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(Circulation. 2000;102:2700.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
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)
From the Centre d’Investigation Clinique INSERM-CHU (F.Z., F.A.) and the Laboratory of Biochemistry (B.D.), Centre Hospitalier Universitaire, University Henri Poincaré, Nancy, France; Searle Monsanto (A.P), Skokie, Ill; and the Department of Internal Medicine (B.P.), Division of Cardiology, University of Michigan, Ann Arbor.
Correspondence to Prof Faiez Zannad, Centre d’Investigation Clinique INSERM-CHU, Hôpital Jeanne d’Arc, 54200 Toul, France. E-mail cic{at}chu-nancy.fr
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.
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, 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 µg/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.
Key Words: heart failure • collagen • tissue • hormones • trials
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 P. Saudan, F. Mach, T. Perneger, B. Schnetzler, C. Stoermann, Z. Fumeaux, M. Rossier, and P.-Y. Martin Safety of low-dose spironolactone administration in chronic haemodialysis patients Nephrol. Dial. Transplant., November 1, 2003; 18(11): 2359 - 2363. [Abstract] [Full Text] [PDF]
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B. I. Jugdutt Ventricular Remodeling After Infarction and the Extracellular Collagen Matrix: When Is Enough Enough? Circulation, September 16, 2003; 108(11): 1395 - 1403. [Full Text] [PDF]
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J. N. Cohn, I. S. Anand, R. Latini, S. Masson, Y.-T. Chiang, and R. Glazer Sustained Reduction of Aldosterone in Response to the Angiotensin Receptor Blocker Valsartan in Patients With Chronic Heart Failure: Results From the Valsartan Heart Failure Trial Circulation, September 16, 2003; 108(11): 1306 - 1309. [Abstract] [Full Text] [PDF]
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K. T Weber, Yao Sun, L. A Wodi, A. Munir, E. Jahangir, R. A Ahokas, I. C Gerling, A. E Postlethwaite, and K. J Warrington Toward a broader understanding of aldosterone in congestive heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 155 - 163. [Abstract] [PDF]
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B. Pitt, C. T Stier Jr, and S. Rajagopalan Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 164 - 168. [Abstract] [PDF]
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M. Domanski, J. Norman, B. Pitt, M. Haigney, S. Hanlon, and E. Peyster Diuretic use, progressive heart failure, and death in patients in the studies of left ventricular dysfunction (SOLVD) J. Am. Coll. Cardiol., August 20, 2003; 42(4): 705 - 708. [Abstract] [Full Text] [PDF]
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A. F. Hernandez and C. M. O'Connor Sparing a little may save a lot: Lessons from the Studies of Left Ventricular Dysfunction (SOLVD) J. Am. Coll. Cardiol., August 20, 2003; 42(4): 709 - 711. [Full Text] [PDF]
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J. S. Williams and G. H. Williams 50th Anniversary of Aldosterone J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2364 - 2372. [Full Text] [PDF]
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J. W. Funder Aldosterone Resurgens--Letter from EPHESUS J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2373 - 2375. [Full Text] [PDF]
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P. C. White Aldosterone: Direct Effects on and Production by the Heart J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2376 - 2383. [Full Text] [PDF]
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B. Pitt Aldosterone Blockade in Patients With Acute Myocardial Infarction Circulation, May 27, 2003; 107(20): 2525 - 2527. [Full Text] [PDF]
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M. Hayashi, T. Tsutamoto, A. Wada, T. Tsutsui, C. Ishii, K. Ohno, M. Fujii, A. Taniguchi, T. Hamatani, Y. Nozato, et al. Immediate Administration of Mineralocorticoid Receptor Antagonist Spironolactone Prevents Post-Infarct Left Ventricular Remodeling Associated With Suppression of a Marker of Myocardial Collagen Synthesis in Patients With First Anterior Acute Myocardial Infarction Circulation, May 27, 2003; 107(20): 2559 - 2565. [Abstract] [Full Text] [PDF]
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N. J. Brown Eplerenone: Cardiovascular Protection Circulation, May 20, 2003; 107(19): 2512 - 2518. [Abstract] [Full Text] [PDF]
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M. R. Mehra, P. A. Uber, and G. S. Francis Heart failure therapy at a crossroad: are there limits to the neurohormonal model? J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1606 - 1610. [Abstract] [Full Text] [PDF]
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S. K.G Koshy, H. K Reddy, and H. H Shukla Collagen cross-linking: new dimension to cardiac remodeling Cardiovasc Res, March 1, 2003; 57(3): 594 - 598. [Full Text] [PDF]
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S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi Effect of spironolactone on cardiacsympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., February 19, 2003; 41(4): 574 - 581. [Abstract] [Full Text] [PDF]
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 R. B. Felder, J. Francis, Z.-H. Zhang, S.-G. Wei, R. M. Weiss, and A. K. Johnson Heart failure and the brain: new perspectives Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R259 - R276. [Abstract] [Full Text] [PDF]
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J. G. F. Bronzwaer, C. Heymes, C. A. Visser, and W. J. Paulus Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human dilated cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H10 - H16. [Abstract] [Full Text] [PDF]
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J. D. Stockand and J. G. Meszaros Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H176 - H184. [Abstract] [Full Text] [PDF]
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 I. Manabe, T. Shindo, and R. Nagai Gene Expression in Fibroblasts and Fibrosis: Involvement in Cardiac Hypertrophy Circ. Res., December 13, 2002; 91(12): 1103 - 1113. [Abstract] [Full Text] [PDF]
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M. F. Rousseau, O. Gurne, D. Duprez, W. Van Mieghem, A. Robert, S. Ahn, L. Galanti, J.-M. Ketelslegers, and Belgian RALES Investigators Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: Results from the RALES neurohormonal substudy J. Am. Coll. Cardiol., November 6, 2002; 40(9): 1596 - 1601. [Abstract] [Full Text] [PDF]
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M. Cicoira, L. Zanolla, A. Rossi, G. Golia, L. Franceschini, G. Brighetti, P. Marino, and P. Zardini Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure J. Am. Coll. Cardiol., July 17, 2002; 40(2): 304 - 310. [Abstract] [Full Text] [PDF]
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J. McMurray and M. A. Pfeffer New Therapeutic Options in Congestive Heart Failure: Part I Circulation, April 30, 2002; 105(17): 2099 - 2106. [Full Text] [PDF]
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 E Allot, C de Chillou, and N Sadoul Ventricular instability and sudden death in patients with heart failure: lessons from clinical trials Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D31 - D42. [Abstract] [PDF]
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F Zannad Evidence-based drug therapy for chronic heart failure Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D66 - D72. [Abstract] [PDF]
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