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Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF

João Pedro Ferreira 1, 2, 3, 4 Job Verdonschot 5 Ping Wang 5 Anne Pizard 1, 3, 4 Timothy Collier 6 Fozia Ahmed 7 Hans-Peter Brunner-La-Rocca 5 Andrew Clark 8 Franco Cosmi 9 Joe Cuthbert 8 Javier Díez 10 Frank Edelmann 11 Nicolas Girerd 1, 2, 3, 4 Arantxa González 10 Stéphanie Grojean 1, 3, 4 Mark Hazebroek 5 Javed Khan 12 Roberto Latini 13 Mamas Mamas 7 Beatrice Mariottoni 9 Blerim Mujaj 14 Pierpaolo Pellicori 12 Johannes Petutschnigg 11 Burkert Pieske 11 Patrick Rossignol 1, 2, 3, 4 Philippe Rouet 15 Jan Staessen 14 John G.F. Cleland 12 Stephane Heymans 5 Faiez Zannad 1, 2, 3, 4
Abstract : 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 (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).
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Submitted on : Thursday, March 18, 2021 - 3:51:34 PM
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João Pedro Ferreira, Job Verdonschot, Ping Wang, Anne Pizard, Timothy Collier, et al.. Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF. JACC: Heart Failure, Elsevier/American College of Cardiology, 2021, S2213-1779 (20), pp.30705-8. ⟨10.1016/j.jchf.2020.11.010⟩. ⟨hal-03166526⟩



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