Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial

Yu, Yu Ling; Siwy, Justyna; An, De Wei; González, Arantxa; Hansen, Tine W.; 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 S; Janssens, Stefan; Cleland, John G.F.; Zannad, Faiez; Diez, Javier; Mischak, Harald; Ferreira, João Pedro; Staessen, Jan A.; Khan, Javed; Cosmi, Franco; Pizard, Anne; Bozec, Erwan; Moreno, María U.; Brunner La Rocca, Hans P.; Hazebroek, Mark; Edelmann, Frank; Pieske, Burkert; Mamas, Mamas A.; McDonald, Ken; Rouet, Philippe; Thijs, L.; Asayama, Kei; Maestre, Gladys E.; López, Begoñia; Latini, Roberto; Grojean, Stephanie; Collier, Tim

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) µg/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.

Citation

Yu, Y. L., Siwy, J., An, D. W., González, A., Hansen, T. W., Latosinska, A., Pellicori, P., Ravassa, S., Mariottoni, B., Verdonschot, J. A., Ahmed, F., Petutschnigg, J., Rossignol, P., Heymans, S., Cuthbert, J. J., Girerd, N., Clark, A. L., Verhamme, P., Nawrot, T. S., Janssens, S., …Collier, T. (in press). Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial. Heart, https://doi.org/10.1136/heartjnl-2023-323796

• Journal Article Type: Article
• Acceptance Date: Apr 28, 2024
• Online Publication Date: May 9, 2024
• Deposit Date: May 22, 2024
• Publicly Available Date: May 23, 2024
• Journal: Heart
• Print ISSN: 1355-6037
• Electronic ISSN: 1468-201X
• Publisher: BMJ Publishing Group
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1136/heartjnl-2023-323796
• Public URL: https://hull-repository.worktribe.com/output/4672280