Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone.
OBJECTIVE
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).
Mak
George J
GJ
St. Vincent's University Hospital, Dublin, Ireland.
Ledwidge
Mark T
MT
Watson
Chris J
CJ
Phelan
Dermot M
DM
Dawkins
Ian R
IR
Murphy
Niamh F
NF
Patle
Anil K
AK
Baugh
John A
JA
McDonald
Kenneth M
KM
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D024042:Collagen Type I / Q000097:blood*; D024061:Collagen Type III / Q000097:blood*; D015150:Echocardiography, Doppler; D000077545:Eplerenone; D005260:Female; D005500:Follow-Up Studies; D054144:Heart Failure, Diastolic / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006801:Humans; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D011347:Procollagen / Q000097:blood*; D011446:Prospective Studies; D011863:Radioimmunoassay; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
D015415:Biomarkers; D024042:Collagen Type I; D024061:Collagen Type III; D000451:Mineralocorticoid Receptor Antagonists; D011347:Procollagen; D013148:Spironolactone; D000077545:Eplerenone