Zannad F, Alla F, Dousset B, Perez A, Pitt B
Centre d'Investigation Clinique INSERM-CHU, Laboratory of Biochemistry, Centre Hospitalier Universitaire, University Henri Poincaré, Nancy, France.
Circulation. 2000 Nov 28;102(22):2700-6. doi: 10.1161/01.cir.102.22.2700.
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.
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.
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.
在充血性心力衰竭（CHF）中，细胞外基质周转是心脏重塑的主要决定因素。已有研究表明，螺内酯可能会减轻心脏纤维化。我们研究了心脏纤维化血清标志物之间的相互作用以及螺内酯对CHF患者预后的影响。
从随机螺内酯评估研究（RALES）中选取261例患者，随机分为安慰剂组或螺内酯组（每日12.5至50毫克）。在基线和6个月时评估血清I型前胶原羧基末端肽、I型前胶原氨基末端肽和III型前胶原氨基末端肽（PIIINP）。基线PIIINP>3.85微克/升与死亡风险增加（相对风险[RR]2.36，95%可信区间1.34至4.18）以及死亡加住院风险增加（RR 1.83，95%可信区间1.18至2.83）相关。在6个月时，螺内酯组的标志物下降，而安慰剂组保持不变。螺内酯对预后的影响仅在基线标志物水平高于中位数的患者中显著。在PIIINP水平高于和低于中位数的亚组中，接受螺内酯治疗的患者死亡的RR（95%可信区间）值分别为0.44（0.26至0.75）和1.11（0.66至1.88）。同样，接受螺内酯治疗的患者死亡加住院的RR（95%可信区间）值分别为0.45（0.29至0.71）和0.85（0.55至1.33）。
在CHF患者中，心脏纤维化合成标志物的高基线血清水平与不良预后显著相关，且在螺内酯治疗期间会降低。螺内酯的益处与较高水平的胶原合成标志物相关。这些结果表明，限制过度的细胞外基质周转可能是螺内酯对CHF患者产生有益作用的多种肾外机制之一。
