colour of FISFA as highly acceptable, respectively., Conclusions: FISFA is an effective approach to increasing serum folate concentrations among women of reproductive age. Findings should be replicated in a larger study.

Fully characterizing the genetic architecture of circulating proteins in multi-ancestry populations provides an unprecedented opportunity to gain insights into the etiology of complex diseases. We characterized and contrasted the genetic associations of plasma proteomes in 9,455 participants of European and African (19.8%) ancestry from the Atherosclerosis Risk in Communities Study. Of 4,651 proteins, 1,408 and 2,565 proteins had protein-quantitative trait loci (pQTLs) identified in African and European ancestry respectively, and twelve unreported potentially causal protein-disease relationships were identified. Shared pQTLs across the two ancestries were detected in 1,113 aptamer-region pairs pQTLs, where 53 of them were not previously reported (all trans pQTLs). Sixteen unique protein-cardiovascular trait pairs were colocalized in both European and African ancestry with the same candidate causal variants. Our systematic cross-ancestry comparison provided a reliable set of pQTLs, highlighted the shared and distinct genetic architecture of proteome in two ancestries, and demonstrated possible biological mechanisms underlying complex diseases., Competing Interests: Conflicts of Interest Proteomic assays in ARIC were conducted free of charge as part of a data exchange agreement with SomaLogic. The authors declare no conflicts of interest related to the work submitted. R.C.H has received research grants from Denka Seiken and is a consultant (personal fees) for Denka Seiken outside the scope of the work submitted.

Background: Relationships of midlife inflammation with late-life mobility and influences of chronic health conditions, race, and social determinants of health (SDoH) on these relationships are poorly understood., Methods: Among 4758 community-dwelling participants (41% men, 20% Black), high-sensitivity C-reactive protein (hsCRP) was measured over 20+ years: in midlife at study visit 2 (V2: 1990-1992, 47-68 years); at V4 (1996-1998, 53-74 years); and with concurrent late-life 4-m gait speed at V5 (2011-2013, 67-88 years, mean 75 years). SDoH measures included race, the national-rank area deprivation index, education, and income. We examined associations of late-life gait speed with midlife hsCRP (V2 continuous and clinically high ≥3 mg/L), with 20-year hsCRP history from midlife (V2-V5 average continuous hsCRP and clinically high ≥3 mg/L) and with inflammation accumulation (visits and years with high hsCRP). Regression models adjusted for demographic, cardiovascular, and SDoH measures; effect modification by the presence of other common chronic conditions (obesity, diabetes, hypertension) and race were examined, with and without accounting for SDoH., Results: High midlife hsCRP was associated with slower late-life gait speed, even among those without chronic conditions in midlife: -4.6 cm/s (95% CI: -6.4, -2.8). Importantly, sustained high hsCRP was associated with a 20-year slowing of -10.0 cm/s (-14.9, -5.1) among those who never experienced obesity, diabetes, or hypertension over the 20-year period. Associations were similar between Black participants, -3.8 cm/s (-6.9, -0.7) and White participants -3.3 (-4.5, -2.2) per interquartile range of midlife hsCRP; effect modifications by chronic conditions and race were unsupported throughout. Results were robust to accounting for SDoH or otherwise; however, worse SDoH was associated with higher inflammation and slower gait speed in both Black and White participants., Conclusions: Inflammation in midlife may contribute to clinically meaningful late-life slowing of gait speed, even among otherwise healthy-appearing adults and regardless of race and socioeconomic disadvantage. Regular monitoring and interventions for inflammation may be warranted from midlife., (© 2024 The American Geriatrics Society.)

The number of assays on highly-multiplexed proteomic platforms has grown tenfold over the past 15 years from less than 1,000 to >11,000. The leading aptamer-based and antibody-based platforms have different strengths. For example, Eldjarn et al 1 demonstrated that the aptamer-based SomaScan 5k (4,907 assays, assessed in the Icelandic 36K) and the antibody-based Olink Explore 3072 (2,931 assays, assessed in the UK BioBank) had a similar number of cis -pQTLs among all targets (2,120 vs. 2,101) but Olink had a greater number of cis -pQTLs among the overlapping targets (1,164 vs. 1,467). Analysis of split plasma measures showed the SomaScan assays to be more precise: median coefficient of variation (CV) of 9.9% vs. 16.5% for Olink. 1 Precision of the newest versions of the platforms-SomaScan 11k (>11,000 assays, released in December 2023) and Olink Explore HT (>5,400 assays, released in July 2023)-has not yet been established. We assessed the reproducibility of the SomaScan 11k and Olink Explore HT using split plasma samples from 102 Atherosclerosis Risk in Communities (ARIC) Study participants. We found that the SomaScan 11k assays had a median CV of 6.8% (vs 6.6% for the subset of assays available on the SomaScan 5k) and the Olink Explore HT assays had a median CV of 35.7% (vs 19.8% for the subset of assays available on the Olink Explore 3072). Across Olink assays, the CVs were strongly negatively correlated with protein detectability, i.e., percent of samples above the limit of detection (LOD). For the 4,443 overlapping assays, the distribution of between-platform correlations was bimodal with a peak at r ~0 and with another smaller peak at r ~0.8. These findings on precision are consistent with the updated results by Eldjarn et al 1 but indicate that precision of these two leading platforms in human plasma has diverged as the number of included proteins has increased., Competing Interests: Dr. Coresh has served on the SomaLogic scientific advisory committee during 2022-2023. SomaLogic provided the assays at no cost but had no control over the design or analysis of the data. Dr. Walker has given unpaid seminars and webinars sponsored or co-sponsored by SomaLogic.

Importance: Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling., Objective: To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes., Design, Setting, and Participants: This was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023., Exposures: CHIP (variant allele frequency [VAF] ≥2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF ≥10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro-B-type natriuretic peptide), and echocardiographic indices., Main Outcome Measure: Incident AF., Results: A total of 199 982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195 851 [97.9%]; mean [SD] age, 56 [8] years; 108 370 female [55%]; 87 481 male [45%]; 3154 Black [2%], 183 747 White [94%], and 7971 other race [4%]), 11 328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197 209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197 209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index., Conclusions and Relevance: Large TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.

Aims: Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk-factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi-racial populations., Methods and Results: Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30 years of follow-up. PRSs of AF, BMI, and CHD were associated with incident HF (P < 0.001), where PRS AF showed the strongest association [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.41-1.53]. Only the addition of PRS AF to the ARIC study HF risk equation improved C statistics for 10 year risk prediction from 0.812 to 0.829 (∆C: 0.017, 95% CI: 0.009-0.026). The PRS AF was associated with both incident HF with reduced ejection fraction (HR: 1.43, 95% CI: 1.27-1.60) and incident HF with preserved ejection fraction (HR: 1.46, 95% CI: 1.33-1.62). The associations between PRS AF and incident HF and its subtypes, as well as the improved risk prediction, were replicated in the ARIC study Blacks and the CHS Whites (P < 0.050). Protein analyses revealed that N-terminal pro-brain natriuretic peptide and other 98 proteins were associated with PRS AF ., Conclusions: The PRS AF was associated with incident HF and its subtypes and had significant incremental value over an established HF risk prediction equation., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: We examined midlife (1990-1992, mean age 57) and late-life (2011-2013, mean age 75) nonalcoholic fatty liver disease (NAFLD) and aminotransferase with incident dementia risk through 2019 in the Atherosclerosis Risk in Communities (ARIC) Study., Methods: We characterized NAFLD using the fatty liver index and fibrosis-4, and we categorized aminotransferase using the optimal equal-hazard ratio (HR) approach. We estimated HRs for incident dementia ascertained from multiple data sources., Results: Adjusted for demographics, alcohol consumption, and kidney function, individuals with low, intermediate, and high liver fibrosis in midlife (HRs: 1.45, 1.40, and 2.25, respectively), but not at older age, had higher dementia risks than individuals without fatty liver. A U-shaped association was observed for alanine aminotransferase with dementia risk, which was more pronounced in late-life assessment., Discussion: Our findings highlight dementia burden in high-prevalent NAFLD and the important feature of late-life aminotransaminase as a surrogate biomarker linking liver hypometabolism to dementia. Highlights Although evidence of liver involvement in dementia development has been documented in animal studies, the evidence in humans is limited. Midlife NAFLD raised dementia risk proportionate to severity. Late-life NAFLD was not associated with a high risk of dementia. Low alanine aminotransferase was associated with an elevated dementia risk, especially when measured in late life., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Cardiac troponins are associated with adverse cardiovascular disease (CVD) outcomes. The value of high-sensitivity cardiac troponin I (hs-cTnI) independently and in concert with troponin T (hs-cTnT) in the management of hypertension has not been well studied., Methods: We assessed the utility of hs-cTnI independently and with hs-cTnT in identifying the highest risk individuals in the Systolic Blood Pressure Intervention Trial (SPRINT). Among 8796 eligible SPRINT participants, hs-cTnI was measured at baseline and 1 year. The association of baseline level and 1-year change in hs-cTnI with CVD events and all-cause death was evaluated using adjusted Cox regression models. We further assessed the complementary value of hs-cTnI and hs-cTnT by identifying concordant and discordant categories and assessing their association with outcomes., Results: hs-cTnI was positively associated with composite CVD risk [myocardial infarction, other acute coronary syndrome, stroke, or cardiovascular death: hazard ratio 1.23, 95% confidence interval 1.08-1.39 per 1-unit increase in log(troponin I)] independent of traditional risk factors, N-terminal pro-B-type natriuretic peptide, and hs-cTnT. Intensive blood pressure lowering was associated with greater absolute risk reduction (4.5% vs 1.7%) and lower number needed to treat (23 vs 59) for CVD events among those with higher baseline hs-cTnI (≥6 ng/L in men, ≥4 ng/L in women). hs-cTnI increase at 1 year was also associated with increased CVD risk. hs-cTnI and hs-cTnT were complementary, and elevations in both identified individuals with the highest risk for CVD and death., Conclusions: Baseline levels and change in hs-cTnI over 1 year identified higher-risk individuals who may derive greater cardiovascular benefit with intensive blood pressure treatment. hs-TnI and hs-TnT have complementary value in CVD risk assessment. ClinicalTrials.gov Registration Number: NCT01206062., (© Association for Diagnostics & Laboratory Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: American College of Cardiology/American Heart Association guidelines recommend distinct risk classification systems for primary and secondary cardiovascular disease prevention. However, both systems rely on similar predictors (eg, age and diabetes), indicating the possibility of a universal risk prediction approach for major adverse cardiovascular events (MACEs)., Objectives: The authors examined the performance of predictors in persons with and without atherosclerotic cardiovascular disease (ASCVD) and developed and validated a universal risk prediction model., Methods: Among 9,138 ARIC (Atherosclerosis Risk In Communities) participants with (n = 609) and without (n = 8,529) ASCVD at baseline (1996-1998), we examined established predictors in the risk classification systems and other predictors, such as body mass index and cardiac biomarkers (troponin and natriuretic peptide), using Cox models with MACEs (myocardial infarction, stroke, and heart failure). We also evaluated model performance., Results: Over a follow-up of approximately 20 years, there were 3,209 MACEs (2,797 for no prior ASCVD). Most predictors showed similar associations with MACE regardless of baseline ASCVD status. A universal risk prediction model with the predictors (eg, established predictors, cardiac biomarkers) identified by least absolute shrinkage and selection operator regression and bootstrapping showed good discrimination for both groups (c-statistics of 0.747 and 0.691, respectively), and risk classification and showed excellent calibration, irrespective of ASCVD status. This universal prediction approach identified individuals without ASCVD who had a higher risk than some individuals with ASCVD and was validated externally in 5,322 participants in the MESA (Multi-Ethnic Study of Atherosclerosis)., Conclusions: A universal risk prediction approach performed well in persons with and without ASCVD. This approach could facilitate the transition from primary to secondary prevention by streamlining risk classification and discussion between clinicians and patients., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). The MESA was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms., Objectives: The aim of this study was to discover novel biomarkers with potentially causal associations with AS., Methods: We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue., Results: Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor-related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis., Conclusions: These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services, under contract nos. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I. This study was also supported by NIH/NHLBI grants R01HL135008, R01HL143224, R01HL150342, R01HL148218, R01HL160025, and K24HL152008 to Dr Shah; R01HL136592 to Drs Matsushita and Blaha; R01HL141917 and R01 HL147095 to Dr Aikawa; K23HL146982 to Dr Bortnick; R01HL144483 to Dr Austin; R01HL142599 and R01HL149706 to Dr Floyd; R01HL128550 to Dr Thanassoulis; and K23HL150311, ASN/KidneyCure Carl W. Gottschalk Research Scholar Grant, and BWH Khoury Innovation Fund to Dr Buckley. Dr Thanassoulis is a Chercheur Boursier Clinicien—Senior from the Fonds de Recherche du Québec—Santé and holds operating grants from the Heart and Stroke Foundation of Canada. Drs Thanassoulis and Engert hold an operating grant from the Canadian Institutes for Health Research. Dr Skali has received consulting fees from Astellas; and has received research support from ABT Associates. Dr Thanassoulis has received consulting fees or participated in advisory boards or speakers bureau for Ionis Pharmaceuticals, Amgen, Sanofi, Novartis, HLS Therapeutics, New Amsterdam, and Silence. Dr Bortnick was the site principal investigator for a clinical trial by CSL-Behring; has received an unrestricted educational grant to her institution from Zoll; and has received a modest honorarium from ClearView Healthcare, outside the present work. Dr Kizer has stock ownership in Abbott, Bristol Myers Squibb, Johnson & Johnson, Medtronic, Merck, and Pfizer. Dr Aikawa is a Scientific Advisory Board member for Elastrin Therapeutics. Dr Hoogeveen has received consulting fees and research funds from Denka Seiken through Baylor College of Medicine, outside the present work. Dr Coresh is a member of the SomaLogic Scientific Advisory Board. Dr Blaha has Advisory Board membership for Novartis, Novo Nordisk, Bayer, Roche, Merck, Vectura, Boehringer Ingelheim, 89BioConsulting, Kowa, and Scene Health. Dr Matsushita has received honoraria from Fukuda Denshi and Kowa, outside the present work. Dr Shah has received consulting fees from Philips Ultrasound; and has received research funds from Novartis through Brigham and Women’s Hospital. The funders had no role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk factors, or left ventricular size and function, including matricellular (e.g. SPON1, MFAP4), senescence-associated (FSTL3, IGFBP7), and inflammatory (SVEP1, CCL15, ITIH3) proteins. Protein co-regulation network analyses identified 5 modules associated with HF risk, two of which were influenced by genetic variants that implicated trans hotspots within the VTN and CFH genes., (© 2024. The Author(s).)

Background: von Willebrand factor (VWF) is a multimeric glycoprotein critically involved in hemostasis, thrombosis, and inflammation. VWF function is regulated by its antigen levels, multimeric structures, and the state of enzymatic cleavage. Population studies in the past have focused almost exclusively on VWF antigen levels in cross-sectional study designs., Objective: To identify subjects in the Atherosclerosis Risk in Community study who had persistently low and high VWF antigen over 10 years and to quantify longitudinal changes in the biological activities and cleavage of VWF in these subjects., Methods: We measured VWF antigen, propeptide, adhesive activities, and cleavage by ADAMTS-13 quantified using a mass spectrometry method that detected the cleaved VWF peptide EQAPNLVY, as well as coagulation factor VIII activity., Results: We determined the mean subject-specific increase in VWF to be 22.0 International Units (IU)/dL over 10 years, with 95% between -0.3 and 59.7 IU/dL. This aging-related increase was also detected in VWF propeptide levels, ristocetin cofactor activity, and VWF binding to collagen. We identified 4.1% and 25.0% of subjects as having persistently low (<50 IU/dL) and high (>200 IU/dL) VWF antigen, respectively. Subjects with persistently low VWF had enhanced ristocetin cofactor activity, whereas those with persistently high VWF had elevated levels of ADAMTS-13, resulting in a comparable rate of VWF cleavage between the 2 groups., Conclusions: These results provide new information about the effects of aging on VWF antigens and adhesive activity and identify a functional coordination between VWF and the rate of its cleavage by ADAMTS-13., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Aims: Interleukin-6 (IL-6) and interleukin-18 (IL-18), important cytokines implicated in atherosclerosis and inflammaging, were assessed for associations with global cardiovascular disease (CVD), atrial fibrillation (AF), and death in older adults., Methods and Results: Participants from Atherosclerosis Risk in Communities study Visit 5 (mean age 75.4 ± 5.1 years) with IL-6 and IL-18 measurements were included (n = 5672). Cox regression models were used to assess associations of IL-6 and IL-18 with coronary heart disease (CHD), ischaemic stroke, heart failure (HF) hospitalization, global CVD (composite of CHD, stroke, and HF), AF, and all-cause death. Over a median follow-up of 7.2 years, there were 1235 global CVD events, 530 AF events, and 1173 deaths. Higher IL-6 [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.44-1.72 per log unit increase] and IL-18 (HR 1.13, 95% CI 1.01-1.26) were significantly associated with global CVD after adjustment for cardiovascular risk factors. Association between IL-6 and global CVD remained significant after further adjustment for high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT) but was no longer significant for IL-18 after further adjustments. Interleukin-6 was also associated with increased risk for CHD, HF, and AF after adjustment for covariates. Both IL-6 and IL-18 were associated with increased risk for all-cause death independent of cardiovascular risk factors and other biomarkers., Conclusion: Among older adults, both IL-6 and IL-18 were associated with global CVD and death. The association between IL-6 with CVD appears to be more robust and was independent of hs-CRP, NT-proBNP, and hs-TnT., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: MMP (matrix metalloproteinase)-2 participates in extracellular matrix regulation and may be involved in heart failure (HF), atrial fibrillation (AF), and coronary heart disease., Methods: Among the 4693 ARIC study (Atherosclerosis Risk in Communities) participants (mean age, 75±5 years; 42% women) without prevalent HF, multivariable Cox proportional hazard models were used to estimate associations of plasma MMP-2 levels with incident HF, HF with preserved ejection fraction (≥50%), HF with reduced ejection fraction (<50%), AF, and coronary heart disease. Mediation of the association between MMP-2 and HF was assessed by censoring participants who developed AF or coronary heart disease before HF. Multivariable linear regression models were used to assess associations of MMP-2 with measures of left ventricular and left atrial structure and function., Results: Compared with the 3 lower quartiles, the highest MMP-2 quartile associated with greater risk of incident HF overall (adjusted hazard ratio, 1.48 [95% CI, 1.21-1.81]), incident HF with preserved ejection fraction (1.44 [95% CI, 1.07-1.94]), incident heart failure with reduced ejection fraction (1.48 [95% CI, 1.08-2.02]), and incident AF (1.44 [95% CI, 1.18-1.77]) but not incident coronary heart disease (0.97 [95% CI, 0.71-1.34]). Censoring AF attenuated the MMP-2 association with HF with preserved ejection fraction. Higher plasma MMP-2 levels were associated with larger left ventricular end-diastolic volume index, greater left ventricular mass index, higher E/e' ratio, larger left atrial volume index, and worse left atrial reservoir and contractile strains (all P <0.001)., Conclusions: Higher plasma MMP-2 levels associate with diastolic dysfunction, left atrial dysfunction, and a higher risk of incident HF and AF. AF is a mediator of MMP-2-associated HF with preserved ejection fraction risk., Competing Interests: Disclosures Dr Hoogeveen reports research support and consultation fees not related to this study from Denka Seiken. Dr Shah reports research support not related to this study from Novartis and Philips Ultrasound and consulting fees from Philips Ultrasound. The other authors report no conflicts.

Aims: Neutrophil activity contributes to adverse cardiac remodelling in experimental acute cardiac injury and is modifiable with pharmacologic agents like colchicine., Methods and Results: Neutrophil activity-related plasma proteins known to be affected by colchicine treatment were measured at Visit 3 (1993-1995) and Visit 5 (2011-2013) of the ARIC cohort study. A protein-based neutrophil activity score was derived from 10 candidate proteins using LASSO Cox regression. Associations with incident heart failure (HF) and with cardiac function using Cox proportional hazards regression and linear regression models, respectively. The mean ages at Visits 3 and 5 were 60 ± 6 and 75 ± 5 years, respectively, and 54% and 57% were women, respectively. Each 1-standard deviation increase in the neutrophil activity score was associated with a higher risk of incident HF in mid-life (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.25-1.37) and late-life (HR 1.23, 95% CI 1.14-1.34), with a higher HR for HF with preserved than reduced ejection fraction (HR 1.30, 95% CI 1.16-1.47 vs. HR 1.13, 95% CI 0.98-1.30). Higher neutrophil activity was associated with greater left ventricular end-diastolic volume index, mass index and diastolic and systolic dysfunction., Conclusions: Plasma proteins related to neutrophil function associate with incident HF in mid- and late-life and with adverse cardiac remodelling. Therapies that modify these proteins, such as colchicine, may represent promising targets for the prevention or treatment of HF., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

We sought to determine how biomarkers known to be associated with hypertension-induced end-organ injury complement the use of systolic blood pressure (SBP) for cardiovascular disease (CVD) risk prediction at different ages. Using data from visits 2 (1990 to 1992) and 5 (2011 to 2013) of the Atherosclerosis Risk in Communities (ARIC) study, 3 models were used to predict CVD (composite of coronary heart disease, stroke, and heart failure). Model A included traditional risk factors (TRFs) except SBP, model B-TRF plus SBP, and model C-TRF plus biomarkers (high-sensitivity troponin T [hsTnT] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]). Harrel's C-statistics were used to assess risk discrimination for CVD comparing models B and A and C and B. At visit 2, the addition of SBP to TRF (model B vs model A) significantly improved the C-statistic (∆C-statistic, 95% confidence interval 0.010, 0.007 to 0.013) whereas the addition of hsTnT to TRF (model C vs model B) decreased the C-statistic (∆C-statistic -0.0038, -0.0075 to -0.0001) compared with SBP. At visit 5, the addition of SBP to TRF did not significantly improve the C-statistic (∆C-statistic 0.001, -0.002 to 0.005) whereas the addition of both hsTnT and NT-proBNP to TRF significantly improved the C-statistic compared with SBP (∆C-statistic 0.028, 0.015 to 0.041 and 0.055, 0.036 to 0.074, respectively). In summary, the incremental value of SBP for CVD risk prediction diminishes with age whereas the incremental value of hsTnT and NT-proBNP increases with age., Competing Interests: Declaration of Competing Interest Dr. de Lemos reports grant support from Roche Diagnostics and Abbott Diagnostics, consulting fees from Ortho Clinical Diagnostics, Quidel Cardiovascular, Inc., Beckman Coulter, Siemens Health Care Diagnostics, Astra Zeneca, Novo Nordisc. Eli Lilly, Regeneron, and Amgen; and has been named a co-owner on a patent awarded to the University of Maryland (United States Patent Application Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.” Dr Ballantyne has received grant/research support from and is a consultant for Abbott Diagnostic and Roche Diagnostic. The remaining authors have no competing interests to declare., (Published by Elsevier Inc.)

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.

In patients with hypertriglyceridemia, a short-term low-saturated fat vs high-saturated fat diet induced lower plasma lipids and improved monocyte phenotypes. These findings highlight the role of diet fat content and composition for monocyte phenotypes and possibly cardiovascular disease risk in these patients. (Effects of Dietary Interventions on Monocytes in Metabolic Syndrome; NCT03591588)., Competing Interests: This work was supported by National Institutes of Health grants R01HL098839, R01DK121348, R01AG065197 (Dr Wu), and R01AI047294 (Dr Simon) and American Heart Association grant 968367 (Dr Wu). Drs Peng, Ni, and Zhang were partially supported by scholarship from the Chinese Scholarship Council. Dr Hoogeveen has received a research grant from Denka Seiken, which provided reagents for small dense LDL-C, RLP-C, and LDL-TG measurements but had no role in the design, analysis, or data interpretation of this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

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.

Introduction-Oxidative stress is linked to cardiovascular diseases (CVD) and is suggested to vary by sex. However, few population-level studies have explored these associations and the majority comprise populations with advanced CVD. We assessed urinary isoprostane concentrations, a standard measure of oxidative stress, in a relatively young and healthy cohort, hypothesizing that higher oxidative stress is associated with an adverse cardiometabolic profile and female sex. Methods-Oxidative stress was measured in 475 women and 266 men, aged 48-55 years, from the Coronary Artery Risk Development in Young Adults (CARDIA) study using urinary 8-isoprostane (IsoP) and 2,3-dinor-8-isoprostane (IsoP-M). Multivariable-adjusted regression was used to evaluate cross-sectional associations. As secondary analysis, previously measured plasma F2-isoprostanes (plasma IsoP) from another CARDIA subset was similarly analyzed. Results-Mean (SD) ages for men and women were 52.1(2.3) and 52.2(2.2) years, respectively ( p = 0.46), and 39% of the participants self-identified as Black (vs. White). Before adjustments, female sex was associated with higher median urinary IsoP (880 vs. 704 ng/g creatinine in men; p < 0.01) and IsoP m (1675 vs. 1284 ng/g creatinine in men; p < 0.01). Higher body mass index (BMI), high-density cholesterol (HDL-C), and triglycerides, current smoking, and less physical activity were associated with higher oxidative stress. Diabetes was not associated with urinary IsoP but was associated with lower IsoP m and plasma IsoP. Higher serum creatinine showed diverging associations with higher plasma and lower urinary isoprostane concentrations. Conclusions-Different isoprostane entities exhibit varying association patterns with CVD risk factors, and therefore are complementary, rather than interchangeable, in assessment of oxidative stress. Still, consistently higher isoprostanes among women, smokers, less active persons, and those with higher BMI and plasma triglycerides could reflect higher oxidative stress among these groups. While urinary isoprostanes are indexed to urinary creatinine due to variations in concentration, caution should be exercised when comparing groups with differing serum creatinine.

Background and Aims: Elevated small dense low-density lipoprotein-cholesterol (sdLDL-C) has been reported to be associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. Our aims were to determine whether direct and calculated sdLDL-C were significant independent ASCVD risk factors in sex and race subgroups., Methods: In a total of 15,933 participants free of ASCVD at baseline (median age 62 years, 56.7% female, 19.7% African American) fasting plasma lipids and sdLDL-C were measured by standardized automated methods. All subjects were followed for 10 years for incident ASCVD, which developed in 9.7% of subjects. SdLDL-C values were also calculated. Univariate and multivariate analyses were carried out to assess for independent associations with incident ASCVD after adjustment for all standard risk factors., Results: All standard risk factors were significantly associated with incident ASCVD on univariate analysis, as were direct and calculated sdLDL-C. These latter parameters were also significant when added to the pooled cohort risk equation. However, associations were significantly stronger for direct sdLDL-C and were not significant for calculated values once direct values were in the model. In contrast to calculated values, top quartile direct sdLDL-C was significantly independently associated with incident ASCVD versus bottom quartile values in all subjects and subgroups, except African Americans (hazard ratios ≥1.50, p < 0.01). Subjects with direct values ≥ 50 mg/dL versus <25 mg/dL had significantly higher independent ASCVD risk in all groups (hazard ratios >1.49, all p < 0.01)., Conclusions: Having a direct small dense low-density lipoprotein cholesterol value ≥ 50 mg/dL is a significant independent ASCVD risk-enhancer., Competing Interests: Declaration of competing interest EJS has served as a consultant for the Denka Corporation, Tokyo, Japan. RCH has received research grants (to his institution) from Denka Corporation; RCH and CMB are consultants for Denka. None of the other authors has any relevant relationships to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The plasma proteome can be quantified using different types of highly multiplexed technologies, including aptamer-based and proximity-extension immunoassay methods. There has been limited characterization of how these protein measurements correlate across platforms and with absolute measures from targeted immunoassays., Methods: We assessed the comparability of (a) highly multiplexed aptamer-based (SomaScan v4; Somalogic) and proximity-extension immunoassay (OLINK Proseek® v5003; Olink) methods in 427 Atherosclerosis Risk in Communities (ARIC) Study participants (Visit 5, 2011-2013), and (b) 18 of the SomaScan protein measurements against targeted immunoassays in 110 participants (55 cardiovascular disease cases, 55 controls). We calculated Spearman correlations (r) between the different measurements and compared associations with case-control status., Results: There were 417 protein comparisons (366 unique proteins) between the SomaScan and Olink platforms. The average correlation was r = 0.46 (range: -0.21 to 0.97; 79 [19%] with r ≥ 0.8). For the comparison of SomaScan and targeted immunoassays, 6 of 18 assays (growth differentiation factor 15 [GDF15], interleukin-1 receptor-like 1 [ST2], interstitial collagenase [MMP1], adiponectin, leptin, and resistin) had good correlations (r ≥ 0.8), 2 had modest correlations (0.5 ≤ r < 0.8; osteopontin and interleukin-6 [IL6]), and 10 were poorly correlated (r < 0.5; metalloproteinase inhibitor 1 [TIMP1], stromelysin-1 [MMP3], matrilysin [MMP7], C-C motif chemokine 2 [MCP1], interleukin-10 [IL10], vascular cell adhesion protein 1 [VCAM1], intercellular adhesion molecule 1 [ICAM1], interleukin-18 [IL18], tumor necrosis factor [TNFα], and visfatin) overall. Correlations for SomaScan and targeted immunoassays were similar according to case status., Conclusions: There is variation in the quantitative measurements for many proteins across aptamer-based and proximity-extension immunoassays (approximately 1/2 showing good or modest correlation and approximately 1/2 poor correlation) and also for correlations of these highly multiplexed technologies with targeted immunoassays. Design and interpretation of protein quantification studies should be informed by the variation across measurement techniques for each protein., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Testican-2 was recently identified as a podocyte-derived protein that is released into circulation by the kidneys and is positively correlated with eGFR and eGFR slope. However, whether higher testican-2 levels are associated with lower risk of ESKD is unknown., Methods: Aptamer-based proteomics assessed blood testican-2 levels among participants in the African American Study of Kidney Disease and Hypertension (AASK, n =703), the Chronic Renal Insufficiency Cohort (CRIC) study ( n =3196), and the Atherosclerosis Risk in Communities (ARIC) study ( n =4378). We compared baseline characteristics by testican-2 tertile and used Cox proportional hazards models to study the association of testican-2 with incident ESKD., Results: Higher testican-2 levels were associated with higher measured GFR (mGFR) in AASK, higher eGFR in the CRIC and ARIC studies, and lower albuminuria in all cohorts. Baseline testican-2 levels were significantly associated with incident ESKD in Cox proportional hazards models adjusted for age, sex, and race (model 1) and model 1+mGFR or eGFR+comorbidities (model 2). In model 3 (model 2+proteinuria), the associations between testican-2 (per SD increase) and incident ESKD were AASK (hazard ratio [HR]=0.84 [0.72 to 0.98], P =0.023), CRIC (HR=0.95 [0.89 to 1.02], P =0.14), ARIC (HR=0.54 [0.36 to 0.83], P =0.0044), and meta-analysis (HR=0.92 [0.86 to 0.98], P =0.0073)., Conclusions: Across three cohorts spanning >8000 individuals, testican-2 is associated with kidney health and prognosis, with higher levels associated with reduced risk of ESKD., (Copyright © 2022 by the American Society of Nephrology.)