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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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 |
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|
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|
|
 |
|
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|
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 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 M. Rahman, A. Nishiyama, P. Guo, Y. Nagai, G.-X. Zhang, Y. Fujisawa, Y.-Y. Fan, S. Kimura, N. Hosomi, K. Omori, et al. Effects of Adrenomedullin on Cardiac Oxidative Stress and Collagen Accumulation in Aldosterone-Dependent Malignant Hypertensive Rats J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1323 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
 |
|
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|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 A. T. Yan, R. T. Yan, and P. P. Liu Narrative Review: Pharmacotherapy for Chronic Heart Failure: Evidence from Recent Clinical Trials Ann Intern Med, January 18, 2005; 142(2): 132 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 B. J Barnes and P. A Howard Eplerenone: A Selective Aldosterone Receptor Antagonist for Patients with Heart Failure Ann. Pharmacother., January 1, 2005; 39(1): 68 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D Struthers Aldosterone blockade in cardiovascular disease Heart, October 1, 2004; 90(10): 1229 - 1234. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
R. Querejeta, B. Lopez, A. Gonzalez, E. Sanchez, M. Larman, J. L. Martinez Ubago, and J. Diez Increased Collagen Type I Synthesis in Patients With Heart Failure of Hypertensive Origin: Relation to Myocardial Fibrosis Circulation, September 7, 2004; 110(10): 1263 - 1268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Mottram, B. Haluska, R. Leano, D. Cowley, M. Stowasser, and T. H. Marwick Effect of Aldosterone Antagonism on Myocardial Dysfunction in Hypertensive Patients With Diastolic Heart Failure Circulation, August 3, 2004; 110(5): 558 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J E Macdonald, N Kennedy, and A D Struthers Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment Heart, July 1, 2004; 90(7): 765 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
I. Mazak, A. Fiebeler, D. N. Muller, J.-K. Park, E. Shagdarsuren, C. Lindschau, R. Dechend, C. Viedt, B. Pilz, H. Haller, et al. Aldosterone Potentiates Angiotensin II-Induced Signaling in Vascular Smooth Muscle Cells Circulation, June 8, 2004; 109(22): 2792 - 2800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lopez, R. Querejeta, A. Gonzalez, E. Sanchez, M. Larman, and J. Diez Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure J. Am. Coll. Cardiol., June 2, 2004; 43(11): 2028 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. T. Bloomgarden Diabetes Complications Diabetes Care, June 1, 2004; 27(6): 1506 - 1514. [Full Text] [PDF]
|
|
|
|
|
|
A Rossi, M Cicoira, G Golia, L Zanolla, L Franceschini, P Marino, M Graziani, and P Zardini Amino-terminal propeptide of type III procollagen is associated with restrictive mitral filling pattern in patients with dilated cardiomyopathy: a possible link between diastolic dysfunction and prognosis Heart, June 1, 2004; 90(6): 650 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Vasan, J. C. Evans, E. J. Benjamin, D. Levy, M. G. Larson, J. Sundstrom, J. M. Murabito, F. Sam, W. S. Colucci, and P. W. F. Wilson Relations of Serum Aldosterone to Cardiac Structure: Gender-Related Differences in the Framingham Heart Study Hypertension, May 1, 2004; 43(5): 957 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. W. Funder Aldosterone Resurgens--Letter from EPHESUS J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2373 - 2375. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
B. Pitt Aldosterone Blockade in Patients With Acute Myocardial Infarction Circulation, May 27, 2003; 107(20): 2525 - 2527. [Full Text] [PDF]
|
|
|
|
|
|
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]
|