Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/43697
Title: Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial
Authors: Yu, Yu-Ling
Siwy, Justyna
An , De-Wei
Gonzalez, Arantxa
Hansen, Tine
Latosinska, Agnieszka
Pellicori, Pierpaolo
Ravassa, Susana
Mariottoni, Beatrice
Verdonschot, Job A. J.
Ahmed, Fozia
Petutschnigg, Johannes
Rossignol, Patrick
Heymans, Stephane
Cuthbert, Joe J.
Girerd, Nicolas
Clark, Andrew L.
Verhamme, Peter
NAWROT, Tim 
Janssens , Stefan
Cleland, John G.
Zannad, Faiez
Diez, Javier
Mischak, Harald
Ferreira, Joao Pedro
Staessen, Jan A.
Issue Date: 2024
Publisher: BMJ PUBLISHING GROUP
Source: Heart (london. 1996),
Status: Early view
Abstract: Objective Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone.Methods In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in >= 30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform.Results Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) mu g/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio.Conclusions Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs.Trial registration number NCT02556450.
Notes: Staessen, JA (corresponding author), Res Inst Alliance Promot Prevent Med, BE-2800 Mechelen, Belgium.
yyl0603@sina.cn; siwy@mosaiques-diagnostics.com; dewei.an@appremed.org;
amiqueo@unav.es; tine.willum.hansen@regionh.dk;
latosinska@mosaiques-diagnostics.com; pierpaolo.pellicori@glasgow.ac.uk;
sravassa@unav.es; beatrice.m91@virgilio.it; job.verdonschot@mumc.nl;
Fozia.Ahmed@mft.nhs.uk; johannes.petutschnigg@charite.de;
p.rossignol@chru-nancy.fr; s.heymans@cardio.unimaas.nl;
Joe.Cuthbert@hey.nhs.uk; n.girerd@chru-nancy.fr; a.l.clark@hull.ac.uk;
peter.verhamme@uzleuven.be; tim.nawrot@uhasselt.be;
stefan.janssens@uzleuven.be; john.cleland@glasgow.ac.uk;
f.zannad@chru-nancy.fr; jadimar@unav.es; mischak@mosaiques.de;
jp7ferreira@hotmail.com; jan.staessen@appremed.org
Keywords: heart failure;biomarkers;epidemiology;pharmacology;clinical
Document URI: http://hdl.handle.net/1942/43697
ISSN: 1355-6037
e-ISSN: 1468-201X
DOI: 10.1136/heartjnl-2023-323796
ISI #: 001289284500001
Rights: Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Category: A1
Type: Journal Contribution
Appears in Collections:Research publications

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