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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.)

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).)

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.)

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 60.0 years, 54% 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<0.0001). During 23 years of follow-up, there were 2429 incident HF events. GDF-15 (in quartiles) was independently associated with HF among those with and without diabetes, with a stronger association among individuals with diabetes (p-for-diabetes-GDF-15 interaction = 0.034): HR for highest vs lowest GDF-15 quartile (reference): 1.64 (95% CI 1.41, 1.91) among those without diabetes and 1.72 (95% CI 1.32, 2.23) among those with diabetes. Individuals with diabetes and elevated GDF-15 had the highest risk of incident HF (HR 2.46; 95% CI 1.99, 3.03). After accounting for HF risk factors, GDF-15 provided additional prognostic information among participants with diabetes (ΔC statistic for model with vs model without GDF-15: +0.008, p = 0.001) and among those without diabetes (+0.006, p<0.0001)., Conclusions/interpretation: In a community-based sample of US adults, GDF-15 provided complementary prognostic information on the HF risk, especially among individuals with diabetes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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-<25 kg/m 2 ]). There were stronger associations of BMI with elevated galectin-3 among women versus men and White versus Black participants (both P -for-interaction <0.05). Elevated galectin-3 was similarly associated with incident HF among people with and without obesity (HR, 1.49; 95% CI, 1.18-1.88; and HR, 1.71; 95% CI, 1.38-2.11, respectively). People with severe obesity and elevated galectin-3 had >4-fold higher risk of HF (HR, 4.19; 95% CI, 2.98-5.88) than those with normal weight and galectin-3 <25th percentile. 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.

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., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background Cyclic guanosine monophosphate (cGMP) is a second messenger regulated through natriuretic peptide and nitric oxide pathways. Stimulation of cGMP signaling is a potential therapeutic strategy for heart failure with preserved ejection fraction (HFpEF) and atherosclerotic cardiovascular disease (ASCVD). We hypothesized that plasma cGMP levels would be associated with lower risk for incident HFpEF, any HF, ASCVD, and coronary heart disease (CHD). Methods and Results We conducted a case-cohort analysis nested in the ARIC (Atherosclerosis Risk in Communities) study. Plasma cGMP was measured in 875 participants at visit 4 (1996-1998), with oversampling of incident HFpEF cases. We used Cox proportional hazard models to assess associations of cGMP with incident HFpEF, HF, ASCVD (CHD+stroke), and CHD. The mean (SD) age was 62.4 (5.6) years and median (interquartile interval) cGMP was 3.4 pmol/mL (2.4-4.6). During a median follow-up of 9.9 years, there were 283 incident cases of HFpEF, 329 any HF, 151 ASCVD, and 125 CHD. In models adjusted for CVD risk factors, the hazard ratios (95% CI) associated with the highest cGMP tertile compared with lowest for HFpEF, HF, ASCVD, and CHD were 1.88 (1.17-3.02), 2.18 (1.18-4.06), 2.84 (1.44-5.60), and 2.43 (1.19-5.00), respectively. In models further adjusted for N-terminal-proB-type natriuretic peptide, associations were attenuated for HFpEF and HF but remained statistically significant for ASCVD (2.56 [1.26-5.20]) and CHD (2.25 [1.07-4.71]). Conclusions Contrary to our hypothesis, higher cGMP levels were associated with incident CVD in a community-based cohort. The associations of cGMP with HF or HFpEF may be explained by N-terminal-proB-type natriuretic peptide, but not for ASCVD and CHD.

Measures of serum cardiac troponins and natriuretic peptides have become established as prognostic heart failure risk markers. In addition to detecting myocardial fibrosis through late gadolinium enhancement (LGE), extracellular volume fraction (ECV) measures by cardiac magnetic resonance (CMR) have emerged as a phenotypic imaging risk marker for incident heart failure outcomes. We sought to examine the relationship between cardiac troponins, natriuretic peptides, ECV and their associations with incident heart failure events in a CMR referral base. Mid short axis T1 maps were divided into 6 cardiac segments, each classified as LGE absent or present. Global ECV was derived from T1 maps using the area-weighted average of only LGE-absent segments. ECV was considered elevated if measured >30%, the upper 95% bounds of a reference healthy group without known cardiac disease (n = 28). Patients were dichotomized by presence of elevated ECV. High-sensitivity cardiac troponin T (hs-cTnT) and N-terminal B-type natriuretic peptide (NT-proBNP) were measured using serum samples acquired and stored at time of CMR scan, and patients were categorized into 3 groups for each blood marker based on recommended cutoff values. Subsequent heart failure admission and any death were ascertained. Relationships with ECV, hs-cTnT, and NT-proBNP were examined separately and as a composite with Cox proportional hazard models. Of 1,604 serial patients referred for a clinical CMR with myocardial T1 maps, 331 were eligible after exclusions and had blood available and were followed over a median 25.0 [interquartile range 21.8, 31.7] months. After adjustments for age (mean 57.3 [standard deviation (SD) 15.1 years), gender (61% male), and ethnicity (12.7% black), elevated ECV remained a predictor of a first composite heart failure outcome for patients with high levels of hs-cTnT (≥14 ng/L; hazard ratio [HR] 2.42 [95% confidence interval (CI) 1.17, 5.03]; p = 0.02) and NT-proBNP (≥300 pg/mL; HR 2.28 [95% CI 1.24, 4.29]; p = 0.01). Similar trends were seen for lower category levels of blood markers, but did not persist with minimal covariate adjustments. Elevated measures of ECV by CMR are associated with incident heart failure outcomes in patients with high hs-cTnT and NT-proBNP levels. This imaging marker may have a role for additional heart failure risk stratification.

Background: We assessed whether plasma troponin I measured by a high-sensitivity assay (hs-TnI) is associated with incident cardiovascular disease (CVD) and mortality in a community-based sample without prior CVD., Methods: ARIC study (Atherosclerosis Risk in Communities) participants aged 54 to 74 years without baseline CVD were included in this study (n=8121). Cox proportional hazards models were constructed to determine associations between hs-TnI and incident coronary heart disease (CHD; myocardial infarction and fatal CHD), ischemic stroke, atherosclerotic CVD (CHD and stroke), heart failure hospitalization, global CVD (atherosclerotic CVD and heart failure), and all-cause mortality. The comparative association of hs-TnI and high-sensitivity troponin T with incident CVD events was also evaluated. Risk prediction models were constructed to assess prediction improvement when hs-TnI was added to traditional risk factors used in the Pooled Cohort Equation., Results: The median follow-up period was ≈15 years. Detectable hs-TnI levels were observed in 85% of the study population. In adjusted models, in comparison to low hs-TnI (lowest quintile, hs-TnI ≤1.3 ng/L), elevated hs-TnI (highest quintile, hs-TnI ≥3.8 ng/L) was associated with greater incident CHD (hazard ratio [HR], 2.20; 95% CI, 1.64-2.95), ischemic stroke (HR, 2.99; 95% CI, 2.01-4.46), atherosclerotic CVD (HR, 2.36; 95% CI, 1.86-3.00), heart failure hospitalization (HR, 4.20; 95% CI, 3.28-5.37), global CVD (HR, 3.01; 95% CI, 2.50-3.63), and all-cause mortality (HR, 1.83; 95% CI, 1.56-2.14). hs-TnI was observed to have a stronger association with incident global CVD events in white than in black individuals and a stronger association with incident CHD in women than in men. hs-TnI and high-sensitivity troponin T were only modestly correlated ( r=0.47) and were complementary in prediction of incident CVD events, with elevation of both troponins conferring the highest risk in comparison with elevation in either one alone. The addition of hs-TnI to the Pooled Cohort Equation model improved risk prediction for atherosclerotic CVD, heart failure, and global CVD., Conclusions: Elevated hs-TnI is strongly associated with increased global CVD incidence in the general population independent of traditional risk factors. hs-TnI and high-sensitivity troponin T provide complementary rather than redundant information.

Background Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40% higher than blacks; 95% CI , 29-53; ARIC : 39% higher; 95% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2%; 95% CI , 23.2-69.2%; ARIC : 24.6%; 95% CI , 14.8-39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed.

Background and Aims: Lipoprotein(a) [Lp(a)] is a proatherogenic lipoprotein associated with coronary heart disease, ischemic stroke, and more recently aortic stenosis and heart failure (HF). We examined the association of Lp(a) levels with incident HF hospitalization in the Atherosclerosis Risk in Communities (ARIC) study. We also assessed the relationship between Lp(a) levels and arterial stiffness as a potential mechanism for development of HF., Methods: Lp(a) was measured in 14,154 ARIC participants without prevalent HF at ARIC visit 1 (1987-1989). The association of Lp(a) quintiles with incident HF hospitalization was assessed using Cox proportional-hazards models. Arterial stiffness parameters were stratified based on Lp(a) quintiles, and p-trend was calculated across ordered groups., Results: At a median follow-up of 23.4 years, there were 2605 incident HF hospitalizations. Lp(a) levels were directly associated with incident HF hospitalization in models adjusted for age, race, gender, systolic blood pressure, history of hypertension, diabetes, smoking status, body mass index, heart rate, and high-density lipoprotein cholesterol (quintile 5 vs. quintile 1: hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.09-1.41; p-trend across increasing quintiles <0.01), but not after excluding prevalent and incident myocardial infarction cases (HR 1.07, 95% CI 0.91-1.27; p-trend = 0.70). When adjusted for age, gender, and race, Lp(a) quintiles were not significantly associated with arterial stiffness parameters., Conclusions: Increased Lp(a) levels were associated with increased risk of incident HF hospitalization. After excluding prevalent and incident myocardial infarction, the association was no longer significant. Lp(a) levels were not associated with arterial stiffness parameters., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background Metabolic syndrome (MetS) is associated with increased risk for cardiovascular disease, but there is heterogeneity in this risk. We evaluated whether high-sensitivity troponin T (hs-cTnT), a marker associated with cardiovascular disease, can stratify risk in MetS. Methods We evaluated associations between MetS (and groups with similar number of MetS components) and incident heart failure hospitalization, coronary heart disease, stroke and death using hs-cTnT categories after adjusting for risk factors/markers between 1996 and 2011 in 8204 individuals in the Atherosclerosis Risk In Communities study. Results The mean age of the population was 63 years (56% women, 19% Blacks). hs-cTnT levels were higher with MetS and with increasing MetS components. In individuals with MetS, higher hs-cTnT levels were associated with increased hazard ratios for heart failure, coronary heart disease and death. Within each number of MetS components, higher hs-cTnT was associated with progressively higher heart failure, coronary heart disease and death hazards. The association was particularly strong for heart failure. With increasing hs-cTnT categories, the hazard ratios (95% confidence interval) for heart failure in individuals with MetS increased gradually from 1.68 (1.31-2.16) to 3.76 (2.69-5.26) ( p-trend < 0.001) compared with those with MetS and hs-cTnT < 5 ng/l; and respective hazard ratios with increasing hs-cTnT categories in those with all five MetS components ranged from 2.22 (1.17-4.21) to 4.23 (1.89-9.50) ( p-trend 0.004) compared with those with all five MetS components and hs-cTnT < 5 ng/l. However, mostly there were no significant interactions of hs-cTnT with MetS or its components. Conclusion hs-cTnT is useful for identifying MetS patients with increased hazards for coronary heart disease, death and particularly heart failure.

Objectives: This study sought to determine whether pre-heart failure (HF) myocardial injury explains the differential mortality after HF across weight categories., Background: Obesity is a risk factor for HF, but pre-HF obesity is associated with lower mortality after incident HF. High-sensitivity cardiac troponin T (hs-cTnT) is a sensitive marker of myocardial injury, and predicts incident HF and mortality., Methods: Stratifying 1,279 individuals with incident HF hospitalizations by their pre-HF hs-cTnT levels (< and ≥ 14 ng/l), we examined the association of pre-HF body mass index (BMI) with mortality after incident HF hospitalization in the ARIC (Atherosclerosis Risk In Communities) study., Results: Mean age at HF was 74 years (53% women, 27% black). Individuals with pre-HF hs-cTnT ≥14 ng/l had higher mortality after incident HF (hazard ratio [HR]: 1.46; 95% confidence interval [CI]: 1.18 to 1.80) compared to individuals with hs-cTnT <14 ng/l in an adjusted model including BMI. Compared with normal weight subjects, the mortality was lower in overweight (HR: 0.69, 95% CI 0.48-0.98) and obese individuals (HR: 0.50; 95% CI: 0.35 to 0.72) with hs-cTnT <14 ng/l; and in those with hs-cTnT ≥14 ng/l (overweight HR: 0.50; 95% CI: 0.30 to 0.83; obese HR: 0.56; 95% CI: 0.34 to 0.91; interaction: p = 0.154 between BMI and hs-cTnT). The lower mortality risk in obese and overweight subjects remained similar when log hs-cTnT was added as a continuous variable to a multivariable model, and in sensitivity analyses after further adjusting for left ventricular hypertrophy or high-sensitivity C-reactive protein., Conclusion: Although greater pre-existing subclinical myocardial injury was associated with higher mortality after incident HF hospitalization, it did not explain the obesity paradox in HF, which was observed irrespective of subclinical myocardial injury. (Atherosclerosis Risk In Communities [ARIC]; NCT00005131)., (Published by Elsevier Inc.)

Background: Experimental studies in animals suggest that circulating soluble receptor for advanced glycation end products (sRAGE) decrease oxidative stress, inflammation, and fibrosis. The association between sRAGE and incident heart failure has not been systematically examined in a prospective study., Methods: We conducted a prospective analysis of a subsample of 1,086 participants from the Atherosclerosis Risk in Communities Study who attended visit 2 (1990-1992) without a history of coronary heart disease, stroke, or heart failure and with measured plasma sRAGE levels. Incident heart failure was defined as death from heart failure or hospitalization due to heart failure during a median of 20 years of follow-up., Results: In this sample of a community-based population (mean age 63 years, 60% women, 78% white), there were 126 incident cases of heart failure. Lower levels of sRAGE were significantly associated with an increased risk of heart failure; the adjusted hazard ratios (95% CIs) of heart failure were 1.0 (reference), 1.81 (0.94-3.49), 1.57 (0.80-3.08), and 3.37 (1.75-6.50), for fourth, third, second, and first quartiles, respectively (P for trend = .001). We did not observe significant interactions by diabetes status or by race or obesity status., Conclusions: Lower circulating levels of sRAGE are independently associated with the development of heart failure in a community-based population. Our results add to the growing evidence that sRAGE is a valuable predictor of cardiovascular disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The study sought to evaluate the association of obesity with a novel biomarker of subclinical myocardial injury, cardiac troponin T measured with a new high-sensitivity assay (hs-cTnT), among adults without clinical cardiovascular disease (CVD)., Background: Laboratory evidence suggests a relationship between obesity and myocardial injury that may play a role in the development of heart failure (HF), but there is limited clinical data regarding this association., Methods: We evaluated 9,507 participants in the ARIC (Atherosclerosis Risk in Communities) study without baseline CVD (Visit 4, 1996 to 1999). We assessed the cross-sectional association of body mass index (BMI) with high (≥14 ng/l) and measurable (≥3 ng/l) hs-cTnT levels after multivariable regression. We further evaluated the independent and combined associations of BMI and hs-cTnT with incident HF., Results: Higher BMI was independently associated with a positive, linear increase in the likelihood of high hs-cTnT, with severe obesity (BMI >35 kg/m(2)) associated with an odds ratio of 2.20 (95% confidence interval: 1.59 to 3.06) for high hs-cTnT after adjustment. Over 12 years of follow-up, there were 869 incident HF events. Obesity and hs-cTnT were both independently associated with incident HF, and individuals with severe obesity and high hs-cTnT had a greater than 9-fold higher risk of incident HF (hazard ratio: 9.20 [95% confidence interval: 5.67 to 14.93]) than individuals with normal weight and undetectable hs-cTnT., Conclusions: Among individuals without CVD, higher BMI has an independent, linear association with subclinical myocardial injury, as assessed by hs-cTnT levels. Obesity and hs-cTnT provide independent and complementary prognostic information regarding the risk of incident HF., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Persons with prediabetes and diabetes mellitus are at high risk for cardiovascular events. However, the relationships of prediabetes and diabetes mellitus to the development of subclinical myocardial damage are unclear., Methods and Results: We measured cardiac troponin T with a highly sensitive assay (hs-cTnT) at 2 time points, 6 years apart, among 9051 participants of the community-based Atherosclerosis Risk in Communities Study with no diabetes mellitus, or prediabetes, and without cardiovascular disease including silent myocardial infarction by ECG. First, we examined the incidence of elevated hs-cTnT (≥14 ng/L) at 6 years of follow-up. Second, we examined clinical outcomes during the subsequent ≈14 years of follow-up among persons with and without incident elevations in hs-cTnT. Cumulative probabilities of elevated hs-cTnT at 6 years among persons with no diabetes mellitus, prediabetes, and diabetes mellitus were 3.7%, 6.4%, and 10.8%, respectively. Compared with normoglycemic persons, the adjusted relative risks for incident elevated hs-cTnT were 1.40 (95% CI, 1.08-1.80) for prediabetes and 2.47 (95% CI, 1.78-3.43) for diabetes mellitus. Persons with diabetes mellitus and incident elevations in hs-cTnT were at a substantially higher risk of heart failure (hazard ratio, 6.37 [95% CI, 4.27-9.51]), death (hazard ratio, 4.36 [95% CI, 3.14-6.07]), and coronary heart disease (hazard ratio, 3.84 [95% CI, 2.52-5.84]) compared with persons without diabetes mellitus and no incident elevation in hs-cTnT., Conclusions: Prediabetes and diabetes mellitus were independently associated with the development of subclinical myocardial damage, as assessed by hs-cTnT, and those persons with evidence of subclinical damage were at highest risk for clinical events. These results support a possible deleterious effect of hyperglycemia on the myocardium, possibly reflecting a microvascular cause., (© 2014 American Heart Association, Inc.)

Background: Among the various cardiovascular diseases, heart failure (HF) is projected to have the largest increases in incidence over the coming decades; therefore, improving HF prediction is of significant value. We evaluated whether cardiac troponin T (cTnT) measured with a high-sensitivity assay and N-terminal pro-B-type natriuretic peptide (NT-proBNP), biomarkers strongly associated with incident HF, improve HF risk prediction in the Atherosclerosis Risk in Communities (ARIC) study., Methods: Using sex-specific models, we added cTnT and NT-proBNP to age and race ("laboratory report" model) and to the ARIC HF model (includes age, race, systolic blood pressure, antihypertensive medication use, current/former smoking, diabetes, body mass index, prevalent coronary heart disease, and heart rate) in 9868 participants without prevalent HF; area under the receiver operating characteristic curve (AUC), integrated discrimination improvement, net reclassification improvement (NRI), and model fit were described., Results: Over a mean follow-up of 10.4 years, 970 participants developed incident HF. Adding cTnT and NT-proBNP to the ARIC HF model significantly improved all statistical parameters (AUCs increased by 0.040 and 0.057; the continuous NRIs were 50.7% and 54.7% in women and men, respectively). Interestingly, the simpler laboratory report model was statistically no different than the ARIC HF model., Conclusions: cTnT and NT-proBNP have significant value in HF risk prediction. A simple sex-specific model that includes age, race, cTnT, and NT-proBNP (which can be incorporated in a laboratory report) provides a good model, whereas adding cTnT and NT-proBNP to clinical characteristics results in an excellent HF prediction model.

Background: Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the associations between Cp and incident heart failure (HF), death, and CVD in the Atherosclerosis Risk in Communities (ARIC) study., Methods and Results: Cp was measured at ARIC visit 4 (1996-1998). We studied 9240 individuals without HF or CVD at ARIC visit 4 and followed them for a mean of 10.5 years. Genome-wide association study was performed to identify genetic determinants of Cp levels and evaluate their association with incident HF in ARIC participants. Cp levels (mean±SD) were higher in women versus men (335±79 versus 258±44 mg/L; P<0.0001), women on versus not on hormone-replacement therapy (398±89 versus 291±60 mg/L; P<0.0001), and African Americans versus whites (299±63 versus 293±74 mg/L; P=0.0005). After adjusting for traditional risk factors, high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and high-sensitivity cardiac troponin T, higher levels of Cp were associated with HF (hazard ratio, 1.44; 95% confidence interval, 1.13-1.83) and mortality (hazard ratio, 1.38; 95% confidence interval, 1.11-1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56±77.60 mg/L; heterozygote 316.72±88.02 mg/L; homozygote 331.04±85.40 mg/L; P=8.3×10(-13)) but not with incident HF. After adjustment for traditional risk factors, Cp levels were also weekly associated with CVD., Conclusions: Cp was associated with incident HF, mortality, and CVD in the ARIC population. A single locus on chromosome 3 was associated with Cp levels but not with HF.

We examined the association of plasma lactate at rest, a marker of oxidative capacity, with incident cardiovascular outcomes in 10,006 participants in the Atherosclerosis Risk in Communities (ARIC) Study visit 4 (1996-1998). We used Cox proportional-hazards models to estimate hazard ratios of incident coronary heart disease, stroke, heart failure, and all-cause mortality by quartiles of plasma lactate (Q1, ≤5.3 mg/dL; Q2, 5.4-6.6; Q3, 6.7-8.6; and Q4 ≥8.7). During a median follow-up time of 10.7 years, there were 1,105 coronary heart disease cases, 379 stroke cases, 820 heart failure cases, and 1,408 deaths. A significant graded relation between lactate level and cardiovascular events was observed in the demographically adjusted model (all P for trend < 0.001). After further adjustment for traditional and other potential confounders, the association remained significant for heart failure (Q4 vs. Q1: hazard ratio (HR) = 1.35, 95% confidence interval (CI): 1.07, 1.71) and all-cause mortality (HR = 1.27, 95% CI: 1.07, 1.51) (P for trend < 0.02 for these outcomes) but not for coronary heart disease (HR = 1.02, 95% CI: 0.84, 1.24) and stroke (HR = 1.26, 95% CI: 0.91, 1.75). The results for heart failure were robust across multiple subgroups, after further adjustment for N-terminal pro-B-type natriuretic peptide and after exclusion of participants with incident heart failure within 3 years. The independent associations of plasma lactate with heart failure and all-cause mortality suggest an important role for low resting oxidative capacity.

Background: A simple and effective heart failure (HF) risk score would facilitate the primary prevention and early diagnosis of HF in general practice. We examined the external validity of existing HF risk scores, optimized a 10-year HF risk function, and examined the incremental value of several biomarkers, including N-terminal pro-brain natriuretic peptide., Methods and Results: During 15.5 years (210 102 person-years of follow-up), 1487 HF events were recorded among 13 555 members of the biethnic Atherosclerosis Risk in Communities (ARIC) Study cohort. The area under curve from the Framingham-published, Framingham-recalibrated, Health ABC HF recalibrated, and ARIC risk scores were 0.610, 0.762, 0.783, and 0.797, respectively. On addition of N-terminal pro-brain natriuretic peptide, the optimism-corrected area under curve of the ARIC HF risk score increased from 0.773 (95% CI, 0.753-0.787) to 0.805 (95% CI, 0.792-0.820). Inclusion of N-terminal pro-brain natriuretic peptide improved the overall classification of recalibrated Framingham, recalibrated Health ABC, and ARIC risk scores by 18%, 12%, and 13%, respectively. In contrast, cystatin C or high-sensitivity C-reactive protein did not add toward incremental risk prediction., Conclusions: The ARIC HF risk score is more parsimonious yet performs slightly better than the extant risk scores in predicting 10-year risk of incident HF. The inclusion of N-terminal pro-brain natriuretic peptide markedly improves HF risk prediction. A simplified risk score restricted to a patient's age, race, sex, and N-terminal pro-brain natriuretic peptide performs comparably to the full score (area under curve, 0.745) and is suitable for automated reporting from laboratory panels and electronic medical records.

Background: We evaluated whether cardiac troponin T (cTnT) measured with a new highly sensitive assay was associated with incident coronary heart disease (CHD), mortality, and hospitalization for heart failure (HF) in a general population of participants in the Atherosclerosis Risk in Communities (ARIC) Study., Methods and Results: Associations between increasing cTnT levels and CHD, mortality, and HF hospitalization were evaluated with Cox proportional hazards models adjusted for traditional CHD risk factors, kidney function, high-sensitivity C-reactive protein, and N-terminal pro-B-type natriuretic peptide in 9698 participants aged 54 to 74 years who at baseline were free from CHD and stroke (and HF in the HF analysis). Measurable cTnT levels (≥0.003 μg/L) were detected in 66.5% of individuals. In fully adjusted models, compared with participants with undetectable levels, those with cTnT levels in the highest category (≥0.014 μg/L; 7.4% of the ARIC population) had significantly increased risk for CHD (hazard ratio=2.29; 95% confidence interval, 1.81 to 2.89), fatal CHD (hazard ratio=7.59; 95% confidence interval, 3.78 to 15.25), total mortality (hazard ratio=3.96; 95% confidence interval, 3.21 to 4.88), and HF (hazard ratio=5.95; 95% confidence interval, 4.47 to 7.92). Even minimally elevated cTnT (≥0.003 μg/L) was associated with increased risk for mortality and HF (P<0.05). Adding cTnT to traditional risk factors improved risk prediction parameters; the improvements were similar to those with N-terminal pro-B-type natriuretic peptide and better than those with the addition of high-sensitivity C-reactive protein., Conclusions: cTnT detectable with a highly sensitive assay was associated with incident CHD, mortality, and HF in individuals from a general population without known CHD/stroke.