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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.
Trial registration number NCT02556450.
- heart failure
- biomarkers
- epidemiology
- pharmacology, clinical
Data availability statement
Data are available on reasonable request. Anonymised participants data can be made available on request directed to the corresponding author. Proposals will be reviewed with scientific merit. After approval of a request, data can be shared via a secure online platform after signing a data access and confidentiality agreement. Data will be made available for a maximum of 2 years after a data sharing agreement has been signed.
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Data availability statement
Data are available on reasonable request. Anonymised participants data can be made available on request directed to the corresponding author. Proposals will be reviewed with scientific merit. After approval of a request, data can be shared via a secure online platform after signing a data access and confidentiality agreement. Data will be made available for a maximum of 2 years after a data sharing agreement has been signed.
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JPF and JAS contributed equally.
Collaborators The HOMAGE investigators are listed in the online supplemental file (pp 2).
Contributors JGC, JD, JPF and JAS are the lead investigators who conceived the research idea and methodology. They are the guarantors for the overall content. Funding acquisition was done by FZ and JAS. NG and JPF supervised data acquisition. YY, D-WA and JAS performed the analyses and wrote the first draft of the manuscript. YY was supervised by PV and TSN. JS, AL and HM did the UPP analyses. AG, SR and JD supervised the measurements of the serum fibrosis markers. All coauthors critically revised the successive drafts of the manuscript and approved the final version.
Funding HOMAGE was funded by the European Union Seventh Framework Programme. OMRON Healthcare, Kyoto, Japan provided a non-binding grant to the Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium.
Competing interests JS and AL are employees of Mosaiques-Diagnostics, Hanover, Germany. HM is the co-founder and co-owner of Mosaiques-Diagnostics. The other authors declare no conflict of interest.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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