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Importance: The risk for atherosclerotic disease is increased 1.5- to 2.0-fold among persons with HIV (PWH). Increased activation of the renin-angiotensin-aldosterone system may contribute to increased arterial inflammation in this population., Objective: To determine the effects of eplerenone on arterial inflammation among well-treated PWH without known cardiovascular disease (CVD)., Design, Setting, and Participants: Well-treated PWH who participated in the double-blinded, placebo-controlled, Mineralocorticoid Receptor Antagonism for Cardiovascular Health in HIV (MIRACLE HIV) study between February 2017 and March 2022 assessing the effects of eplerenone on myocardial perfusion were invited to participate in the Mineralocorticoid Receptor Antagonism By Eplerenone to Lower Arterial Inflammation in HIV (MIRABELLA) substudy if there was no current statin use. Participants were enrolled in the MIRABELLA study and underwent additional 18F-fludeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) imaging of the aorta and carotid arteries to assess arterial inflammation over 12 months of treatment with eplerenone vs placebo., Interventions: Eplerenone, 50 mg, twice a day vs identical placebo., Main Outcomes and Measures: The primary outcome was change in target to background ratio (TBR), a measure of arterial wall inflammation, in the index vessel after 12 months of treatment. The index vessel was defined as the vessel (aorta, left carotid artery, or right carotid artery) with the highest TBR at baseline in each participant., Results: A total of 26 participants (mean [SD] age, 54 [7] years; 18 male [69%]) were enrolled in the study. Treatment groups (eplerenone, 13 vs placebo, 13) were of similar age, sex, and body mass index. Eplerenone was associated with a reduction in TBR of the primary end point, the index vessel (eplerenone vs placebo: model treatment effect, -0.31; 95% CI, -0.50 to -0.11; P = .006; percentage change, -12.4% [IQR, -21.9% to -2.6%] vs 5.1% [IQR, -1.6% to 11.0%]; P = .003). We further observed a significant reduction of the TBR of the most diseased segment (MDS) of the index vessel (eplerenone vs placebo: -19.1% [IQR, -27.0% to -11.9%] vs 6.8% [IQR, -9.1% to 12.1%]; P = .007). A similar result was seen assessing the index vessel of the carotids (eplerenone vs placebo: -10.0% [IQR, -21.8% to 3.6%] vs 9.7% [IQR, -9.8% to 15.9%]; P = .046). Reduction in the TBR of MDS of the index vessel on 18F-FDG PET/CT correlated with improvement in the stress myocardial blood flow on cardiac magnetic resonance imaging (Spearman ρ = -0.67; P = .01)., Conclusion and Relevance: In this small randomized clinical trial, eplerenone was associated with reduction in arterial inflammation among well-treated PWH without known CVD. In addition, reductions in arterial inflammation as measured by 18F-FDG PET/CT were related to improvements in stress myocardial perfusion. Further larger studies should explore whether eplerenone is a potential treatment strategy for inflammatory-mediated CVD in PWH., Trial Registration: ClinicalTrials.gov Identifier: NCT02740179.

Abnormalities in myocardial substrate, including diffuse and replacement fibrosis, increase the risk of cardiovascular disease (CVD). Data are sparse on whether electrocardiogram (ECG) measures, coupled with circulating biomarkers, may aid in identifying cardiac fibrosis. This study aimed to determine whether 12-lead ECG and biomarkers together augment the prediction of cardiac fibrosis in participants who are free of known CVD. This is a cross-sectional analysis in the MESA (Multiethnic Study of Atherosclerosis) study at visit 5 (2010 to 2012), with measurements of biomarkers (cardiac troponin T and growth differentiation factor-15), gadolinium-enhanced cardiac magnetic resonance imaging, and ECG. Logistic regression associations of ECG measures with cardiac magnetic resonance surrogates of fibrosis (highest quartile extracellular volume [interstitial fibrosis] and late gadolinium enhancement [replacement fibrosis]) were adjusted for demographics and risk factors. Using the C-statistic, we evaluated whether adding ECG measures and biomarkers to clinical characteristics improved the prediction of either type of fibrosis. There were 1,170 eligible participants (aged 67.1 ± 8.6 years). Among the ECG measures, QRS duration (odds ratio [OR] 1.41 per 10 ms, 95% confidence interval [CI] 1.10 to 1.81), major ST-T abnormalities (OR 3.03, 95%CI 1.20, 7.65), and abnormal QRS-T angle (OR 6.32, 95%CI 3.00, 13.33) were associated with replacement fibrosis, whereas only abnormal QRS-T angle (OR 3.05, 95%CI,1.69, 5.48) was associated with interstitial fibrosis. ECG markers, in addition to clinical characteristics, improved the prediction of replacement fibrosis (p = 0.002) but not interstitial fibrosis. The addition of cardiac troponin T and growth differentiation factor-15 to the ECG findings did not significantly improve the model discrimination for either type of cardiac fibrosis. In CVD free participants, simple ECG measures are associated with replacement fibrosis and interstitial fibrosis. The addition of these measures improves identification of replacement but not interstitial fibrosis. These findings may help refine the identification of myocardial scar in the general population., Competing Interests: Declaration of Competing Interest Dr. deFilippi has received funding for Inova to measure biomarkers from Roche Diagnostics. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD)., Methods and Results: This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB]., Conclusion: The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment., Competing Interests: Conflict of interest statement F.R. reported receiving funding support from the National Heart, Lung, and Blood Institute, National Institutes of Health (1K01HL144607), Doris Duke Charitable Foundation, and the American Heart Association/Robert Wood Johnson Harold Amos Medical Faculty Development Program and consulting fees from Novartis, NovoNordisk, Amgen, and HealthPals. C.d.F. has received consulting fees from Abbott Diagnostics, FujiRebio, Ortho Diagnostics, Quidell, Roche Diagnostics, Siemens Healthineers, and a patent entitled ‘Methods for assessing differential risk for developing heart failure’ (patent number: PCT/US2015/029838). M.B. reported receiving funding support from the National Institutes of Health, the American Heart Association, the Food and Drug Administration, and NovoNordisk and consulting fees from Kowa. A.P. reported receiving funding support from the National Institute on Minority Health and Disparities (R01MD017529), National Institute on Aging GEMSSTAR Grant (1R03AG067960–01), Gilead Sciences, and has received consulting fees from Tricog Health Inc and Cytokinetics. M.V. has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. M.D.S. reported receiving funding support from the National Institute Health, Amgen, Novartis, Regeneron and served on scientific advisory boards for Amgen, Novartis, Novo Nordisk, Esperion, Regeneron, Ionis. All other authors declare that they have no competing interests., (© 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.)

Study Objectives: To assess whether the association between insomnia and subclinical myocardial injury, as measured by cardiac troponin T (cTnT), differs across insomnia phenotypes., Methods: We measured cTnT in 2188 participants in the Multi-Ethnic Study of Atherosclerosis study who had completed sleep questionnaires and undergone unattended polysomnography (PSG) and 7-day actigraphy. Insomnia symptoms were defined as reporting at least one of the following ≥5 nights/week over the past 4 weeks: trouble falling asleep, waking up several times a night, having trouble getting back to sleep after waking up too early, or taking sleeping pills to help falling asleep. Obstructive sleep apnea (OSA) was defined as an apnea-hypopnea index (AHI >15 events/h). Participants were classified into insomnia phenotypes, including comorbid insomnia and OSA (COMISA) and insomnia associated with actigraphy-estimated short sleep (<6 h) or sleep fragmentation., Results: The mean age was 68.8 (SD 9.2) years, 53.6% were male. In total, 47.8% met threshold levels for insomnia symptoms, and 43.1% had an AHI >15. In adjusted linear regression models COMISA (β 0.08 [standard error (SE) 0.03], p < .01) and insomnia with short sleep duration (β 0.07 [SE 0.03], p < .05) were each associated with higher cTnT compared to a reference group with no insomnia. Insomnia with fragmented sleep (β 0.03 [SE 0.02]) was not associated with higher cTnT (p > .05) in adjusted analyses. OSA was associated with higher cTnT (β 0.09 [SE 0.03], p < .01) in adjusted models., Conclusions: COMISA and insomnia with short sleep duration, but not insomnia symptoms alone or fragmented sleep, were associated with increased circulating cTnT in older adults., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)

Background: Cardiac magnetic resonance imaging (CMR) determines the extent of interstitial fibrosis, measured by increased extracellular volume (ECV), and replacement fibrosis with late gadolinium myocardial enhancement (LGE). Despite advances in detection, the pathophysiology of subclinical myocardial fibrosis is incompletely understood. Targeted proteomic discovery technologies enable quantification of low abundance circulating proteins to elucidate cardiac fibrosis mechanisms., Methods: Using a cross-sectional design, we selected 92 LGE+ cases and 92 LGE- demographically matched controls from the Multi-Ethnic Study of Atherosclerosis. Similarly, we selected 156 cases from the highest ECV quartile and matched with 156 cases from the lowest quartile. The plasma serum proteome was analyzed using proximity extension assays to determine differential regulation of 92 proteins previously implicated with cardiovascular disease. Results were analyzed using volcano plots of statistical significance vs. magnitude of change and Bayesian additive regression tree (BART) models to determine importance., Findings: After adjusting for false discovery, higher ECV was significantly associated with 17 proteins. Using BART, Plasminogen activator inhibitor 1, Insulin-like growth factor-binding protein 1, and N-terminal pro-B-type natriuretic peptide were associated with higher ECV after accounting for other proteins and traditional cardiovascular risk factors. In contrast, no circulating proteins were associated with replacement fibrosis., Interpretations: Our results suggest unique circulating proteomic signatures associated with interstitial fibrosis emphasizing its systemic influences. With future validation, protein panels may identify patients who may develop interstitial fibrosis with progression to heart failure., Funding: This research was supported by contracts and grants from NHLBI, NCATS and the Inova Heart and Vascular Institute., Competing Interests: Declaration of interests Dr. deFilippi receives funding from the National Center for Advancing Translational Science of the National Institutes of Health Award UL1TR003015, R01-HL154768-01 and R21 AG072095. Dr. deFilippi reports consulting fees from Abbott Diagnostics, FujiRebio, Ortho/Quidel Diagnostics, Roche Diagnostics and Siemens Healthineers, a travel grant from Olink and is on advisory boards for Abbott and Ortho/Quidel. Dr. Seliger has received funding from Roche Diagnostics. Drs. Seliger and deFilippi are co-owners on a patent awarded to the University of Maryland (US Patent Application Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.” Dr.Bruce has received grant funding from Inova Heart and Vascular Institute which was awarded to Texas A&M University with him as the principal investigator. The following individuals declare no disclosures or conflict of interest: Hooman Bakhshi, Sam Michelhaugh, Xiaoxiao Qian, Bharath Ambale Venkatesh, Vinithra Varadarajan, Pramita Bagchi, Joao A C Lima., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: We investigated the associations of high-sensitivity cardiac Troponin T (hs-cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels with risk of developing clinical peripheral artery disease (PAD) or a low ankle-brachial index (ABI)., Methods: Hs-cTnT and NT-proBNP were measured in 6692 and 5458 participants respectively without baseline PAD between 2000 and 2002 in the Multi-ethnic Study of Atherosclerosis. A significant number also had repeat biomarker measurement between 2004 and 2005. Incident clinical PAD was ascertained through 2017. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15 from baseline, was assessed among 5920 eligible individuals who had an ABI >0.9 at baseline and at least one follow-up ABI measurement 3-10 years later. Multivariable Cox proportional hazards and logistic regression modeling were used to determine the association of these biomarkers with clinical PAD and low ABI, respectively., Results: Overall, 121 clinical PAD and 118 low ABI events occurred. Adjusting for demographic and clinical characteristics, each log unit increment in hs-cTnT and NT-proBNP was associated with a 30% (adjusted hazard ratio (HR) 1.3, 95% confidence interval (CI): 1.1, 1.6) and 50% (HR) 1.5, 95% CI: 1.2, 1.8) higher risk of clinical PAD respectively. No significant associations were observed for incident low ABI. Change in these biomarkers was not associated with either of the PAD outcomes., Conclusions: NT-proBNP and hs-cTnT are independently associated with the development of clinical PAD. Further study should determine whether these biomarkers can help to better identify those at higher risk for PAD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Persons living with HIV (PLWH) well treated on antiretroviral therapies remain at risk for ensuing arterial disease. We investigated the relationship between adipose depots and biomarkers of arterial injury and inflammation to gain insight into the link between body composition and CVD risk., Designs/methods: One hundred and fifty-five HIV-infected and 70 non-HIV infected individuals were well phenotyped for body composition. Adipose depots were assessed via single-slice abdominal computed tomography (CT). Circulating markers of arterial disease and generalized inflammation [lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), high-sensitivity cardiac troponin T (hs-cTnT), high-sensitivity C-reactive protein (hsCRP)] were evaluated., Results: Despite similar BMI and visceral adipose tissue (VAT), HIV-infected individuals had significantly lower subcutaneous adipose tissue [SAT, 199 (126-288) vs. 239 (148-358) cm(2), P = 0.04] than non-HIV infected individuals. Among HIV-infected individuals, reduced SAT inversely correlated with LpPLA2 (ρ = -0.19, P = 0.02) and hs-cTnT (ρ = -0.24, P = 0.004), whereas increased VAT significantly and positively related to LpPLA2 (ρ = 0.25, P = 0.003), oxLDL (ρ = 0.28, P = 0.0005), hs-cTnT (ρ = 0.28, P = 0.0007) and hsCRP (ρ = 0.32, P =  < 0.0001). Similar analyses among the non-HIV infected individuals revealed significant relationships between SAT and LpPLA2 (ρ = -0.24, P = 0.05), as well as VAT and LpPLA2 (ρ = 0.37, P = 0.002), oxLDL (ρ = 0.24, P = 0.05) and hsCRP (ρ = 0.29, P = .02). In modelling performed among the HIV group, simultaneously controlling for VAT, SAT, age and relevant HIV-related parameters, reduced SAT was an independent predictor of LpPLA2 (P = 0.04) and hs-cTnT (P = 0.005) and increased VAT was an independent predictor of LpPLA2 (P = 0.001), oxLDL (P = 0.02), hs-cTnT (P = 0.04) and hsCRP (P = 0.04)., Conclusion: Fat redistribution phenotypes, characterized by SAT loss and/or VAT accumulation, may be linked to arterial injury and inflammation in HIV.

Context: Sex hormones may influence sex differences in cardiovascular disease (CVD). N-terminal pro-B-type natriuretic peptide (NT-proBNP), a predictor of CVD, is higher in women than men, which may relate to sex hormones., Objective: To evaluate whether total testosterone (T), bioavailable T, free T, estradiol, dehydroepiandrosterone (DHEA), and SHBG are associated with NT-proBNP., Design: Cohort study., Participants: Cross-sectional sample included 2371 postmenopausal women and 2688 men free of CVD, of which 2041 women and 2348 men were included longitudinally., Main Outcome Measures: NT-proBNP at baseline (2000 to 2002) and one or more repeat NT-proBNPs (through 2012). Analyses adjusted for CVD risk factors., Results: Women had higher NT-proBNP than men (median 79.9 vs 38.5 pg/mL). Cross-sectionally, higher bioavailable T, free T, DHEA, and lower SHBG levels were independently associated with lower NT-proBNP among both women and men (all P < 0.05). Higher total T in women and estradiol in men were also associated with lower NT-proBNP (both P < 0.05). Longitudinally, in women, higher total T, bioavailable T, free T, DHEA, and lower estradiol and SHBG were associated with greater 10-year increase in NT-proBNP (all P < 0.05). In men, higher free T and estradiol were associated with greater NT-proBNP increase (both P < 0.05)., Conclusions: A more androgenic sex hormone pattern was inversely associated with NT-proBNP cross-sectionally and may contribute to sex differences in NT-proBNP. Longitudinally, a more androgenic sex hormone pattern was associated with greater increase in NT-proBNP in women, which may reflect a mechanism for CVD risk after menopause.

Natriuretic peptides (NP) are cardiac-derived hormones with favorable cardiometabolic actions. Low NP levels are associated with increased risks of hypertension and diabetes mellitus, conditions with variable prevalence by race and ethnicity. Heritable factors underlie a significant proportion of the interindividual variation in NP concentrations, but the specific influences of race and ancestry are unknown. In 5597 individuals (40% white, 24% black, 23% Hispanic, and 13% Chinese) without prevalent cardiovascular disease at baseline in the Multi-Ethnic Study of Atherosclerosis, multivariable linear regression and restricted cubic splines were used to estimate differences in serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels according to, ethnicity, and ancestry. Ancestry was determined using genetic ancestry informative markers. NT-proBNP concentrations differed significantly by race and ethnicity (black, median 43 pg/ml [interquartile range 17 to 94], Chinese 43 [17 to 90], Hispanic 53 [23 to 107], white 68 [34 to 136]; p = 0.0001). In multivariable models, NT-proBNP was 44% lower (95% confidence interval -48 to -40) in black and 46% lower (-50 to -41) in Chinese, compared with white individuals. Hispanic individuals had intermediate concentrations. Self-identified blacks and Hispanics were the most genetically admixed. Among self-identified black individuals, a 20% increase in genetic European ancestry was associated with 12% higher (1% to 23%) NT-proBNP. Among Hispanic individuals, genetic European and African ancestry were positively and negatively associated with NT-proBNP levels, respectively. In conclusion, NT-proBNP levels differ according to race and ethnicity, with the lowest concentrations in black and Chinese individuals. Racial and ethnic differences in NT-proBNP may have a genetic basis, with European and African ancestry associated with higher and lower NT-proBNP concentrations, respectively., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Although small elevations of high-sensitive cardiac troponin T (hs-cTnT) are associated with incident heart failure (HF) in the general population, the underlying mechanisms are not well defined. Evaluating the association of hs-cTnT with replacement fibrosis and progression of structural heart disease before symptoms is fundamental to understanding the potential of this biomarker in a HF prevention strategy., Methods: We measured hs-cTnT at baseline among 4986 participants in MESA (Multi-Ethnic Study of Atherosclerosis), a cohort initially free of overt cardiovascular disease (CVD). Cardiac magnetic resonance imaging was performed at baseline. Repeat cardiac magnetic resonance was performed 10 years later among 2831 participants who remained free of interim CVD events; of these, 1723 received gadolinium-enhanced cardiac magnetic resonance for characterization of replacement fibrosis by late gadolinium enhancement. Progression of subclinical CVD was defined by 10-year change in left ventricular structure and function. Associations of hs-cTnT with incident HF, CV-related mortality, and coronary heart disease were estimated using Cox regression models., Results: Late gadolinium enhancement for replacement fibrosis was detectable in 6.3% participants without interim CVD events by follow-up cardiac magnetic resonance. A graded association was observed between higher baseline hs-cTnT categories and late gadolinium enhancement (≥7.42 ng/L versus 12% (highest category versus

Background: During atrial fibrillation (AF), a high rate of myocyte activation causes cellular stress and initiates the process of atrial remodeling, which further promotes persistence of AF. Although heat shock proteins (HSPs) have been shown to prevent atrial remodeling and suppress the occurrence of AF in cellular and animal experimental models, increased levels of HSP-60 have been observed in patients with postoperative AF, likely reflecting a response to cellular stress. To better understand the role of HSP-60 in relation to AF, we examined the association of HSP-60 levels in relation to the future development of AF in the Multi-Ethnic Study of Atherosclerosis (MESA)., Methods: MESA is a cohort study that recruited 6,814 participants aged 45-84 years and free of known cardiovascular disease at baseline (2000-2002) from six field centers. We investigated 983 participants, selected at random from the total cohort, who had HSP-60 measured and were free of AF at baseline. We tested the association of HSP-60 levels with the incidence of AF using multivariate Cox models after adjustment for demographics, clinical characteristics, and biomarkers., Results: During an average of 10.6 years of follow-up, 77 participants developed AF. We did not observe a significant association between the log-transformed HSP-60 levels and development of AF on either unadjusted or multivariate analysis (adjusted hazard ratio: 1.02 per unit difference on natural log scale, 95% confidence interval: 0.77-1.34 ln (ng/mL)., Conclusion: Contrary to the findings from the preclinical studies, which demonstrated an important role of HSP-60 in the pathogenesis of AF, we did not observe a significant association between HSP-60 and occurrence of AF., (© 2016 Wiley Periodicals, Inc.)

Background: N-terminal-pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (TnT) predict cardiovascular disease (CVD) risk in a variety of populations. Whether their predictive value varies by ethnicity is unknown. We sought to determine whether NT-proBNP and TnT improve prediction of incident coronary heart disease (CHD) and CVD, independent of CVD risk factors, in a multiethnic population; whether NT-proBNP improves prediction compared with the Framingham Risk Score or the Pooled Cohort Risk Equation; and whether a second NT-proBNP further improves prediction., Methods: Both NT-proBNP and TnT were measured in 5,592 MESA white, black, Hispanic, and Chinese participants (60% nonwhite; mean age 62.3 ± 10.3 years) in 2000 to 2002 and 2004 to 2005. We evaluated adjusted risk of incident CHD and CVD based on baseline and change in biomarker concentration., Results: Participants were followed up through 2011 and incurred 370 CVD events (232 CHD). Concentrations of NT-proBNP and TnT varied by ethnicity. Both NT-proBNP and TnT were associated with an increased risk of events (adjusted hazard ratio [HR] for CHD [95% CI] for fifth quintile vs other 4 quintiles of NT-proBNP, 2.03 [1.50-2.76]; HR for CHD for detectable vs undetectable TnT, 3.95 [2.29-6.81]). N-terminal-pro-B-type natriuretic peptide improved risk prediction and classification compared with the Framingham Risk Score and the Pooled Cohort Risk Equation. Change in NT-proBNP was independently associated with events (HR for CHD per unit increase in ΔlogNT-proBNP, 1.95 [1.16-3.26]). None of the observed associations varied by ethnicity., Conclusions: Both NT-proBNP and TnT are predictors of incident CHD, independent of established risk factors and ethnicity, in a multiethnic population without known CVD. Change in NT-proBNP may add additional prognostic information., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: There is controversy regarding whether to report concentrations of high-sensitivity cardiac troponin T (hs-cTnT) to the limit of blank (LOB) (3 ng/L) or the limit of detection (LOD) (5 ng/L) of the assay in community-based cohorts. We hypothesized that hs-cTnT concentrations between the LOB and LOD would be associated with poorer cardiovascular outcomes compared to concentrations below the LOB., Methods: hs-cTnT was analyzed in a total of 10 723 participants from the Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, and Dallas Heart Study (DHS). Participants were divided into 2 groups, those with hs-cTnT concentrations below the limit of blank (LOB) (<3 ng/L) and those with hs-cTnT between the LOB and limit of detection (LOD) (3-4.99 ng/L). Cross-sectional associations with traditional cardiovascular risk factors and cardiac structural measurements, and longitudinal associations with long-term cardiovascular outcomes of incident heart failure and cardiovascular death, were determined., Results: Participants with hs-cTnT between the LOB and LOD for all 3 cohorts were older, more likely to be male, and have a higher burden of cardiovascular risk factors and structural pathology. A metaanalysis of the 3 cohorts showed participants with hs-cTnT between the LOB and LOD were at increased risk of new-onset heart failure (hazard ratio, 1.18; 95% CI, 1.02-1.38) and cardiovascular mortality (hazard ratio, 1.29; 95% CI, 1.06-1.57)., Conclusions: hs-cTnT concentrations between the LOB and LOD (3-4.99 ng/L) are associated with a higher prevalence of traditional risk factors, more cardiac pathology, and worse outcomes than concentrations below the LOB (<3 ng/L)., (© 2015 American Association for Clinical Chemistry.)

Background: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels., Methods and Results: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004)., Conclusions: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.

IntroductionCoronary artery calcium (CAC) scans contain useful information beyond the Agatston CAC score that is not currently reported. We recently reported that artificial intelligence (AI)-enabled cardiac chambers volumetry in CAC scans (AI-CAC™) predicted incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we investigated the performance of AI-CAC cardiac chambers for prediction of incident heart failure (HF).MethodsWe applied AI-CAC to 5750 CAC scans of asymptomatic individuals (52% female, White 40%, Black 26%, Hispanic 22% Chinese 12%) free of known cardiovascular disease at the MESA baseline examination (2000-2002). We used the 15-year outcomes data and compared the time-dependent area under the curve (AUC) of AI-CAC volumetry versus NT-proBNP, Agatston score, and 9 known clinical risk factors (age, gender, diabetes, current smoking, hypertension medication, systolic and diastolic blood pressure, LDL, HDL for predicting incident HF over 15 years.ResultsOver 15 years of follow-up, 256 HF events accrued. The time-dependent AUC [95% CI] at 15 years for predicting HF with AI-CAC all chambers volumetry (0.86 [0.82,0.91]) was significantly higher than NT-proBNP (0.74 [0.69, 0.77]) and Agatston score (0.71 [0.68, 0.78]) (p ​

IntroductionWe investigated the associations of high-sensitivity cardiac Troponin T (hs-cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels with risk of developing clinical peripheral artery disease (PAD) or a low ankle-brachial index (ABI).MethodsHs-cTnT and NT-proBNP were measured in 6692 and 5458 participants respectively without baseline PAD between 2000 and 2002 in the Multi-ethnic Study of Atherosclerosis. A significant number also had repeat biomarker measurement between 2004 and 2005. Incident clinical PAD was ascertained through 2017. Incident low ABI, defined as ABI 0.9 at baseline and at least one follow-up ABI measurement 3-10 years later. Multivariable Cox proportional hazards and logistic regression modeling were used to determine the association of these biomarkers with clinical PAD and low ABI, respectively.ResultsOverall, 121 clinical PAD and 118 low ABI events occurred. Adjusting for demographic and clinical characteristics, each log unit increment in hs-cTnT and NT-proBNP was associated with a 30% (adjusted hazard ratio (HR) 1.3, 95% confidence interval (CI): 1.1, 1.6) and 50% (HR) 1.5, 95% CI: 1.2, 1.8) higher risk of clinical PAD respectively. No significant associations were observed for incident low ABI. Change in these biomarkers was not associated with either of the PAD outcomes.ConclusionsNT-proBNP and hs-cTnT are independently associated with the development of clinical PAD. Further study should determine whether these biomarkers can help to better identify those at higher risk for PAD.

AimsThe association of subclinical atherosclerotic disease in the coronary arteries and thoracic aorta with incident peripheral arterial disease (PAD) is unknown. We investigated the association between coronary artery calcium score (CACs) and thoracic aortic calcium score (TACs) with incident clinical and subclinical PAD.Methods and resultsThe Multi-Ethnic Study of Atherosclerosis (MESA) recruited 6814 men and women aged 45-84 from four ethnic groups who were free of clinical cardiovascular disease at enrolment. Coronary artery calcium score and thoracic aortic calcium score were measured from computed tomography scans. Participants with a baseline ankle-brachial index (ABI) ≤0.90 or >1.4 were excluded. Abnormal ABI was defined as ABI ≤0.9 or >1.4 at follow-up exam. Multivariable logistic regression and Cox proportional hazards models were used to test the associations between baseline CACs and TACs with incident abnormal ABI and clinical PAD, respectively. A total of 6409 participants (female: 52.8%) with a mean age of 61 years were analysed. Over a median follow-up of 16.7 years, 91 participants developed clinical PAD. In multivariable analysis, each unit increase in log (CACS + 1) and log (TACs + 1) were associated with 23% and 13% (P < 0.01for both) higher risk of incident clinical PAD, respectively. In 5725 (female: 52.6%) participants with an available follow-up ABI over median 9.2 years, each 1-unit increase in log (CACs + 1) and log (TACs + 1) were independently associated with 1.15-fold and 1.07-fold (P < 0.01for both) higher odds of incident abnormal ABI, respectively.ConclusionHigher baseline CACs and TACs predict abnormal ABI and clinical PAD independent of traditional cardiovascular risk factors and baseline ABI.

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

BackgroundCurrent strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD.MethodsWe included participants from MESA (Multi-Ethnic Study of Atherosclerosis) (n=6621) and the Dallas Heart Study (n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein. Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction, stroke, coronary or peripheral revascularization, incident heart failure, or atrial fibrillation) and ASCVD (fatal or nonfatal myocardial infarction or stroke) were assessed over >10 years of follow-up. Multivariable analyses for the primary global CVD end point adjusted for traditional risk factors plus statin use and creatinine (base model).ResultsEach test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results (P

ObjectivesChest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR-proADM) in prediction of mortality and major adverse cardiac events (MACE).MethodsThis was a subanalysis of the CHOPIN study, a 16-center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6-month all-cause mortality and the secondary endpoint was 30-day and 6-month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure.ResultsMR-proADM performed similarly to troponin (cTnI; c-statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR-proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6-month mortality risk versus 0.9% risk for those in the bottom nine deciles (p

Background: Cyclic GMP (cGMP) is a second messenger that inhibits maladaptive cardiac remodeling. The cGMP pathway is of interest as a therapeutic target in heart failure with preserved ejection fraction (HFpEF), but it has not been previously studied on a population level. Animal/ in vitro studies show that cGMP is activated by either a nitric oxide (NO) or natriuretic peptide (NP) modulated mechanism. Estrogen stimulates the NO pathway, which may contribute to sex differences in HFpEF. Blood pressure (BP) is associated with NT-proBNP and is a major risk factor for HFpEF. We hypothesized that cGMP is associated with sex hormones (SH), N-terminal pro-B type NP (NT-proBNP) and BP in a community cohort free of HF. Methods: We studied 549 men and 503 postmenopausal women in MESA with cGMP, NT-proBNP, SHs (total testosterone [T], free T, dehydroepiandroesterone [DHEA], estradiol and SH binding globulin [SHBG]), and BP measured at baseline. Multivariable adjusted linear regression models were used to analyze cross-sectional associations with log(cGMP), and coefficients were then exponentiated. Results: Mean (SD) cGMP was 4.8 (2.6) pmol/L, with no difference between the sexes. Among women, after adjusting for demographics and HFpEF risk factors, SHBG was positively associated with cGMP, while free T and DHEA were inversely associated with cGMP (Table). In men, the same associations were present only in the unadjusted model. In both sexes, higher NT-proBNP and systolic BP (SBP) were correlated with higher cGMP levels. Conclusion: We found that a more androgenic SH profile in women was associated with lower cGMP levels, which may be one mechanism leading to the female predominance of HFpEF after menopause. NT-proBNP and SBP were positively associated with cGMP, confirming the NP-cGMP pathway established in preclinical studies. These novel associations, not previously studied in a community cohort, may serve as a basis for future population-based studies on the cGMP pathway. [ABSTRACT FROM AUTHOR]

Background: High-sensitive cardiac Troponin T (hs-cTnT), a biomarker for myocyte injury, is an independent predictor for incident heart failure (HF) and cardiovascular disease (CVD) events. We sought to determine the prognostic role of hs-cTnT in predicting incident HF and CVD events in a population absent of clinical CVD stratified according to having no diabetes, pre-diabetes, and diabetes. Methods and Results: We studied participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who had recorded fasting blood glucose data at baseline along with plasma hs-cTnT. We determined incident HF rates per 1000 person-years according to hs-cTnT quartiles in participants with diabetes, pre-diabetes, or neither condition. We utilized Cox regression to assess the hazard ratio (HR) and corresponding 95% confidence intervals (CIs) for incident HF by quartile of hs-cTnT (lowest quartile as reference) within each glucose group and adjusted for age, sex, and other risk factors. Mean follow-up time was 12.4 ± 3.8 years. The figure shows higher quartiles of hs-cTnT to be associated with higher rates of HF, within each glucose group, with the highest rates seen in those with diabetes in the highest quartile of hs-cTnT. The highest quartile of relative to lowest quartile of hs-cTnT in participants with diabetes, pre-diabetes, or neither condition was associated with adjusted HR's (95% CI's) of 28.6 (3.8 - 214.3), 1.5 (0.5 - 4.8), and 7.2 (3.4 - 15.3), respectively (all p<0.01 except pre-diabetes, p=0.45). The addition of hs-cTnT to risk factors increased C statistics from 0.63 (0.56 - 0.69) to 0.74 (0.69 - 0.79) in those with diabetes. Similar associations also existed for the prediction of total CVD events. Conclusion: Hs-cTnT plays a role in providing prognostic information with respect to incident HF and CVD in those with and without diabetes. The greatest risk lies in patients with diabetes and the highest hs-cTnT quartile. [ABSTRACT FROM AUTHOR]

Background: NT-proBNP and glucose status are both independent risk predictors for incident heart failure (HF) and cardiovascular disease (CVD) events. We sought to determine the prognostic role of NT-proBNP in predicting incident HF and CVD events in a population absent of clinical CVD stratified according to having no diabetes, pre-diabetes, and diabetes. Methods and Results: We studied participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who had recorded fasting blood glucose data at baseline along with plasma NT-proBNP. We determined incident HF rates per 1000 person-years according to NT-proBNP quartiles in participants with diabetes, pre-diabetes, or neither condition. We utilized Cox regression to assess the hazard ratio (HR) and corresponding 95% confidence intervals (CIs) for incident HF by quartile of NT-proBNP (lowest quartile as reference) within each glucose group and adjusted for age, sex, and other risk factors. Mean follow-up time was 12.4 ± 3.8 years. The figure shows higher quartiles of NT-proBNP to be associated with higher rates of HF, within each glucose group, with the highest rates seen in those with diabetes in the highest quartile of NT-proBNP. The highest quartile relatively to lowest quartile of NT-proBNP in participants with diabetes, pre-diabetes, or neither condition was associated with adjusted HR's (95% CI's) of 7.9 (3.4 - 18.3), 8.7 (1.8 - 40.8), and 10.8 (4.5 - 26.0), respectively (all p<0.01). The addition of NT-proBNP to other risk factors increased C statistics (95% CI's) from 0.63 (0.56 - 0.69) to 0.74 (0.68 - 0.80) in those with diabetes. Similar associations also existed for the prediction of total CVD events. Conclusion: Small elevations in NT-proBNP levels within a range currently regarded as normal is associated with increased risk of incident HF and CVD events in patients within glucose status groups. The greatest risk lies in patients with diabetes and the highest NT-proBNP quartile. [ABSTRACT FROM AUTHOR]

Introduction: High-sensitivity cardiac troponin T (hs-cTnT) plasma levels are associated with cardiac injury and incident heart failure. The mechanisms for biomarker release leading to cardiac injury are unclear, and the sole previous genome-wide association study (GWAS; Yu, 2013) suggested genetic variants near NCOA2 and TNNT2 are associated with hs-cTnT. Hypothesis: The Multi-Ethnic Study of Atherosclerosis (MESA), by incorporating multi-omics data, will validate previous findings, refine loci mapping, provide mechanistic insights, and identify novel loci of cardiac injury. Methods: Baseline plasma hs-cTnT levels were measured in 6,131 MESA participants free of clinical cardiovascular disease (mean age 62.2±10.2 yrs; 47.6% men, 39% White, 26% African-American, 23% Hispanic, 12% Chinese). We conducted a GWAS of the log hs-cTnT level (>11M post-QC single nucleotide polymorphisms (SNPs)) and specific candidate SNPs for hs-cTnT dichotomized at the upper percentile of risk. We meta-analyzed the four ethnic groups under fixed effects and ancestry-adjusted meta-regression models. Results: We validated the NCOA2 locus with a different index SNP (rs10091864) 44kb upstream of NCOA2 (p=3x10-9), consistent in all ethnic groups. In Genotype-Tissue Expression analysis, rs10091864 is an expression quantitative trait locus (eQTL) for XKR9 and is co-localized with eQTLs for an intergenic non-coding RNA (LOC101926892). We identified a novel association with a missense coding SNP (rs79412473) in TBCK (imputed well only in whites, p=4x10-8). A gene with strong physiological impact and gene expression evidence (BCL2) had an associated intronic SNP (rs899967) that was consistent in effect, directionally and size, with the Yu report, but did not reach GWAS significance (joint p=1.5x10-7). The dichotomous trait (TNNT2) association was replicated only in African-Americans (p=0.03). Conclusions: In summary, we have evidence for additional novel genetic loci associated with cardiac injury as measured by hs-cTnT and replicated the NCOA2 association in MESA. Use of these genetic findings may provide better mechanistic insights into the pathophysiology of cardiac injury and incident heart failure. [ABSTRACT FROM AUTHOR]