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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over activation of the renin-angiotensin-aldosterone system is known to be cardiotoxic but the potential injurious effects on the skeletal musculature have not been investigated. Male Wistar rats were given subcutaneous injections of aldosterone (1 microg-10 mg kg-1) and killed 7 h later, or continuous infusion (1 mg kg-1 d-1) and killed 48 h later. The role of the mineralocorticoid receptor in mediating aldosterone-induced apoptosis in vivo was investigated using spironolactone (200 mg kg-1). The number of apoptotic (caspase 3 positive) myocytes was counted on cryosections of the heart, soleus and Tibialis Anterior muscles. Injections of aldosterone induced significant (P<0.05) cardiomyocyte apoptosis (peak=2.46+/-0.6 per 10(4) viable myocytes) over the range of 100 microg-10 mg kg-1, whereas only administration of 1 mg kg-1 induced significant (P<0.05) apoptosis (2.47+/-0.8 per 10(4) viable myocytes) in the soleus muscle. In contrast, no apoptosis was detected in the striated muscles after administration of only the vehicle. Infusion of aldosterone induced less apoptosis than the same dose (1 mg kg-1) given as a single injection. Prior administration of spironolactone significantly (P<0.05) protected the heart (90%) and soleus muscle (79%) against the apoptosis induced by a single injection of 1 mg kg-1 aldosterone. These data confirm a myotoxic effect of aldosterone on the heart and provide the first description of aldosterone-induced myocyte apoptosis in skeletal muscle. High circulating levels of aldosterone are clearly capable of damaging all types of striated muscle and this may lend support to the concept that heart failure is a generalised, rather than cardiac-specific, myopathy.
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PMID:Aldosterone induces myocyte apoptosis in the heart and skeletal muscles of rats in vivo. 1597 10

Aldosterone is the major mineralocorticoid hormone produced by the zona glomerulosa of the adrenal cortex. Aldosterone secretion is mainly regulated by the renin-angiotensin system, and to a minor extent by serum concentration of potassium, sodium, adrenocorticotropic hormone. and dopamine. This hormone, as well as other adrenal corticosteroids, exert many of its physiological actions through modulation of gene expression. It binds cytosolic receptors that translocate to the nucleus in a ligand-dependent manner and induces transcription of specific genes that encode for proteins involved in the cardiovascular homeostasis. Such proteins act regulating vascular tone, sympathetic nervous system activity, and hydroelectrolyte transport in epithelial tissues. Classical aldosterone target tissues are kidney, colon, sweat and salivary glands. Apart from the genomic effects, which imply a direct action on DNA, rapid non-genomic actions of aldosterone have been recently described in both epithelial and non-epithelial tissues and structures such as heart, vasculature, and kidney. At these sites aldosterone contributes to the development of cardiac fibrosis, myocardial hypertrophy, heart failure and arrhythmias; other deleterious effects exerted by aldosterone include vascular remodeling, endothelial dysfunction, perivascular inflammation, renal fibrosis, and progressive renal failure. Finally, recent evidence has focused on the possible implications of aldosterone excess on metabolic alterations, as described in patients with primary aldosteronism. On these premises lies the pathogenetic role of aldosterone in the development of cardiovascular diseases and the rationale for the use of mineralocorticoid receptor antagonists in the primary and secondary prevention of the complications related to these diseases.
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PMID:[Endocrinology of aldosterone]. 1594 95

Aldosterone was discovered in 1953, and until the beginning of the 1960s, when spironolactone was developed, it was the focus of considerable interest among the scientific community. The following 30 years represented a sort of Dark Age, interrupted by the Weber's classic studies. He first demonstrated the pivotal role of aldosterone in the promotion of cardiac hypertrophy and fibrosis and such an observation represented a solid background for the implementation of large survival trials, the RALES and the EPHESUS. These landmark studies showed that aldosterone receptor blockade prolongs survival in advanced and postinfarction heart failure, respectively. After a myocardial infarction, there is a significant upregulation of the local steroidogenic system in the area remote from the scar, that leads to a remarkable fibroblast activation, collagen deposition, and reactive fibrosis. Fibrosis in turn further impairs systolic and diastolic function, and induces electrical heterogeneity with attendant ominous arrhythmias. The following review will dwell upon the importance of fibrosis in postinfarction heart failure, the role of aldosterone, and the novel therapeutic approach based on mineralocorticoid receptor blockade.
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PMID:[The role of aldosterone in the development of postinfarction fibrosis]. 1594 99

The RALES study has shown that spironolactone reduces the risk of morbidity and mortality both from progressive heart failure and sudden death in patients with NYHA class III or IV heart failure. This favorable effect was clearly independent of a diuretic effect. EPHESUS extended these results to eplerenone in patients with acute myocardial infarction complicated by left ventricular dysfunction and signs of heart failure. Antialdosterone drugs may be effective because they oppose the effects of aldosterone to sodium retention, loss of magnesium and potassium, sympathetic activation, baroreceptor function and vascular compliance. Antialdosterone treatment may also antagonize the effect of aldosterone in promoting cardiac fibrosis. In a RALES substudy baseline serum PIIINP, a marker of extracellular matrix turnover, showed an independent negative correlation with survival and chronic heart failure hospitalizations in the placebo group. Therefore it seems interesting to evaluate the effect of canrenone, an aldosterone receptor blocker, on the progression of left ventricular dysfunction in patients with mild heart failure assuming standard therapy.
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PMID:[The AREA IN-CHF trial (antiremodeling effect of aldosterone receptors blockade with canrenone in mild chronic heart failure): rationale and design]. 1594 1

Spironolacotone and eplerenone are mineralocorticoid-blocking agents used for their ability to block both the epithelial and non-epithelial actions of aldosterone. Spironolactone is a non-selective mineralocorticoid receptor antagonist with moderate affinity for both progesterone and androgen receptors. The latter property increases the likelihood of endocrine side effects with spironolactone including loss of libido, menstrual irregularities, gynecomastia and impotence. Eplerenone is a next generation aldosterone receptor antagonist selective for aldosterone receptors alone. This lesser affinity for progesterone and androgen receptors was arrived at by replacing the 17-alpha -thioacetyl group of spironolactone with a carbomethoxy group. Eplerenone is further distinguished from spironolactone by its shorter half-life and the fact that it does not have any active metabolites. Both eplerenone and spironolactone are effective antihypertensive agents and each has been shown to improve the morbidity and mortality of heart failure. Eplerenone or spironolactone use can increase serum potassium values and occasionally results in clinically relevant hyperkalemia. This is more apt to occur with spironolactone due to the very long half-life of several of its active metabolites.
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PMID:Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. 1594 88

Neurohormonal dysfunction is an important and potentially modifiable part of the disease process of heart failure. In this review we will discuss the ways in which the autonomic system is deranged in congestive cardiac failure and the different ways we have of monitoring these abnormalities i.e.: heart rate variability, plasma norephinephrine activity, MIBG scanning, heart rate turbulence, baroreceptor function and briefly, microneurographic techniques and QT interval analysis. We will then discuss the direct effects of aldosterone and of aldosterone blockade on some of these parameters. We conclude that neurohormonal dysfunction is an important component of chronic heart failure, which is affected by aldosterone and can be modified by the use of aldosterone receptor blockade.
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PMID:Autonomic effects of spironolactone and MR blockers in heart failure. 1594 93

Collagen is the major extracellular matrix protein in the heart and represents a crucial target for anti-remodeling and cardioprotective therapy. Collagen quantity and quality have been shown to be regulated under various physiological and pathologic conditions. Excessive deposition of collagen, leading to cardiac fibrosis, is a major determinant of cardiac dysfunction and arrhythmogenecity associated with sudden death. Serological markers of collagen turnover were proven as a noninvasive reliable tool for monitoring from a distance cardiac tissue repair and fibrosis, both in experimental and clinical conditions. Some markers of collagen synthesis and degradation were shown to have a prognostic significance in myocardial infarction, cardiomyopathy and heart failure, and were reported as independent predictors of mortality. Aldosterone represents the end-product of the renin angiotensin aldosterone system and may play a role in cardiac collagen deposition independent of its effect on blood pressure. Production of aldosterone is mainly regulated by angiotensin II and is activated in the failing human ventricle in proportion to heart failure severity. Circulating or locally produced aldosterone stimulates fibrillar collagen accumulation in the heart directly via mineralocorticoid receptors or, indirectly, modifying angiotensine II receptors number and/or function. The use of mineralocorticoid receptor antagonists counters collagen deposition, even when used on top of classical RAAS inhibitors, such as ACE inhibitors and angiotensine II receptor blockers. There is now accumulating evidence from experimental and clinical studies showing antifibrotic and cardioprotective effect for aldosterone antagonists, spironolactone and eplerenone. In chronic heart failure and post myocardial infarction patients, aldosterone receptor blockade benefit was associated with decreased serum levels of collagen synthesis marker PIIINP (procollagen type III amino-terminal peptide), without affecting collagen degradation. Understanding various autocrine/paracrine mechanisms involved in extracellular matrix remodeling in heart failure represents a major challenge, essential for developing new cardioreparative and cardioprotective strategies.
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PMID:Effect of MR blockade on collagen formation and cardiovascular disease with a specific emphasis on heart failure. 1594 94

Activation of the renin-angiotensin-aldosterone system (RAAS) is a prominent feature of left ventricular dysfunction and plays an important role in the progression of chronic heart failure. Clinical and animal studies investigating agents that interrupt this hormonal system have focused primarily on the proximal constituents of the RAAS, namely angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists, and have largely neglected the possible pathological consequences of another hormone in the system, aldosterone. Clinical evidence indicates that aldosterone plays an important role in chronic heart failure, even when other RAAS inhibiting agents are employed. Moreover, animal studies have indicated that aldosterone, in addition to important renal effects, has direct cardiac and vascular effects. These data suggest that an anti-aldosterone therapeutic may provide important protection in chronic heart failure. Currently, only one therapeutic is available, spironolactone (Aldactone), and recent clinical studies support the contention that the addition of spironolactone to standard heart failure therapy provides additional benefit. A highly selective aldosterone receptor antagonist, eplerenone, is currently in clinical development. Data from this new agent should provide important evidence supporting the benefit of anti-aldosterone therapy in chronic heart failure, which may encourage physicians to include an anti-aldosterone agent in the armamentarium of therapeutics currently used to combat chronic heart failure.
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PMID:Anti-aldosterone therapy in the treatment of heart failure: new thoughts on an old hormone. 1599 66

Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific 'aldosterone-induced' proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety of actions of aldosterone that contribute to blood pressure homeostasis. These include key actions on endothelial cells and on cardiac tissue. There is also evidence that aldosterone can be synthesised in other tissues; the most convincing evidence relates to the central nervous system. However, suggestions that aldosterone is produced in the heart remain controversial, and adrenal derived aldosterone is the principal source of circulating and locally available hormone. Recent studies have shown major therapeutic benefits of mineralocorticoid receptor antagonism in cardiac failure, which emphasise the importance of aldosterone in causing adverse cardiovascular pathophysiological effects. Additional evidence demonstrates that aldosterone levels predict development of high blood pressure in normotensive subjects, while it is now clear that increased aldosterone action contributes to hypertension and cardiovascular damage in approximately 10% of patients with established hypertension. These new findings highlight the role of aldosterone as a key cardiovascular hormone and extend our understanding of its role in determining adverse cardiovascular outcomes.
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PMID:The new biology of aldosterone. 1600 31

Results of the Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study indicate aldosterone receptor antagonism, together with angiotensin-converting enzyme inhibition and loop diuretics, is a most effective strategy in reducing risk for all-cause and cardiovascular-related mortality and morbidity in patients with symptomatic heart failure. Responsible mechanisms are likely multifactoral. As a circulating hormone, aldosterone has well-known endocrine properties that contribute to the pathophysiology of congestive heart failure. This includes Na+ resorption at the expense of K+ excretion in such tissues as kidneys, colon, sweat, and salivary glands. Mg2+ excretion at these sites is likewise enhanced by aldosterone, whereas adrenal aldosterone secretion is regulated by extracellular Mg2+. Other endocrine actions of aldosterone receptor-ligand binding include: a reduction in biologically active cytosolic-free Mg2+, with intracellular Ca2+ loading in nonepithelial cells such as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions, including the choroid plexus, activity of the hypothalamic paraventricular nucleus, and autonomic nervous system. De novo generation of aldosterone within the cardiovasculature is recognized and findings suggest its auto/paracrine properties contribute to tissue repair. Each of these actions is interrupted by aldosterone receptor antagonism and therefore may contribute to its salutary response in heart failure.
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PMID:Efficacy of aldosterone receptor antagonism in heart failure: potential mechanisms. 1603 25


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