QUARTERLY FOCUS ISSUE: HEART FAILURE: CLINICAL RESEARCH
Natural History of Markers of Collagen Turnover in Patients With Early Diastolic Dysfunction and Impact of Eplerenone
George J. Mak, MD*, ,
Mark T. Ledwidge, PhD*,
Chris J. Watson, PhD,
Dermot M. Phelan, MD*,,
Ian R. Dawkins, DPhil*,
Niamh F. Murphy, MD, PhD*,
Anil K. Patle, BTech*,
John A. Baugh, PhD and
Kenneth M. McDonald, MD*,*
* Heart Failure Unit, St. Vincent's University Hospital, Dublin, Ireland
Conway Institute of Biomolecular and Biomedical Research, University College, Dublin, Ireland
Manuscript received June 29, 2009;
revised manuscript received August 26, 2009,
accepted August 31, 2009.
* Reprint requests and correspondence: Prof. Kenneth M. McDonald, Director, Heart Failure Unit, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland (Email: kenneth.mcdonald{at}ucd.ie).
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)
Key Words: preserved systolic function heart failure • collagen • aldosterone • fibrosis • eplerenone
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Abbreviations and Acronyms
| | ACE-I = angiotensin-converting enzyme inhibitor | | ARB = angiotensin-II receptor blocker | | BNP = B-type natriuretic peptide | | CITP = carboxy-terminal telopeptide of collagen type-I | | E' = maximum velocity of lateral mitral valve annulus | | HF = heart failure | | HFPSF = preserved systolic function heart failure | | HHD = hypertensive heart disease | | IL = interleukin | | MMP = matrix metalloproteinase | | NYHA = New York Heart Association | | PICP = carboxy-terminal peptide of pro-collagen type-I | | PINP = amino-terminal peptide of pro-collagen type-I | | PIIINP = amino-terminal peptide of pro-collagen type-III | | RAAS = renin-angiotensin-aldosterone system | | TNF = tumor necrosis factor |
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