Pierpaolo Pellicori, Blerim Mujaj, Stephane Heymans, Fozia Z Ahmed, N. Girerd, Ping Wang, Arantxa González, Hans-Peter Brunner-La-Rocca, Javier Díez, Franco Cosmi, Frank T. Edelmann, Mark R. Hazebroek, João Pedro Ferreira, Joe Cuthbert, Andrew L. Clark, Johannes Petutschnigg, Mamas A. Mamas, Roberto Latini, Job A J Verdonschot, John G.F. Cleland, Beatrice Mariottoni, Patrick Rossignol, Javed Khan, Jan A. Staessen, Burkert Pieske, Faiez Zannad, Anne Pizard, Stéphanie Grojean, Timothy Collier, Philippe Rouet, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], London School of Hygiene and Tropical Medicine (LSHTM), University of Manchester [Manchester], University of Hull [United Kingdom], Cortona Hospital, Universidad de Navarra [Pamplona] (UNAV), German Heart Institute Berlin, University of Glasgow, Mario Negri Institute, Center for Human Genetics, University of Leuven School of Medicine, SCHOOL of MEDICINE [Louvain], Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre d'anthropologie et de génomique de Toulouse (CAGT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), 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., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), DE CARVALHO, Philippe, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Heart OMics in AGEing - HOMAGE - - EC:FP7:HEALTH2013-02-01 - 2019-01-31 - 305507 - VALID, RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), and MUMC+: MA Med Staf Artsass Cardiologie (9)
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 knowledgebased 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) (C) 2021 by the American College of Cardiology Foundation.