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

Ravassa, Susana; López, Begoña; Ferreira, João Pedro; Girerd, Nicolas; Bozec, Erwan; Pellicori, Pierpaolo; Mariottoni, Beatrice; Cosmi, Franco; Hazebroek, Mark; Verdonschot, Job A.J.; Cuthbert, Joe; Petutschnigg, Johannes; Moreno, María U.; Heymans, Stephane; Staessen, Jan A.; Pieske, Burkert; Edelmann, Frank; Clark, Andrew L.; Cleland, John G.F.; Zannad, Faiez; Díez, Javier; González, Arantxa; HOMAGE Trial Committees and Investigators

Abstract

Aims
The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) 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 ratio (CITP:MMP-1), 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 (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% confidence interval, CI −2.94 to −0.59) and −2.52 (95% CI −4.46 to −0.58) mL/m2; interaction pacross-tertiles = 0.005; interaction pthird tertile = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide 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 pthird tertile < 0.001].
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).

Citation

Ravassa, S., López, B., Ferreira, J. P., Girerd, N., Bozec, E., Pellicori, P., Mariottoni, B., Cosmi, F., Hazebroek, M., Verdonschot, J. A., Cuthbert, J., Petutschnigg, J., Moreno, M. U., Heymans, S., Staessen, J. A., Pieske, B., Edelmann, F., Clark, A. L., Cleland, J. G., Zannad, F., …HOMAGE Trial Committees and Investigators. (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. European journal of heart failure, 24(2), 321-331. https://doi.org/10.1002/ejhf.2394

• Journal Article Type: Article
• Acceptance Date: Nov 22, 2021
• Online Publication Date: Nov 28, 2021
• Publication Date: Feb 1, 2022
• Deposit Date: Oct 24, 2024
• Publicly Available Date: Oct 24, 2024
• Journal: European Journal of Heart Failure
• Print ISSN: 1388-9842
• Electronic ISSN: 1879-0844
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 2
• Pages: 321-331
• DOI: https://doi.org/10.1002/ejhf.2394
• Keywords: Heart failure; Spironolactone; Atrial remodelling; Collagen cross-linking
• Public URL: https://hull-repository.worktribe.com/output/3894203