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

Autor:	Yu YL; Research Unit Environment and Health, KU Leuven Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium.; Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium., Siwy J; Mosaiques-Diagnostics GmbH, Hannover, Germany., An DW; Research Unit Environment and Health, KU Leuven Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium.; Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium.; Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China., González A; Program of Cardiovascular Diseases, CIMA, Universidad de Navarra and IdiSNA, Pamplona, Spain CIBERCV, Carlos III Institute of Health, Madrid, Spain., Hansen T; Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium.; Steno Diabetes Center Copenhagen, the Capital Region of Denmark, Gentofte, Denmark., Latosinska A; Mosaiques-Diagnostics GmbH, Hannover, Germany., Pellicori P; Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France., Ravassa S; Program of Cardiovascular Diseases, CIMA, Universidad de Navarra and IdiSNA, Pamplona, Spain CIBERCV, Carlos III Institute of Health, Madrid, Spain., Mariottoni B; Department of Cardiology, Cortona Hospital, Arezzo, Italy., Verdonschot JA; Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands., Ahmed F; Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK., Petutschnigg J; Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité University Medicine Berlin, Berlin Institute of Health and German Center for Cardiovascular Research, Partner Site Berlin, Germany., Rossignol P; Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France., Heymans S; Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands., Cuthbert JJ; Department of Cardiology, University of Hull, Castle Hill Hospital, Cottingham, East Riding of Yorkshire, UK., Girerd N; Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France., Clark AL; Department of Cardiology, University of Hull, Castle Hill Hospital, Cottingham, East Riding of Yorkshire, UK., Verhamme P; Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium., Nawrot TS; Research Unit Environment and Health, KU Leuven Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium.; Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium., Janssens S; Research Unit Cardiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium., Cleland JG; British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK., Zannad F; Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France., Diez J; Program of Cardiovascular Diseases, CIMA, Universidad de Navarra and IdiSNA, Pamplona, Spain CIBERCV, Carlos III Institute of Health, Madrid, Spain., Mischak H; Mosaiques-Diagnostics GmbH, Hannover, Germany., Ferreira JP; Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France.; Cardiovascular R&D Centre UniC@rRISE, Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto Portugal, Porto, Portugal.; Portugal % Heart Failure Clinics, Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia/Espinho, Portugal., Staessen JA; Non-Profit Research Association Alliance for the Promotion of Preventive Medicine (APPREMED), Mechelen, Belgium jan.staessen@appremed.org.; Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.; Biomedical Science Group, University of Leuven, Leuven, Belgium.
Jazyk:	angličtina
Zdroj:	Heart (British Cardiac Society) [Heart] 2024 Sep 16; Vol. 110 (19), pp. 1180-1187. Date of Electronic Publication: 2024 Sep 16.
DOI:	10.1136/heartjnl-2023-323796
Abstrakt:	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. Competing Interests: 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. (© 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.)
Databáze:	MEDLINE
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