eplerenone and Ventricular-Dysfunction--Left

Topics: Animals; Clinical Trials as Topic; Eplerenone; Evidence-Based Medicine; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Percutaneous Coronary Intervention; Recovery of Function; Risk Factors; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Heart failure (HF), with or without reduced ejection fraction, and multidrug-resistant hypertension (RHT) are major worldwide health problems of ever-increasing proportions. The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have proved valuable additions to the overall management of these disorders in patients without significant renal dysfunction.. Neurohormonal activation, including aldosteronism, in HF and RHT, has provided the pathophysiologic basis for the inclusion of MRA in the overall management of these disorders and the respective survival benefit and control of blood pressure. Furthermore, MRAs attenuate the appearance of secondary hyperparathyroidism that accompanies excretory Ca2+ losses induced by aldosteronism in which elevated parathyroid hormone levels raise the risk of adverse cardiovascular events and atraumatic bone fracture. Serial surveillance of serum electrolytes and creatinine levels is mandated to avoid serious hyperkalemia (potassium concentration >5.5 mEq/L) and its attendant risks in patients receiving MRAs.. Mineralocorticoid receptor antagonists are a valuable addition to the practice of medicine. Their judicious use in patients with HF or RHT can improve treatment of these patients.

Topics: Eplerenone; Heart Failure; Humans; Hyperkalemia; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left

Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post-infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co-morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence-based approach with personalized medicine.

Topics: Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left

Mineralocorticoid receptor antagonists (MRA's) have been shown to be effective in patients with HFREF while their role in patients with HFPEF remains controversial. Despite a class one indication in both the ESC and AHA/ACC heart failure guidelines in patients with HFREF MRA's remain underused, in large part due to the fear of hyperkalaemia and renal dysfunction. While hyperkalaemia is a potential risk of MRA's, their use when potassium and renal function monitoring is properly carried out is minimal compared with their benefits in appropriate patients. New nonsteroidal MRA's and new potassium binding polymers currently under development hold the promise of further reducing the risks of hyperkalaemia while allowing higher doses of MRA's. They have been shown to overcome diuretic resistance and to potentially extend their benefits to patients with acute decompensated heart failure and those with chronic renal disease. While we await the results of studies with these new agents; application of current guidelines recommended therapies, including MRA's hold the best promise to further reduce cardiovascular mortality, hospitalisations for heart failure, and therefore, health care costs in patients with heart failure.

Topics: Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left

In this article, we review the evidence supporting the use of eplerenone for improving cardiovascular prognosis. Activation of the renin-angiotensin-aldosterone system plays a major role in the pathogenesis of heart disease, and blockage of this system has been shown to improve prognosis in several cardiovascular conditions. The 2 marketed aldosterone antagonists, spironolactone and eplerenone, improve prognosis in patients with left ventricular (LV) dysfunction and are effective antihypertensive medications. In addition, a potential role for aldosterone antagonists in the treatment of patients with heart failure and preserved LV function has been suggested and is currently being evaluated in clinical trials. In patients with myocardial infarction having LV dysfunction and evidence of heart failure, eplerenone improves cardiovascular outcomes and attenuates myocardial remodeling. In addition, eplerenone is effective for the treatment of hypertension, where it regresses both LV hypertrophy and proteinuria (2 powerful markers of increased cardiovascular risk). In contrast to spironolactone, eplerenone essentially lacks the sexual side effects that sometimes limit the use of spironolactone. Hyperkalemia is the main potential side effect of eplerenone, especially when used in combination with other medications that can cause hyperkalemia. Adequate patient selection and monitoring are therefore of utmost importance when using this medication. In conclusion, eplerenone is a medication that offers the cardiovascular therapeutic and prognostic benefits of aldosterone antagonism but with fewer side effects compared to spironolactone.

Topics: Cardiovascular Diseases; Eplerenone; Heart Failure; Humans; Hyperkalemia; Hypertension; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Renin-Angiotensin System; Risk; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Fifty years after its discovery, aldosterone continues to stimulate interest as a therapeutic target. Early studies focused on aldosterone's actions on hypertension, the kidney, and electrolyte handling. More recently, its actions on the heart and cardiovascular system have become more apparent. Aldosterone causes cardiac fibrosis and remodeling, and stimulates neurohormonal systems that adversely affect the cardiovascular system. Aldosterone antagonism attenuates these negative effects. Clinical studies have applied this science and demonstrated improved morbidity and mortality with aldosterone blockade, specifically in patients with chronic heart failure and patients who are postmyocardial infarction and with depressed left ventricular function. This article will address the pathophysiology of aldosterone in cardiac fibrosis and remodeling, review the current clinical trial data, and explore the application of aldosterone blockade in an expanded heart failure population. The Randomized Aldactone Evaluation Study showed that the aldosterone antagonist spironolactone reduced mortality when compared to placebo in patients with chronic advanced heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study demonstrated a significant reduction in mortality and hospitalizations for patients randomized to the aldosterone antagonist eplerenone. A more provocative question is whether aldosterone antagonism will afford the same protection in patient populations with heart failure and preserved left ventricular function. Clinical trials are underway, and results are eagerly awaited.

Topics: Aldosterone; Cardiovascular Agents; Drug Therapy, Combination; Eplerenone; Fibrosis; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardium; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

The presence of heart failure or left ventricular systolic dysfunction in the setting of acute myocardial infarction is associated with poor prognosis. Aldosterone is an important downstream mediator of the renin-angiotensin-aldosterone system that promotes myocardial collagen deposition, myocardial fibrosis, apoptosis, ventricular remodeling, and endothelial dysfunction. It may play an important role in the increased morbidity and mortality and the development and progression of heart failure after acute myocardial infarction. Extending the findings from the Randomized Aldactone Evaluation Study (RALES) in patients with chronic heart failure, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone offered a significant survival benefit, attenuation of progression of heart failure, and prevention of sudden cardiac death when used in addition to optimal medical therapy. The current evidence-based guidelines now suggest that aldosterone blockade should be an integral component of heart failure therapy to improve outcomes in this high-risk population.

Topics: Eplerenone; Evidence-Based Medicine; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Receptors, Mineralocorticoid; Risk Factors; Spironolactone; Ventricular Dysfunction, Left

Based on the RALES study, in patients with moderate to severe chronic heart failure and reduced left ventricular function, the nonselective aldosterone antagonist spironolactone has a well-established role in combination with ACE inhibition, beta-blockade and diuretics. This indication was recently reinforced by the guideline for chronic heart failure therapy of the German Cardiac Society, although there is no formal approval for spironolactone for this indication in Germany.. Heart failure after acute myocardial infarction represents a new indication for aldosterone receptor blockade. In the EPHESUS trial of patients with acute myocardial infarction, reduced ejection fraction, and clinical signs of heart failure, the selective aldosterone antagonist eplerenone in combination with ACE inhibition and beta-blockade significantly reduced mortality. The best benefit was achieved by early treatment, i. e., starting 3-7 days post myocardial infarction. In addition, as early as after 30 days, eplerenone-treated patients had significantly reduced mortality and hospitalization. Eplerenone was approved for the indication heart failure after acute myocardial infarction in late 2004 in Germany.. The present review summarizes the pathophysiological basis, the experimental and clinical trials that constitute the rationale for therapy with aldosterone antagonists in patients with acute myocardial infarction and heart failure. Tips for use in clinical practice are given which allow to profit from the effective potential for mortality and morbidity reduction of aldosterone receptor blockade and to minimize the risk of serious hyperkalemia.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diuretics; Drug Approval; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Practice Guidelines as Topic; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setting. However, lack of practical experience with aldosterone blockade may make clinicians hesitant to use these therapies. This review is based on a consensus cardiology conference that occurred in May 2005 (New York City) concerning these topics. Potential barriers to the use of aldosterone blockade are discussed and an algorithm for appropriate in-hospital pharmacologic management of AMI with LVSD and/or HF is presented.

Topics: Algorithms; Cardiac Output, Low; Eplerenone; Humans; Hyperkalemia; Hypotension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Risk Factors; Spironolactone; Systole; Ventricular Dysfunction, Left

Aldosterone blockade has been shown to be effective in reducing total mortality as well as hospitalization for heart failure in patients with systolic left ventricular dysfunction (SLVD) due to chronic heart failure and in patients with SLVD post acute myocardial infarction. The evidence for the effectiveness of aldosterone blockade in chronic heart failure comes from the randomized aldactone evaluation study (RALES) while that for patients post infarction from the eplerenone post acute myocardial infarction efficacy and survival study (EPHESUS). These studies suggest that mineralocorticoid receptor activation remains important despite the use of an angiotensin converting enzyme-inhibitor/angiotensin receptor blocking (ARB) agent and a beta blocker. Increasing evidence suggest that aldosterone blockade has important effects not only on the kidney but on ventricular remodeling, myocardial fibrosis, autonomic balance, fibrinolysis, oxidative stress, and activation of the NF-kappaB and AP-1 signaling pathways. The results of these studies in patients with SLVD has important implications not only for patients with chronic heart failure and post infarction but also for the therapy of patients with essential hypertension and other cardiovascular diseases.

Topics: Aldosterone; Angiotensin Receptor Antagonists; Digoxin; Enzyme Inhibitors; Eplerenone; Female; Humans; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Systole; Ventricular Dysfunction, Left

Aldosterone can cause cardiovascular injury in animals and men. The aldosterone blocker, spironolactone, has been shown to reduce mortality in patients with congestive heart failure. The use of this drug in arterial hypertension has been limited by the high frequency of adverse effects. Recently published data with a new aldosterone blocker, eplerenone, have confirmed the benefits of aldosterone blockade in patients post-myocardial infarction, as well as in the regression of left ventricular hypertrophy in hypertensive patients and of microalbuminuria in Type 2 diabetic patients. The fact that eplerenone is much better tolerated open the possibility of this therapy in cardiovascular, as well as in renal disease.

Topics: Animals; Eplerenone; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

We investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin II type 1 receptor antagonist on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI). Adding an aldosterone antagonist to an ACE inhibitor reduces mortality and morbidity in heart failure. Starting 1 day after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the angiotensin type 1 receptor antagonist candesartan (1 mg/kg/day), or a combination of both for nine weeks. Both monotherapies attenuated the rise in LV end-diastolic dimension (LVDd) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVDd and LVEDV and significantly improved LV function. Increased collagen type I and III gene expressions in the noninfarcted LV myocardium from MI placebo rats was attenuated by candesartan, but almost completely prevented by eplerenone and eplerenone/candesartan. The addition of eplerenone to candesartan prevented the increases in LV gene expression of ANP and BNP more effectively than either monotherapy. The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an candesartan substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.

Topics: Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Eplerenone; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Rats; Spironolactone; Tetrazoles; Ventricular Dysfunction, Left; Ventricular Remodeling

Eplerenone (Inspra) is a selective aldosterone blocker. Oral eplerenone is approved for use in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI) in the US and in European countries (e.g. the UK and The Netherlands). The addition of eplerenone to standard medical therapy significantly improved mortality and morbidity in patients with LV systolic dysfunction and clinical evidence of heart failure following acute MI in the large, well designed EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study) trial. The beneficial effects of eplerenone on all-cause mortality and cardiovascular mortality were seen within 30 days of randomisation. Eplerenone was generally well tolerated. Although a higher incidence of hyperkalaemia occurred with eplerenone than with placebo, the incidence of hypokalaemia was significantly lower with eplerenone treatment. Thus, the addition of eplerenone to standard medical therapy is an important new strategy for further improving mortality and morbidity in post-MI patients with LV systolic dysfunction and heart failure.

Topics: Animals; Area Under Curve; Economics, Pharmaceutical; Eplerenone; Half-Life; Heart Failure; Humans; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Rats; Spironolactone; Ventricular Dysfunction, Left

The American College of Cardiology provided much useful new information to inform those who care for patients with heart failure about what they should and should not adopt into current clinical practice. The EPHESUS trial suggests a much wider role for aldosterone antagonists for the management of heart failure and left ventricular systolic dysfunction. SPORTIF-III indicates we may have a safer, simpler warfarin substitute soon. ASCOT reinforces the potential futility of statin therapy unless it is well targeted. The results of the COMPANION study investigating cardiac resynchronisation devices and implantable defibrillators were encouraging but inconclusive and/or hard to interpret. UK-PACE again questions the use of dual chamber pacing. T-wave alternans is an interesting experimental technique that may be useful in selecting which patients need an implantable defibrillator, although the technology needs testing in an appropriate patient population.

Topics: Anticoagulants; Cardiac Pacing, Artificial; Defibrillators, Implantable; Electrocardiography; Eplerenone; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mineralocorticoid Receptor Antagonists; Pacemaker, Artificial; Spironolactone; Ventricular Dysfunction, Left; Warfarin

Topics: Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Aldosterone; Eplerenone; Forecasting; Heart Failure; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Patient Selection; Randomized Controlled Trials as Topic; Spironolactone; Systole; Ventricular Dysfunction, Left

Mineralocorticoid receptor (MR) blockade is effective in reducing total mortality and the incidence of heart failure in patients with systolic left ventricular dysfunction (SLVD) associated with chronic heart failure or post myocardial infarction. Pre-clinical and clinical studies in SLVD have shown that MR blockade reduces sudden cardiac death, left ventricular remodelling, left ventricular hypertrophy, endothelial dysfunction, autonomic imbalance, renal dysfunction and improves fibrinolysis. While MR blockade promotes sodium excretion and the combination of an angiotensin-converting enzyme inhibitor and a MR blocker have been shown to be more effective than either alone in causing natriuresis, it is unlikely that their beneficial effects can be explained solely on this basis. Aldosterone has been shown to have a number of adverse effects, including activation of other neurohumeral mediators, stimulation of active reactive oxygen species (ROS), activation of the NF-Greek small letter kappa kappabeta and AP-1 signalling pathways, vascular inflammation and fibrosis, myocardial hypertrophy, autonomic imbalance, and a decrease in fibrinolysis. MR blockade is, however, effective both in situations with and without an increase in serum aldosterone level, since the MR can be occupied and activated by cortisol as well as by aldosterone. In view of these mechanisms, MR blockade may play an important role not only on SLVD, but also in essential hypertension with normal systolic function, diastolic heart failure, valvular heart disease, vascular stiffening with ageing, progression of renal disease, and diabetes mellitus. This hypothesis will, however, require further prospective evaluation.

Topics: Animals; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Spironolactone; Ventricular Dysfunction, Left

The role of the renin-angiotensin-aldosterone system in the pathophysiology and treatment of hypertension and heart failure has been extensively studied. Angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers have been shown to effectively reduce blood pressure, protect the kidney, and reduce morbidity and mortality in patients with heart failure. Therefore, there is increased interest in the effects of aldosterone and the use of aldosterone-receptor antagonists in the treatment of cardiovascular disease. Eplerenone is the first selective aldosterone-receptor antagonist approved for the treatment of hypertension and left ventricular (LV) dysfunction after acute myocardial infarction (AMI).. The goal of this article was to review the pharmacologic properties, clinical efficacy, and tolerability of eplerenone in the treatment of hypertension, LV dysfunction, and proteinuria.. Relevant English-language articles were identified through searches of MEDLINE (1966-May 2003), Current Contents, and International Pharmaceutical Abstracts (1970-May 2003) using the terms hypertension, heart failure, eplerenone, aldosterone, and aldosterone antagonist. Other pertinent publications were identified from the reference lists of the identified articles. Information was also obtained from abstracts presented at national meetings and data on file with the manufacturer.. In clinical trials, eplerenone alone and in combination with renin-angiotensin blockade significantly reduced both systolic and diastolic blood pressure compared with placebo (P < 0.05 to P < 0.001). In EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), the addition eplerenone to optimal medical therapy reduced morbidity and mortality in patients with AMI and LV dysfunction, although the incidence of serious hyperkalemia was also significantly greater. In comparisons with spironolactone, eplerenone was associated with a lower incidence of gynecomastia and other sex hormone-related adverse effects.. Either alone or in combination with other antihypertensive agents, eplerenone appears to be effective for the treatment of hypertension. Morbidity and mortality were reduced when eplerenone was added to standard therapy for LV dysfunction complicating AMI. The use of eplerenone for hypertension or heart failure may be limited in patients at risk for hyperkalemia.

Topics: Area Under Curve; Clinical Trials as Topic; Drug Interactions; Eplerenone; Humans; Hyperkalemia; Hypertension; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; Proteinuria; Spironolactone; Ventricular Dysfunction, Left

There is no evidence that loop diuretics improve ventricular remodeling in patients with heart failure. Aldosterone receptor antagonists, which have an effect on natriuresis and diuresis, especially in conjunction with an angiotensin converting enzyme-inhibitor, have been shown to improve ventricular remodeling in patients with left ventricular systolic dysfunction. The mechanisms for this beneficial effect and a reduction in death due to progressive heart failure seen in the randomized aldosterone evaluation study (RALES) is likely related to the effect of aldosterone receptor antagonism on myocardial collagen formation and ventricular hypertrophy. Further proof of this hypothesis should be forthcoming from the results of the Eplerenone Heart Failure Efficacy and Survival Study (EPHESUS) early in 2003 in which the aldosterone receptor antagonist eplerenone is being evaluated in patients with systolic left ventricular dysfunction post myocardial infarction.

Topics: Diuretics; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left; Ventricular Remodeling

Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure.. In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100-200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment.. In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography.. Date of registration 25/08/2015 (EudraCT number: 2015-002,519-14).

Topics: Diabetes Mellitus, Type 2; Echocardiography; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Sodium changes are common in myocardial infarction (MI) complicated with left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). Sodium handling is fine-tuned in the distal nephron, were eplerenone exhibits some of its pleotropic effects. Little is known about the effect of eplerenone on serum sodium and the prognostic relevance of sodium alterations in patients with MI complicated with LVSD and/or HF.. The EPHESUS trial randomized 6632 patients to either eplerenone or placebo. Hyponatremia and hypernatremia were defined as sodium < 135 mmol/L or > 145 mmol/L, respectively. Linear mixed models and time updated Cox regression analysis were used to determine the effect of eplerenone on sodium changes and the prognostic importance of sodium changes, respectively. The primary outcomes were all-cause mortality and a composite of cardiovascular (CV) mortality and CV-hospitalization.. A total of 6221 patients had a post-baseline sodium measurement, 797 patients developed hyponatremia (mean of 0.2 events/per patient) and 1476 developed hypernatremia (mean of 0.4 events/per patient). Patients assigned to eplerenone had a lower mean serum sodium over the follow-up (140 vs 141 mmol/L; p < 0.0001) and more often developed hyponatremia episodes (15 vs 11% p = 0.0001) and less often hypernatremia episodes (22 vs. 26% p = 0.0003). Hyponatremia, but not hypernatremia was associated with adverse outcome for all outcome endpoints in the placebo group but not in the eplerenone group (interaction p value < 0.05 for all). Baseline sodium values did not influence the treatment effect of eplerenone in reducing the various endpoints (interaction p value > 0.05 for all). Development of new-onset hyponatremia following eplerenone initiation did not diminish the beneficial eplerenone treatment effect.. Eplerenone induces minor reductions in serum sodium. The beneficial effect of eplerenone was maintained regardless of the baseline serum sodium or the development of hyponatremia. Sodium alterations should not refrain clinicians from prescribing eplerenone to patients who had an MI complicated with LVSD and/or HF.. ClinicalTrials.gov identifier: NCT00232180. Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.

Topics: Eplerenone; Heart Failure; Humans; Myocardial Infarction; Sodium; Treatment Outcome; Ventricular Dysfunction, Left

Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians' clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients' status.. Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients.. A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of -2.2 mg/day (-2.9 to -1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75-0.92];. Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.

Topics: Aged; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Recovery of Function; Sodium Potassium Chloride Symporter Inhibitors; Systole; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI.. In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients.. When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint).. Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies.. In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.

Topics: Aged; Biomarkers; Endothelin-1; Eplerenone; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Natriuretic Peptide, Brain; Predictive Value of Tests; Spironolactone; Survival Rate; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left

An excessive production of aldosterone influences outcome in patients with heart failure (HF) and in obese patients. Findings from laboratory studies suggest that chronic aldosterone blockade maybe more beneficial in abdominally obese HF-prone rats. In the current study, we investigated if the clinical response to a mineralocorticoid receptor antagonist in mildly symptomatic HF patients varied by abdominal obesity.. A total of 2587 NYHA class II, reduced ejection fraction HF (HFrEF) patients enrolled in the EMPHASIS-HF trial were randomly assigned to eplerenone and placebo. In this post hoc analysis, patients were categorized according to waist circumference (WC) (normal if WC < 102 cm in men and < 88 cm in women; abdominal obesity if WC ≥ 102 cm in men and ≥ 88 cm women). The potential statistical interaction between the treatment and WC was assessed on the primary endpoint of death from cardiovascular causes or hospitalization for HF and other secondary endpoints. Over a median follow-up of 21 months, a significant benefit of eplerenone for the primary outcome was noted in both normal [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.61-0.98, P = 0.03] and increased (HR 0.48, 95% CI 0.37-0.63, P < 0.0001) WC subgroups, but the latter patients appeared to receive greater benefit than patients with normal WC (P for interaction = 0.01). This suggests a significant quantitative (treatment effect varies in magnitude by subgroup, but is always in same direction) rather than a qualitative interaction (direction of the treatment effect varies by subgroup) between eplerenone and WC in the adjusted analysis. Mean doses of eplerenone, blood pressure and serum potassium changes and adverse events were similar between WC subgroups.. In EMPHASIS-HF, eplerenone improved outcomes in HFrEF patients with and without abdominal obesity, although the benefit appeared to be more pronounced among those with abdominal obesity. The findings are potentially hypothesis generating and need to be replicated in other HFrEF populations.

Topics: Aged; Aldosterone; Drug Monitoring; Eplerenone; Female; Heart Failure, Systolic; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Obesity, Abdominal; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

The Thrombolysis in Myocardial Infarction (TIMI) risk score remains a robust prediction tool for short-term and midterm outcome in the patients with ST-elevation myocardial infarction (STEMI). However, the validity of this risk score in patients with STEMI with reduced left ventricular ejection fraction (LVEF) remains unclear. A total of 2,854 patients with STEMI with early coronary revascularization participating in the randomized EPHESUS (Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial were analyzed. TIMI risk score was calculated at baseline, and its predictive value was evaluated using C-indexes from Cox models. The increase in reclassification of other variables in addition to TIMI score was assessed using the net reclassification index. TIMI risk score had a poor predictive accuracy for all-cause mortality (C-index values at 30 days and 1 year ≤0.67) and recurrent myocardial infarction (MI; C-index values ≤0.60). Among TIMI score items, diabetes/hypertension/angina, heart rate >100 beats/min, and systolic blood pressure <100 mm Hg were inconsistently associated with survival, whereas none of the TIMI score items, aside from age, were significantly associated with MI recurrence. Using a constructed predictive model, lower LVEF, lower estimated glomerular filtration rate (eGFR), and previous MI were significantly associated with all-cause mortality. The predictive accuracy of this model, which included LVEF and eGFR, was fair for both 30-day and 1-year all-cause mortality (C-index values ranging from 0.71 to 0.75). In conclusion, TIMI risk score demonstrates poor discrimination in predicting mortality or recurrent MI in patients with STEMI with reduced LVEF. LVEF and eGFR are major factors that should not be ignored by predictive risk scores in this population.

Topics: Aged; Cause of Death; Double-Blind Method; Electrocardiography; Eplerenone; Female; Follow-Up Studies; France; Humans; Male; Mineralocorticoid Receptor Antagonists; Myocardial Revascularization; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Spironolactone; ST Elevation Myocardial Infarction; Stroke Volume; Survival Rate; Thrombolytic Therapy; Time Factors; Ventricular Dysfunction, Left

Although hypertension contributes significantly to worsen cardiovascular risk, blood pressure increment in subjects with heart failure is paradoxically associated with lower risk. The objective was to determine whether pulse pressure and pulse wave velocity (PWV) remain prognostic markers, independent of treatment in heart failure with reduced left ventricular function. The investigation involved 6632 patients of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study. All subjects had acute myocardial infarction with left ventricular ejection fraction <40% and signs/symptoms of heart failure. Carotid-femoral PWV was measured in a subpopulation of 306 subjects. In the overall population, baseline mean arterial pressure <90 mm Hg was associated with higher all-cause death (hazard ratio, 1.14 [95% confidence interval, 1.00-1.30]; P<0.05), whereas higher left ventricular ejection fraction or pulse pressure was associated with lower rates of all-cause death, cardiovascular death/hospitalization, and cardiovascular death. In the subpopulation, increased baseline PWV was associated with worse outcomes (all-cause death: 1.16 [1.03-1.30]; P<0.05 and cardiovascular deaths: 1.16 [1.03-1.31]; P<0.05), independent of age and left ventricular ejection fraction. Using multiple regression analysis, systolic blood pressure and age were the main independent factors positively associated with pulse pressure or PWV, both in the entire population or in the PWV substudy. In heart failure and low ejection fraction, our results suggest that pulse pressure, being negatively associated with outcome, is more dependent on left ventricular function and thereby no longer a marker of aortic elasticity. In contrast, increased aortic stiffness, assessed by PWV, contributes significantly to cardiovascular death.

Topics: Aged; Arterial Pressure; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Predictive Value of Tests; Prognosis; Pulse Wave Analysis; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left

EPHESUS was a multicentre, double-blind clinical trial in which 6632 patients with acute myocardial infarction (AMI) complicated by LV systolic dysfunction (LVSD) were randomized to receive eplerenone (n = 3319) or placebo (n = 3313). A total of 1580 EPHESUS patients were treated with PCI, which is now the standard treatment for AMI. This EPHESUS substudy examined the effects of eplerenone upon cardiovascular outcomes in PCI-treated patients.. EPHESUS patients were divided into PCI-treated and non-PCI-treated cohorts, and the effect of eplerenone upon mortality and other major adverse cardiovascular outcomes was assessed in each cohort. The PCI-treated patients (n = 1580) were younger, and had better renal function and fewer co-morbidities than non-PCI-treated patients (n = 5052). Cardiovascular mortality was significantly lower in PCI-treated patients as compared with non-PCI-treated patients (7% vs. 16%, P < 0.0001). However, the incidence of non-fatal events was similar in PCI-treated and non-PCI-treated cohorts. There was no statistical difference between the PCI-treated and non-PCI-treated cohorts in the primary or secondary outcomes of the trial. Eplerenone administration, compared with placebo, in the PCI-treated cohort did not affect PCI-related clinical outcomes, including recurrence of angina, the occurrence of acute coronary syndromes, or the need for further revascularization.. The beneficial effects of eplerenone in the EPHESUS trial exist for both PCI- and non-PCI-treated AMI patients with LVSD. Eplerenone has minimal, if any, effect upon reducing PCI-related adverse events in the PCI-treated cohort.

Topics: Aged; Aged, 80 and over; Comorbidity; Double-Blind Method; Eplerenone; Female; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Percutaneous Coronary Intervention; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Galectin-3 is a biomarker associated with inflammation and fibrosis that predicts adverse outcome and relates to biomarkers of extracellular matrix turnover in patients with heart failure, particularly when left ventricular (LV) systolic function is preserved. Whether galectin-3 is related to LV remodeling after acute myocardial infarction is unknown.. Circulating galectin-3 and various extracellular matrix biomarkers were measured in 100 patients (age, 58.9±12.0 years; 77% men) admitted with acute myocardial infarction and LV dysfunction, at baseline (mean 46 hours) and at 24 weeks, with cardiac MRI at each time-point. LV remodeling was defined as change in LV end-systolic volume index. Relationships among galectin-3, biomarkers, and LV remodeling were analyzed across the entire cohort, then according to median baseline LV ejection fraction. Galectin-3 levels were elevated in 22 patients (22%) at baseline and increased significantly over time from 14.7±5.5 to 16.3±6.6 ng/mL (P=0.007). Baseline galectin-3 did not correlate with any LV parameters at baseline or change in any parameter over time. Galectin-3 was positively associated with remodeling in patients with supramedian baseline LV ejection fraction (ie, >49.2%; r=0.40; P=0.01) but not when LV ejection fraction was ≤49.2%. Galectin-3 correlated significantly with matrix metalloproteinase-3 and monocyte chemoattractant protein-1 at baseline, biomarkers that have been shown to relate to LV remodeling in this cohort.. Galectin-3 correlated significantly with certain biomarkers involved in extracellular matrix turnover, although no definite relationship was identified with LV remodeling. Whether galectin-3 plays a pathological role in remodeling remains unclear but merits further study.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00132093.

Topics: Aged; Eplerenone; Extracellular Matrix; Female; Galectin 3; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Remodeling

We evaluated the effect of the selective mineralocorticoid receptor antagonist eplerenone on renal function and the interaction between changes in renal function and subsequent cardiovascular outcomes in patients with heart failure and left ventricular systolic dysfunction after an acute myocardial infarction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).. Serial changes in estimated glomerular filtration rate (eGFR) were available in 5792 patients during a 24-month follow-up. Patients assigned to eplerenone had a decline in eGFR with an adjusted mean difference of -1.4±0.3 mL · min(-1) · 1.73 m(-2) compared with placebo (P<0.0001), an effect that appeared within the first month (-1.3±0.4 mL · min(-1) · 1.73 m(-2)) and persisted throughout the study. Overall, 914 patients experienced a decline in eGFR >20% in the first month, 16.9% and 14.7% in the eplerenone and placebo groups, respectively (odds ratio, 1.15; 95% confidence interval, 1.02-1.30; P=0.017). In multivariate analyses, determinants of this early decline in eGFR were female sex, age ≥65 years, smoking, left ventricular ejection fraction <35%, and use of eplerenone and loop diuretic. An early decline in eGFR by >20% was associated with worse cardiovascular outcomes independently of baseline eGFR and of the use of eplerenone, which retained its prognostic benefits even under these circumstances.. In patients with heart failure after acute myocardial infarction and receiving standard medical care, an early decline in eGFR is not uncommon and is associated with poor long-term outcome. Eplerenone induced a moderately more frequent early decline in eGFR, which did not affect its clinical benefit on cardiovascular outcomes.

Topics: Aged; Eplerenone; Glomerular Filtration Rate; Heart Failure; Heart Failure, Systolic; Humans; Kidney; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Hyperglycemia predicts death in cardiovascular disease, but intensive glucose-lowering strategies increase mortality rates in diabetes. The present analysis investigated the prognostic value of postadmission blood glucose (BG) concentration on clinical outcomes in high-risk patients with heart failure after acute myocardial infarction.. A total of 6,496 patients from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) were categorized into 4 groups by plasma glucose concentration: ≤4.5 mmol/L (hypoglycemia), 4.5-5.5 mmol/L (normoglycemia), 5.5-8.3 mmol/L (elevated glucose level), and >8.3 mmol/L (severe hyperglycemia). We evaluated the time to all-cause death (primary end point) and time to cardiovascular death or hospitalization (secondary end point). Hypo- and severe hyperglycemia were prevalent in 509 (8%) and 1,588 (24%) patients, respectively. There was a U-shaped relationship between BG level and incidence of all-cause death (11.8% in patients with normoglycemia vs 15.1% and 19.9% in those with hypo- and severe hyperglycemia; P < .001). The incidence of the secondary end point was increased only in hyperglycemic patients (36% vs 23% in normoglycemic patients; P < .001). In multivariate Cox regression analysis, hypoglycemia (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.06-1.81; P = .002) and severe hyperglycemia (HR 1.52, CI 1.27-1.83; P < .0001) proved to be strong predictors of all-cause death. There was no significant interaction between eplerenone treatment and blood glucose levels regarding clinical outcomes.. In heart failure after acute myocardial infarction, both hypo- and hyperglycemia at the postacute phase identify patients with increased risk of death during long-term follow-up.

Topics: Aged; Blood Glucose; Diabetes Complications; Double-Blind Method; Eplerenone; Female; Humans; Hyperglycemia; Hypoglycemia; Incidence; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Proportional Hazards Models; Risk Factors; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Following acute myocardial infarction (AMI), the acute inflammatory response contributes to wound healing but also to progressive myocardial injury. Interleukin-21 (IL-21) plays a key role in immunoregulation; whether IL-21 is associated with left ventricular (LV) remodelling after AMI is unknown.. Plasma IL-21 concentrations were measured in 100 patients (age 58.9 ± 12.0 years, 77% male) admitted with AMI and LV dysfunction, at baseline (mean 46 h) and again at 24 weeks; cardiac magnetic resonance and measurement of B-type natriuretic peptide, monocyte chemoattractant protein-1, matrix metalloproteinase (MMP)-2, -3, -9, and tissue inhibitor of metalloproteinase (TIMP)-1, -2, -4 occurred at both time-points. Remodelling was defined as change in LV end-systolic volume index (ΔLVESVI).. Plasma IL-21 concentration was unchanged over time (48.1 [SD 35.4]pg/mL at baseline vs. 48.8 [61.3]pg/mL at 24 weeks, p=0.92). Baseline IL-21 correlated significantly with ΔLVESVI (r=0.30, p=0.005) and change in LV end-diastolic volume index (r=0.33, p=0.003). On multivariate analysis, plasma IL-21 was an independent predictor of remodelling. IL-21 was also significantly associated with higher TIMP-4 concentrations and lower MMP-9 concentrations at baseline.. IL-21 predicts adverse remodelling following AMI in patients with LV dysfunction. Whether it plays a direct pathophysiological role in remodelling merits further study.

Topics: Aged; Biomarkers; Double-Blind Method; Eplerenone; Female; Humans; Interleukins; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Middle Aged; Mineralocorticoid Receptor Antagonists; Multivariate Analysis; Myocardial Infarction; Predictive Value of Tests; Spironolactone; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-4; Tissue Inhibitor of Metalloproteinases; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Mineralocorticoid receptor (MR) antagonists improve cardiovascular outcomes in patients with heart failure complicating acute myocardial infarction (AMI) and in chronic heart failure. It is unclear whether these beneficial effects are due solely to aldosterone blockade, as MR has a similar affinity for cortisol. We examined the relationships between plasma and urinary steroid hormones and left ventricular (LV) remodelling in patients with LV dysfunction following AMI.. Plasma concentrations of renin, aldosterone, and N-terminal pro-brain natriuretic peptide (NT-proBNP), and 24 h urinary excretion rates of tetrahydroaldosterone (THAldo) and total cortisol metabolites were measured in 93 patients at a mean of 46 h following AMI prior to contrast-enhanced cardiac magnetic resonance (ceCMR). Patients were then randomized to 24 weeks of placebo or eplerenone therapy in addition to standard treatment, after which ceCMR was repeated. In placebo-treated patients, aldosterone, NT-proBNP, and excretion rates of THAldo and total cortisol metabolites were univariate predictors of remodelling (i.e. change in LV end-systolic volume index); aldosterone (P = 0.040) and total cortisol metabolite excretion (P = 0.038) remained independent predictors on multivariate analysis. None of the measured biomarkers predicted remodelling in the presence of eplerenone. Plasma and urinary aldosterone measures, and urinary cortisol metabolites, were not only related to larger infarct volumes and greater infarct remodelling over time, but were also higher in patients with microvascular obstruction on baseline ceCMR.. Aldosterone and cortisol are associated with medium-term LV remodelling when measured early after AMI. The beneficial effects of MR antagonism may relate to blockade of both aldosterone- and cortisol-induced MR activation.

Topics: Aldosterone; Biomarkers; Double-Blind Method; Echocardiography; Electrocardiography; Eplerenone; Female; Follow-Up Studies; Heart Ventricles; Humans; Hydrocortisone; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prospective Studies; Spironolactone; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Aldosterone antagonism has been studied in patients with advanced heart failure (HF) and also in patients with post-myocardial infarction and left ventricular (LV) dysfunction with HF symptoms. Few data are available on effects of aldosterone antagonism in patients with mild-to-moderate HF.. In a multicenter, randomized, double-blind, placebo-controlled study in patients with mild-to-moderate HF and LV systolic dysfunction, patients with New York Heart Association class II/III HF and LV ejection fraction (EF) < or =35% were randomly assigned to receive eplerenone 50 mg/d versus placebo in addition to contemporary background therapy. Quantitative radionuclide ventriculograms to assess LV volumes and ejection fraction were performed at baseline and again after 9 months of double-blind treatment and were analyzed in a central core laboratory, blinded to treatment. The primary efficacy analysis was the between-group comparison of the change in LV end-diastolic volume index. Secondary analyses examined changes in LV end-systolic volume index and ejection fraction as well as markers of collagen turnover. Of the total 226 patients enrolled, 117 were randomly assigned to receive eplerenone and 109 to receive placebo. There was high use of contemporary background therapy at baseline, with > 90% use of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers and > 90% use of beta-blockers. Over 36 weeks of treatment, there was no apparent between-group difference in the changes in end-diastolic volume index or end-systolic volume index. There was a reduction in the collagen turnover marker procollagen type I N-terminal propeptide and plasma B-type natriuretic peptide in the eplerenone group compared with placebo (P=0.01 and P=0.04, respectively). There was no change in symptom status or quality-of-life measures.. In a clinically stable, well-treated population of patients with mild-to-moderate HF symptoms and LV dysfunction, 36 weeks of treatment of aldosterone antagonism with eplerenone at a dose of 50 mg daily had no detectable effect on parameters of LV remodeling.

Topics: Aged; Cohort Studies; Double-Blind Method; Eplerenone; Female; Gated Blood-Pool Imaging; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Procollagen; Quality of Life; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Microvascular obstruction (MO) is associated with large acute myocardial infarction and lower left ventricular (LV) ejection fraction and predicts greater remodeling, but whether this effect is abolished by contemporary antiremodeling therapies is subject to debate. We examined the influence of several infarct characteristics, including MO, on LV remodeling in an optimally treated post-acute myocardial infarction cohort, using contrast-enhanced cardiac magnetic resonance.. One hundred patients (mean age, 58.9+/-12 years, 77%men) underwent contrast-enhanced cardiac magnetic resonance at baseline (approximately 4 days) and at 12 and 24 weeks. The effects on LV remodeling (ie, change in LV end-systolic volume index [DeltaLVESVi]) of infarct site, transmurality, endocardial extent, and the presence of early and late MO were analyzed. Mean baseline infarct volume index decreased from 34.0 (21.2) mL/m(2) to 20.9 (12.9) mL/m(2) at 24 weeks (P<0.001). Infarct site had no influence on remodeling, but greater baseline infarct transmurality (r=0.47, P<0.001) and endocardial extent (r=0.26, P<0.01) were associated with higher DeltaLVESVi. Early MO was seen in 69 patients (69%) and persisted as late MO in 56 patients (56%). Patients with late MO underwent significantly greater remodeling than those without MO (DeltaLVESVi, +4.1 [13.4] versus -7.0 [12.7] mL/m(2), respectively, P=0.001); those with early MO only displayed an intermediate DeltaLVESVi (-4.9 [13.0] mL/m(2)). Importantly, late MO was seen frequently despite optimal coronary blood flow having been restored at angiography.. Late MO on predischarge contrast-enhanced cardiac magnetic resonance remains an ominous predictor of adverse LV remodeling despite powerful antiremodeling therapy and may be useful in the risk stratification of survivors of acute myocardial infarction.

Topics: Chi-Square Distribution; Contrast Media; Double-Blind Method; Eplerenone; Female; Gadolinium DTPA; Humans; Image Processing, Computer-Assisted; Linear Models; Magnetic Resonance Angiography; Male; Microcirculation; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Placebos; Predictive Value of Tests; Spironolactone; Statistics, Nonparametric; Systole; Ventricular Dysfunction, Left; Ventricular Remodeling

Although a variety of prognostic tools have been shown to predict rehospitalization and mortality in heart failure patients, their utility in assessing future costs is less clear. We assessed whether health status assessment with the Kansas City Cardiomyopathy Questionnaire (KCCQ) predicts future costs in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction.. We evaluated 12-month cost utilization data from 1516 heart failure outpatients enrolled in the Quality-of-Life Substudy of the Eplerenone Post-Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Multivariable hierarchical models assessed whether the KCCQ (categorized as 0 to <25, 25 to <50, 50 to <75, and 75 to 100) was an independent predictor of future resource use. At baseline, 685 patients (45.2%) had good health status (KCCQ scores > or =75), whereas 510 (33.6%), 262 (17.3%), and 59 (3.9%) had fair (KCCQ, 50 to 74), poor (KCCQ, 25 to 49), and the worst (KCCQ <25) health status, respectively. After multivariable adjustment, compared with patients with good health status, patients with fair health status incurred incremental 1-year costs of $1520 (cost ratio, 1.23; 95% confidence interval, 1.05 to 1.43), whereas patients with poor and the worst health status incurred incremental 1-year costs of $4265 (cost ratio, 1.63; 95% confidence interval, 1.34 to 1.99) and $8999 (cost ratio, 2.34; 95% confidence interval, 1.62 to 3.38), respectively (P<0.0001 for association with KCCQ). Further adjustment for New York Heart Association class led to only partial attenuation of this relationship (P=0.0002).. Health status assessment predicts resource use and costs over the next year in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction.

Topics: Acute Disease; Aged; Cohort Studies; Eplerenone; Female; Follow-Up Studies; Health Care Costs; Health Status; Heart Failure; Humans; Internationality; Male; Middle Aged; Myocardial Infarction; Spironolactone; Survival Rate; Ventricular Dysfunction, Left

Apelin, a novel peptide with a putative role in cardiovascular homeostasis, has gained interest as an endogenous inotrope, but has yet to be described following acute myocardial infarction (AMI) in man. We aimed to characterize plasma apelin concentrations following AMI and to examine its relationship with clinical and prognostic biomarkers.. Plasma concentrations of apelin, N-terminal probrain natriuretic peptide (NT-proBNP), norepinephrine, and arginine vasopressin were measured in 100 patients [mean age 58.9 +/- 12 (SD) years, 77% male] admitted with AMI, with echocardiographic left ventricular (LV) ejection fraction <40%, at mean 46 h after admission and at 24 weeks. Cardiac magnetic resonance imaging was performed pre-discharge and at 24 weeks. Thirty-eight subjects with no cardiac history acted as controls. Apelin concentration was reduced early after AMI (0.54 +/- 0.25 vs. 3.22 +/- 3.01 ng/mL, P <0.001) and remained low at 24 weeks, although it did increase significantly from baseline to 0.62 +/- 0.36 ng/mL, P = 0.030. Apelin had no relationship with any parameter of LV function over time. A relationship was found between baseline apelin and norepinephrine (r = 0.26, P = 0.008). Both NT-proBNP and norepinephrine correlated with adverse ventricular function after AMI.. Plasma apelin concentration is reduced early after AMI, increases significantly over time, but remains depressed at 24 weeks.

Topics: Apelin; Biomarkers; Chromatography, High Pressure Liquid; Double-Blind Method; Echocardiography; Eplerenone; Female; Follow-Up Studies; Heart Ventricles; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Magnetic Resonance Imaging; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Remodeling

Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with congestive heart failure and left ventricular systolic dysfunction after acute myocardial infarction.. In a substudy of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), which evaluated the effects of the selective aldosterone receptor antagonist eplerenone versus placebo, serum levels of collagen biomarkers were measured in 476 patients with congestive heart failure after acute myocardial infarction complicated with left ventricular systolic dysfunction. The combination of the type I collagen telopeptide and brain natriuretic peptide levels above median at baseline was associated with all-cause mortality and the composite end point of cardiovascular death or heart failure hospitalization, with hazard ratios of 2.49 (P=0.039) and 3.03 (P=0.002), respectively. During follow-up, levels of aminoterminal propeptide of type I and type III procollagen were found to be consistently lower in the eplerenone group and significantly lower beginning at 6 months.. Changes in biomarkers of collagen synthesis and degradation suggest that extracellular matrix remodeling is an active process in patients with congestive heart failure and left ventricular systolic dysfunction after acute myocardial infarction. High type I collagen telopeptide and high brain natriuretic peptide serum levels are associated with the highest event rate. Eplerenone suppresses post-acute myocardial infarction collagen turnover changes.

Topics: Aged; Biomarkers; Collagen Type I; Collagen Type III; Death, Sudden, Cardiac; Eplerenone; Extracellular Matrix; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Placebos; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Spironolactone; Ventricular Dysfunction, Left

Heart rate turbulence (HRT) is a promising marker for risk of mortality after acute myocardial infarction (AMI). We investigated HRT for risk stratification in high-risk patients after MI. HRT from 24-hour Holter monitoring in 481 hospitalized patients after AMI with heart failure and/or diabetes with left ventricular dysfunction before randomization in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Over a 1-year follow-up, 55 died, 49 of cardiovascular causes. HRT onset (TO) and slope (TS) were calculated using previous and cohort-optimized cutpoints and their independent contribution to risk of cardiovascular death determined. Models were tested with <5 ventricular premature complexes (PVCs) categorized as normal (n = 452) and with <5 VPCs excluded (n = 342). In EPHESUS, optimal cutpoints were TS < or = 3.0 and TO > or = 0.0. The strongest model for predicting cardiovascular mortality used EPHESUS cutpoints excluding subjects with <5 VPCs. On 3-category HRT model multivariate analysis (TS and TO normal, TS or TO abnormal, TS and TO abnormal), both TS and TO abnormal (relative risk 3.64, 95% confidence interval 1.55 to 8.55, p = 0.003) and left ventricular ejection fraction < or =30% (relative risk 1.97, 95% confidence interval 1.04 to 3.73, p = 0.037) independently predicted cardiovascular death. In conclusion, HRT is an independent predictor of cardiovascular death in a high-risk population after AMI, with a possibly higher optimal cutpoint for HRT slope than previously reported.

Topics: Aged; Electrocardiography, Ambulatory; Eplerenone; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Risk Assessment; Spironolactone; Ventricular Dysfunction, Left

Heart failure (HF) with reduced left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) is associated with increased readmission rates. This study evaluated the effects of eplerenone, a selective aldosterone blocking agent, on the duration of subsequent hospitalizations for HF in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).. The EPHESUS study included 6,632 patients post-AMI with LVEF < or =40% and clinical HF or diabetes, receiving standard therapy, randomized to either eplerenone 25 mg, titrated to 50 mg daily, or placebo, with a mean follow-up of 16 months. Analyses of the length of stay and total number of days of HF hospitalizations per patient were conducted on a subgroup of 828 patients with subsequent HF hospitalizations, overall and across 5 distinct geographic regions.. Eplerenone was associated with a 1.6-day reduction in the mean length of HF hospitalization (9.2 vs 10.8 days with placebo; P = .019) and 3.6-day reduction in the total days spent in the hospital for HF (13.3 vs 16.9 days with placebo; P = .0006). These benefits were observed in all geographic regions.. In patients post-AMI with reduced LVEF and HF or diabetes, eplerenone added to standard therapy reduced the mean length and total days of HF hospitalizations compared to placebo in all regions. Given the high cost of hospital care for HF, these findings may translate into an economic benefit to health care worldwide.

Topics: Aged; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Length of Stay; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

To test the hypothesis that an earlier post-acute myocardial infarction (AMI) eplerenone initiation in patients with left ventricular systolic dysfunction (LVSD) and heart failure (HF) is associated with better long-term outcomes.. The 6632 patients of the EPHESUS study were randomized from day 3 to 14 after the index AMI (median = 7 days), of these 3319 were assigned to eplerenone. We analysed the differential effects of time-to-eplerenone initiation vs. placebo, based on the median time to initiation of treatment (<7 days-'earlier', > or =7days-'later'). Effects on outcomes were evaluated over a mean 16-month follow-up, using Cox proportional hazards regression analysis. The earlier eplerenone initiation (<7 days) reduced the risk of all-cause mortality by 31% (P = 0.001) when compared with the 'earlier' placebo' and also reduced the risks of cardiovascular (CV) hospitalization/CV mortality by 24% (P < 0.0001) and sudden cardiac death (SCD) by 34% (P < 0.0001). In contrast, later eplerenone initiation (> or =7 days) had no significant effect on outcomes. Interactions between time-to-randomization and treatment were significant. These associations remained substantially unchanged after risk adjustment in multivariable models.. An earlier eplerenone administration (3-7days) post-AMI improved outcomes in patients with LVSD and HF. This benefit was not observed when eplerenone was initiated later (> or =7days).

Topics: Death, Sudden, Cardiac; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Proportional Hazards Models; Risk Factors; Spironolactone; Survival Rate; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left

The aim of the study is to determine whether the selective aldosterone-receptor antagonist eplerenone delays onset of left ventricular (LV) systolic dysfunction or reduces LV hypertrophy in asymptomatic patients with moderate to severe aortic stenosis. Effects of eplerenone on LV diastolic function and progression of valve stenosis were also evaluated.. Sixty-five asymptomatic patients with a peak aortic valve velocity >3.0 m/s and normal LV function were randomized double blind to eplerenone, 100 mg daily (n = 33), or placebo (n = 32) for a median of 19 (interquartile range 15 to 25) months. Cardiac magnetic resonance imaging and echocardiography were performed and N-terminal pro-brain natriuretic peptide was measured at baseline and follow-up.. Symptomatic deterioration occurred in 13 subjects randomized to eplerenone and 11 to placebo (P = .34). Change in LV mass index (mean change +/- SD -0.3 +/- 14.6 vs +5.1 +/- 15 g/m(2) per year, P = .3), LV ejection fraction (+0.0% +/- 5.7% vs +0.8% +/- 5.7% per year, P = .9), and LV end-systolic volume index (-1.2 +/- 9 vs +0.04 +/- 12 mL/m(2) per year, P = .8) were small and similar for patients randomized to eplerenone and placebo, respectively. Decrease of aortic valve area (-0.11 +/- 0.22 vs -0.18 +/- 0.24 cm(2)/y, P = .2), worsening of LV diastolic dysfunction by echo-Doppler (E/E' +0.49 +/- 0.7 vs +1.32 +/- 2.0/year, P = .4), increase in the plasma level of N-terminal pro-brain natriuretic peptide (+63% vs +12% per year, P = .1), and decline in physical function score (9 +/- 34 vs 12 +/- 37/year, P = .7) were similar for subjects randomized to eplerenone and placebo, respectively.. In asymptomatic patients with moderate-severe aortic stenosis, eplerenone did not slow onset of LV systolic or diastolic dysfunction, decrease LV mass, or reduce progression of valve stenosis.

Topics: Aged; Aortic Valve Stenosis; Blood Flow Velocity; Echocardiography, Doppler; Eplerenone; Female; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Mineralocorticoid Receptor Antagonists; Spironolactone; Statistics, Nonparametric; Ventricular Dysfunction, Left

Aldosterone blockade is recommended for patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction; however, the perceived risk of hyperkalemia may limit implementation of this therapeutic approach. This subanalysis examined the relationship between eplerenone, serum potassium (K(+)), and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).. Hospitalized patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction (left ventricular ejection fraction < or =40%) treated with standard therapy were randomized 3 to 14 days after the acute myocardial infarction to additional treatment with eplerenone (25 to 50 mg/d; n=3319) or placebo (n=3313). Patients were excluded if baseline K(+) was >5.0 mEq/L or serum creatinine was >2.5 mg/dL. In patients receiving standard therapy, the addition of eplerenone resulted in a 4.4% absolute increase in the incidence of K(+) >5.5 mEq/L, a 1.6% increase of K(+) > or =6.0 mEq/L, and a 4.7% absolute decrease in hypokalemia (K(+) <3.5 mEq/L). Four independent baseline predictors of hyperkalemia (defined as > or =6.0 mEq/L) were identified: potassium (K(+) greater than the median; 4.3 mEq/L), estimated glomerular filtration rate (< or =60 mL . min(-1) . 1.73 m(-2)), history of diabetes mellitus, and prior use of antiarrhythmic agents. None of these independent baseline risk factors significantly impacted the cardiovascular benefit of eplerenone for reducing all-cause mortality.. Use of selective aldosterone blockade with eplerenone within the dose range of 25 to 50 mg/d in post-acute myocardial infarction patients with heart failure and left ventricular systolic dysfunction who are treated with standard therapy improves outcomes without an excess of risk of hyperkalemia (> or =6.0 mEq/L) when periodic monitoring of serum K(+) is instituted.

Topics: Aged; Eplerenone; Female; Heart Failure; Humans; Hyperkalemia; Incidence; Logistic Models; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Potassium; Predictive Value of Tests; Risk Factors; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

The EPHESUS study demonstrated that aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction (LVSD) and heart failure after acute myocardial infarction (AMI). The EPHESUS pharmacoeconomic analysis was performed to evaluate the cost-effectiveness of eplerenone in the Swiss setting.. A total of 6,632 patients with LVSD and heart failure after AMI were randomized to eplerenone or placebo and followed for a mean of 16 months. The co-primary endpoints were all-cause death and the composite of cardiovascular death/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Survival beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained was estimated. The perspective of the Swiss third party payers was used. Daily treatment costs of eplerenone were set at CHF 3.88. All other resources were valued on the basis of official tariffs. Discounting of the results was performed at a rate of 3%.. The number of life-years gained with eplerenone was 0.1083 based on Framingham, 0.0661 with Saskatchewan and 0.1518 with Worcester survival estimates. Total costs were CHF 1,028 higher over the trial period in the eplerenone arm, due to drug cost. The incremental cost-effectiveness ratio was CHF 10,145 per life-year gained with Framingham, CHF 16,178 with Saskatchewan, and CHF 7,693 with Worcester survival estimates. The corresponding costs per QALY were CHF 15,219, CHF 23,965 and CHF 11,337, respectively.. Eplerenone is effective in reducing mortality and, in Switzerland, is also cost-effective in increasing years of life for patients with LVSD after AMI.

Topics: Adult; Aged; Cost-Benefit Analysis; Eplerenone; Female; Health Care Costs; Humans; Male; Middle Aged; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. The present study was performed to evaluate the cost-effectiveness of eplerenone compared with placebo in these patients.. A total of 6632 patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction were randomized to eplerenone or placebo and followed up for a mean of 16 months. The coprimary end points were all-cause mortality and the composite of cardiovascular mortality/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Eplerenone was priced at the average wholesale price, 3.60 dollars per day. Survival beyond the trial period was estimated from data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained compared with placebo was estimated. The number of life-years gained with eplerenone was 0.1014 based on Framingham (95% CI, 0.0306 to 0.1740), 0.0636 with Saskatchewan (95% CI, 0.0229 to 0.1038), and 0.1337 with Worcester (95% CI, 0.0438 to 0.2252) data. Cost was 1391 dollars higher over the trial period in the eplerenone arm (95% CI, 656 to 2165) because of drug cost. The incremental cost-effectiveness ratio was 13,718 dollars per life-year gained with Framingham (96.7% under 50,000 dollars per life-year gained), 21,876 dollars with Saskatchewan, and 10,402 dollars with Worcester.. Eplerenone compared with placebo in the treatment of heart failure after acute myocardial infarction is effective in reducing mortality and is cost-effective in increasing years of life by commonly used criteria.

Topics: Aged; Cause of Death; Comorbidity; Cost-Benefit Analysis; Double-Blind Method; Drug Costs; Eplerenone; Female; Health Care Costs; Heart Failure; Humans; Life Expectancy; Male; Middle Aged; Mortality; Myocardial Infarction; Quality-Adjusted Life Years; Spironolactone; Ventricular Dysfunction, Left

This study sought to assess the impact of the selective aldosterone blocker eplerenone on mortality 30 days after randomization in patients after acute myocardial infarction (AMI) with a left ventricular ejection fraction (LVEF) < or =40% and clinical signs of heart failure.. In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), eplerenone reduced all-cause mortality by 15% (p = 0.008) over a mean follow-up of 16 months when used with standard therapy in patients after AMI with an LVEF < or =40% and clinical signs of heart failure.. We analyzed the effect of eplerenone 25 mg/day initiated 3 to 14 days after AMI (mean, 7.3 days) on the co-primary end points of time to death from any cause and the composite end point of time to death from cardiovascular (CV) causes or hospitalization for CV events, and the secondary end points of CV mortality, sudden cardiac death, and fatal/nonfatal hospitalization for heart failure, after 30 days of therapy in the EPHESUS trial.. At 30 days after randomization, eplerenone reduced the risk of all-cause mortality by 31% (3.2% vs. 4.6% in eplerenone and placebo-treated patients, respectively; p = 0.004) and reduced the risk of CV mortality/CV hospitalization by 13% (8.6% vs. 9.9% in eplerenone and placebo-treated patients, respectively; p = 0.074). Eplerenone also reduced the risk of CV mortality by 32% (p = 0.003) and the risk of sudden cardiac death by 37% (p = 0.051).. Eplerenone 25 mg/day significantly reduced all-cause mortality 30 days after randomization (when initiated at a mean of 7.3 days after AMI) in addition to conventional therapy in patients with an LVEF < or =40% and signs of heart failure. Based on its early survival benefit, eplerenone should be administered in the hospital after AMI.

Topics: Aged; Coronary Angiography; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Eplerenone; Female; Follow-Up Studies; Heart Failure; Heart Function Tests; Humans; Male; Middle Aged; Myocardial Infarction; Probability; Proportional Hazards Models; Reference Values; Severity of Illness Index; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.. Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.. During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).. The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

Topics: Aged; Blood Pressure; Death, Sudden, Cardiac; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Potassium; Spironolactone; Survival Analysis; Ventricular Dysfunction, Left

The American College of Cardiology provided much useful new information to inform those who care for patients with heart failure about what they should and should not adopt into current clinical practice. The EPHESUS trial suggests a much wider role for aldosterone antagonists for the management of heart failure and left ventricular systolic dysfunction. SPORTIF-III indicates we may have a safer, simpler warfarin substitute soon. ASCOT reinforces the potential futility of statin therapy unless it is well targeted. The results of the COMPANION study investigating cardiac resynchronisation devices and implantable defibrillators were encouraging but inconclusive and/or hard to interpret. UK-PACE again questions the use of dual chamber pacing. T-wave alternans is an interesting experimental technique that may be useful in selecting which patients need an implantable defibrillator, although the technology needs testing in an appropriate patient population.

Topics: Anticoagulants; Cardiac Pacing, Artificial; Defibrillators, Implantable; Electrocardiography; Eplerenone; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mineralocorticoid Receptor Antagonists; Pacemaker, Artificial; Spironolactone; Ventricular Dysfunction, Left; Warfarin

Topics: Aged; Defibrillators, Implantable; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Pacemaker, Artificial; Spironolactone; Ventricular Dysfunction, Left

Eplerenone is a selective mineralocorticoid receptor antagonist. Its approved for the therapy of patients with chronic heart failure with left ventricular systolic dysfunction and for the patients after myocardial infarction complicated by heart failure and left ventricular dysfunction. It´s also recommended for the therapy of primary hyperaldosteronism and the treatment of drug resistant hypertension.

Topics: Cardiovascular Diseases; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left

The mineralocorticoid receptor antagonists (MRAs) eplerenone and spironolactone are beneficial in heart failure with reduced ejection fraction (HFrEF), but have not been prospectively compared. We compared clinical outcomes, daily dosages, and discontinuation rates for the two drugs in a nationwide cohort.. We identified all patients with HFrEF in the period 2016-2020, who were alive and had initiated MRA treatment at study start, 180 days after HF diagnosis. We estimated the 2-year risk of a composite of death and HF hospitalization, as well as each component separately, using Kaplan-Meier, cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, and comorbidities. Secondly, we assessed treatment withdrawal, cross-over, and daily drug dosage.. We included 7479 patients; 653 (9%) on eplerenone and 6840 (91%) on spironolactone. Patients in the eplerenone group were younger (median age 65 vs. 69 years), and more often men (91% vs. 68%), both P < 0.001. In adjusted analyses, with spironolactone as reference, there were no differences in the risk of the composite of all-cause death and HF hospitalization (HR 1.02, 95% CI 0.82-1.27), all-cause death (HR 0.93, 95% CI 0.67-1.30), or HF hospitalization (HR 1.10, 95% CI 0.84-1.42). Treatment withdrawal occurred in 34% in the eplerenone group and 53% in the spironolactone group (P < 0.001), treatment cross-over in 3%, and 10%, respectively. Daily dose >25 mg at 12 months, was observed in 230 patients (37%) in the eplerenone group and 771 patients (12%) in the spironolactone (P < 0.001).. In a contemporary nationwide cohort of patients with new-onset HFrEF who initiated MRA, we found no differences in clinical outcomes associated with initiation of eplerenone vs. spironolactone. Treatment was more frequently withdrawn, and daily drug dosage was lower among patients treated with spironolactone.

Topics: Aged; Cohort Studies; Eplerenone; Heart Failure; Humans; Male; Spironolactone; Stroke Volume; Treatment Adherence and Compliance; Ventricular Dysfunction, Left

The aim: To study the parameters of the left ventricular (LV) diastolic function in patients with HT with concomitant T2DM and without it before and after complex treatment with the inclusion of Eplerenone 50 mg per day and Trimetazidine 80 mg per day during 3 months.. Materials and methods: The study included 50 patients, aged 45-54 years (mean age 51.3«1.5 years), women - 24 and men 26 with HT stage II. All patients were divided into 2 groups: 1 group (n=25) - patients with HT stage II (HbA1c level of 5.01«0.13%) and 2 group (n=25) - patients with HT stage II and concomitant T2DM (HbA1c level of 7.6«0.34%). The control group consisted of 20 healthy individuals (HbA1c level of 4.68«0.49%).. Results: When analyzing the findings on left atrial volume index (LAVI), the highest indicators were observed in patients with HT with T2DM, but slightly lower in HT, and even lower in the control group, but the differences at this stage were not significant. This suggests that functional changes in cardiomyocyte kinetics, which develop in patients with comorbid pathology and are caused by metabolic and hemodynamic disorders, can progress steadily.. Conclusions: After a three-month course of treatment with Eplerenone and Trimetazidine, the rate of myocardial relaxation in diastole likely increased in both groups of those examined. The prescribed treatment with Eplerenone and Trimetazidine has led to a decrease in the rate of progression of heart failure and a reduction in cardiovascular risks.

Topics: Diabetes Mellitus, Type 2; Eplerenone; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Trimetazidine; Ventricular Dysfunction, Left

Topics: Eplerenone; Heart Failure; Hospitals; Humans; Mineralocorticoid Receptor Antagonists; Patient Discharge; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

In the absence of previous direct comparative studies, we aimed to evaluate the effectiveness of spironolactone and eplerenone in patients with heart failure and reduced ejection fraction (HFrEF) in a real-world clinical setting.. Using Fine-Gray´s competing risk regression, we compared the clinical outcomes of 293 patients with chronic HF and left ventricular ejection fraction <40% treated with eplerenone and 293 propensity-score matched individuals treated with spironolactone. Study subjects were selected from a prospective cohort of 1404 ambulatory patients with HFrEF seen since 2010 to 2019 in a single specialized HF clinic, among which 992 received a mineralocorticoid receptor antagonist at baseline. Median follow-up was 3.95 years.. No statistically significant differences between patients treated with eplerenone versus spironolactone were observed with regard to the risk of the primary composite end-point cardiovascular death or HF hospitalization (HR 0.95; 95% CI 0.73-1.23; p= 0.677). However, eplerenone use was associated to lower cardiovascular mortality (HR 0.55; 95% CI 0.35-0.85; p= 0.008) and lower all-cause mortality (HR 0.67; 95% CI 0.47-0.95; p= 0.027). The incidence of drug suspension due to side effects (HR 0.58, 95% CI 0.40-0.85; p= 0.005) and drug suspension due to any reason (HR 0.70, 95% CI 0.51-0.97; p= 0.033) were lower among patients treated with eplerenone.. In this observational, real-world, propensity-score matched study of patients with HFrEF, eplerenone was associated to lower cardiovascular mortality and lower all-cause mortality than spironolactone.

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Prospective Studies; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Background Guidelines recommend mineralocorticoid receptor antagonist (MRA) use in patients with left ventricular ejection fraction ≤40% following a myocardial infarction plus heart failure or diabetes mellitus, based on mortality benefit in the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial. The objective of this study was to evaluate the real-world utilization of MRAs for patients with ST-segment-elevation myocardial infarction (STEMI) with left ventricular dysfunction. Methods and Results The prospective, population-based, Vancouver Coastal Health Authority STEMI database was linked with local outpatient cardiology records from 2007 to 2018. EPHESUS criteria were used to define post-STEMI MRA eligibility (left ventricular ejection fraction ≤40% plus clinical heart failure or diabetes mellitus, and no dialysis-dependent renal dysfunction). The primary outcome was MRA prescription among eligible patients at discharge and the secondary outcome was MRA prescription within 3 months postdischarge. Of 2691 patients with STEMI, 317 (12%) were MRA eligible, and 70 (22%) eligible patients were prescribed an MRA at discharge. Among eligible patients with no MRA at discharge, 12/126 (9.5%) with documented postdischarge follow-up were prescribed an MRA within 3 months. In multivariable analysis, left ventricular ejection fraction (odds ratio [OR], 1.55 per 5% left ventricular ejection fraction decrease; 95% CI, 1.26-1.90) and calendar year (OR, 1.23 per year, 95% CI, 1.11-1.37) were associated with MRA prescription at discharge. Other prespecified variables were not associated with MRA prescription. Conclusions In this contemporary STEMI cohort, only 1 in 4 MRA-eligible patients were prescribed an MRA within 3 months following hospitalization despite high-quality evidence for use. Novel decision-support tools are required to optimize pharmacotherapy decisions during hospitalization and follow-up to target this gap in post-STEMI care.

Topics: Aged; Aged, 80 and over; Canada; Databases, Factual; Drug Prescriptions; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Logistic Models; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Multivariate Analysis; Prospective Studies; ST Elevation Myocardial Infarction; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

Visit-to-visit office blood pressure (BP) variability (BPV) has been associated with morbidity and mortality outcomes in several cardiovascular conditions. The aim of this study was to evaluate the association between BPV and outcomes in patients with heart failure and reduced ejection fraction and the effect of eplerenone on BPV.. We evaluated the associations between BPV, calculated as SBP coefficient of variation (SBP-CoV = SD/mean × 100%), and the primary composite endpoint of cardiovascular mortality or heart failure hospitalization (HFH), and its components, in 2549 patients from the Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms trial. Lower SBP-CoV was independently associated with a higher risk of all the studied outcomes, while higher as well as lower SBP-CoV were associated with a higher risk of cardiovascular death. After a median follow-up period of 21 months the risk of the composite outcome of cardiovascular death or HFH was almost double in the lower SBP-CoV tertile as compared with the intermediate tertile [adjusted hazard ratio: 2.01, 95% confidence interval (1.62-2.51), P < 0.001]. The relationship between SBP-CoV and outcomes was not modified by eplerenone (P value for interaction = 0.48). An interaction was detected between mean SBP and SBP-CoV for the primary outcome (P = 0.048) and for HFH (P = 0.018). The effect modification was slight, but lower SBP-CoV was associated with worse outcomes in patients with both low and high SBP, while this interaction was less clear for patients with SBP in the 'normal' range.. In our patients with heart failure and reduced ejection fraction and mild symptoms, both a lower and higher SBP-CoV were associated with worse outcomes. SBP-CoV did not modify the benefit of eplerenone. Further studies are warranted to clarify the role of BPV in heart failure. CLINICALTRIALS.. NCT00232180.

Topics: Aged; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Eplerenone; Female; Heart Failure, Systolic; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Office Visits; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Stroke Volume; Ventricular Dysfunction, Left

Topics: Collagen Type I; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Peptide Fragments; Procollagen; Spironolactone; Ventricular Dysfunction, Left

Topics: Eplerenone; Female; Health Services Misuse; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Stroke Volume; Time; Ventricular Dysfunction, Left

Anthracyclines such as doxorubicin are widely used in cancer therapy but their use is limited by cardiotoxicity. Up to date there is no established strategy for the prevention of anthracyclin-induced heart failure. In this study, we evaluated the role of the cardiac myocyte mineralocorticoid receptor (MR) during doxorubicin-induced cardiotoxicity.. A single high-dose or repetitive low-dose doxorubicin administration lead to markedly reduced left ventricular function in mice. Treatment with the MR antagonist eplerenone prevented doxorubicin-induced left ventricular dysfunction. In order to identify the cell types and molecular mechanisms involved in this beneficial effect we used a mouse model with cell type-specific MR deletion in cardiac myocytes. Cardiac myocyte MR deletion largely reproduced the effect of pharmacological MR inhibition on doxorubicin-induced cardiotoxicity. RNAseq from isolated cardiac myocytes revealed a repressive effect of doxorubicin on gene expression which was prevented by MR deletion.. We show here that (i) eplerenone prevents doxorubicin-induced left ventricular dysfunction in mice, and (ii) this beneficial effect is related to inhibition of MR in cardiac myocytes. Together with present clinical trial data our findings suggest that MR antagonism may be appropriate for the prevention of doxorubicin-induced cardiotoxicity.

Topics: Animals; Atrophy; Cardiotoxicity; Disease Models, Animal; Doxorubicin; Eplerenone; Female; Fibrosis; Mice, Inbred C57BL; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Clinical studies suggest beneficial effects of renin-angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicin-induced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity.. Acute DIC was induced by a single injection of Dox at 15 mg/kg and chronic DIC applied 5 injections of Dox at 4 mg/kg/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K/AKT/mTOR pathway along with normal levels of CTGF.. Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K/AKT/mTOR axis and normal CTGF levels suggesting potential therapeutic implications.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotoxicity; Connective Tissue Growth Factor; Disease Models, Animal; Doxorubicin; Enalapril; Eplerenone; Male; Mice, Inbred C57BL; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Phosphatidylinositol 3-Kinase; Primary Prevention; Proto-Oncogene Proteins c-akt; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Renin-Angiotensin System; Signal Transduction; TOR Serine-Threonine Kinases; Ventricular Dysfunction, Left; Ventricular Function, Left

This study aimed to evaluate the role of eplerenone on the modulation of interleukin (IL)-1β and IL-33/sST2 signaling pathway in an experimental model of left ventricular (LV) systolic dysfunction after acute myocardial infarction (MI). MI rats were randomly assigned to no treatment (MI group, n = 10), to receive eplerenone (Epl group, n = 10), or anakinra (Ana group, n = 10). LV function was assessed by echocardiography. IL-1β, IL-33/sST2, and cardiac fibrosis biomarkers were analyzed by quantitative real-time reverse transcription polymerase chain reaction (PCR). Rats with MI showed significant reduction of LV systolic function, but treatment with eplerenone or anakinra improved left ventricular end-diastolic volume (LVEDV) and LVEDV/mass values. In the infarcted myocardium, compared with sham animals, the MI group had higher level of IL-33, sST2, and IL-1β, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with anakinra downregulated sST2 but with no effects on IL-33. Eplerenone reduced levels of sST2 and IL-1β significantly. Both anakinra and eplerenone treatments were associated with lower levels of fibrosis and inflammatory markers. IL-1β could induce expression of sST2, accelerating the progression of heart failure after acute MI. Eplerenone could improve LV function by reducing expression of IL-1β and sST2.

Topics: Acute Disease; Animals; Antihypertensive Agents; Eplerenone; Interleukin-1beta; Interleukin-33; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1; Signal Transduction; Ventricular Dysfunction, Left

Mineralocorticoid receptor(MR) antagonism reduces sudden cardiac death in heart failure, but the underlying mechanism remains poorly understood. Concurrent treatment with an MR antagonist during rapid ventricular pacing (RVP) prevents development of adverse ventricular electrophysiological remodeling, interstitial fibrosis, inflammatory cytokine gene activation, and ventricular tachyarrhythmia inducibility without diminishing the extent of systolic dysfunction. We hypothesized that attenuating preexistent inflammatory pathways and myocardial fibrosis with eplerenone after systolic heart failure is established by rapid pacing can reduce electrical activation delays and arrhythmia vulnerability.. Dogs subjected to RVP for 8 weeks in the absence or presence of eplerenone treatment during the final 4 weeks of pacing were assessed by echocardiography, electrophysiology study,ventricular fibrosis measurements, and inflammatory cytokine mRNA expression analysis. Eplerenone reversed preexistent ventricular activation delays, interstitial fibrosis, inflammatory cytokine (interleukin-6, tumor necrosis factor-α) gene overexpression, and arrhythmia vulnerability in ventricular paced dogs with heart failure. Eplerenone failed to improve left ventricular systolic dysfunction or chamber enlargement. A correlation between severity of fibrosis and ventricular arrhythmia inducibility was found.. MR antagonism regresses rapid pacing-induced electrical delays, inflammatory cytokine gene activation, and fibrosis in heart failure. Ventricular arrhythmia vulnerability in heart failure is correlated with extent of fibrosis and electrical activation delays during premature excitation.

Topics: Action Potentials; Animals; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Cardiovascular Agents; Disease Models, Animal; Dogs; Eplerenone; Fibrosis; Heart Failure; Hypertrophy, Left Ventricular; Inflammation Mediators; Interleukin-6; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Spironolactone; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Diabetes mellitus (DM) has deleterious influence on cardiac performance independent of coronary artery disease and hypertension. The objective of the present study was to investigate the role of the renin-angiotensin-aldosterone system, especially angiotensin II type 1a receptor (AT1aR) and mineralocorticoid receptor (MR) signaling, in left ventricular (LV) dysfunction induced by diabetes mellitus (DM).. DM was induced by intraperitoneal injection of streptozotocin (200 mg/kg BW) in wild-type (WT) or AT1aR knockout (KO) male mice, and they were bred during 6 or 12 weeks. Some KO mice were administered the MR antagonist eplerenone (100 mg/kg body weight). At 6 weeks, LV diastolic function was impaired in WT-DM, but preserved in KO-DM. At that time point MR mRNA expression was upregulated, NADPH oxidase subunit (p47phox) and glutathione peroxidase (GPx1) mRNA expression were upregulated, the staining intensities of LV tissue for 4-hydroxy-2-nonenal was stronger in immunohistochemistry, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positive cells was increased, Bcl-2 protein expression was significantly downregulated, and the expression of SERCA2a and phosphorylated phospholamban was depressed in WT-DM, while these changes were not seen in KO-DM. At 12 weeks, however, these changes were also noted in KO-DM. Eplerenone arrested those changes. The plasma aldosterone concentration was elevated in WT-DM but not in KO-DM at 6 weeks. It showed 3.7-fold elevation at 12 weeks even in KO-DM, which suggests "aldosterone breakthrough" phenomenon. However, the aldosterone content in LV tissue was unchanged in KO-DM.. DM induced diastolic dysfunction was observed even in KO at 12 weeks, which was ameliorated by minelarocorticoid receptor antagonist, eplerenone. AT1-independent MR activation in the LV might be responsible for the pathogenesis of diabetic cardiomyopathy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Eplerenone; Male; Mice; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Spironolactone; Ventricular Dysfunction, Left

Evidence-based medicine aims to apply best evidences to medical decision making. Although evidence are established using the scientific method, decision making has received less priority. Decision making is a mental process requiring a systematic analysis of evidences for a specific use, leading to a final choice of action. In many scientific disciplines involving decision and control, this process has been significantly improved by making it as a system (a set of interacting entities forming an integrated whole). Hypothesizing that most medical decisions can be described as a system, we present a schematic systematic loop, based on four traditional medical steps (nosology, semeiology, pathophysiology, and therapy), and on the four transitions between these steps. Steps are evaluated by reproducibility, transitions are evaluated by predictability. This leads to formulate eight basic questions for testing the reliability of any loop. We applied this approach to a specific study (EPHESUS) to show its interest in the control of the medical knowledge provided by a study and in indicating where evidence is missing. A systematic approach helps evidence-based medicine in structuring evidences for better medical decisions and in determining which research needs priority.

Topics: Decision Making; Eplerenone; Evidence-Based Medicine; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Reproducibility of Results; Spironolactone; Survival Rate; Ventricular Dysfunction, Left

Aldosterone antagonists (or mineralocorticoid receptor antagonists [MRAs]) are guideline-recommended therapy for patients with moderate to severe heart failure (HF) symptoms and reduced left ventricular ejection fraction (LVEF), and in postmyocardial infarction patients with HF. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated the MRA eplerenone in patients with mild HF symptoms. Eplerenone reduced the risk of the primary endpoint of cardiovascular death or HF hospitalization (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54-0.74, P < .001) and all-cause mortality (adjusted HR 0.76, 95% CI 0.62-0.93, P < .008) after a median of 21 months. Based on EMPHASIS-HF, an MRA is recommended for patients with New York Heart Association (NYHA) Class II-IV symptoms and reduced LVEF (<35%) on standard therapy (Strength of Evidence A). Patients with NYHA Class II symptoms should have another high-risk feature to be consistent with the EMPHASIS-HF population (age >55 years, QRS duration >130 msec [if LVEF between 31% and 35%], HF hospitalization within 6 months or elevated B-type natriuretic peptide level). Renal function and serum potassium should be closely monitored. Dose selection should consider renal function, baseline potassium, and concomitant drug interactions. The efficacy of eplerenone in patients with mild HF symptoms translates into a unique opportunity to reduce morbidity and mortality earlier in the course of the disease.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Eplerenone; Heart; Heart Failure; Hospitalization; Humans; Kidney; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left

The typical presentation of heart failure in primary care is insidious, with progressive breathlessness on exertion, ankle swelling, orthopnoea or paroxysmal nocturnal dyspnoea. Not all patients will have all these symptoms, and in many patients there may be other causes. If a GP suspects heart failure, then the key blood test is B-type natriuretic peptide (BNP). If the BNP is normal then heart failure is unlikely and other diagnoses should be considered. If it is raised, or if there is a past history of myocardial infarction, the patient requires further assessment, which must include echocardiography and a specialist assessment. The underlying cardiac abnormality should be identified. An ECG is often very useful and if it is completely normal it makes heart failure less likely. Both the NICE and the ESC guidance emphasise the importance of lifestyle management (regular appropriate exercise, avoiding excessive salt and alcohol consumption). ACE inhibitors (or angiotensin receptor blockers) and beta-blockers licensed for heart failure (carvedilol, bisoprolol, nebivolol) remain the mainstay of treatment in addition to as small a dose of diuretic as possible to control any fluid retention. Aldosterone antagonism is recommended by the 2012 ESC guidance for all patients who remain symptomatic despite an ACE inhibitor and beta-blocker. If the rhythm is sinus but the heart rate is 75 beats per minute, therapy needs to be optimised, perhaps by increasing the beta-blocker dose, if possible, or by the addition of ivabradine.

Topics: Algorithms; Benzazepines; Cyclic Nucleotide-Gated Cation Channels; Eplerenone; Heart Failure; Humans; Ivabradine; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Patient Care Team; Peptide Fragments; Spironolactone; Ventricular Dysfunction, Left

Topics: Aged; Controlled Clinical Trials as Topic; Creatinine; Dose-Response Relationship, Drug; Eplerenone; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left

This study examined the role of the renin-angiotensin-aldosterone system (RAAS) in mediating cardiovascular and renal damage in spontaneously hypertensive rats (SHR) given salt excess. Since the circulating RAAS is inhibited in this model, it permits examination of the role of local tissue RAASs in mediating this injury. To this end, male 8-wk SHR were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl chow. In addition, group 2 was given placebo, group 3 the mineralocorticoid receptor blocker eplerenone (100 mg.kg(-1).day(-1)), group 4 the angiotensin converting enzyme inhibitor quinapril (3 mg.kg(-1).day(-1)), group 5 the angiotensin II type 1 receptor blocker candesartan (10 mg.kg(-1).day(-1)), and groups 6 and 7 eplerenone and either quinapril or candesartan. The treatments lasted 8 wk. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Left ventricular mass and fibrosis as well as proteinuria were also markedly increased by salt overload. Eplerenone induced only slight changes, whereas quinapril and candesartan normalized all indexes except MAP. Combination therapy also normalized all indexes, including MAP. These data suggest that 1) cardiovascular and renal damage induced by salt excess in the SHR were not pressure dependent; 2) mineralocorticoids were only marginally involved in this model; and 3) local tissue generation of angiotensin II may be, at least in part, responsible for the other adverse effects.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cardiomyopathies; Cardiovascular System; Eplerenone; Hypertension; Hypertrophy; Kidney; Male; Mineralocorticoid Receptor Antagonists; Quinapril; Rats; Rats, Inbred SHR; Receptors, Mineralocorticoid; Regional Blood Flow; Renin-Angiotensin System; Sodium Chloride, Dietary; Spironolactone; Tetrahydroisoquinolines; Tetrazoles; Ventricular Dysfunction, Left

In a pressure overload model, sympathetic activity is augmented in response to salt intake. Mineralocorticoid receptors and epithelial Na channels (ENaCs) are thought to contribute to Na-processing, but the underlying mechanism is unknown. Here, we investigated the contribution of the brain mineralocorticoid receptor- ENaC pathway to salt-induced sympathetic activation in a pressure overload model.. Aortic banding was performed to produce a mouse pressure overload model. Four weeks after aortic banding (AB-4), left-ventricular (LV) wall thickness was increased without a change in percentage fractional shortening (%FS). Sympathetic activity increased in response to a 5-day high-salt diet in AB-4, but not in Sham-4. Brain mineralocorticoid receptor, alphaENaC, and angiotensin II type 1 receptor (AT1R) expression levels were greater in AB-4 than in Sham-4. The increase in sympathetic activity and in the expression of these proteins was blocked by intracerebroventricular (ICV) infusion of eplerenone, a mineralocorticoid receptor blocker. In another protocol, AB-4 mice were fed a high-salt diet (AB-H) for 4 additional weeks. At 4 weeks, %FS was decreased and sympathetic activity was increased in AB-H compared with Sham. Expression of mineralocorticoid receptors and AT1R in the brain was higher in AB-H than in Sham. ICV infusion of eplerenone in AB-H attenuated salt-induced sympathoexcitation and the decreased %FS. ICV infusion of eplerenone also decreased brain AT1R expression.. These findings indicate that activation of brain alphaENaC and AT1R through mineralocorticoid receptors contributes to the acquisition of Na sensitivity to induce sympathoexcitation. Therefore, high salt intake accelerates sympathetic activation and LV systolic dysfunction in a pressure overload model.

Topics: Animals; Brain; Epithelial Sodium Channels; Eplerenone; Hypertension; Male; Mice; Mice, Inbred ICR; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Sodium Chloride, Dietary; Spironolactone; Sympathetic Nervous System; Systole; Ventricular Dysfunction, Left

Topics: Aortic Valve Stenosis; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Potassium; Spironolactone; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Salt status plays a pivotal role in angiotensin-II-induced organ damage by regulating reactive oxygen species status, and it is reported that reactive oxygen species activate mineralocorticoid receptors.. To clarify the role of reactive oxygen species-related mineralocorticoid receptor activation in angiotensin-II-induced cardiac dysfunction, we examined the effect of the following: salt status; an MR antagonist, eplerenone; and an antioxidant, tempol in angiotensin-II-loaded Sprague-Dawley rats.. Angiotensin-II/salt-loading elevated blood pressure, and neither eplerenone nor tempol antagonized the rise in blood pressure significantly. Left ventricular diastolic function was monitored by measuring peak velocity of a mitral early inflow (E), the ratio of mitral early inflow to atrial contraction related flow (E/A), deceleration time of mitral early inflow and -dP/dt, the time constant (T), and filling pressure (left ventricular end-diastolic pressure) by echocardiography or cardiac catheterization. Despite the suppressed serum aldosterone, left ventricular diastolic function was deteriorated with angiotensin II/high salt, but not affected by angiotensin II/low salt. However, angiotensin-II/salt-induced cardiac dysfunction was restored by eplerenone and tempol. Nicotinamide adenine dinucleotide phosphateoxidase-derived superoxide formation was greater in the hearts of the angiotensin II/high-salt rats than of the angiotensin II/low-salt rats. The expression of the Na(+) -H(+) exchanger isoform 1, a target of mineralocorticoid receptor activation, was significantly increased in the angiotensin II/high-salt group. Both tempol and eplerenone inhibited the angiotensin-II/salt-induced upregulation of Na(+) -H(+) exchanger isoform 1.. These findings demonstrate that mineralocorticoid receptor activation by oxidative stress can cause left ventricular diastolic dysfunction in a rat model of mild hypertension.

Topics: Angiotensin II; Animals; Antioxidants; Cyclic N-Oxides; Diastole; Disease Models, Animal; Eplerenone; Male; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Sodium Chloride, Dietary; Spin Labels; Spironolactone; Vasoconstrictor Agents; Ventricular Dysfunction, Left

Metabolic syndrome is a highly predisposing condition for cardiovascular disease and could be a cause of excess salt-induced organ damage. Recently, several investigators have demonstrated that salt loading causes left ventricular diastolic dysfunction associated with increased oxidative stress and mineralocorticoid receptor activation. We, therefore, investigated whether excess salt induces cardiac diastolic dysfunction in metabolic syndrome via increased oxidative stress and upregulation of mineralocorticoid receptor signals. Thirteen-week-old spontaneously hypertensive rats and SHR/NDmcr-cps, the genetic model of metabolic syndrome, were fed a normal salt (0.5% NaCl) or high-salt (8% NaCl) diet for 4 weeks. In SHR/NDmcr-cps, salt loading induced severe hypertension, abnormal left ventricular relaxation, and perivascular fibrosis. Salt-loaded SHR/NDmcr-cps also exhibited overproduction of reactive oxygen species and upregulation of mineralocorticoid receptor-dependent gene expression, such as Na(+)/H(+) exchanger-1 and serum- and glucocorticoid-inducible kinase-1 in the cardiac tissue. However, in spontaneously hypertensive rats, salt loading did not cause these cardiac abnormalities despite a similar increase in blood pressure. An antioxidant, tempol, prevented salt-induced diastolic dysfunction, perivascular fibrosis, and upregulation of mineralocorticoid receptor signals in SHR/NDmcr-cps. Moreover, a selective mineralocorticoid receptor antagonist, eplerenone, prevented not only diastolic dysfunction but also overproduction of reactive oxygen species in salt-loaded SHR/NDmcr-cps. These results suggest that metabolic syndrome is a predisposed condition for salt-induced left ventricular diastolic dysfunction, possibly via increased oxidative stress and enhanced mineralocorticoid receptor signals.

Topics: Aldosterone; Animals; Blood Pressure Determination; Disease Models, Animal; Echocardiography, Doppler; Eplerenone; Heart Failure, Diastolic; Heart Function Tests; Male; Metabolic Syndrome; Random Allocation; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Reference Values; Sensitivity and Specificity; Sodium Chloride; Spironolactone; Urinalysis; Ventricular Dysfunction, Left

The Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial demonstrated that selective aldosterone blockade with eplerenone significantly reduced total mortality by 15%, combined cardiovascular (CV) mortality/CV hospitalization by 13%, CV mortality by 17% and sudden cardiac death by 21%, vs. placebo when added to standard care in patients with left ventricular systolic dysfunction (LVSD) and signs of congestive heart failure (CHF) following acute myocardial infarction (AMI). We retrospectively evaluated the effect of eplerenone vs. placebo in a subset of 1483 diabetic patients with LVSD and signs of CHF following AMI.. Diabetic status was determined from medical histories at screening. Analyses were based on time to first occurrence of an event. Results were based on a Cox's proportional hazards regression model stratified by region with treatment, subgroup and treatment-by-subgroup interaction as factors. The 95% confidence intervals for the risk ratios were based on the Wald's test.. Treatment with eplerenone in diabetic patients with CHF following AMI reduced the risk of the primary endpoint, a composite of CV mortality or CV hospitalization, by 17% (p = 0.031). The absolute risk reduction of the primary endpoint was greater in the diabetic cohort (5.1%) than in the non-diabetic cohort (3%). Hyperkalaemia occurred more often with eplerenone than with placebo (5.6 vs. 3%, p = 0.015). Among the diabetic cohorts, the prespecified endpoint of 'any CV disorder' occurred in 28% of the eplerenone group and 35% of the placebo group (p = 0.007).. Eplerenone treatment may reduce adverse CV events in diabetic patients with LVSD and signs of CHF following AMI.

Topics: Aged; Clinical Trials as Topic; Diabetes Complications; Eplerenone; Female; Heart Failure; Humans; Hyperkalemia; Hyperuricemia; Hypokalemia; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Retrospective Studies; Risk Factors; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Aldosterone has been implicated as one of the mediators of cardiovascular injury in various diseases. This study examines whether mineralocorticoid antagonism ameliorates or prevents the adverse cardiac effects of hypertension and aging. Male 22-wk-old spontaneously hypertensive rats (SHR) were divided into two groups, 15 rats in each. One group received no treatment; the other was given eplerenone ( approximately 100 mg.kg(-1).day(-1)). At the age of 54 wk, indexes of cardiovascular mass, systemic and regional hemodynamics, including coronary, left ventricular function, and myocardial collagen content, were determined in all rats. Hemodynamic studies were done in conscious rats. Arterial pressure was lowered only slightly in eplerenone-treated rats, and cardiac output and total peripheral resistance did not differ from control rats. Left and right ventricular and aortic mass indexes were unaffected by eplerenone; however, concentration of hydroxyproline in the right and left ventricle was decreased significantly (P < 0.05) by eplerenone. This was accompanied by an improvement in left ventricular diastolic function and coronary hemodynamics. In conclusion, long-term therapy with the mineralocorticoid receptor antagonist eplerenone ameliorated adverse cardiac effects of both hypertension and aging in SHR. Thus reduction in myocardial fibrosis, paralleled by improvements in left ventricular function and coronary hemodynamics, was observed in eplerenone-treated SHR.

Topics: Animals; Blood Pressure; Coronary Circulation; Eplerenone; Fibrosis; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Rats; Rats, Inbred SHR; Spironolactone; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Renin-angiotensin-aldosterone system activation may be involved in the pathogenesis of atrial arrhythmias in congestive heart failure (CHF). The effects of aldosterone blockade on atrial tachyarrhythmias have not been evaluated. This study's aim was to determine whether selective aldosterone blockade suppresses atrial tachyarrhythmia inducibility and modifies atrial electrical and/or structural remodeling in a canine model of rapid ventricular pacing (RVP)-induced CHF.. Dogs were assigned randomly to treatment with oral placebo or eplerenone (50 mg/day) and divided into four groups: two sham-operated (no RVP) and two RVP groups. After 5 weeks of no RVP or RVP at 230 beats/min along with concurrent placebo or eplerenone treatment, dogs underwent electrophysiologic and echocardiographic studies. Sustained atrial tachyarrhythmia inducibility (>10-minute duration), atrial effective refractory periods (ERPs), systolic and diastolic function, and left atrial and left ventricular (LV) chamber sizes were assessed. Placebo-treated RVP dogs developed CHF with LV systolic and diastolic dysfunction, left atrial and LV enlargement, increased atrial ERPs, and inducible sustained atrial tachyarrhythmias. Eplerenone treatment in RVP dogs significantly suppressed sustained atrial tachyarrhythmia inducibility, nonuniformly prolonged atrial ERPs and attenuated LV diastolic dysfunction without modifying left atrial or LV dilation or ejection fractions in CHF. Isoproterenol (2-4 microg/min) reversed eplerenone's atrial antiarrhythmic and ERP prolonging effects in CHF. Eplerenone did not alter atrial ERPs in sham (no RVP) dogs without CHF.. Eplerenone suppresses inducibility of sustained atrial tachyarrhythmias, selectively prolongs atrial ERPs, and attenuates LV diastolic remodeling in RVP-induced CHF. Aldosterone blockade may be a promising new approach for atrial tachyarrhythmia prevention in CHF.

Topics: Administration, Oral; Animals; Dogs; Eplerenone; Heart Atria; Heart Conduction System; Heart Failure; Mineralocorticoid Receptor Antagonists; Random Allocation; Spironolactone; Tachycardia; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Administration, Oral; Animals; Dogs; Eplerenone; Heart Atria; Heart Conduction System; Heart Failure; Mineralocorticoid Receptor Antagonists; Random Allocation; Spironolactone; Tachycardia; Treatment Outcome; Ventricular Dysfunction, Left

Aldosterone blockade reduces morbidity and mortality in patients with heart failure. We studied the effects of eplerenone, a novel aldosterone blocker, on the progression of left ventricular dysfunction and remodeling in rats with dilated cardiomyopathy after autoimmune myocarditis. Twenty-eight days after immunization, the surviving Lewis rats were randomized to 1 month's oral treatment with low-dose eplerenone (group L), high-dose eplerenone (group H) or vehicle (group V). Five of 15 (33%) rats in group V and 3 of 15 (20%) rats in group L died during the course of treatment. High-dose eplerenone significantly reduced cardiomyocyte hypertrophy, heart weight and heart weight to body weight ratio. Eplerenone improved left ventricular function in a dose-dependent manner. Central venous pressure and left ventricular end-diastolic pressure were lower, and +/-dP/dt and fractional shortening were higher in group H than group V. Eplerenone also attenuated myocardial fibrosis and reduced left ventricular mRNA expressions of TGF-beta(1) and collagen-III. Our results indicate that treatment with eplerenone improved left ventricular dysfunction and attenuated left ventricular remodeling in rats with heart failure.

Topics: Animals; Autoimmune Diseases; Cardiomyopathy, Dilated; Collagen Type III; Dose-Response Relationship, Drug; Electrocardiography; Eplerenone; Fibrosis; Hemodynamics; Male; Mineralocorticoid Receptor Antagonists; Myocarditis; Myocardium; Rats; Rats, Inbred Lew; RNA, Messenger; Spironolactone; Transforming Growth Factor beta; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone; Ventricular Dysfunction, Left

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Heart Failure; Humans; Myocardial Infarction; Neurotransmitter Agents; Prognosis; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left

Topics: Cost-Benefit Analysis; Drug Costs; Eplerenone; Health Care Costs; Humans; Myocardial Infarction; Placebos; Spironolactone; Ventricular Dysfunction, Left

Topics: Death, Sudden, Cardiac; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Risk; Spironolactone; Stroke Volume; Time Factors; Ventricular Dysfunction, Left

Topics: Aldosterone; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11beta-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse alpha-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Aldosterone; Animals; Blood Pressure; Cardiomegaly; Disease Models, Animal; Echocardiography; Eplerenone; Female; Fibrosis; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Heart Failure; Hydroxysteroid Dehydrogenases; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Myocardium; Myocytes, Cardiac; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spironolactone; Up-Regulation; Ventricular Dysfunction, Left

Topics: Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Research Design; Spironolactone; Ventricular Dysfunction, Left

Topics: Death, Sudden, Cardiac; Eplerenone; Humans; Hypokalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

Topics: Contraindications; Creatinine; Eplerenone; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

We investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin-converting enzyme (ACE) inhibition on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI).. Adding an aldosterone antagonist to ACE inhibition reduces mortality and morbidity in heart failure.. Starting 10 days after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the ACE inhibitor trandolapril (0.3 mg/kg/day), or a combination of both for nine weeks.. Both monotherapies attenuated the rise in LV end-diastolic pressure (LVEDP) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVEDP and LVEDV, significantly improved LV function and reduced plasma norepinephrine levels. The time constant of LV pressure isovolumic decay (tau) was prolonged in placebo MI rats, significantly shortened by eplerenone, and normalized by eplerenone/trandolapril. Increased collagen type I gene expression and collagen content in the noninfarcted LV myocardium from MI placebo rats was attenuated by trandolapril, but almost completely prevented by eplerenone and eplerenone/trandolapril. The addition of eplerenone to ACE inhibition prevented sarcoplasmic-reticulum calcium ATPase downregulation and the increases in LV gene expression of beta-MHC and atrial natriuretic factor more effectively than either monotherapy. Furthermore, combination treatment attenuated the increase in myocardial angiotensin II type 1 receptor expression and increased phosphorylated endothelial nitric oxide synthase protein levels.. The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an ACE inhibitor substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Drug Synergism; Drug Therapy, Combination; Endothelium, Vascular; Eplerenone; Hemodynamics; Indoles; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Nitric Oxide Synthase; Rats; Spironolactone; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Controlled Clinical Trials as Topic; Death, Sudden, Cardiac; Diuretics; Double-Blind Method; Eplerenone; Female; Follow-Up Studies; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Multicenter Studies as Topic; Myocardial Infarction; Placebos; Prospective Studies; Retrospective Studies; Risk Factors; Spironolactone; Time Factors; Ventricular Dysfunction, Left

There is growing evidence that aldosterone plays an important role in the development of endorgan-damage e.g. vascular and cardiac fibrosis, remodeling and endothelial dysfunction. Aldosterone-antagonism has become a novel therapeutic principle beyond its sodium retention properties in the treatment of cardiovascular diseases. In patients with severe left ventricular dysfunction spironolactone could reduce death and hospitalisation. A new selective aldosterone antagonist, eplerenone, was effective in patients with left ventricular dysfunction after myocardial infarction added to optimal medical therapy.

Topics: Aldosterone; Clinical Trials as Topic; Eplerenone; Germany; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Survival Rate; Treatment Outcome; Ventricular Dysfunction, Left

In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF.. HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, n=7) or no therapy at all (control, n=7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62+/-4 versus 68+/-4 mL, P<0.001, and 38+/-3 versus 47+/-3 mL, P<0.001, respectively), and EF decreased significantly (38+/-1% versus 31+/-2%, P<0.001). In contrast, end-diastolic volume, end-systolic volume, and EF remained unchanged during the 3 months of treatment in eplerenone-treated dogs. LV end-diastolic wall stress increased significantly in control dogs but decreased significantly in eplerenone-treated dogs. Compared with control, eplerenone was associated with a 28% reduction in cardiomyocyte cross-sectional area, a 37% reduction of volume fraction of reactive interstitial fibrosis, and a 34% reduction of volume fraction of replacement fibrosis.. Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Topics: Administration, Oral; Animals; Chronic Disease; Disease Models, Animal; Disease Progression; Dogs; Echocardiography; Enzyme Activation; Eplerenone; Fibroblast Growth Factor 2; Heart; Heart Failure; Hemodynamics; Mineralocorticoid Receptor Antagonists; Myocardium; RNA, Messenger; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling