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BACKGROUND: Low endogenous estrogen concentrations after menopause may contribute to higher oxidative stress and greater cardiovascular disease (CVD) risk. However, differences in oxidative stress between similarly aged premenopausal and postmenopausal women are not well-characterized on a population level. We hypothesized that urinary isoprostane concentrations, a standard measure of systemic oxidative stress, are higher in women who have undergone menopause compared to premenopausal women. METHODS AND RESULTS: We examined differences in urinary 8-isoprostane (iPF(2α)-III) and 2,3-dinor-8-isoprostane (iPF(2α)-III-M) indexed to urinary creatinine between 279 postmenopausal and 196 premenopausal women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, using linear regression with progressive adjustment for sociodemographic factors and traditional CVD risk factors. Unadjusted iPF(2α)-III-M concentrations were higher among postmenopausal compared to premenopausal women (Median [25th, 75th percentile]: 1762 [1178, 2974] vs. 1535 [1067, 2462] ng/g creatinine; p = 0.01). Menopause was associated with 25.5% higher iPF(2α)-III-M (95% confidence interval [6.5–47.9]) adjusted for age, race, college education, and field center. Further adjustments for tobacco use (21.2% [2.9–42.6]) and then CVD risk factors (18.8% [0.1–39.6]) led to additional partial attenuation. Menopause was associated with higher iPF(2α)-III in Black but not White women. CONCLUSIONS: We conclude that postmenopausal women had higher oxidative stress, which may contribute to greater CVD risk. ClinicalTrials.gov Identifier: NCT00005130.

Background Growth differentiation factor 15 (GDF-15) is a stress-responsive biomarker associated with several types of cardiovascular diseases. However, conflicting results have been reported regarding its association with incident atrial fibrillation (AF) in the general population. Methods In 10 234 White and Black Atherosclerosis Risk in Communities (ARIC) Study participants (mean age 60 years, 20.5% Blacks) free of AF at baseline (1993 to 1995), we quantified the association of GDF-15 with incident AF using Cox regression models. GDF-15 concentration was measured by an aptamer-based proteomic method. AF was defined as AF diagnosis by electrocardiogram at subsequent ARIC visits or AF diagnosis in hospitalization records or death certificates. Harrell’s c-statistic and categorical net reclassification improvement were computed for risk discrimination and reclassification. Results There were 2217 cases of incident AF over a median follow-up of 20.6 years (incidence rate 12.3 cases/1000 person-years). After adjusting for potential confounders, GDF-15 was independently associated with incident AF, with a hazard ratio (HR) of 1.42 (95% CI, 1.24–1.62) for the top vs bottom quartile. The result remained consistent (HR 1.23 [95% CI, 1.07–1.41]) even after further adjusting for 2 cardiac biomarkers, cardiac troponin T and natriuretic peptide. The results were largely consistent across demographic subgroups. The addition of GDF-15 modestly improved the c-statistic by 0.003 (95% CI, 0.001–0.006) beyond known risk factors of AF. Conclusions In this community-based biracial cohort, higher concentrations of GDF-15 were independently associated with incident AF, supporting its potential value as a clinical marker of AF risk.

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: Associations of nonalcoholic fatty liver disease (NAFLD) with dementia are controversial. The full spectrum of NAFLD from simple steatosis to fibrosis has been less investigated. Hypothesis: The severity of NAFLD, especially with the stage of liver fibrosis, is associated with dementia. Methods: The associations between midlife (1990-92, N=9283, mean age 57, female 55%) and late-life (2011-13, N=5138, mean age 75, female 58%) NAFLD and all cause dementia were quantified by Cox regression. NAFLD was characterized using the fatty liver index and liver fibrosis assessment model (FIB-4). Dementia was adjudicated and ascertained through Dec. 31, 2019 from neuropsychological assessments, annual participant or informant contact, and medical record surveillance. We used Cox models with adjustment for demographics, APOE ε4, alcohol, and kidney function. Additional adjustments were made for metabolic factors to explore the independent contribution of NAFLD to dementia. Results: During a median follow-up of 24.5 years after midlife NAFLD assessment, 1854 participants developed dementia. During a median of 6.3 years in late-life, there were 893 dementia cases. A graded increase in dementia risk across the spectrum of NAFLD was observed at midlife (p-trend Figure ). In fact, NAFLD in late-life tended to be protective against dementia. After adjusting for the metabolic factors, the associations remained statistically significant in some categories. Conclusions: Remodeling of hepatic architecture and dysregulation in hepatocellular function in NAFLD at midlife plausibly induce peripheral promoters of neurodegeneration and may expose a large segment of the population to increased risk of dementia. The inverse association of NAFLD with dementia at late-life requires further investigation, possibly reflecting the depletion of susceptibles, the reversibility of NAFLD due to weight loss, and the lack of accuracy in identifying NAFLD using clinical prediction models at older age.

Introduction: Eicosanoids play an important role in regulating inflammation response, which influences the development of heart failure (HF). However, the association between eicosanoids and the risk of HF remains unclear. Hypothesis: We hypothesize that eicosanoid metabolites are associated with incident HF and may improve HF prediction. Methods: We measured plasma eicosanoids via liquid chromatography-mass spectrometry among HF-free participants at visit 2 (1990-1992) from the Atherosclerosis Risk in Communities (ARIC) study. The Cox proportional hazard regression was performed to evaluate the relationship between eicosanoids and incident HF controlling for clinical risk factors. The least absolute shrinkage and selection operator was applied to identify a representative subset of eicosanoids towards constructing an eicosanoid risk score (ERS). We further conducted genome-wide association analyses to examine the genetic determinants for HF related eicosanoids in black and white participants respectively. Results: During an average of 21 years of follow up, 2,202 (28.0 % blacks, 50.3% women) out of 9,519 participants developed HF. Out of 200 eicosanoids analyzed, six with hazard ratio between 0.89 to 1.10 were found associated with the risk of HF (FDR UGT2B7 , where its T allele was associated with lower EPA [M-H+Acetate] level while positively affect the risk of HF and systolic blood pressure level. ERS constructed from 52 eicosanoids showed a 39% increase in HF risk per SD increment and twice the risk between the highest and the lowest ERS quartile (p < 0.001). The addition of ERS to the HF 10-years prediction model modestly improved the C-statistics from 0.799 to 0.808, 95%CI ΔC : 0.004-0.015. Conclusion: We identified a set of eicosanoids that significantly associated with increased risk of HF. The contributing genetic variation of eicosanoids may depict the biological pathways related to HF.

Background: Inflammation plays an important role in the pathophysiology of atherosclerosis. However, inflammatory biomarkers have been found to have a weak association with coronary artery calcium (CAC), a representative measure of subclinical atherosclerosis. Moreover, the existing evidence does not sufficiently explore extra coronary calcium (ECC) in this context. Aim: To characterize the association of two inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) and galectin-3, with CAC and ECC in a community-based cohort. Methods: Cardiac CT was performed among 1,934 ARIC participants (age 53-74 years) without coronary heart disease at visit 7 (2018-19). We examined the associations of hs-CRP and galectin-3 measured in middle age at visit 4 (1996-98) by quartile with the presence of CAC and ECC (Agatston score >0 vs. 0) using multivariable logistic regression. Results: Higher hs-CRP was associated with calcifications in the ascending aorta, aortic valve ring, mitral valve and right coronary artery in the unadjusted model (Table). These associations were mostly attenuated after adjusting for potential confounders, but the associations with ascending aorta and right coronary artery calcifications remained significant (adjusted odds ratio (aOR) = 1.45 [95% CI = 1.02-2.07]) and (1.55 [1.12-2.16]) for the highest vs. lowest quartiles, respectively). Galectin-3 was also independently associated with right coronary artery calcification after adjusting for potential confounders (aOR 1.48 [1.02 - 2.01]) for the highest vs. lowest quartiles). These associations were generally consistent in demographic subgroups. Conclusions: Both hs-CRP and galectin-3 were associated with calcification of some but not all vascular beds tested, suggesting potentially unique atherosclerotic pathophysiology across different vascular beds. Robust associations of inflammatory markers with right coronary artery calcification deserve further investigation.

Introduction: Measures of cardiac structure and function provide important diagnostic and prognostic information for heart failure (HF). Few studies have assessed the associations of circulating metabolites with cardiac structure and function. Hypothesis: We hypothesize that circulating metabolites that reflect aging process are associated with cardiac structure and function measures and incident HF. Methods: Participants from the Atherosclerosis Risk in Communities (ARIC) study visit 5 and the Hispanic Community Health Study / Study of Latinos (HCHS/SOL) study visit 1 who had serum metabolite measures but not prevalent HF were included. Linear regressions were used to examine the associations of metabolites with ten cardiac structure and function variables adjusting for clinical risk factors in each race and study strata, followed by random-effect meta-analyses. The Cox regression was applied to examine the relationship between those identified metabolites and incident HF post visit 5 in ARIC. Results: Among 589 analyzed metabolites, 179 were associated with cardiac structure or function measures in 706 Blacks, 3,358 Whites, and 1,380 Hispanics (FDR < 0.05). Forty-one metabolites were related to two or more measures, where 22 were associated with incident HF (308 HF cases, p Conclusions: We identified multiple metabolites associated with cardiac structure and function measures in multi-ethnic populations, highlighting metabolic pathways in aging and their impact on HF.

Introduction: Proteins are involved in the pathophysiology of hypertension (HTN), but there are no large scale prospective proteomic analyses of incident HTN. Hypothesis: To identify and validate plasma proteins associated with incident HTN among a bi-racial cohort in the US. Methods: We quantified the associations of 4,955 plasma proteins (measured by SomaScan version 4 assay) with incident HTN over median follow-up of 11 years among 5,080 participants without baseline hypertension at ARIC visit 3 (1993-95). We then validated significant proteins from the primary analysis with incident HTN between visit 2 (n=6,810 during 1990-92) and visit 3 (median follow-up of 3.1y), to avoid including the same incident HTN cases in both analyses. Incident HTN was defined as systolic blood pressure (BP) ≥140, diastolic BP ≥90 mmHg, or HTN medication use. We ran multivariable Cox models and applied Benjamin-Hochberg procedure, with false discovery rate of 0.05, to account for multiple comparisons. Results: In the primary analysis with visit 3 as baseline (mean age 59y, 54% women, 13% Black), 3,828 participants (75%) developed HTN, and we found 55 proteins significantly associated with incident HTN. Among them, 14 proteins were validated using visit 2 data (Figure). Of those, 11 showed positive associations with HTN, and they are involved in glycoprotein degradation (e.g., MMP7, HTRA1, ASGR1, GUSB, CPM), cell adhesion (e.g., LGALS3BP and RET), and inflammation (e.g., CRP). In contrast, 3 proteins, renin ([REN]), netrin receptor ([UNC5D] apoptosis) and secretogranin-3([SCG3] endothelial cell growth), had inverse relationships with incident HTN. Further exploration showed a U-shaped association between renin and incident HTN. Conclusion: We identified several proteins associated with incident HTN, with plausible functions contributing to the development of HTN. These findings have implications on understanding mechanisms of HTN and potential targets for prevention and treatment.

Background: Physical activity (PA) patterns over time influence diabetes risk through incompletely understood mechanisms. Adipokines secreted by adipose tissue have myriad endocrine effects and are affected by PA. It is unknown the extent to which adipokines mediate the association between changes in PA and diabetes. Methods: We conducted a cross-sectional study of 10,908 ARIC participants (mean age 54; 55% female; 21% Black adults) who attended Visits 1 (V1; 1987-1989) and 3 (V3; 1993-1995) of the ARIC Study. We used mediation analyses to determine the extent to which the association of changes in PA from V1 to V3 and diabetes status at V3 was explained by adipokines. Analyses were stratified by obesity status. PA was defined using American Heart Association guidelines as inactive, intermediate, and recommended (150 minutes of moderate-vigorous activity/week); the intermediate group was further divided into low and moderate (below or above the median activity level). Participants were categorized by PA at V1 and V3 - (1) stable low: inactive or low at both visits; (2) increasing: higher category at V3 than V1; (3) decreasing: lower category at V3 than V1; and (4) stable high: moderate or high at both visits. Results: Increasing PA was associated with higher adiponectin and lower leptin at V3 compared to stable low PA, while decreasing PA was associated with lower adiponectin and higher leptin compared to stable high PA (p Conclusions: The associations between changes in PA and diabetes may be mediated in part by adipokines.

Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

Summary: Background: Galectin-3 (gal-3) is a β-galactoside-binding lectin associated tissue fibrosis and inflammation. There is limited understanding of the relationship between gal-3 and vascular health. Our aim was to assess the association between gal-3 and arterial stiffness in older adults. Methods: We conducted a cross-sectional study of 4275 participants (mean age of 75 years) from the Atherosclerosis Risk in Communities (ARIC) Study. Central arterial stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). We evaluated the association of gal-3 with cfPWV using multivariable linear regression. Results: The median (interquartile range) gal-3 concentration was 16.5 (13.8, 19.8) ng/mL and mean cfPWV was 1163±303 cm/s. Higher gal-3 concentration was associated with greater central arterial stiffness after adjustment for age, sex, race-center, heart rate, systolic blood pressure, anti-hypertensive medication use, and current smoking status (β=36.4 cm/s change in cfPWV per log unit change in gal-3; 95% CI: 7.2, 65.5, p=0.015). The association was attenuated after adjusting for additional cardiovascular risk factors (β=17.3, 95% CI: −14.4, 49.0). Conclusions: In community-dwelling older adults, gal-3 concentration was associated with central arterial stiffness, likely sharing common pathways with traditional cardiovascular risk factors.

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.

Background Plasma lipoprotein(a) (Lp[a]) concentrations are primarily determined by genetic factors and are believed to remain stable throughout life. However, data are scarce on longitudinal trends in Lp(a) concentrations over time. Therefore, it is unclear whether measurement of Lp(a) once in a person's life is sufficient for cardiovascular risk assessment in all adults. Methods and Results Lp(a) concentrations, specifically apolipoprotein(a) concentrations, were measured at visits 4 and 5, ≈15 years apart, in 4734 adult participants of the ARIC (Atherosclerosis Risk in Communities) study (mean age at visits 4 and 5, 60.7±5.1 and 75.5±5.2 years, respectively). Participants were categorized by baseline (visit 4) Lp(a) concentrations as normal ( Conclusions Our results suggest that adults with borderline‐high Lp(a) concentrations may be considered for repeat monitoring of Lp(a) over time, particularly if they are Black, women, or have diabetes, hypertension, and/or elevated albuminuria.

Background Circulating high sensitivity cardiac troponin T (hs‐cTnT) is associated with incidence of atrial fibrillation (AF), but the association of changes in hs‐cTnT over time on incident AF has not been explored. Hypothesis Six‐year increase in circulating hs‐cTnT will be associated with increased risk of AF and will contribute to improved prediction of incident AF. Methods We conducted a prospective cohort analysis of 8431 participants from the Atherosclerosis Risk in Communities (ARIC) study. hs‐cTnT change was categorized at visit 2 and 4 as undetectable (

Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values

Introduction Laboratory studies suggest an involvement of growth differentiation factor 15 (GDF-15) in metabolic dysregulation. However, the utility of GDF-15 for assessing risk of cardiometabolic outcomes has not been rigorously examined among older adults. Methods We conducted a cross-sectional analysis of older adults who attended visit 6 (2016–2017) of the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to quantify cross-sectional associations of GDF-15 (in quartiles) with prevalent diabetes, obesity, atherosclerotic cardiovascular disease (ASCVD), subclinical myocardial stress/injury (assessed by NT-proB-type Natriuretic Peptide [NT-proBNP] and high-sensitivity cardiac troponin T [hs-cTnT]), and heart failure (HF). Results Among 3792 ARIC study participants (mean age 80 years, 59% women, 23% Blacks and 77% Whites, mean GDF-15: 2094.9 pg/mL [SD: 1395.6]), higher GDF-15 concentrations (highest vs. lowest quartile) were positively associated with diabetes (adjusted odds ratio [aOR]:] : 2.48, 95% CI : 1.89, 3.26), ASCVD (aOR: 1.57, 95% CI: 1.16, 2.11), increased hscTnT (aOR: 2.27, 95%CI: 1.54, 3.34), increased NT-proBNP (aOR: 1.98, 95%CI: 1.46, 2.70), and HF (aOR: 3.22, 95%CI : 2.13, 4.85), in models adjusted for demographics and traditional cardiovascular risk factors. Conclusions In this sample of older US black and whites, increased GDF-15 was positively associated with diabetes, ASCVD, HF, and markers of subclinical myocardial stress or injury. These results illustrate the diverse aspects of the link between GDF-15 and diseases states, and its potential utility as robust biomarker of adverse cardiometabolic outcomes.

Background Although intensive blood pressure reduction has cardiovascular benefits, the absolute benefit is greater in those at higher cardiovascular disease (CVD) risk. Objectives This study examined whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) helps identify subjects at higher risk for CVD events across systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) categories. Methods Participants from the ARIC (Atherosclerosis Risk In Communities) study visit 4 (1996 to 98) were grouped according to SBP, DBP, or PP categories and further stratified by NT-proBNP categories. Cox regression models were used to estimate hazard ratios for incident CVD (coronary heart disease, ischemic stroke, or heart failure hospitalization) and mortality across combined NT-proBNP and/or BP categories, adjusting for CVD risk factors. Results There were 9,309 participants (age: 62.6 ± 5.6 years; 58.3% women) with 2,416 CVD events over a median follow-up of 16.7 years. Within each SBP, DBP, or PP category, a higher category of NT-proBNP (100 to Conclusions Elevated NT-proBNP is independently associated with CVD and mortality across SBP, DBP, and PP categories and helps identify subjects at the highest risk. Participants with stage 1 hypertension but elevated NT-proBNP had greater cardiovascular risk compared with those with stage 2 SBP but lower NT-proBNP. Future studies are needed to evaluate use of biomarker-based strategies for CVD risk assessment to assist with initiation or intensification of BP treatment.

Background Lipoprotein(a) (Lp(a)) is a potent causal risk factor for cardiovascular events and mortality. However, its relationship with subclinical atherosclerosis, as defined by arterial calcification, remains unclear. This study uses the ARIC (Atherosclerosis Risk in Communities Study) to evaluate the relationship between Lp(a) in middle age and measures of vascular and valvular calcification in older age. Methods and Results Lp(a) was measured at ARIC visit 4 (1996–1998), and coronary artery calcium (CAC), together with extracoronary calcification (including aortic valve calcium, aortic valve ring calcium, mitral valve calcification, and thoracic aortic calcification), was measured at visit 7 (2018–2019). Lp(a) was defined as elevated if >50 mg/dL and CAC/extracoronary calcification were defined as elevated if >100. Logistic and linear regression models were used to evaluate the association between Lp(a) and CAC/extracoronary calcification, with further stratification by race. The mean age of participants at visit 4 was 59.2 (SD 4.3) years, with 62.2% women. In multivariable adjusted analyses, elevated Lp(a) was associated with higher odds of elevated aortic valve calcium (adjusted odds ratio [aOR], 1.82; 95% CI, 1.34–2.47), CAC (aOR, 1.40; 95% CI, 1.08–1.81), aortic valve ring calcium (aOR, 1.36; 95% CI, 1.07–1.73), mitral valve calcification (aOR, 1.37; 95% CI, 1.06–1.78), and thoracic aortic calcification (aOR, 1.36; 95% CI, 1.05–1.77). Similar results were obtained when Lp(a) and CAC/extracoronary calcification were examined on continuous logarithmic scales. There was no significant difference in the association between Lp(a) and each measure of calcification by race or sex. Conclusions Elevated Lp(a) at middle age is significantly associated with vascular and valvular calcification in older age, represented by elevated CAC, aortic valve calcium, aortic valve ring calcium, mitral valve calcification, thoracic aortic calcification. Our findings encourage assessing Lp(a) levels in individuals with increased cardiovascular disease risk, with subsequent comprehensive vascular and valvular assessment where elevated.

It remains unclear whether elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) can serve as a "risk equivalent" for cardiovascular disease to adults at high cardiovascular risk.We included 9789 participants (mean age 63.2 years, 55% women, 19.4% Black, 13% with a history of cardiovascular disease) who attended Atherosclerosis Risk in Communities Study Visit 4 (1996-1998). We classified participants as having a history of cardiovascular disease at baseline and, among those without cardiovascular disease, we defined categories of NT-proBNP (125, 125-449, ≥450 pg/mL). We used Cox regression to estimate associations of NT-proBNP with incident cardiovascular disease and mortality.Over a median 20.5 years of follow-up, there were 4562 deaths (917 cardiovascular deaths). There were 2817 first events and 806 recurrent events (in those with a history of cardiovascular disease at baseline). Among individuals without a history of cardiovascular disease, those adults with NT-proBNP ≥450 pg/mL had significantly higher risks of all-cause death (hazard ratio [HR] 2.12; 95% confidence interval [CI], 1.78-2.53), cardiovascular mortality (HR 2.92; 95% CI, 2.15-3.97), incident total cardiovascular disease (HR 2.59; 95% CI, 2.13-3.16), atherosclerotic cardiovascular disease (HR 2.20; 95% CI, 1.72-2.80), and heart failure (HR 3.81; 95% CI, 3.01-4.81), compared with individuals with NT-proBNP125 pg/mL. The elevated cardiovascular risk in persons with high NT-proBNP and no history of cardiovascular disease was similar to, or higher than, the risk conferred by a history of cardiovascular disease.Our findings suggest that it might be appropriate to manage adults with NT-proBNP ≥450 pg/mL as if they had a history of clinical cardiovascular disease.

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/m 2 ] versus normal weight [BMI 18.5‐2 ]). There were stronger associations of BMI with elevated galectin‐3 among women versus men and White versus Black participants (both P ‐for‐interaction 4‐fold higher risk of HF (HR, 4.19; 95% CI, 2.98–5.88) than those with normal weight and galectin‐3 Conclusions Obesity is strongly associated with elevated galectin‐3. Additionally, the combination of obesity and elevated galectin‐3 is associated with marked HF risk, underscoring the importance of elucidating pathways linking obesity with cardiac inflammation and fibrosis.

Background Cardiac markers such as high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B natriuretic peptide (NTproBNP) are predictors of developing acute kidney injury (AKI) during hospitalization for surgery or revascularization. However, their associations with the long-term risk of AKI in the general population are uncharacterized. Methods We conducted a prospective cohort study in 10 669 participants of the Atherosclerosis Risk in Communities Study (visit 4, 1996–1998, mean age, 63 years, 56% female, 22% black race) to examine the association of plasma concentrations of hs-cTnT and NTproBNP with the incident hospitalization with AKI. We used multivariable Cox regression analysis to estimate hazard ratios (HRs). Results During follow-up, 1907 participants had an incident hospitalization with AKI. Participants with higher concentrations of hs-cTnT had a higher risk of hospitalization with AKI in a graded fashion (adjusted HR, 1.88 [95%CI , 1.59–2.21] for ≥14 ng/L, 1.36 [1.18–1.57] for 9–13 ng/L, and 1.16 [1.03–1.30] for 5-8 ng/L compared to Conclusions In middle-aged to older black and white adults in the community, higher concentrations of hs-cTnT and NTproBNP were robustly associated with an increased risk of hospitalization with AKI. These results suggest the usefulness of hs-cTnT and NT-proBNP to identify people at risk of AKI in the general population.

Context Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events. Objective Assess associations between low DHEA-S/DHEA-S change and incident HF hospitalization, CHD, and mortality in older adults. Design DHEA-S was measured in stored plasma from visits 4 (1996-1998) and 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Follow-up for incident events: 18 years for DHEA-S level; 5.5 years for DHEA-S change. Setting General community. Participants Individuals without prevalent cardiovascular disease (n = 8143, mean age 63 years). Main Outcome Measure Associations between DHEA-S and incident HF hospitalization, CHD, or mortality; associations between 15-year change in DHEA-S (n = 3706) and cardiovascular events. Results DHEA-S below the 15th sex-specific percentile of the study population (men: 55.4 µg/dL; women: 27.4 µg/dL) was associated with increased HF hospitalization (men: hazard ratio [HR] 1.30, 95% confidence interval [CI], 1.07-1.58; women: HR 1.42, 95% CI, 1.13-1.79); DHEA-S below the 25th sex-specific percentile (men: 70.0 µg/dL; women: 37.1 µg/dL) was associated with increased death (men: HR 1.12, 95% CI, 1.01-1.25; women: HR 1.19, 95% CI, 1.03-1.37). In men, but not women, greater percentage decrease in DHEA-S was associated with increased HF hospitalization (HR 1.94, 95% CI, 1.11-3.39). Low DHEA-S and change in DHEA-S were not associated with incident CHD. Conclusions Low DHEA-S is associated with increased risk for HF and mortality but not CHD. Further investigation is warranted to evaluate mechanisms underlying these associations.

Context Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes. Objective To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). Design Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years. Setting General community. Participants 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively. Exposure Plasma sex hormone levels were measured at visit 4 (1996-1998). Main Outcome Measures Incident HF events were identified through hospital discharge codes and death certificates. Results The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant. Conclusion In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.

OBJECTIVE Incorporation of comorbidity burden to inform diabetes management in older adults remains challenging. High-sensitivity cardiac troponins are objective, quantifiable biomarkers that may improve risk monitoring in older adults. We assessed the associations of elevations in high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) with comorbidities and improvements in mortality risk stratification. RESEARCH DESIGN AND METHODS We used logistic regression to examine associations of comorbidities with elevations in either troponin (≥85th percentile) among 1,835 participants in the Atherosclerosis Risk in Communities (ARIC) Study with diabetes (ages 67–89 years, 43% male, 31% black) at visit 5 (2011–2013). We used Cox models to compare associations of high cardiac troponins with mortality across comorbidity levels. RESULTS Elevations in either troponin (≥9.4 ng/L for hs-cTnI, ≥25 ng/L for hs-cTnT) were associated with prevalent coronary heart disease, heart failure, chronic kidney disease, pulmonary disease, hypoglycemia, hypertension, dementia, and frailty. Over a median follow-up of 6.2 years (418 deaths), both high hs-cTnI and high hs-cTnT further stratified mortality risk beyond comorbidity levels; those with a high hs-cTnI or hs-cTnT and high comorbidity were at highest mortality risk. Even among those with low comorbidity, a high hs-cTnI (hazard ratio 3.0 [95% CI 1.7, 5.4]) or hs-cTnT (hazard ratio 3.3 [95% CI 1.8, 6.2]) was associated with elevated mortality. CONCLUSIONS Many comorbidities were reflected by both hs-cTnI and hs-cTnT; elevations in either of the troponins were associated with higher mortality risk beyond comorbidity burden. High-sensitivity cardiac troponins may identify older adults at high mortality risk and be useful in guiding clinical care of older adults with diabetes.

AIMS/HYPOTHESIS: Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. METHODS: We evaluated 10,570 participants free of HF at Visit 3 (1993–1995) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. RESULTS: Among a total of 10,570 individuals (mean age of 60.5 years, 58% women, 27% black adults), elevated GDF-15 (≥75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p

Introduction: Animal studies and emerging population data link liver function and integrity to brain health, although mostly based on cross-sectional estimates. We reported that low liver transaminases are associated with risk of dementia, but prospective studies on liver biomarkers and altered brain morphology are lacking. Methods: We studied 1,596 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort examined in 1996-98 (mean age: 62 years, 59% female, 27% Black) free of chronic liver disease, cirrhosis, and stroke, and with alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio ≤2. Brain magnetic resonance imaging (MRI) scans were performed in 2011-13, at the time of re-examination. Serum transaminases (ALT, AST) and gamma-glutamyl transferase (GGT) at baseline were analyzed as sex-specific quintiles, with the first quintile further subdivided into a th and 10 th -20 th percentiles to allow for nonlinear associations at low biomarker levels. Brain MRI markers were measured with 3 Tesla MRI. Multinomial logistic and linear regressions were used, adjusted for demographics and APOE-ε4. Results: Monotonic associations were observed between higher GGT levels and smaller cortical volume and temporal lobe volume meta regions of interest (Figure) . The lowest GGT levels were associated with smaller volumes of white matter hyperintensities. In contrast, associations of transaminases with brain morphological measures were inconclusive. Conclusions: GGT levels measured in late mid-life are associated vascular sequelae on brain MRI among older adults. As a potent regulator of antioxidant capacity and a predictor of atherosclerosis, GGT may point to vascular pathways that influence brain health. The lack of association between low transaminases and brain MRI findings suggests non-vascular pathways for their association with incident dementia. A deeper understanding of the links between hepatic metabolic dysregulation and brain health is warranted.

Introduction: Heart Failure (HF) has shared genetic architecture with its risk factors, including atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). The risk prediction performance of polygenic risk scores (PRS) for those HF risk factors and HF itself over an established risk equation warrants investigation. Methods: Within the Atherosclerosis Risk in Communities (ARIC) study, six PRSs were constructed for AF, BMI, CHD, SBP, T2D, and HF by summing the product of pre-computed weights from genome-wide association studies and SNP allele dosages in European and African Americans separately. The association between PRSs and incident HF was assessed using cox proportional hazard models, and the 10-, 20-, and 30-year risk prediction performance of PRS over the ARIC HF risk equation was assessed using C-statistics. Associations between AF PRS and HF subtypes, echocardiographic measures, and 4,877 proteins were examined. Results: Over 30 years follow-up, 1,922 (22%) and 735 (29%) HF cases developed in 8,624 European (mean age=54.2, 52% female) and 2,525 African (mean age=53.3, 61% female) Americans. The PRSs for AF and HF were associated with incident HF in both European and African Americans (P-4 ). Protein analyses revealed that 61 proteins were associated with AF PRS, where NT-proBNP and Coagulation factor X showed the strongest positive and negative associations respectively. Conclusions: The PRS of AF was associated with incident HF, and had significant incremental value over an established HF risk prediction equation. These findings suggest that PRS may be useful in identifying individuals with high risk of HF.

Introduction: Frailty, an increased vulnerability to stressors, is associated with adverse health outcomes. Cardiovascular disease (CVD) is associated with frailty, but whether circulating cardiac biomarkers of subclinical myocardial injury and strain (e.g., high-sensitivity cardiac troponin T [hs-cTnT] and natriuretic peptide [NT-proBNP]) are associated with frailty is unknown. Methods: We conducted a cross-sectional analysis of levels of hs-cTnT and NT-proBNP assessed among participants of the ARIC study at visit 5 (2011-2013, mean age: 75.5 years, 42% male, 21% Black). We used the Fried frailty phenotype that counts the presence of each component (weight loss, low physical activity, slow gait, exhaustion, and low grip strength) to classify participants as frail (≥3), pre-frail (1-2), or robust (0 components). Participants without prevalent CVD (stroke, myocardial infarction, or heart failure) were classified into hs-cTnT and NT-proBNP quartiles; those with prevalent CVD were considered in a separate group. Using adjusted multinomial logistic regression models, we tested the hypothesis that hs-cTnT and NT-proBNP are positively associated with odds of being pre-frail and frail, vs. robust. Results: Among 5,162 participants, 1,039 had prevalent CVD (20%), 2,447 (48%) were pre-frail, and 358 (7%) frail. Biomarker concentrations had graded associations with frailty and pre-frailty, vs. robust. Estimates comparing the 4 th vs. 1 st quartile, (e.g., hs-cTnT frail vs. robust OR=4.37 [95% CI: 2.69-7.09]) were similar to those observed for prevalent CVD vs. 1 st quartile (e.g., hs-cTnT frail vs. robust OR=5.11 [3.19-8.17]). All frailty components were positively associated with cardiac biomarker concentrations and CVD (Table), except exhaustion with NT-proBNP. Conclusions: Cardiac biomarker concentrations, even in the absence of CVD, may help identify people at greater risk for frailty. Future research should examine the role of changes in biomarkers from mid-life on the risk of frailty

Background: PAD is associated with substantial morbidity and mortality, yet it is underdiagnosed mainly because many patients are asymptomatic and its screening is not widely conducted. Proteomic analysis may help identify predictors of PAD. Aims: To identify protein predictors of PAD and examine their predictive performance of incident and prevalent PAD beyond traditional risk factors in the ARIC study. Methods: Of 4,877 plasma proteins measured by SOMAscan, we first selected panels of proteins at ARIC visit 3 (N=10,302 participants free of PAD; 1993-95) associated with incident PAD in two steps: 1) we identified significant proteins using multivariable Cox models accounting for multiple comparisons; and 2) we selected proteins using LASSO Cox regression. We constructed 4 protein panels according to λ in LASSO and parsimony. We then evaluated c-statistics after adding each protein panel to a base model with established CVD risk factors. We finally used cross-sectional data at visit 5 (N=4,525; 2011-13) and logistic models to assess if these panels better identify older adults with prevalent PAD beyond traditional predictors. Incident PAD since visit 3 was based on hospitalization with PAD diagnosis; prevalent PAD at visit 5 was defined by ankle-brachial index ≤0.9. Results: There were 450 incident PAD cases after visit 3 (median follow-up: 23 years) and 344 prevalent PAD cases at visit 5. Of 103 proteins significantly associated with incident PAD, 4 protein panels were selected, including 5, 10, 34, and 56 proteins (e.g., angiopoietin-2 and renin), respectively. All 4 protein panels significantly improved c-statistics for incident PAD (e.g., 0.854 for base plus panel 4 vs. 0.807 for base model) (Figure 1A). The same protein panels improved the c-statistic for prevalent PAD at visit 5 compared to the base model (Figure 1B). Conclusions: Protein panels improved risk discrimination for both incident and prevalent PAD beyond established risk factors, with implications for targeted preventive therapies and screening of PAD.

Introduction: Matrix metalloproteinases (MMPs), belong to a family of zinc-dependent endopeptidases, have been found to induce stroke through its role in extracellular matrix destruction. MMPs also affect the stroke prognosis by disrupting blood brain barrier during stroke. Genetic association studies suggest that MMPs are involved in the pathogenesis of both ischemic and hemorrhagic stroke. Hypothesis: High MMP-2, MMP-9 and ratio of MMP-9/TIMP-1 are associated with higher risk of ischemic and hemorrhagic stroke. Method: After exclusion of missing data and prevalent stroke, 11,393 ARIC participants were followed from midlife (visit 3; 1993-1995) and 4,924 participants followed from late life (visit 5; 2011-2013) to 2019. Plasma levels of MMPs were measured by SOMAscan version 4 assay. Stroke cases were reviewed and adjudicated by neurologists. We used Cox models to examine the relationship between MMPs and stroke risk. Result: Mean age of participants were 60±5.7 at visit 3 and 76±5.2 at visit 5. At visit 3 55% were female and 21% Black. A total of 1,013 ischemic and 127 hemorrhagic strokes occurred over 22.34 years of follow-up for the visit 3 analysis and 319 ischemic and 30 hemorrhagic strokes over 7.24 years for the visit 5 analysis. A significant and positive association was detected for MMP-2 at visit 3 baseline for hemorrhagic stroke (HR (95% CI): 2.28 (1.14-4.57)) and at visit 5 baseline with ischemic stroke (1.65 (1.08-2.53)), after covariate adjustment. No associations were observed with MMP-9 and TIMP-1. Conclusion: Results of MMP-2 indicate a possible relationship with MMPs and stroke subtypes, but were not consistent. Though no significance were found for MMP-9 and TIMP-1, their direction of associations with stroke was consistent with the hypothesis.

Background: Cardiac troponins are the cornerstone for the detection of heart attacks. Beyond the acute setting, there is growing evidence that high-sensitivity cardiac troponin T (hs-cTnT) is associated with long-term cardiovascular disease (CVD) risk. The implications of minute elevations in hs-cTnT on short-term CVD risk in the general population has not been investigated. Methods: We included 12,632 adults (43% men, 25% black, mean age: 57 years) in the Atherosclerosis Risk in Communities (ARIC) study who had at least one measurement of hs-cTnT (Roche) across visits 2 (1990-1992), 3 (1996-1998), and 4 (2011-2013) without diagnosed CVD, defined as coronary heart disease, heart failure, or stroke. We used bootstrapping to generate confidence intervals for the cumulative incidence of CVD and generalized estimating equation log-binomial models to quantify the short-term relative rates of incident CVD. Results: Overall, 3.8% (n=479) had elevated hs-cTnT ≥ 14ng/L at their earliest visit; of whom 65% (n=311) had intermediate or lower predicted 10-year risk by the Pooled Cohort Equation. The cumulative 1-year incidence of CVD among those with hs-cTnT ≥ 14ng/L was 5.7% (95% CI: 4.0%, 7.4%) compared to 1.0% (0.9%, 1.1%) among those with hs-cTnT < 6 ng/L and 1.7% (1.3%, 2.2%) among those with hs-cTnT between 6 to 14 ng/L. Among those with hs-cTnT ≥ 14ng/L, the cumulative incidence of CVD at 2 years was 9.6% (7.3%, 11.8%) and at 3-years was 12.7% (10.0%, 15/3%) (Figure 1A). After accounting for traditional CVD risk factors, hs-cTnT ≥ 14ng/L was associated with 2.9 (2.0, 4.1) times higher incidence of CVD at 1-year compared to 1.9 (1.5, 2.4) times incidence at 3-years (Figure 1B). Conclusions: Middle-aged adults in the general population without CVD who had an elevated hs-cTnT experienced a 5.7% 1-year risk of CVD compared to 1% among those with low hs-cTnT. The relative risk associated with elevations in hs-cTnT was most pronounced within the first year, supporting its use for short-term risk monitoring as part of annual preventive visits.

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: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. Methods: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. Results: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2 , TRAM1 , and BCL2 . One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P =2.80×10 −9 ). We observed pleiotropic loci located at BAG3 and ANO5 . The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25–1.54] for hs-cTnT and 1.21 [95% CI, 1.06–1.37] for hs-cTnI). Conclusions: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

Background: Osteoprotegerin (OPG), a protein involved in bone metabolism, is associated with cardiac fibrosis and remodeling in animal models. Circulating OPG levels correlate with left ventricular mass index and plasma brain natriuretic peptide levels in humans, but the association with incident heart failure (HF) is not known. Methods: Among 10,261 participants in the community-based Atherosclerosis Risk in Communities (ARIC) Study free of prevalent HF at study Visit 3, we investigated the association of plasma OPG levels at Visit 3 with incident HF hospitalization post-Visit 3 using multivariable Cox proportional hazard models. OPG was measured using a high-throughput DNA aptamer-based proteomic platform (Somalogic, Boulder, CO), and relative fluorescence unit values were log2 transformed. All models adjusted for age, sex, race, study field center, body mass index, hypertension, diabetes, estimated glomerular filtration rate, smoking status, prevalent coronary artery disease, and atrial fibrillation. Results: Mean age was 60±6 years, 54% were women, and 20% of participants were Black. Higher OPG levels were associated with older age, female gender, Black race, and higher prevalence of hypertension, diabetes, and smoking (all p Conclusion: In this large community-based cohort, higher plasma OPG levels were significantly associated with incident HF hospitalization, independent of traditional cardiovascular risk factors and NT-proBNP. Further studies are warranted to clarify whether OPG could be a new therapeutic target for HF prevention.