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Aldosterone and myocardial fibrosis in heart failure
1Division of Cardiology, Philipps University of Marburg, Germany. brilla@t-online.de
Insights
Aldosterone promotes myocardial fibrosis by stimulating collagen synthesis in cardiac fibroblasts. Spironolactone, an aldosterone receptor blocker, effectively prevents this fibrosis, offering cardioprotective effects in hypertension and heart failure models.
Area of Science:
- Cardiovascular Research
- Endocrinology
- Fibrosis Research
Background:
- Aldosterone, a mineralocorticoid, is implicated in myocardial interstitial fibrosis.
- Fibrosis is a key factor in pathological cardiac hypertrophy and chronic heart failure.
Purpose of the Study:
- To investigate the role of aldosterone in promoting myocardial fibrosis.
- To assess the efficacy of spironolactone in preventing aldosterone-induced fibrosis in vivo and in vitro.
Main Methods:
- Rats were subjected to renovascular hypertension or continuous aldosterone administration.
- Spironolactone (low and high doses) was administered to assess its antifibrotic effects.
- Collagen volume fraction was quantified using videodensitometry.
- Aldosterone's effect on collagen synthesis was measured in cultured cardiac fibroblasts via 3H-proline incorporation.
Main Results:
- Both renovascular hypertension and aldosterone administration increased myocardial fibrosis and cardiac hypertrophy.
- High-dose spironolactone normalized blood pressure and cardiac weight in hypertensive rats.
- Spironolactone prevented myocardial fibrosis in both ventricles, irrespective of hypertension or hypertrophy.
- In vitro, aldosterone dose-dependently stimulated collagen synthesis in cardiac fibroblasts, an effect abolished by spironolactone.
Conclusions:
- Aldosterone plays a critical role in promoting myocardial fibrosis.
- Spironolactone effectively antagonizes aldosterone's profibrotic effects.
- These findings support the cardioprotective potential of spironolactone in heart failure and hypertension.
Abstract:
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.