Abstract 17827: Impact of Spironolactone on Profibrotic Markers in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT)
Introduction: The balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) reflects myocardial collagen turnover. Increases in collagen and Galectin-3 (Gal-3) are associated with cardiac fibrosis, a critical element in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Mineralocorticoid receptor antagonists (MRAs) reduce myocardial fibrosis in HF with reduced EF, however their role in HFpEF remains uncertain.
Hypothesis: Several biomarkers associated with myocardial fibrosis are activated in HFpEF and the MRA spironolactone modifies their levels.
Methods: Biomarkers were measured at baseline (n=443) and 1-year (n=367) in serum samples obtained for TOPCAT. Changes in Gal-3, procollagen type III amino-terminal propeptide (PIIINP), procollagen type I carboxy-terminal peptide (PICP), carboxy-terminal telopeptide of collagen type I (CITP), MMPs 2 and 9, TIMP-1 and MMP-2, 9/TIMP-1 ratios were analyzed using ANCOVA models adjusted for baseline biomarker levels and relevant clinical characteristics (Table). All biomarker levels were log transformed (non-normal distributions). We also explored regional variations in the effect of spironolactone on biomarker levels.
Results: Use of spironolactone was associated with reductions in MMP-2 and increases in MMP-9, while TIMP-1 remained unchanged. MMP-9/TIMP-1 ratio and aldosterone increased significantly in all patients (Table). In North America, PICP levels were also significantly decreased (adjusted treatment effect -15%, P=0.015), but not in Russia. Gal-3, PIIINP and CITP levels were not affected by treatment in either region.
Conclusions: The use of spironolactone in HFpEF is associated with significant changes in biomarkers that favor the degradation of collagen. Collagen type I (PICP, North America) appears most affected while collagen type III is unchanged (PIIINP); findings in agreement with a pressure overload model of HFpEF.
Author Disclosures: E. O’Meara: Research Grant; Modest; Fonds de Recherche Québec Santé support for research on remodeling and biomarkers in HF. S. de Denus: Research Grant; Significant; Pfizer research grant for a study on eplerenone. B.L. Claggett: None. M.R. Zile: None. I.S. Anand: None. S.J. Shah: None. M.G. Sirois: None. S.D. Solomon: None. P. Bertram: Other; Significant; Chairman- Steering Committee for TOPCAT. M.A. Pfeffer: Consultant/Advisory Board; Modest; Bayer, Genzyme, GlaxoSmithKline, Janssen, Lilly, Medicines Company, Merck, Novartis, Novo Nordisk, Relypsa, Salix, Sanofi, Thrasos and Vericel. Other; Modest; The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in survivors of MI with Novartis, with licensing agreement is irrevocably transferred to charity. Research Grant; Significant; Amgen, Celladon, Novartis, Sanofi. Consultant/Advisory Board; Significant; Boehringer Ingelheim, DalCor, Teva. J.L. Rouleau: Other; Modest; Member of the Executive Committee for TOPCAT. A.S. Desai: Research Grant; Significant; grant support from AtCor Medical to support the vascular stiffness ancillary study from TOPCAT.
- © 2016 by American Heart Association, Inc.