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

Recent studies suggest that a dysregulation of the aldosterone system is involved in the pathophysiology of different cardiovascular diseases, including myocardial failure and several cases of essential hypertension. In both rat models and in humans, aldosterone action has been shown to induce heart remodeling and interstitial and perivascular fibrosis of the myocardium. For these reasons, a rationale for the use of aldosterone antagonists (ARAs) of the spirolactone family, which have been available for decades in the treatment of aldosterone excess syndromes, has now emerged. Moreover, the recent validation of their use, in combination with the current therapy, for the treatment of these cardiovascular diseases by trials like the RALES Study has further strenghtened this approach. The development of compounds, like eplerenone, with a greater selectivity for mineralocorticoid receptors, seems promising also in terms of reduction of endocrine side effects. The addition of aldosterone antagonists to the conventional therapy of myocardial failure and of selected cases of hypertension thus appears beneficial, resulting in an improved survival rate and a reduced incidence of cardiac complications. This review article, after a brief recall of the physiology of the aldosterone system, addresses the emerging role of aldosterone in cardiovascular diseases, considers the pharmacology of ARAs and the novel therapeutical applications of these compounds in hypertension and heart failure.
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PMID:Aldosterone receptor antagonists: biology and novel therapeutical applications. 1466 38

Heart failure is associated with neurohormonal activation, including activation of the renin-angiotensin-aldosterone system. Plasma aldosterone levels are elevated in patients with heart failure in spite of the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers because of angiotensin-independent stimuli for aldosterone production. In addition to its long recognized role in sodium retention, aldosterone has a number of other deleterious effects, including the increase in myocardial and vascular fibrosis and myocardial remodeling in patients with heart failure. Based on strong clinical trial data, low-dose aldosterone receptor blockers are recommended to improve morbidity and mortality in patients with severe chronic heart failure due to left ventricular systolic dysfunction and in patients with heart failure associated with left ventricular systolic dysfunction after acute myocardial infarction, and in patients already on standard therapy including ACE inhibitors (or angiotensin receptor blockers) and beta blockers. In view of the potential for serious hyperkalemia with the use of aldosterone receptor blockers, it is essential to monitor serum potassium closely and to adjust the dose of aldosterone antagonists based on serum potassium levels. Close adherence to the dosing regimens used in the clinical trials (RALES and EPHESUS ) is recommended. These agents should not be initiated in patients with severe renal insufficiency and closer monitoring is warranted in those with mild to moderate renal insufficiency or diabetes.
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PMID:Aldosterone Receptor Blockers in the Treatment of Heart Failure. 1521 27

The two major outcome trials on the combination of angiotensin-converting enzyme (ACE) inhibitors and mineralocorticoid receptor (MR) antagonists in heart failure are RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). There have also been studies in essential hypertension, and in diabetic hypertensive patients, on the cardiac and renal effects of ACE inhibitors and MR antagonists, individually and in combination. In the clinical studies on heart failure, in outcome trials and the smaller studies using surrogate end points, a combination of ACE inhibition and MR blockade is superior to ACE inhibition alone, and in the hypertension studies to either agent alone. Some insight into their distinct sites of protective action may be gained from studies on experimental animal preparations. The principal caveat in the use of combination therapy is the possibility of hyperkalemia, which should be minimal in patients with creatine clearance greater than 30 mL/min and with the low doses of MR antagonist shown to be effective in outcome trials.
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PMID:ACE inhibitors and mineralocorticoid receptor blockade in patients with congestive heart failure. 1566 15

The role of aldosterone-antagonists in the treatment of congestive heart failure. Despite the advances of the treatment of congestive heart failure, nearly half of the patients diagnosed with this disease five years ago are alive today. Experimental and human studies have demonstrated, that under special pathologic condition, the heart extracts aldosterone, and aldosterone extraction in the heart stimulates increased collagen turnover culminating in ventricular remodeling. Aldosterone blockade has been shown to be effective in reducing total mortality and hospitalization for heart failure in patients with systolic left ventricular dysfunction due to chronic heart failure (RALES study with spironolactone) and in patients with systolic left ventricular dysfunction post acute myocardial infarction (EPHESUS study with eplerenone). These clinical studies have shown that mineralocorticoid receptor activation remains important despite the use of angiotensin converting enzyme inhibitor or angiotensin receptor blocking agent and a beta blocker. In the ACC/AHA (and in the European and Hungarian) guidelines for the evolution and management of chronic heart failure, the indication of spironolactone was defined of Class Ila, Level of Evidence: B in CHF of stage C. The eplerenone (in US: INSPRA) was approved for the management of CHF patients after myocardial infarction with ejection fraction < 40%. Eplerenone, compared with spironolactone, is associated with a lower incidence of gynecomastia and other sex hormone-related adverse effect (breast pain, menstrual abnormalities). The spironolactone should not be used in patients with a creatinine above 220 mikromol/l. Despite the guidelines recommendation, spironolactone has been widely used in patients without consideration of their functional class or ejection fraction, without optimization of background treatment with ACE inhibitors and beta-blockers.
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PMID:[The role of aldosterone-antagonists in the treatment of congestive heart failure]. 1588 38

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

Mineralocorticoid receptors (MR) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone >/= aldosterone = cortisol), and are found in both Na(+) transporting epithelia (e.g. kidney, colon) and nonepithelial tissues (e.g. heart, brain). MR evolved before aldosterone synthase, consistent with their acting in nonepithelial tissues as high affinity glucocorticoid receptors, essentially always occupied by normal levels of endogenous glucocorticoids. In epithelial tissues the enzyme 11beta hydroxysteroid dehydrogenase Type 2 (11betaHSD2) allows aldosterone to selectively activate MR, by converting cortisol to cortisone and NAD to NADH. 11betaHSD2 debulks intracellular cortisol by 90%, to levels approximately 10-fold those of aldosterone, so that when the enzyme is operating most epithelial MR are occupied but not activated by cortisol. When intracellular redox state is changed-by inhibition of 11beta HSD2, generation of reactive oxygen species, or intracellular introduction of oxidised glutathione (GSSG)-cortisol changes from an MR antagonist to an MR agonist. This bivalent activity of cortisol appears to underlie the therapeutic efficacy of MR blockade in heart failure (RALES, EPHESUS) and in essential hypertension, providing a rationale for MR blockade in cardiovascular disease not characterized by elevated aldosterone levels. Its wider (patho)physiologic implications, particularly for neurobiology, remain to be explored.
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PMID:Mineralocorticoid receptors: distribution and activation. 1594 87

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

Aldosterone not only contributes to salt and water homeostasis, but also exerts direct cardiovascular and renal effects. Numerous experimental and clinical studies indicate that aldosterone participate in cardiac alterations associated with hypertension, heart failure, diabetes and other pathological entities. It is important to mention that dietary salt is a key factor in aldosterone-mediated cardiovascular damage, since damage was more evident in animals on a high-salt diet than animals on a low salt diet. A pathophysiological action of aldosterone involves development of extracellular matrix and fibrosis, inflammation, stimulation of reactive oxygen species production, endothelial dysfunction, cell growth and proliferation. Many studies showed local extra-adrenal production of aldosterone in brain blood vessel, and the heart, which contribute in an important manner to the pathological actions of this mineralocorticoid. Several studies such as RALES, EPHESUS, 4E and others, recently showed that mineralocorticoid-receptor (MR) antagonists, alone or in combination with ACE inhibitors or ARBs, reduced the risk of progressive target organ damage and hospitalization in patients with hypertension and heart failure. These clinical benefits support the therapeutic usefulness of MR antagonists.
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PMID:Aldosterone and its blockade: a cardiovascular and renal perspective. 1660 52

Aldosterone is a mineralocorticoid primarily produced in the zona glomerulosa of the adrenal gland. For many years, aldosterone (Aldo) was thought to have its sole site of action in the kidney, where it regulated sodium excretion and potassium reabsorption. It is now known that Aldo is produced in cardiovascular tissues, and has been implicated in the development of ventricular hypertrophy and cardiac fibrosis. The precise mechanisms whereby Aldo acts in cardiac tissues are diverse. It was assumed that Aldo production could be limited by angiotensin-converting enzyme (ACE) inhibition, but serial measurements during therapy reveal only a transient decrease in Aldo levels. Moreover, the effects of Aldo on cardiac tissues occur even when angiotensin II (Ang II) has been suppressed or eliminated. Multiple investigators have examined effects of Aldo receptor blockade in human subjects and various animal models using the two Aldo receptor antagonists (ARAs), spironolactone and eplerenone. Major clinical trials involving spironolactone (RALES) and eplerenone (EPHESUS) ARAs have shown significant benefits in the treatment of congestive heart failure (CHF). In RALES, patients with New York Heart Association (NYHA) Class III or IV systolic heart failure treated with spironolactone had a 30% relative risk decrease in mortality. Although spironolactone is an effective competitive inhibitor of the mineralocorticoid receptor (MR), progestational and antiandrogenic side effects limit its use in some patients. Eplerenone, a more selective ARA, lacks these undesirable side effects. Although eplerenone is 20-fold less potent at the MR, it demonstrates efficacy similar to spironolactone, possibly due to decreased protein binding. Eplerenone has fewer side effects than spironolactone, which has been attributed to the low cross-reactivity with androgen and progesterone receptors. In EPHESUS, patients with left ventricular systolic dysfunction [Ejection Fraction (EF) <40%] and CHF following an acute myocardial infarction (AMI), were treated with eplerenone, resulting in a 17% reduction in cardiovascular mortality. However, these studies were limited in that diastolic function was not evaluated, although approximately 1/2 of CHF is due to diastolic dysfunction alone. To date, neither ARA has been studied for the treatment of diastolic dysfunction in a major clinical trial. However, numerous animal studies employing ARAs have shown a decrease in cardiac hypertrophy and fibrosis, indicating the potential benefits of these agents in the treatment of diastolic heart failure. In this review, we discuss possible underlying mechanisms responsible for Aldo effects on cardiovascular function and compare the beneficial effects of spironolactone and eplerenone in the treatment of heart disease.
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PMID:Aldosterone receptor antagonists and cardiovascular disease: do we need a change of the guard? 1661 Oct 48


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