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

In RALES, low doses of the mineralocorticoid receptor (MR) antagonist spironolactone, added to standard of care for severe heart failure, improved survival by 30% and lowered hospitalization by 35%. Animal studies with the selective MR antagonist eplerenone have similarly shown MR blockade to prevent the cerebral, renal and coronary vascular inflammatory response to elevated aldosterone levels. There is now general acceptance that aldosterone concentrations inappropriate for salt status have major deleterious effects on the cardiovascular system. In many instances, however (e.g. Randomized Aldactone Evaluation Study (RALES), EPHESUS) aldosterone levels are normal and salt status unremarkable and yet MR blockade has unquestioned benefits. In these instances, there is increasing evidence that coronary and cardiac MR are activated by normal circulating cortisol levels, in the cellular context of generation of reactive oxygen species (ROS) and/or alteration in intracellular redox status. MR in VSMC and cardiomyocytes are normally predominantly occupied by cortisol in tonic inhibitory mode. Blockade of 11beta hydroxysteroid dehydrogenase type II (11betaHSD2) or ROS generation both serve to activate cortisol-MR complexes, thus mimicking the effects of mineralocorticoid/salt imbalance on blood vessels and the heart. In RALES and EPHESUS, it is likely that the antagonists are blocking normal levels of cortisol, not aldosterone, from activating MR in the context of tissue damage and ROS generation. If this is the case, MR antagonists may be of wide therapeutic potential in cardiovascular disease and not confined to those characterized by aldosterone/salt excess. Finally, the pathophysiologic roles of always-occupied MR in 'unprotected' tissues such as cardiomyocytes or neurons in response to altered intracellular redox status remain to be explored.
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PMID:RALES, EPHESUS and redox. 1586 Feb 54

A dysregulation of the aldosterone system has been involved in the pathophysiology of cardiovascular diseases, including myocardial failure and, partially, essential hypertension. In humans and in rat models, aldosterone action induces heart remodeling and interstitial and perivascular myocardial fibrosis. Therefore, a rationale for using aldosterone antagonists (ARAs) of the spironolactone family, which have been available for decades for the treatment of aldosterone excess syndromes, has now emerged. The development of compounds such as eplerenone, with a greater selectivity for mineralocorticoid receptors, is promising also in terms of reduction of endocrine side effects. The use of ARAs for the treatment of myocardial failure and selected cases of hypertension, in combination with the current therapy, has been strongly supported by trials such as the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS). Thus, the addition of ARAs to the conventional therapy appears beneficial, leading to an improved survival rate and a reduced incidence of cardiac complications.
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PMID:Aldosterone receptor antagonists: biology and novel therapeutic applications. 1591 96

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

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

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

Aldosterone produces adverse effects on the vasculature (endothelial dysfunction) and on the myocardium (myocardial fibrosis). These effects have adverse clinical consequences that result in increases in deaths caused by sudden death and by progressive heart failure. The Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study show this clearly. Aldosterone blockade should become a regular third neuroendocrine-blocking drug in patients with chronic heart failure.
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PMID:Aldosterone in heart failure: pathophysiology and treatment. 1603 41

Spironolactone and eplerenone are mineralocorticoid- blocking agents used for their ability to block a host of epithelial and nonepithelial actions of aldosterone. These compounds are of proven benefit in reducing blood pressure and urine protein excretion, and in conferring cardiovascular gain in diverse circumstances of heart failure. However, as enthusiasm grows for use of mineralocorticoid-blocking agents, the risks inherent to use of such drugs become more pertinent. Whereas the endocrine side effects of spironolactone are in reality little more than a cosmetic disfigurement, the potassium-sparing properties of spironolactone and eplerenone can prove life-threatening if hyperkalemia develops. However, for most patients the risk of developing hyperkalemia should not dissuade the prudent clinician from use of these compounds. Hyperkalemia should be considered as a possibility in any patient receiving these medications and as such is best addressed preemptively.
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PMID:The risks and benefits of aldosterone antagonists. 1603 53

In 1999 a great multi-site clinical trial known as the randomised Aldactone evaluation study (RALES) showed that the use of spironolactone importantly reduced complications attributable to chronic heart failure without major negative side effects. Recently, RALES has been questioned by a large scale observational study in the Ontario population. In contrast with predictions, the complications and mortality increased dramatically because of hyperkalaemia, reaching dimensions that from a public health perspective are comparable to an epidemic. This review analyses both researches in the light of Karl Popper's science theory applying the modus tollens syllogism to the reality proposed by the main empirical enunciations that ensue from its epidemiological designs. RALES is deductively refuted because of the non-fulfillment of auxiliary assumptions that would act as reciprocal potential falsifiers in both studies, taking the logical form of a bi-conditional argument of the type: (a) P-then-Q and (b) Q-if-X(P), X(P) being a set of potential falsifiers of Q as part of the explicit falsity content of P. From this popperian model, implications for clinical research are discussed.
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PMID:A landmark for popperian epidemiology: refutation of the randomised Aldactone evaluation study. 1623 30

Aldosterone is elevated in heart failure and exerts multiple detrimental effects. In addition to playing key roles in sodium and volume regulation, aldosterone is involved in regulation of autonomic tone, endothelial dysfunction, tissue collagen turnover, myocyte fibrosis, and release of inflammatory modulators. Aldosterone receptor antagonists have proven to be a valuable treatment tool in the management of heart failure due to systolic dysfunction. Blocking the effects of aldosterone can improve many of the functions that are deranged in patients with heart failure, as well as promote excretion of sodium and water and preservation of potassium and hydrogen in the distal renal tubule. These medications can be especially effective at removing fluid from the periphery and soft tissues. Prevention of hypokalemia, which may predispose patients to arrhythmia, is an added benefit. Spironolactone and eplerenone are the two agents in this class that have been studied in patients with heart failure and left ventricular dysfunction. However, aldosterone antagonist therapy may not be appropriate for all patients with heart failure. Therefore, guidelines in managing patients on these medications should be followed to avoid serious electrolyte abnormalities and renal dysfunction. This review examines some of the mechanisms of action and the usefulness of aldosterone blockade in the management of heart failure.
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PMID:Aldosterone antagonists in the treatment and prevention of heart failure. 1628 69

Recent clinical trials have explored whether angiotensin receptor blockers (ARBs) or aldosterone blockade should be added to standard angiotensin-converting enzyme (ACE) inhibitor/beta blocker treatment in heart failure. Both strategies are of some value but it is unclear which strategy should be used first in patients with mild but symptomatic heart failure. The arguments for and against each strategy are discussed. The strongest argument for aldosterone blockade is the consistency in the results of the RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study) studies, but what is lacking is a trial of aldosterone blockade in patients with mild, symptomatic heart failure as such. The strongest argument for ARBs is that the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) Added trial result was positive in the precise patient population of interest (mild, symptomatic heart failure). The strength of this argument is diminished by the somewhat different results in Val-HeFT (Valsartan Heart Failure Trial). A third possibility is to use neither an ARB nor an aldosterone blocker and arguments can be marshalled for this position also. Clinicians should now assess these various arguments to select what they believe would be best for their patients.
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PMID:Angiotensin blockade or aldosterone blockade as the third neuroendocrine-blocking drug in mild but symptomatic heart failure patients. 1633 14


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