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)

Background-In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that s pironolactone may decrease cardiac fibrosis, We investigated the interactio ns between serum markers of cardiac fibrosis and the effect of spironolacto ne on outcome in patients with CHF. Methods and 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, procol lagen type I amino-terminal peptide, and procollagen type III amino-termina l peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIII NP >3.85 mug/L was associated with an increased risk of death (relative ris k [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 gr oup but remained unchanged in the placebo group. The spironolactone effect on outcome was significant only in patients with above-median baseline leve ls of markers. RR (95% CI) values for death among patients receiving spiron olactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of P IIINP levels above and below the median, respectively. Similarly, RR (95% C I) 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 a nd decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These resu lts suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the benefic ial effect of spironolactone in patients with CHF.