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Spironolactone and Fibrosis in Heart Failure Risk: Machine Learning Analysis of HOMAGE Trial Plasma Proteomics

Susana Ravassa1,2, Nicolas Girerd3, Frank Edelman4,5

  • 1Laboratory of Heart Failure CIMA Universidad de Navarra and IdiSNA Pamplona Spain.

Medcomm
|February 20, 2026
PubMed

Insights

Spironolactone reduces fibrosis biomarker PICP in heart failure patients. Mechanistic studies suggest it impacts collagen, inflammation, and metabolism, particularly via galectin-9 and thrombospondin-2.

Area of Science:

  • Cardiovascular research
  • Proteomics
  • Pharmacology

Background:

  • Spironolactone treatment reduced procollagen Type I C-terminal propeptide (PICP), a fibrosis biomarker, in the HOMAGE trial.
  • Understanding the mechanisms behind spironolactone's effect on fibrosis is crucial for heart failure management.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which spironolactone reduces PICP.
  • To identify protein biomarkers mediating spironolactone's antifibrotic effects.

Main Methods:

  • Proteomic analysis of plasma from 488 HOMAGE trial participants using Olink panels.
  • Machine learning algorithms (MLAs) to identify proteins associated with PICP changes.
  • Linear regression and mediation analyses in HOMAGE and Aldo-DHF trial cohorts.

Main Results:

  • MLAs linked PICP reduction to altered collagen (COL1A1), fatty acid metabolism (FABP4), immune function (CCL24, IL6RA, FLT3L), neurological function (DNER), and cell-matrix interactions (GAL9, THBS2).
  • Mediation analysis indicated galectin-9 (GAL9) and thrombospondin-2 (THBS2) changes mediated spironolactone's effect on PICP.
  • Findings were confirmed in heart failure with preserved ejection fraction patients from the Aldo-DHF trial.

Conclusions:

  • Spironolactone may inhibit collagen synthesis through inflammatory, metabolic, and extracellular matrix pathways.
  • Modulation of GAL9 and THBS2 is a key mechanism underlying spironolactone's antifibrotic action.
  • These findings offer novel insights into spironolactone's therapeutic effects in heart failure.

Keywords:
biomarkersfibrosisheart failuremachine learning algorithms (MLA)procollagen Type I C‐terminal propeptide (PICP)spironolactone

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