Ferreira, JP, Verdonschot, J, Wang, P, Pizard, A, Collier, T, Ahmed, FZ, Brunner-La-Rocca, H-P, Clark, AL, Cosmi, F, Cuthbert, J, Díez, J, Edelmann, F, Girerd, N, González, A, Grojean, S, Hazebroek, M, Khan, J, Latini, R, Mamas, MA, Mariottoni, B, Mujaj, B, Pellicori, P, Petutschnigg, J, Pieske, B, Rossignol, P, Rouet, P, Staessen, JA, Cleland, JGF, Heymans, S, Zannad, F and Consortium, HOMAGE (Heart Omics in AGEing) (2021) Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF. JACC: Heart Failure, 9 (4). 268 - 277. ISSN 2213-1779

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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).

Item Type: Article
Additional Information: © 2021 by the American College of Cardiology Foundation. Published by Elsevier. The published version of this article is now freely available under Open Archive
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > School of Medicine
Related URLs:
Depositing User: Symplectic
Date Deposited: 09 May 2023 08:46
Last Modified: 09 May 2023 08:46
URI: https://eprints.keele.ac.uk/id/eprint/12496

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