Document Detail

Aldosterone and myocardial fibrosis in heart failure.
MedLine Citation:
PMID:  10904856     Owner:  NLM     Status:  MEDLINE    
Cardiac fibroblasts are known to have high affinity corticoid receptors for aldosterone and account for the accumulation of collagen within the interstitium of the rat myocardium in acquired and genetic hypertension. This interstitial fibrosis is an important determinant of pathologic hypertrophy in chronic heart failure. To examine the relationship between aldosterone and myocardial fibrosis, collagen volume fraction of the left and right ventricles were analyzed by videodensitometry of sirius red stained tissue in the following rat models: 2 kidney/1 clip model of renovascular hypertension; continuous aldosterone administration via osmotic minipumps (0.75 microgram/hour s.c.), or in each model of primary and secondary hyperaldosteronism with concomitant treatment with either low (20 mg/kg/day) or high doses (200 mg/kg/day) of s.c. spironolactone for 8 weeks as well as in age matched controls. Systolic arterial pressure and left ventricular weight normalized to body weight were each increased with either model of experimental hypertension and were normalized with high-dose spironolactone treatment. Myocardial fibrosis induced by chronic aldosterone administration was comparable to renovascular hypertension and occurred in the pressure overloaded, hypertrophied left and in the normotensive, nonhypertrophied right ventricle. The competitive aldosterone receptor antagonist, spironolactone, was able to prevent fibrosis in both ventricles in either model of arterial hypertension irrespective of the development of left ventricular hypertrophy and hypertension. To examine whether aldosterone stimulates collagen synthesis in adult rat cardiac fibroblasts collagen synthesis, normalized per total protein synthesis, was measured by 3H-proline incorporation in cultured fibroblasts after 24 hours incubation with aldosterone at 10(-11) to 10(-6) M concentrations, or with 10(-9) M aldosterone + 10(-9) M spironolactone. Under serum-free conditions, aldosterone was able to stimulate collagen synthesis in a dose-dependent manner and at concentrations (10(-9) M) which were comparable to stimulated states in vivo (e.g., renovascular hypertension, or chronic heart failure). At equimolar concentrations, spironolactone abolished the aldosterone-mediated increase in collagen synthesis. Thus, in-vivo and in-vitro evidence could be provided that the mineralocorticoid, aldosterone, plays a pivotal role in promoting myocardial fibrosis and that could be antagonized by its competitive receptor blocker, spironolactone. These cardioprotective effects of spironolactone may explain the prognostic value of anti-aldosterone therapy in patients with severe chronic heart failure evaluated in the RALES mortality trial.
C G Brilla
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Herz     Volume:  25     ISSN:  0340-9937     ISO Abbreviation:  Herz     Publication Date:  2000 May 
Date Detail:
Created Date:  2000-10-02     Completed Date:  2000-10-02     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7801231     Medline TA:  Herz     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  299-306     Citation Subset:  IM    
Division of Cardiology, Philipps University of Marburg, Germany.
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MeSH Terms
Aldosterone / physiology*
Cardiomyopathies / pathology,  physiopathology*
Dose-Response Relationship, Drug
Heart Failure / pathology,  physiopathology*
Myocardium / pathology
Spironolactone / pharmacology
Reg. No./Substance:
52-01-7/Spironolactone; 52-39-1/Aldosterone

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