Biomarker-based assessment of collagen cross-linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the HOMAGE clinical trial

Ravassa, S. et al. (2022) Biomarker-based assessment of collagen cross-linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the HOMAGE clinical trial. European Journal of Heart Failure, 24(2), pp. 321-331. (doi: 10.1002/ejhf.2394) (PMID:34841615)

Abstract

Aims: The HOMAGE randomised trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (PICP) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 (CITP:MMP-1) ratio, associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial. Methods and Results: Patients at risk of HF were randomized to spironolactone (n=260) or not (n=255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 ratio (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (P=0.003) and nine (P=0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) (mean-differencesspiro/control: -1.77 [95%CI:-2.94 to -0.59] and -2.52 [95%CI:-4.46 to -0.58] mL/m2; interaction-Pacross-tertiles=0.005; interaction-P3rd tertile=0.008) with a similar trend for NT-proBNP which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile (mean-differencesspiro/control:-0.47[95%CI:-0.66 to -0.28] and -0.31[95% CI:-0.59 to -0.04] ng/L; interaction-Pacross-tertiles=0.09; interaction-P3rd tertile<0.0001). Conclusions: These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).

• Item Type: Articles
• Additional Information: Funding: This work was supported by the European Commission HOMAGE project (grant 305507); JD and AG are supported by the Ministry of Science and Innovation, Spain (Instituto de Salud Carlos III: CB16/11/00483 and PI18/01469 co-financed by FEDER funds). MH is supported by a Kootstra Talented Post-doc Fellowship (Netherlands). JGFC and PP are supported by the British Heart Foundation Centre of Research Excellence (grant number RE/18/6/34217). PPREMED (URL: http://www.appremed.orf) received a non-binding grant from Omron Healthcare Co., Ltd., Kyoto, Japan.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cleland, Professor John and Pellicori, Dr Pierpaolo
• Authors: Ravassa, S., López, B., Ferreira, J. P., Girerd, N., Bozec, E., Pellicori, P., Mariottoni, B., Cosmi, F., Hazebroek, M., Verdonschot, J. A.J., Cuthbert, J., Petutschnigg, J., Moreno, M. U., Heymans, S., Staessen, J. A., Pieske, B., Edelmann, F., Clark, A. L., Cleland, J. G.F., Zannad, F., Díez, J., and González, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: European Journal of Heart Failure
• Publisher: Wiley
• ISSN: 1388-9842
• ISSN (Online): 1879-0844
• Published Online: 28 November 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in European Journal of Heart Failure 24(2): 321-331
• Publisher Policy: Reproduced under a Creative Commons Licence

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
303944		BHF Centre of Excellence	Rhian Touyz	British Heart Foundation (BHF)	RE/18/6/34217	CAMS - Cardiovascular Science