Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone

George J Mak, Mark T Ledwidge, Chris J Watson, Dermot M Phelan, Ian R Dawkins, Niamh F Murphy, Anil K Patle, John A Baugh, Kenneth M McDonald

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Abstract

OBJECTIVES: This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF).

BACKGROUND: Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown.

METHODS: We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained.

RESULTS: The mean age of the patients was 80 +/- 7.8 years; 46% were male; 64% were receiving an angiotensin-converting enzyme inhibitor, 34% an angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide.

CONCLUSIONS: This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).

Original languageEnglish
Pages (from-to)1674-82
Number of pages9
JournalJournal of the American College of Cardiology
Volume54
Issue number18
DOIs
Publication statusPublished - 27 Oct 2009

Keywords

  • Aged
  • Aged, 80 and over
  • Biomarkers
  • Collagen Type I
  • Collagen Type III
  • Echocardiography, Doppler
  • Female
  • Follow-Up Studies
  • Heart Failure, Diastolic
  • Heart Ventricles
  • Humans
  • Male
  • Mineralocorticoid Receptor Antagonists
  • Procollagen
  • Prospective Studies
  • Radioimmunoassay
  • Spironolactone
  • Treatment Outcome

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    Mak, G. J., Ledwidge, M. T., Watson, C. J., Phelan, D. M., Dawkins, I. R., Murphy, N. F., Patle, A. K., Baugh, J. A., & McDonald, K. M. (2009). Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone. Journal of the American College of Cardiology, 54(18), 1674-82. https://doi.org/10.1016/j.jacc.2009.08.021