Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators.
BACKGROUND
In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that spironolactone may decrease cardiac fibrosis. We investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF.


RESULTS
A sample of 261 patients from the Randomized Aldactone Evaluation Study (RALES) were randomized to placebo or spironolactone (12.5 to 50 mg daily). Serum procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIIINP >3.85 microgram/L was associated with an increased risk of death (relative risk [RR] 2.36, 95% CI 1.34 to 4.18) and of death+hospitalization (RR 1.83, 95% CI 1.18 to 2.83). At 6 months, markers decreased in the spironolactone group but remained unchanged in the placebo group. The spironolactone effect on outcome was significant only in patients with above-median baseline levels of markers. RR (95% CI) values for death among patients receiving spironolactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of PIIINP levels above and below the median, respectively. Similarly, RR (95% CI) values for death+hospitalization among patients receiving spironolactone were 0.45 (0.29 to 0.71) and 0.85 (0.55 to 1.33), respectively.


CONCLUSIONS
In patients with CHF, high baseline serum levels of markers of cardiac fibrosis synthesis are significantly associated with poor outcome and decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These results suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with CHF.
Zannad
F
F
Centre d'Investigation Clinique INSERM-CHU, Laboratory of Biochemistry, Centre Hospitalier Universitaire, University Henri Poincaré, Nancy, France. cic@chu-nancy.fr
Alla
F
F
Dousset
B
B
Perez
A
A
Pitt
B
B
D000368:Aged; D000369:Aged, 80 and over; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D011347:Procollagen / Q000097:blood; D013148:Spironolactone / Q000627:therapeutic use*; D016019:Survival Analysis; D015996:Survival Rate; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D016896:Treatment Outcome
D000451:Mineralocorticoid Receptor Antagonists; D011347:Procollagen; D019715:Tissue Inhibitor of Metalloproteinase-1; D013148:Spironolactone; D020781:Matrix Metalloproteinase 1