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

In chronic heart failure, angiotensin-converting enzyme inhibitors produce an acute decrease in aldosterone levels. Long-term angiotensin-converting enzyme inhibition is, however, associated with aldosterone suppression that is weak, variable, and unsustained (ie, aldosterone escapes). The possible harmful effects of this residual aldosterone are multiple Magnesium loss caused by aldosterone and by diuretics could contribute to coronary artery spasm and arrhythmias. Aldosterone blocks norepinephrine uptake by the myocardium; extracellular catecholamines may, therefore, lead to arrhythmias and ischemia. Aldosterone has been shown to have an acute arrhythmogenic effect as well as a detrimental effect on parasympathetic and baroreflex function. Both angiotensin II and aldosterone stimulate myocardial fibrosis, which may lead to a higher incidence of malignant ventricular arrhythmias. Spironolactone therapy added to the regimen of an angiotensin-converting enzyme inhibitor and diuretic has been shown to cause natriuresis, magnesium retention, increased myocardial norepinephrine uptake, and reduced incidence of ventricular arrhythmias. It may well be that residual aldosterone mediates many harmful effects in chronic heart failure and that to optimize the benefit of blocking the renin-angiotensin-aldosterone system may require specific blockade of residual aldosterone as well as traditional angiotensin-converting enzyme inhibition.
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PMID:Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. 879 5

In experimental models where chronic inappropriate (relative to sodium intake and intravascular volume) elevations in circulating mineralocorticoids (aldosterone or deoxycorticosterone) are created, a reactive fibrosis with vascular remodeling is observed in systemic organs and the heart. Until recently, it was assumed that aldosterone was derived solely from adrenal glands via the circulation; however, there is now convincing evidence that cells of the heart and vasculature express genes responsible for the formation of both aldosterone and corticosterone and are capable of producing these steroids. Vascular endothelial and smooth muscle cells express CYP11B1 and CYP11B2, genes responsible for 11 beta -hydroxylase and aldosterone synthase, respectively. Furthermore, smooth muscle cells elaborate aldosterone. There is evidence that similar regulatory mechanisms operate in vascular cells as in adrenal cortex, since aldosterone synthase and 11 beta -hydroxylase expression are differentially modulated by low sodium/high potassium, angiotensin II and ACTH. It is likely that such localized corticosteroid production also occurs at sites of tissue repair, where populations of collagen-producing myofibroblasts, nourished by a neovasculature, predominate. Using a subcutaneous pouch model of granulation tissue we have obtained compelling data which would support such a notion. The mineralocorticoid receptor antagonist, spironolactone, severely attenuates pouch formation over a 2-week period and significantly reduces pouch wall hydroxyproline concentration. This effect is apparent even following adrenalectomy, when circulating corticosteroids are undetectable; however, with adrenalectomy alone, pouch formation is barely affected. This we took to be a possible indication of an effect of local, non-adrenal steroids in maintaining pouch tissue. Spironolactone inhibits angiogenesis. A recent clinical study demonstrates the efficacy of low-dose spironolactone in enhancing survival in patients with advanced chronic cardiac failure. Although it is not known how spironolactone brings about such an improvement in survival, we would propose that inhibition of fibrous tissue formation and/or angiogenesis might be important contributory factors. Further studies are required to address the relative contributions of circulating vs local aldosterone in promoting normal vs pathologic connective tissue formation.
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PMID:Extra-adrenal mineralocorticoids and cardiovascular tissue. 1037 93

New guidelines for managing heart failure urge physicians to identify patients likely to benefit from therapy, obtain an echocardiogram to measure the ejection fraction, and, in patients with systolic dysfunction (i.e., an ejection fraction < or = 40%), institute therapy with an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker if at all possible. Digoxin and diuretics can relieve symptoms but do not affect the mortality rate. Spironolactone in low nondiuretic doses may reduce mortality when added to baseline drug regimens. The proper role of angiotensin II receptor blocking agents has yet to be determined.
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PMID:Heart failure: highlights from new consensus guidelines. 1064 72

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

An intracardiac aldosterone system which responds to short- and long-term physiological stimuli has been described. This cardiac generated aldosterone has possibly autocrine or paracrine actions. Normal cardiac tissue contains mineralocorticoid receptors (MR) and cardiac high affinity MR are localized in cardiac myocytes and endothelial cells. Data concerning the presence of MR in cardiac fibroblasts are, however, controversial. MR are not specific for aldosterone but they also bind glucocorticoids. Cardiac fibroblasts however contain the enzyme 11beta-hydroxy-steroid dehydrogenase II which converts these glucocorticoids to inactive metabolites. Discordant findings on the in vitro effect of aldosterone on the collagen synthesis in cardiac fibroblasts are reported and can at least partly attributed to the presence of various fibroblasts phenotypes. During chronic aldosterone infusion in uninephrectomized rats on a high-salt diet, a marked accumulation of interstitial and to a lesser extent perivascular collagen occurs in the heart in both ventricles. This cardiac fibrosis in this aldosteronism model is prevented by spironolactone. This effect of aldosterone is crucially dependent on the salt status of the rat. Indeed, rats on a restricted salt intake infused with aldosterone had no cardiac fibrosis above control levels. During the continuous infusion of aldosterone in the rat the appearance of fibrosis was delayed and starts 4 weeks after the beginning of the infusion which argues against a direct effect of aldosterone. The mechanism of aldosterone-salt induced cardiac fibrosis possibly involves angiotensin II acting through upregulated AT1 receptors and the cardiac AT1 receptor is the target for aldosterone. An accumulation of collagen in the heart has also been found in patients with adrenal adenomas and during chronic activation of the renin-angiotensin-aldosterone system such as in surgically induced unilateral renal ischemia, unilateral renal artery banding or renovascular hypertension. Spironolactone prevents aortic collagen accumulation in spontaneously hypertensive rats. In patients with stable chronic heart failure spironolactone treatment in addition to diuretics and angiotensin-converting enzyme (ACE) inhibition reduced circulating levels of procollagen type III N-terminal aminopeptide. Also, in the Randomized Aldactone Evaluation Study spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics and digitalis in patients with symptomatic heart failure defined as NYHA classes III-IV reduces total mortality by 30%.
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PMID:Induction of cardiac fibrosis by aldosterone. 1088 42

Recent data show that blockade of aldosterone receptors by spironoloctone reduces the risk of morbidity and death among patients with severe heart failure. Heart failure secondary to ischemia is characterized by an imbalance of the autonomic nervous system, which can be assessed by analysis of the heart rate variability (HRV). Spironolactone's effects on HRV are not well defined. If spironolactone has beneficial effects on HRV, this would contribute to favorable results. We therefore measured Holter-derived HRV indexes in a group of 126 patients with heart failure, aged 36 to 83 years, with angiographically proved coronary artery disease, on 3 separate occasions. Patients' sodium intake was restricted; therapy with enalapril, furosemide, and digoxin was begun, and 2 weeks after this standard therapy, spironolactone 50 mg/day was added. Evaluations were done at baseline, and the first and 12th months. After spironolactone, the triangular interpolation of the NN histogram (from 233.0 +/- 98 to 291.7 +/- 74 ms and 340.5 +/- 130 ms, p <0.001) and the percentage of differences between successive normal RR intervals differing >50 ms over a 24-hour electrocardiography (from 2.9 +/- 2.4% to 4.3 +/- 5.2% and 3.9 +/- 2.6%, p <0.002) increased significantly. Ejection fraction and functional classes were also improved. These data imply that in patients with heart failure who are taking conventional drugs, the addition of spironolactone induces a favorable sympathovagal balance. These changes, as assessed by the triangular interpolation of the NN histogram and the percentage of differences between successive normal RR intervals differing >50 ms over a 24-hour electrocardiography, and observed at 1 month after therapy, persisted in the long term.
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PMID:Effects of spironolactone on heart rate variability and left ventricular systolic function in severe ischemic heart failure. 1098 Feb 17

Spironolactone is an aldosterone antagonist which has been used as a mild potassium-sparing diuretic and in treatment of ascites in liver failure. Recent studies have shown that it has an additive effect to those of ACE inhibitors in heart failure treatment.
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PMID:Spironolactone in heart failure--a revived role for an old drug. 1109 72

Physicians must aggressively treat heart failure in the early stages to prevent disease progression and improve survival. Early treatment implies early diagnosis of left ventricular (LV) dysfunction, before the onset of symptoms. Patients with risk factors for the development of heart failure, especially coronary disease or hypertension, should undergo echocardiography to evaluate LV function. Patients with LV systolic dysfunction should be further evaluated to determine the type of cardiac dysfunction, uncover correctable etiologic factors, determine prognosis, and guide treatment. Angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking drugs improve survival and are integral to the treatment plan. Physicians should prescribe an ACE inhibitor as initial therapy for all patients with LV systolic dysfunction unless there are specific contraindications. The combination of hydralazine and isosorbide dinitrate is an acceptable alternative therapy for patients who cannot take ACE inhibitors. Diuretics should be used if there are signs or symptoms of volume overload. Beta-adrenergic blocking drugs should be added to therapy in stable patients with mild to moderate heart failure after optimal treatment with ACE inhibitors, diuretics, or other vasodilators. Digoxin should be used routinely in patients with severe heart failure and should be added to therapy in patients with mild to moderate heart failure who remain symptomatic despite optimal doses of ACE inhibitors and diuretics. Spironolactone should be added, but electrolytes should be closely monitored. Warfarin anticoagulation should be considered in patients with a left ventricular ejection fraction (LVEF) of 35% or less. Until survival data exist, angiotensin receptor blockers (ARBs) should not be used as initial therapy or as sole therapy but can be used for ACE-intolerant patients or can be added to standard heart failure therapy. Outpatient use of intravenous inotropic therapy should be avoided. Patients with severe heart failure should have peak oxygen consumption measured to quantify functional impairment, determine prognosis, and identify the need for advanced heart failure therapy. Patients who remain symptomatic while receiving optimal standard therapy should be referred early to a specialized heart failure center.
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PMID:Chronic Heart Failure. 1109 88

Aldosterone escape during chronic angiotensin-converting enzyme (ACE) inhibition may contribute to the high mortality among patients with heart failure. Aldosterone exerts several detrimental effects in the pathophysiology of heart failure. Spironolactone, an aldosterone antagonist, has proved beneficial when added to ACE inhibitors in patients with severe heart failure. However, spironolactone has substantial side effects mostly due to anti-androgen and anti-progestagen actions. This may limit its use in less severe heart failure. Recently, more selective aldosterone antagonists have been developed, which appear to have the same potential as spironolactone with fewer side effects. Trials to assess efficacy of these drugs in hypertension and mild heart failure are now being started.
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PMID:[Effect of aldosterone antagonism in heart failure: pharmacotherapeutic options]. 1121 45


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