Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In clinical trials of heart failure, spironolactone, an antagonist of the mineralocorticoid receptor (MR), reduced mortality rates by unknown mechanisms. We hypothesized that spironolactone functions by upregulating expression of certain cardiovascular genes. An RNA differential display technique was used to identify genes whose expression was increased by spironolactone in an Xenopus kidney epithelial cell line (A6), a known target of aldosterone. We found that integrin beta3 gene expression was increased by spironolactone, and reversed by aldosterone or dexamethasone in a dose dependent manner. Competition binding studies and RT-PCR indicate the presence of MR in A6 cells, suggesting that regulation of expression occurred primarily through MR. Spironolactone also increased integrin beta3 expression in rat neonatal cardiomyocytes. In summary, spironolactone increases integrin beta3 gene expression in kidney epithelial cells and cardiomyocytes. The findings suggest new mechanisms for spironolactone actions with possible relevance to treatment of heart disease.
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PMID:Spironolactone increases integrin beta3 gene expression in kidney and heart muscle cells. 1224 40

Reduction of excessive neurohumoral activation in chronic heart failure (CHF) improves the prognoses. In addition to reduction of angiotensin production or angiotensin II action and the influence of the sympathoadrenal system also blocking of aldosterone effects becomes part of the therapeutic procedure in patients with CHF. Excessive systemic and probably also local aldosterone production promotes undesirable fluid retention, hypokalaemia and hypomagnesaemia, induction of hypertrophy and fibrosis of the heart muscle and blood vessels and the development of endothelial dysfunction, peripheral vasoconstriction and depression of the baroreflex. In addition to classical effects also the existence of a rapid, so-called non-genomic effect of aldosterone is assumed. Adding a blocker of aldosterone receptors to ACE inhibition was not recommended due to possibility development of hyperkalaemia. Later it was revealed that ACE inhibitors are unable to block sufficiently the action of aldosterone and that addition of spironolactone in small amounts to ACE inhibition and diuretics does not cause in patients with CHF a major increase of the potassium level. In the RALES study (Randomized Aldacton Evaluation Study) comprising 1663 patients with serious heart failure (NYHA III, IV) addition of 25 mg spironolactone to standard treatment with ACE inhibitor, diuretic and as rule also digoxin reduced the mortality by another 30% as compared with the addition of placebo. Undesirable effects were minimal. As to potential protective mechanisms of spironolactone the greatest importance is ascribed to the reduction of excessive fibrosis of the heart muscle. Spironolactone reduces the level of the circulating N-terminal aminopeptide procollagen type III the high level of which is associated with deterioration of the prognosis.
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PMID:[The significance of aldosterone in chronic heart failure: the RALES study]. 1242 9

The Randomized Aldactone Evaluation Study (RALES) demonstrated a substantial clinical benefit to blocking the effects of aldosterone (Aldo) in patients with heart failure. We recently demonstrated that the enhanced renal conservation of sodium and water in rats with heart failure can be reduced by blocking the central nervous system effects of Aldo with the mineralocorticoid receptor (MR) antagonist spironolactone (SL). Preliminary data from our laboratory suggested that central MR might contribute to another peripheral mechanism in heart failure, the release of proinflammatory cytokines. In the present study, SL (100 ng/h for 21 days) or ethanol vehicle (Veh) was administered via the 3(rd) cerebral ventricle to one group of rats after coronary ligation (CL) or sham CL (Sham) to induce congestive heart failure (CHF). In Veh-treated CHF rats, tumor necrosis factor-alpha (TNF-alpha) levels increased during day 1 and continued to increase throughout the 3-wk observation period. In CHF rats treated with SL, started 24 h after CL, TNF-alpha levels rose initially but retuned to control levels by day 5 after CL and remained low throughout the study. These findings suggest that activation of MR in the central nervous system plays a critical role in regulating TNF-alpha release in heart failure rats. Thus some of the beneficial effect of blocking MR in heart failure could be due at least in part to a reduction in TNF-alpha production.
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PMID:Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats. 1252 82

In studies of animals, increases in aldosterone are associated with myocardial necrosis and fibrosis, and treatment with spironolactone, an antagonist of aldosterone, improved clinical outcomes in patients with heart failure. In the present study, we explored nitric oxide (NO), a signaling molecule involved in cardiac function, as a potential mediator of aldosterone's effects on the heart. Levels of both inducible NO synthase (iNOS) and NO from isolated rat neonatal cardiomyocytes pretreated with IL-1 were found to be decreased with exposure to aldosterone or dexamethasone in a dose-dependent manner. Spironolactone increased iNOS expression and prevented inhibition by aldosterone, consistent with a mineralocorticoid receptor-mediated mechanism for iNOS down-regulation. Aldosterone had no effect on iNOS mRNA levels, indicating a posttranscriptional mechanism for the inhibition of iNOS. Neutralization of TGF-beta 1 using a specific antibody reversed aldosterone-dependent iNOS and NO down-regulation. In summary, aldosterone inhibited IL-1-induced iNOS expression posttranscriptionally by a TGF-beta -dependent mechanism. The decrease in NO synthesis could have relevance to known cardiac effects of aldosterone.
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PMID:Aldosterone inhibits inducible nitric oxide synthase in neonatal rat cardiomyocytes. 1269 75

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional cardiac disorder impairing the ability of the ventricles to fill with or eject blood. The approach to pharmacologic treatment has become a combined preventive and symptomatic management strategy. Ideally, treatment should be initiated in patients at risk, preventing disease progression. In patients who have progressed to symptomatic left ventricular dysfunction, certain therapies have been demonstrated to improve survival, decrease hospitalizations, and reduce symptoms. The mainstay therapies are angiotensin-converting enzyme (ACE) inhibitors and beta-blockers (bisoprolol, carvedilol, and metoprolol XL/CR), with diuretics to control fluid balance. In patients who cannot tolerate ACE inhibitors because of angioedema or severe cough, valsartan can be substituted. Valsartan should not be added in patients already taking an ACE inhibitor and a beta-blocker. Spironolactone is recommended in patients who have New York Heart Association (NYHA) class III to IV symptoms despite maximal therapies with ACE inhibitors, beta-blockers, diuretics, and digoxin. Low-dose digoxin, yielding a serum concentration <1 ng/mL can be added to improve symptoms and, possibly, mortality. The combination of hydralazine and isosorbide dinitrate might be useful in patients (especially in African Americans) who cannot tolerate ACE inhibitors or valsartan because of hypotension or renal dysfunction. Calcium antagonists, with the exception of amlodipine, oral or intravenous inotropes, and vasodilators, should be avoided in HF with reduced systolic function. Amiodarone should be used only if patients have a history of sudden death, or a history of ventricular fibrillation or sustained ventricular tachycardia, and should be used in conjunction with an implantable defibrillator [corrected]. Finally, anticoagulation is recommended only in patients who have concomitant atrial fibrillation or a previous history of cerebral or systemic emboli.
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PMID:Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations. 1272 48

Ischemic heart failure is induced by myocardial ischemia, which is probably the commonest cause of left ventricular systolic dysfunction. Theoretically, there are two main strategies to treat the patients with ischemic heart failure; to retard progression of the dysfunction, and to relief and prevent myocardial ischemia. The management with angiotensin converting enzyme(ACE) inhibitor and beta-blocker improve the prognosis of ischemic heart failure by enhancing the left ventricular function and preventing coronary event. Spironolactone also seems to improve their prognosis. In contrast, treatments directed specifically at coronary arteries, such as antithrombotic agents and revascularization, have not been proven to be effective and safe to these patients yet. Large scale clinical trials are currently underway investigating the effect of treatment, such as aspirin, warfarin, clopidogrel and revascularization which are targeted to the coronary syndrome.
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PMID:[Ischemic heart failure]. 1275 16

Clinical trials have demonstrated that angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and spironolactone improve survival in patients with heart failure. Because patients with heart failure and renal insufficiency have been underrepresented in these trials, little evidence is available to guide clinicians in the optimal management of patients with both conditions. Approximately one third to one half of patients with heart failure have renal insufficiency (estimated glomerular filtration rate [GFR] <60 mL/min per 1.73 m2), and renal insufficiency is among the strongest predictors of mortality in patients with heart failure. Evidence supports the use of ACE inhibitors to improve survival in patients with moderate renal insufficiency (GFR, 30 to 60 mL/min per 1.73 m2), but there is little evidence with which to weigh the risks and benefits in patients with more advanced renal dysfunction. beta-Blockers improve survival in patients with heart failure, and their beneficial effect is unlikely to differ according to renal function. Spironolactone improves outcomes in patients with advanced heart failure, but renal insufficiency appears to increase risk for hyperkalemia and limits the use of the drug in patients with severe renal insufficiency. Future clinical trials in heart failure should include a representative number of patients with renal insufficiency to improve the evidence base and outcomes in this vulnerable population.
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PMID:Pharmacotherapy for heart failure in patients with renal insufficiency. 1517 12

Hyperkalemia is a common occurrence in patients with congestive heart failure, particularly when renal failure coexists. The level of renal function in congestive heart failure is often difficult to ascertain because good measurement tools for estimation of renal function are not available. Serum creatinine values have often been offered as a good gauge of renal function, although in most cases true renal function is appreciably lower than the estimate derived from a specific serum creatinine value. Thus, patients with congestive heart failure very commonly, particularly in the advanced stages of the disease, have moderate renal insufficiency, either due to specific heart failure-related renal perfusion changes or as the result of renal involvement from the same processes having caused the heart failure, as is the case with diabetes. It is in this setting of mild-to-moderate levels of renal failure that therapies, such as angiotensin-converting inhibitors, angiotensin-receptor blockers, and aldosterone-receptor antagonists, are administered either individually or collectively. Each of these drug classes reduces the homeostatic ability to eliminate ingested potassium loads by the renal route and increase the tendency to evolve into a hyperkalemic state. This is noteworthy because aldosterone-receptor antagonists are increasingly considered as important therapies in the long-term management of heart failure. Spironolactone has been employed in this capacity and a new aldosterone-receptor antagonist, eplerenone, will become available in the near future, which further increases the importance of evaluating and treating the hyperkalemia risk in a timely manner.
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PMID:Hyperkalemia, congestive heart failure, and aldosterone receptor antagonism. 1293 59

Metabolic balance studies were carried out on five patients with resistant heart failure treated with spironolactone and other diuretics. Spironolactone alone had little effect. When it was used in a daily dose of 400-600 mg. in combination with hydrochlorothiazide 100 mg. daily, the results were excellent in two patients. One of these was still free of failure after 12 months on combined therapy. In the other patient the serum potassium became elevated after a good diuresis, though on subsequent intermittent therapy with the drug the patient remained well for 12 months. In two other patients administration of spironolactone had to be discontinued because of elevation of the serum potassium before a good diuresis could take place. The fifth patient died.Spironolactone can be a useful adjunct to the therapy of resistant heart failure, but there appears to be a real danger of causing the serum potassium to rise to toxic levels in patients so treated.
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PMID:Metabolic studies on patients with resistant heart failure treated by spironolactone. 1396 89

Aldosterone has been implicated for many years as an important substance in the pathogenesis of heart disease. Elevated aldosterone concentrations have been documented in patients with hypertension and heart failure, leading to the use of aldosterone antagonists for the treatment of these conditions. Spironolactone has been used for nearly 2 decades for the treatment of hypertension, and more recently, has become a standard agent for the treatment of systolic heart failure. Spironolactone, however, is a nonselective antagonist of the aldosterone receptor, binding also to other steroid receptors and causing a significant percentage of patients to have sex hormone-related adverse effects such as gynecomastia. Eplerenone is the first of a new class of drugs known as selective aldosterone receptor antagonists, which selectively block the aldosterone receptor with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Eplerenone has been shown to be beneficial both as monotherapy and combination therapy for lowering elevated blood pressure in patients with hypertension. The antihypertensive efficacy of eplerenone is roughly similar to that of other antihypertensive agents, although in 1 study black patients responded better with eplerenone than losartan. In addition, eplerenone has demonstrated some renoprotective effects in diabetic patients with hypertension. Recently, eplerenone was shown to significantly reduce mortality and cardiovascular morbidity in post-myocardial infarction patients with systolic heart failure currently taking standard heart failure medications. Eplerenone is generally well tolerated, although hyperkalemia with this agent is of some concern. Eplerenone is metabolized by CYP3A4 and administration with potent inhibitors of this enzyme is contraindicated because of the risk of hyperkalemia. In summary, eplerenone has proven to be beneficial in treating hypertension and post-myocardial infarction heart failure. Its exact place in therapy will in large part be determined by its cost and whether or not future studies will be able to demonstrate a clinical benefit of this agent over spironolactone or other currently available treatments.
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PMID:Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure. 1450 34


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