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

For more than 30 years after the discovery of aldosterone, scientists believed that its sole site of action was at epithelial tissues, most notably the kidney, where it mediated the transport of Na and K. It was soon recognized aldosterone contributed to several diseases by causing edema. Armed with this information, scientists set out more than 30 years ago to develop an antagonist of the mineralocorticoid receptor for the treatment of edematous states. From this effort, spironolactone (Aldactone was discovered. Spironolactone acts functionally as a competitive inhibitor of the mineralocorticoid (aldosterone) receptor, and although spironolactone is an effective mineralocorticoid receptor antagonist, it is not without limitations. These limitations include unwanted progestational and antiadrogenic side effects that limit its use in the chronic treatment of disease. In addition to its actions at the collecting tubule, aldosterone can participate in pathophysiology by actions at the heart, vasculature, and kidney, and it is likely that the most significant contributions to cardiovascular disease are due to actions at these sites rather than those related to Na and water retention. This is underscored by the recent clinical results from the RALES-004 Trial in which treatment with Aldactone demonstrated a significant benefit on mortality in patients with severe heart failure. The limited utility of spironolactone owing to the aforementioned steroid-related side effects has been especially frustrating, given the newly recognized role of aldosterone in cardiovascular disease. To obviate these limitations, eplerenone is currently being developed by Searle. Eplerenone is a competitive antagonist of the mineralocorticoid receptor that takes advantage of replacing the 17alpha-thoacetyl group of spironolactone with a carbomethoxy group, conferring excellent selectivity for the mineralocorticoid receptor over other steroid receptors. The pharmacological profile of eplerenone positions it to be an effective and selective mineralocorticoid receptor antagonist.
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PMID:Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology. 1076 75

Spironolactone, a competitive aldosterone receptor antagonist (ARA), has traditionally been the treatment of first choice in idiopathic hyperaldosteronism (IHA) and for preoperative management of aldosterone producing adenoma (APA). Spironolactone is partially absorbed, is extensively metabolized mainly by the liver and its therapeutic properties are attributable to active metabolite canrenone. At therapeutic doses of 25 to 400 mg per day, spironolactone effectively controls blood pressure and hypokalemia in the majority of cases. Endocrine side effect are often associated and mainly consist of gynecomastia, decreased libido and impotence in man and menstrual irregularities in women. Canrenone and the K+ salt of canrenoate are also in clinical use: they avoid the formation of intermediate products with anti-androgenic and progestational actions, resulting in a decreased incidence of side effects. Furthermore, a relatively new selective ARA compound (eplerenone) with reduced affinity for androgen and progesterone receptors, is currently undergoing clinical trials. In essential hypertension aldosterone can contribute to hypertension and increases the incidence of myocardial hypertrophy and cardiovascular events. On the other hand, inhibition of Renin-Angiotensin-Aldosterone System (RAAS) is associated with a decrease in blood pressure, with a regression of left ventricular hypertrophy and a reduction of target organ damage. Thus, ARA have been proposed as complementary treatment associated to ACE inhibitors and angiotensin receptor antagonists. Aldosterone is also known to play an important role in pathophysiolgy of congestive heart failure (CHF). In vitro and in vivo evidences suggest that aldosterone promotes myocardial fibrosis. This effect reflects direct, extra-epithelial actions of aldosterone via cardiac MR which are counteracted by ARAs in animal models. The RAAS is chronically activated in CHF. Non potassium-sparing diuretics further stimulate the RAAS and cause hypokalemia. Thus, use of ARAs in CHF was first proposed to correct potassium and magnesium depletion. At present ARAs are indicated in the management of primary hyperaldosteronism, in oedematous conditions in patients with CHF, in cirrhosis of the liver accompanied by oedema and ascites, in essential hypertension and in hypokalemic states. Its indication as adjunctive therapy of heart failure is currently under investigation. In fact, it is well known that even high doses of ACE inhibitors may not completely suppress the RAAS; aldosterone 'escape' may occur through non angiotensin II dependent mechanisms. Addition of spironolactone to an ACE inhibitor causes marked diuresis and symptomatic improvement. During the last few years, the RALES study (Randomized Aldactone Evaluation Study) was organized to explore the efficacy of combination therapy with spironolactone and ACE inhibitor in patients with CHF, class III or IV NYHA. The study was stopped 18 months early because the results were so statistically and clinically significant that it would be unethical to continue the trial. It is reported a 30 percent decrease in mortality and hospitalisation for cardiac causes in spironolactone-treated group vs placebo group.
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PMID:Aldosterone antagonists in hypertension and heart failure. 1079 May 93

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.
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PMID:Aldosterone and myocardial fibrosis in heart failure. 1090 56

Morbidity and mortality of heartfailure are decreasing because of improved medical treatment. The recompensation balance can however be very fragile, which is illustrated by three patients. A woman aged 73 and a man aged 62, both known with heart failure, became seriously ill after diarrhoea; examination revealed uraemia, hyperpotassaemia and raised digitalis levels. A man aged 72, also with heart failure and diarrhoea, developed sensory disorders in both feet. He, also, was found to suffer from renal insufficiency. All patients used an angiotensin converting enzyme inhibitor or an angiotensin-II-antagonist and an aldosterone receptor blocker as well. During the (innocent) intercurrent disease by which their intravascular volume diminished they developed a severe renal insufficiency which needed clinical, intensive treatment. After haemodialysis, all three recovered well. Renal function plays an essential role in the fragile treatment balance that exists in recompensated cardiac patients. The medication that is beneficial for the cardiac functioning may at the same time compromise the renal perfusion. Good monitoring and good instructions about what to do in case of intercurrent diseases are of vital importance in these patients.
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PMID:[Acute renal insufficiency due to vomiting or diarrhea: the Achilles heel of medical support for heart failure]. 1102 Aug 33

These two issues of Progress in Pediatric Cardiology comprehensively illustrate the wealth of currently available information on the pathophysiology of heart failure, age-related myocardial responsiveness, energy metabolism, cardiopulmonary interactions, the pressure-volume relationship, the systemic inflammatory response, the management of heart failure, pediatric pharmacology, the use of heart failure therapies including digoxin, ACE inhibitors, beta-adrenergic blockers, inotropic agents, diuretics, vasodilators, calcium sensitizers, angiotensin and aldosterone receptor blockers, growth hormone, and future gene therapy. The etiology and course of ventricular dysfunction in children is poorly characterized. Furthermore, many changing developmental properties of the pediatric myocardium and differences in the etiologies of ventricular dysfunction in children compared with adults are illustrated in these articles, invalidating the concept that children can safely be considered small adults for the purpose of understanding heart failure pathophysiology and treatment. However, these articles reveal that strikingly little research in children with ventricular dysfunction exists in terms of well-designed large-scale studies of the epidemiology or multicenter controlled clinical therapeutic trials. A future research agenda is proposed to improve understanding etiologies, course and treatment of ventricular dysfunction in children that is based on organized and funded cooperative groups since no one pediatric cardiac center treats enough children with a particular etiology of ventricular dysfunction. In conclusion, significant understanding of basic mechanisms of pediatric ventricular dysfunction and effective therapies for adults with ventricular dysfunction exist. A multicenter pediatric cardiac ventricular dysfunction network would allow improved understanding of diseases and treatments, and result in evidence-based medicine for pediatric patients with ventricular dysfunction.
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PMID:Ventricular dysfunction clinical research in infants, children and adolescents. 1111 43

Long-lasting problem on the differentiation of adenohypophyseal cell, which prepares them for their specific tasks (somatotropic, lactotropic ect.), becomes elucidated after recognition of the differentiational effect of transcription factor Pit-1. Expression of that factor in somatotrops results in STH secretion, contrary to lactotrops producing prolactin. Subclinical hypothyreosis (increased TSH with normal T3 and T4) endangers vessel not because of hypercholesterolemia, but because of changes in the dynamics of the blood flow. The idea of cardiotropic effect of thyroidal hormones is supported by the finding that administration of trijodthyronine to children after the surgical correction of heart malformations (cardiopulmonary bypass) improves myocardial function--it elevates cardiac output and decreases requirements on the intensive care. Receptors for hormones in tissues are flexible, they can be "heterooligomers" for dopamine and somatostatin. Mutations of mineralocorticoid receptor may cause hypertension in pregnancy and progesterone receptors have several isoforms. Receptors can be also activated by short exposition to a hormone. Glucocorticoids have probably also membrane receptors. Diabetes mellitus "type I" needn't to be immunogenic and DM type II not only results from down-regulation of receptors and subsequent insulin resistance, but it can be also caused by defects in insulin secretion. Insulin has receptors in the brain and participates in the appetite regulation. The attempt to use "desensibilisation" by peroraly administered insulin in patients with immunogenic DM had no effect. Stress affects memory mechanisms, heavy emotional stress during gravidity can bring congenital malformations. The decrease of mental functions in aged women depends on the level of free estradiol (the fraction, which is not bound to plasma proteins). Activation of dopaminergic neurons can be achieved by neurotropic growth factors. Nesiritide is a recombinant brain natriuretic hormone successfully tested in heart failure. The role of leptin in the appetite regulation in man is still not clear, other signalling molecules may have also an effect, e.g., ghrelin, which primarily stimulates STH secretion and brings about weight gain. Sildenafil influences nitrergic neurons elsewhere than in penis, for example it has positive effects in patients with oesophageal achalasia.
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PMID:[Endocrinology 1999-2000]. 1128 21

Mineralocorticoids mediate a number of effects besides regulation of fluid and electrolyte balance. Recent evidence has revealed several nontraditional roles, sites of synthesis, and action for these steroids. Aldosterone, the principal mineralocorticoid in humans, appears to be synthesized in physiologically relevant amounts in both the heart and the vasculature, and plays an important role in vessel wall and myocardial remodeling. The genomic effects of aldosterone are mediated through activation of the classic mineralocorticoid receptor, whereas rapid nongenomic effects seem to involve a distinct receptor and result in activation of multiple downstream signaling pathways. Recently, several lines of evidence seem to suggest an important interaction between the nitric oxide and the aldosterone pathway in the adrenal gland and vasculature. The evolution of selective aldosterone receptor antagonists will help us understand the role that mineralocorticoids play in the pathogenesis of hypertension, heart failure, and atherosclerosis.
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PMID:Aldosterone antagonists in the treatment of hypertension and target organ damage. 1135 75

An extremely ill patient, with Cushing's syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg x d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, as well as by the significant reversal of the patient's heart failure, the resolution of his psychotic depression, and the eventual unusual return of his adrenal axis to normal. His 18-month-long mifepristone treatment course was notable for development of severe hypokalemia that was attributed to excessive cortisol activation of the mineralocorticoid receptor, which responded to spironolactone administration. This case illustrates the efficacy of high-dose long-term treatment with mifepristone in refractory Cushing's syndrome. The case also demonstrates the potential need for concomitant mineralocorticoid receptor blockade in mifepristone-treated Cushing's disease, because cortisol levels may rise markedly, reflecting corticotroph disinhibition, to cause manifestations of mineralocorticoid excess.
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PMID:Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486). 1150 80

Despite major advances many cardiovascular disorders remain poorly controlled. As a result the search for newer agents goes on. Anti-neurohormonal agents have been the most successful agents: beta-blockers, ACE inhibitors and angiotensin receptor blockers. To these we now add anti-aldosterone strategies with the phenomenal success of spironolactone in reducing mortality in severe heart failure. A more recent and more selective aldosterone receptor antagonist has been developed, eplerenone, and it shows considerable promise in managing and preventing the complications of hypertension. It may have a role both being anti-fibrotic and anti-neurohormonal in mild to moderate heart failure, in post-MI left ventricular dysfunction and in progressive renal disease. The EPHESUS trial which randomised patients with heart failure due to impaired left ventricular systolic function aims to randomise 6,200 patients to eplerenone or placebo on top of standard therapy and follow subjects until 1,012 deaths have occurred (approx. 2.5 years of follow up). This and other trials with the novel strategy of selective aldosterone antagonism are eagerly awaited. The beneficial effects established by the earliest anti-neurohormonal agents give us confidence that further benefits could be obtained by this intellectual strategy.
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PMID:Exciting new drugs on the horizon - eplerenone, a selective aldosterone receptor antagonist (SARA). 1153 39

Eplerenone, an aldosterone receptor antagonist from Searle is being developed as a potential treatment for renal disease, congestive heart failure and hypertension. It is in phase III clinical trials 1312280], [353548]. Monsanto (now Pharmacia) expects to launch the compound in 2002 [370466]. Pharmacia anticipates filing for congestive heart failure in 2002 [374505]. A global phase III survival trial was initiated in the US and approximately 30 other countries in January 2000. The trial will evaluate whether eplerenone can reduce the rate of mortality in patients who have recently had a heart attack that resulted in a diagnosis of heart failure 13535481.
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PMID:Eplerenone (GD Searle & Co). 1156 10


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