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Background: The recent heart failure (HF) guideline recommends the inclusion of cardiac biomarkers in defining Stage B HF., Objectives: The authors evaluated the impact of incorporating cardiac biomarkers to reclassify HF in 5,324 participants (mean age: 75.8 years) without prevalent HF enrolled in the ARIC (Atherosclerosis Risk In Communities) study and assessed prognosis of Stage B using cardiac biomarkers., Methods: Using N-terminal pro-B-type natriuretic peptide (<125 pg/mL or ≥125 pg/mL), high-sensitivity troponin T (<14 ng/L or ≥14 ng/L), and abnormal cardiac structure/function by echocardiography, individuals were classified as Stage A new and Stage B new HF, respectively. Stage B new was further evaluated as elevated biomarker only, abnormal echocardiogram only, and abnormalities in both (echo + biomarker). The authors assessed risk for incident HF and all-cause death using Cox regression., Results: Overall, 4,326 (81.3%) individuals were classified as Stage B new with 1,123 (21.1%) meeting criteria for elevated biomarkers only. Compared with Stage A new , Stage B new was associated with increased risk for incident HF (HR: 3.70 [95% CI: 2.58-5.30]) and death (HR: 1.94 [95% CI: 1.53-2.46]). Stage B biomarkers only and Stage B echo only were associated with increased HF risk, whereas Stage B biomarkers only was also associated with increased death. Stage B echo+biomarker had the highest risk for HF (HR: 6.34 [95% CI: 4.37-9.19]) and death (HR: 2.53 [95% CI: 1.98-3.23])., Conclusions: Incorporating biomarkers based on the new HF guideline reclassified approximately 1 in 5 older adults without prevalent HF to Stage B. The routine measurement of biomarkers can help to identify individuals at higher HF risk who may benefit most from HF prevention efforts., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract numbers (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). Dr Bozkurt has received consulting fees from Bristol Myers Squibb, scPharmaceuticals, Baxter Healthcare Corporation, Sanofi-Aventis, Relypsa, Amgen; serves on the Clinical Event Committee for GUIDE HF Trial sponsored by Abbott Vascular, and Data Safety Monitoring Committee of ANTHEM trial (Autonomic REGULATION Therapy to Enhance Myocardial Function and Reduce progression of Heart Failure with reduced ejection fraction) sponsored by Liva Nova. Dr Ballantyne has received research support from National Institutes of Health grant R01HL134320 (relevant to study), Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Novartis, Regeneron, Roche Diagnostic, National Institutes of Health, AHA, and ADA; is a consultant for Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Matinas BioPharma Inc, Merck–New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo. Dr Hoogeveen has received research grants from Denka Seiken and serves as a consultant to Denka Seiken. Dr de Lemos has received grant support from Abbott Diagnostics and Roche Diagnostics; and consulting income from Siemen’s Health Care Diagnostics, Quidel, Beckman Coulter, and Ortho Clinical Diagnostics; and is the co-inventor on a patent awarded to University of Maryland using high sensitivity cardiac troponin T and left ventricular hypertrophy as markers of heart failure risk (patent number: 61990386). Dr Nambi has stock ownership in Abbott labs. Dr Shah has received research support from Novartis and Philips Ultrasound; and consulting fees from Philips Ultrasound and Janssen. Dr Selvin has received research funding support from the National Institutes of Health grant R01HL134320 (relevant to study). Dr Virani has received grant support from the U.S. Department of Veterans Affairs, National Institutes of Health, Tahir, and the Jooma Family; and has received honorarium from the American College of Cardiology (Associate Editor for Innovations, acc.org). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Objectives: This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways., Background: In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF., Methods: Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis., Results: A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B)., Conclusions: Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450)., Competing Interests: FUNDING SUPPORT AND AUTHOR DISCLOSURES HOMAGE was funded by a grant from the European Union 7th Framework Programme for Research and Technological Development (HEALTH-F7-305507 HOMAGE (EU FP7 305507 http://www.homage-hf.eu). Drs. Ferreira, Rossignol, Girerd, and Zannad are supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program (reference: ANR-15-RHUS-0004); the French PIA project “Lorraine Université d’Excellence” (reference: ANR-15-IDEX-04-LUE); Contrat de Plan Etat Lorraine IT2MP; and FEDER Lorraine. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) continues to grow as a cause of morbidity and mortality in our community and presents a significant public health problem, predominantly in individuals ≥65 years of age. Early intervention in asymptomatic HF subjects (Stage A/B) at risk of progression to symptomatic HF (Stage C/D) may provide an opportunity to halt this epidemic. The ability of cardiac imaging to assess cardiac structure and function permits early identification of those at increased risk of developing symptomatic HF. Systolic, diastolic, and structural left ventricular parameters each predict symptomatic HF, but no single parameter has sufficient sensitivity for screening to identify individuals with Stage A/B HF who are at increased risk of disease progression. Transthoracic echocardiography (TTE) has the advantage over other imaging modalities in being able to measure systolic, diastolic, and structural left ventricular parameters, and it identified at least 1 abnormal parameter in >50% of individuals with Stage A/B HF ≥65 years of age. Moreover, identification of at least 1 abnormality according to TTE in individuals with Stage A/B HF ≥65 years of age had 72% to 82% sensitivity for detection of those who subsequently developed symptomatic HF. Therefore, a case can be made for cardiac imaging by using TTE for community-dwelling populations with Stage A/B HF ≥65 years of age to identify those with increased risk of symptomatic HF who can be offered preventative therapies. Further studies are required to determine the best strategy for identifying the risk of symptomatic HF in younger individuals., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)