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)

Heart failure continues to significantly impact morbidity and mortality after acute myocardial infarction (AMI), especially when associated with left ventricular systolic dysfunction (LVSD). Therefore, routine use of optimal therapy for patients with heart failure after AMI is needed in the future. Data from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) has demonstrated that addition of eplerenone to standard therapy in patients with LVSD and clinical heart failure post-AMI significantly improves outcomes in these patients, providing the basis for acceptance of aldosterone blockade as an integral component of therapy. However, further studies are needed to more broadly explore the usefulness of aldosterone blockade in heart failure therapy. As research clarifies the many complex pathophysiologic processes involved in post-AMI remodeling, treatment should continue to move beyond symptom-targeted therapies to disease- and mechanism-targeted therapies that will further improve outcomes in the setting of heart failure post-AMI and beyond.
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PMID:Role of aldosterone blockade for treatment of heart failure and post-acute myocardial infarction. 1669 33

There is increasing evidence that aldosterone exerts major adverse cardiovascular effects through classical mineralocorticoid receptors (MR) in nonepithelial tissues such as the brain and heart. This nonepithelial role of aldosterone has been underscored by the recent Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS). These studies also showed that when using MR antagonist as an "organ protecting" drug, further organ protection could be derived by the addition of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 receptor blocker (ARB). The long-term effect of aldosterone was not inhibited in some subjects, so the possibility of organ damage due to so-called "breakthrough" aldosterone cannot be ignored. Nonepithelial MR-mediated effects played a major role in this aldosterone effect. These effects can be inhibited by MR antagonist at a small dose, not lower blood pressure. Therefore, the idea is now to combine a small dose of MR antagonist with an ACE inhibitor or ARB. However, warnings have been given recently due to the emergence of hyperkalemia and other adverse effects associated with inappropriate combination therapy. It is important to note that, if the eligibility criteria of RALES and EPHESUS are fulfilled, the potassium level will rarely become problematic. Therefore, the recent increase in the incidence of adverse effects can be attributed to the incorrect application of combination therapy. Elderly patients or those with dehydration, renal dysfunction, and aggravated heart failure require further close monitoring or termination of spironolactone administration. The combination of an MR antagonist and renin-angiotensin inhibitors should be a useful strategy if subjects are carefully selected, and carefully monitored. Adverse effects will occur only if the usage recommendations based on previous researches are not followed.
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PMID:Combination therapy with aldosterone blockade and renin-angiotensin inhibitors confers organ protection. 1677 27

Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-alpha in heart failure (HF) rats. TNF-alpha and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E2 by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-alpha, interleukin (IL)-1beta and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-alpha, IL-1beta, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E2 in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.
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PMID:Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure. 1696 Jan

Aldosterone plays a pivotal role in sodium and water homeostasis, in particular in patients with heart failure or high blood pressure. These medications, when used on top of a standard therapy, improve the outcome of patients with heart failure and are also effective in lowering blood pressure of hypertensive patients. The major risk associated with the use of these antagonists is hyperkalemia, which can be prevented in avoiding their prescription in patients with impaired renal function. Eplerenone has the advantage, compared with spironolactone, to be better tolerated in terms of "hormonal" adverse effects.
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PMID:[The revived interest in aldosterone antagonists]. 1701 41

Recent evidence points to a role for the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of atherosclerosis and its complications, including acute angina pectoris. Two large trials in heart failure have clearly demonstrated that blocking aldosterone improves mortality and that this benefit occurs over and above standard therapy with angiotensin-converting enzyme (ACE) inhibitors. The question that naturally arises from these landmark studies is whether aldosterone blockade would produce the same benefits in patients with coronary artery disease (CAD) but no heart failure. There are three reasons to believe this might be the case. Firstly, angiotensin II (Ang II) and aldosterone produce similar biological effects and Ang II withdrawal has been shown to benefit patients with angina; aldosterone blockade may therefore follow in the footsteps of ACE inhibitors, as it did in heart failure, and produce benefits in vascular patients without heart failure. Secondly, one of the main mechanisms which is thought to be responsible for the benefit of aldosterone blockade in the Randomised ALdactone Evaluation Study (RALES) and Eplerenone Post-AMI Heart Failure Survival Study (EPHESUS), is that it improves endothelial/vascular function and endothelial/vascular dysfunction is the fundamental abnormality in angina pectoris. Finally, aldosterone blockade has been shown to reduce atherosclerosis in animal studies of atherosclerosis without heart failure, which are analogous to CAD patients.
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PMID:Aldosterone blockade over and above ACE-inhibitors in patients with coronary artery disease but without heart failure. 1708 70

We investigated the role of nuclear factor kappaB (NF-kappaB) in the cytokine-mediated induction of cyclooxygenase-2 activity in the paraventricular nucleus of hypothalamus (PVN), a critical cardiovascular and autonomic center, in rats with heart failure (HF). Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. HF rats were treated orally for 6 weeks with vehicle (tap water), the NF-kappaB inhibitor pyrrolidine dithiocarbamate (150 mg/kg per day), or the mineralocorticoid receptor antagonist eplerenone (30 mg/kg per day), which has been shown to reduce circulating proinflammatory cytokines in this model. Compared with sham surgery, HF rats had higher (P<0.05) levels of aldosterone, interleukin-1beta and norepinephrine in plasma and prostaglandin E2 in cerebrospinal fluid. In the PVN, NF-kappaB p50 precursor p105 mRNA increased, and mRNA for its inhibitor, IkappaB, decreased (P<0.05). Cyclooxygenase-2 mRNA and protein expression was increased in perivascular cells of the PVN. Both pyrrolidine dithiocarbamate and eplerenone reduced (P<0.05) p105 mRNA and increased IkappaB mRNA in PVN. Both also reduced (P<0.05) cyclooxygenase-2 mRNA and protein expression in PVN, cerebrospinal fluid prostaglandin E2, and plasma norepinephrine. Eplerenone, but not pyrrolidine dithiocarbamate, reduced plasma interleukin-1beta. Pyrrolidine dithiocarbamate and eplerenone had no effect on plasma aldosterone. The results suggest that activation of NF-kappaB is an intermediary step in cytokine-mediated induction of cyclooxygenase-2 in the PVN of HF rats. By enhancing access of prostaglandin E2 to hypothalamic neurons, this mechanism may contribute to augmented sympathetic nerve activity in HF.
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PMID:Increased cyclooxygenase-2 expression in hypothalamic paraventricular nucleus in rats with heart failure: role of nuclear factor kappaB. 1724 97

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the American College of Cardiology meeting in March 2007. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. The ALPHA study suggested that patients with heart failure (HF) due to idiopathic dilated cardiomyopathy who have a negative T-wave alternans test have a good prognosis and are unlikely to benefit from ICD therapy. EVEREST provides some evidence of short-term symptom benefit of tolvaptan in patients with acute decompensated HF but no clinically important long-term benefit. FUSION II failed to show a benefit of nesiritide in patients with chronic decompensated HF. Reducing blood pressure in hypertensive patients improved diastolic dysfunction in VALIDD. Eplerenone did not improve left ventricular remodelling in mild to moderate chronic HF. Selecting HF patients for revascularisation using FDG-PET imaging did not significantly improve outcome. Crataegus extract added to standard HF therapy did not reduce morbidity or mortality in SPICE. The COURAGE study, conducted in patients without HF or major cardiac dysfunction, showed that PCI did not reduce cardiac morbidity or mortality and can be safely deferred in patients with stable coronary disease on optimal medical therapy. The COACH study failed to show that HF nurse-intervention could reduce hospitalisations but did show trends to lower mortality, especially amongst patients with reduced ejection fraction; however, the smaller REMADHE study suggested striking benefits on morbidity and mortality. A large study of BNP provided additional information on its ability to distinguish cardiac and pulmonary breathlessness. The importance of dietary intervention in post-MI patients was highlighted by the findings of THIS-diet study.
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PMID:Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet. 1748 46

Mineralocorticoid receptor (MR) antagonists decrease the incidence of sudden cardiac death in patients with heart failure, as has been reported in two clinical trials (Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). Aldosterone has been shown to increase the propensity to arrhythmias by changing the expression or function of various ion channels. In this study, we investigate the effect of aldosterone on the expression of hyperpolarization-activated current (I(f)) channels in cultured neonatal rat ventricular myocytes, using the whole cell patch-clamp technique, real-time PCR, and Western blotting. Incubation with 10 nM aldosterone for 17-24 h significantly accelerates the rate of spontaneous beating by increasing diastolic depolarization. I(f) current elicited by hyperpolarization from -50 to -130 mV significantly increases aldosterone by 10 nM (by 1.9-fold). Exposure to aldosterone for 1.5 h increases hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 mRNA by 26.3% and HCN4 mRNA by 47.2%, whereas HCN1 mRNA expression remains unaffected. Aldosterone (24-h incubation) increases the expression of HCN2 protein (by 60.0%) and HCN4 protein (by 84.8%), but not HCN1 protein. MR antagonists (1 microM eplerenone or 0.1 microM spironolactone) abolish the increase of I(f) channel expression (currents, mRNA, and protein levels) by 10 nM aldosterone. In contrast, 1 microM aldosterone downregulated I(f) channel gene expression. Glucocorticoid receptor antagonist (100 nM RU-38486) did not affect the increase of I(f) current by 10 nM aldosterone. These findings suggest that aldosterone in physiological concentrations upregulates I(f) channel gene expression by MR activation in cardiac myocytes and may increase excitability, which may have a potential proarrhythmic bearing under pathophysiological conditions.
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PMID:Aldosterone modulates I(f) current through gene expression in cultured neonatal rat ventricular myocytes. 1764 63

Aldosterone, a neurohormone known to affect electrolytes, has recently been implicated as playing a major role in the progression of heart failure, particularly in patients with systolic dysfunction. Major clinical trials designed to analyze clinical outcomes using an aldosterone antagonist have been done in two groups with heart failure. The first was the Randomized Aldactone Evaluation Study, which was done in symptomatic chronic advanced heart failure patients and showed that an aldosterone antagonist, spironolactone, reduced mortality significantly compared with placebo. Very few of these patients were on standard therapy with beta blockade. Another study, the Eplerenone Post myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS), done in post-myocardial infarction patients with heart failure, demonstrated a significant reduction in mortality and hospitalizations for patients randomized to the aldosterone antagonist eplerenone. These trial results provide the background for aldosterone antagonist therapy in chronic advanced heart failure patients as well as post-myocardial infarction heart failure patients with reduced ejection.
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PMID:Aldosterone antagonism in heart failure. 1807 11

Increasing recognition of the role of aldosterone in cardiovascular disease has been supported by a significant body of evidence from animal models. This evidence has been translated into clinical practice, and large-scale, randomized, placebo-controlled trials have confirmed the beneficial effects of mineralocorticoid blockade in patients with heart failure. As a consequence, there has been a resurgence in the use of mineralocorticoid-receptor antagonists in clinical practice that has prompted the search for a potent and specific antagonist without the sexual side effects of spironolactone. Eplerenone, a mineralocorticoid-receptor antagonist with minimal binding to the progesterone and androgen receptors, is now licensed for treatment of heart failure in Europe and heart failure and hypertension in the US; it has also been proposed as a treatment for a variety of cardiovascular conditions. This article reviews the current concepts of the actions of aldosterone at a cellular level. Recent findings regarding its role as a cardiovascular hormone, both in animal models and human studies, are discussed. We also describe the development of mineralocorticoid-receptor blockers following the isolation of aldosterone and discuss the subsequent search for a specific mineralocorticoid antagonist. In addition we detail the effects of eplerenone in a number of clinical situations and outline its potential future applications.
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PMID:Drug Insight: eplerenone, a mineralocorticoid-receptor antagonist. 1808 45


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