Eplerenone Post-Acute Myocardial Infarction Heart Research Articles

Serum microRNAs and antifibrotic response to eplerenone in acute myocardial infarction complicated by systolic dysfunction

BackgroundAfter myocardial infarction (MI) complicated by heart failure (HF), eplerenone reduced serum concentrations of amino-terminal propeptide of type III collagen (PIIINP) and carboxy-terminal propeptide of type I collagen (PICP). Determining a subgroup who are more prone to decrease their collagen content and to respond better to the antifibrotic effects of mineralocorticoid receptor antagonists (MRA) may be relevant for a personalized treatment approach. Whether circulating microRNAs may identify a subgroup that have experienced a more pronounced antifibrotic effect of eplerenone as measured by a PICP and PIIINP decrease is unclear. MethodsA set of circulating microRNAs linked to cardiac fibrosis (mir-1, mir-21, mir-29a, mir-29b, mir-101, mir-122, mir-133a) were measured at baseline in 198 patients in the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Associations between baseline microRNA levels and changes in both PIIINP and PICP from baseline to month 9 were studied using multivariable analysis of covariance, adjusting for age, sex, history of hypertension and diabetes mellitus, prescription of ACE-inhibitors or angiotensin receptor blockers, baseline PIIINP or PICP, and eplerenone treatment. Furthermore, a treatment-by-microRNA interaction was studied. ResultsFrom the selected microRNAs, only mir-133a was associated with a PICP decrease (ß-6.43, 95%CI-12.71 to −0.15,p = 0.045). None of the microRNAs was associated with a PIIINP change. The microRNAs did not predict an effect of eplerenone on PICP and PIIINP changes. ConclusionAlthough serum mir-133a was associated with PICP change, none of the microRNAs previously linked to cardiac fibrosis predicted an antifibrotic response to eplerenone. Further study is needed to identify other suitable targets for a personalized treatment approach.

Determinants of anti-fibrotic response to mineralocorticoid receptor antagonist therapy: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) and Early Eplerenone Treatment in Patients with Acute ST-elevation Myocardial Infarction without Heart Failure (REMINDER) trials.

After myocardial infarction complicated by heart failure or diabetes, eplerenone (compared to placebo) significantly decreases amino-terminal propeptide of type III procollagen (PIIINP). Determining the subset of patients who are more prone to have a decrease in PIIINP and those who may respond better to the anti-fibrotic effects of mineralocorticoid receptor antagonists (MRA) therapy may be relevant for a personalized treatment approach. The aim of this study is to identify predictors of a PIIINP decrease and assess potential subgroups of "responders" to eplerenone. Clinical factors and biomarkers were evaluated as predictors of a PIIINP decrease from randomization to month 9 in 323 patients from the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Additionally, the association between PIIINP decrease and the composite of cardiovascular (CV) death or CV hospitalization were also explored. External validation was performed in the REMINDER trial. Female sex, eplerenone, reperfusion therapy, potassium < 4mmol/L, circulating levels of PIIINP ≥ 3.6ng/mL and PINP ≥ 27ng/mL predicted a PIIINP decrease (AUC = 0.75). Randomization PIIINP showed a significant interaction with the treatment allocation: patients with PIIINP ≥ 3.6ng/mL had a better response (decrease in PIIINP) to eplerenone (OR for PIIINP ≥ 3.6 = 2.9, 95% CI 1.46-5.89, p = 0.003) and OR for PIIINP < 3.6 = 1.09, 95% CI 0.55-2.2, p = 0.8; interactionp = 0.026). These findings were internally robust using another statistical approach (LOESS). External validation showed good discrimination (AUC = 0.70). There was a tendency toward a lower rate of CV death/CV hospitalizations in patients with decreased PIIINP (adjusted HR = 0.52, 95% CI 0.26-1.02, p = 0.058). In patients who had a myocardial infarction, clinical factors used in combination and treatment with eplerenone were associated with a PIIINP decrease. Interestingly, higher randomization PIIINP levels might help in identifying patients more prone to have an "anti-fibrotic response" when treated with MRAs. Predictors of an antifibrotic response after MI complicated by HF. Several clinical factors and biomarkers predicted a PIIINP decrease after an MI complicated by HF. There was a significant interaction between baseline PIIINP levels and eplerenone treatment: patients with baseline PIIINP ≥ 3.6 mmol/L treated with eplerenone had the best response (PIIINP decrease).

Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study

ObjectiveIncreased 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. MethodsIn 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. ResultsWhen 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). ConclusionsBoth 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. Key messagesIn 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.

Prognostic Value of Estimated Plasma Volume in Heart Failure

ObjectivesThe purpose of this study was to assess the prognostic value of the estimation of plasma volume or of its variation beyond clinical examination in a post-hoc analysis of EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). BackgroundAssessing congestion after discharge is challenging but of paramount importance to optimize patient management and to prevent hospital readmissions. MethodsThe present analysis was performed in a subset of 4,957 patients with available data (within a full dataset of 6,632 patients). The study endpoint was cardiovascular death or hospitalization for heart failure (HF) between months 1 and 3 after post-acute myocardial infarction HF. Estimated plasma volume variation (ΔePVS) between baseline and month 1 was estimated by the Strauss formula, which includes hemoglobin and hematocrit ratios. Other potential predictors, including congestion surrogates, hemodynamic and renal variables, and medical history variables, were tested. An instantaneous estimation of plasma volume at month 1 was defined and also tested. ResultsMultivariate analysis was performed with stepwise logistic regression. ΔePVS was selected in the model (odds ratio: 1.01; p = 0.004). The corresponding prognostic gain measured by integrated discrimination improvement was significant (7.57%; p = 0.01). Nevertheless, instantaneous estimation of plasma volume at month 1 was found to be a better predictor than ΔePVS. ConclusionsIn HF complicating myocardial infarction, congestion as assessed by the Strauss formula and an instantaneous derived measurement of plasma volume provided a predictive value of early cardiovascular events beyond routine clinical assessment. Prospective trials to assess congestion management guided by this simple tool to monitor plasma volume are warranted.

Prognostic value of low QRS voltage in patients with acute coronary syndrome

I have read the article by Tan et al. [ [1] Tan N.S. Goodman S.G. Yan R.T. et al. GRACE ECG substudy and Canadian ACS I Registry investigators. Prognostic significance of low QRS voltage on the admission electrocardiogram in acute coronary syndromes. Int. J. Cardiol. 2015; 190: 34-39 Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar ] with great interest, recently published in your journal. Authors reported that low QRS voltage was found to be an independent predictor of in-hospital mortality, and there was a consistent trend toward higher 6-month cumulative mortality in patients with acute coronary syndrome (ACS) and low QRS voltage. In the present study of Tan et al. there are no data about patient group medications on admission and at discharge. It is well known that optimal medical therapy significantly reduces in-hospital and long term mortality in ACS patients. According to guidelines, it is recommended to use statins, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB), oral beta-blockers, long term acetylsalicylic acid, and dual antiplatelet therapy for at least 12 months to reduce the mortality in ACS patients [ 2 Steg P.G. James S.K. Atar D. et al. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur. Heart J. 2012; 33: 2569-2619 Crossref PubMed Scopus (139) Google Scholar , 3 Hamm C.W. Bassand J.P. Agewall S. et al. ESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 2011; 32: 2999-305 Google Scholar ]. In addition, approximately half of the patients have impaired left ventricle systolic function in the present study of Tan et al. It has been demonstrated that aldosterone antagonists reduce mortality significantly in post-ST elevation myocardial infarction patients with left ventricle systolic dysfunction (ejection fraction <40%) [ [4] Pitt B. Remme W. Zannad F. et al. Eplerenone post-acute myocardial infarction heart failure efficacy and survival study investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 2003; 348: 1309-1321 Crossref PubMed Scopus (4028) Google Scholar ]. Therefore, Authors should state the incidence of treatment with statins, dual antiplatelet therapy, beta-blockers, aldosterone antagonists, and ACEI/ARB for both groups and compare the groups regarding their medications. Less medication with optimal medical therapy may be another significant reason for higher mortality rates in patients with low QRS voltage.

22 Retrospective Regional Audit of In-Patient Assessment of Left Ventricular Systolic Function and Guideline-Recommended Prescription of Eplerenone following St-elevation Myocardial Infarction

Introduction The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial demonstrated that eplerenone reduces all-cause mortality and death or hospitalisation for cardiovascular events in patients with symptomatic left ventricular (LV) systolic dysfunction (ejection fraction ≤40%) or diabetes following ST-elevation myocardial infarction (STEMI). Current national and international guidelines recommend initiation of eplerenone in this patient group. We conducted a retrospective audit of assessment of LV systolic function and subsequent prescribing of eplerenone in eligible patients presenting with acute STEMI over a 4-month period. Aims and objectives 1. Establish what proportion of patients presenting with STEMI had in-patient assessment of LV systolic function 2. Identify whether LV systolic function assessment was performed qualitatively or quantitatively 3. Determine what proportion of eligible patients were prescribed eplerenone on hospital discharge Methods Patients from NHS Greater Glasgow and Clyde (GG&C) who underwent primary percutaneous coronary intervention (PPCI) for STEMI were retrospectively (01/08/13–30/11/13) identified using the coronary intervention patient-database at the West of Scotland Regional Heart and Lung Centre (Golden Jubilee National Hospital). Data were collected using electronic patient records and national radiology archive. Qualitative assessment was defined as a subjective description of LV systolic function (normal, mild, moderate or severe impairment). Quantitative assessment was defined as a documented ejection fraction (EF). Patients were considered eligible for eplerenone if they had a qualitative assessment of LV systolic function documented as moderately or severely impaired, or EF ≤ 40% on quantitative assessment, and symptomatic LV systolic dysfunction or diabetes. Results 172 patients were identified. 90% of the total population had in-patient assessment of LV systolic function ([Table 1][1]). All of these patients had qualitative assessment ([Table 1][1]). LV systolic function was quantitatively assessed in 27% (10% modified Simpson’s Biplane method, 11% estimated EF, 5% unspecified) ([Table 1][1]). 8% of patients were considered eligible for eplerenone ([Table 2][2]). Of those eligible, eplerenone was appropriately prescribed on discharge in 21% ([Table 2][2]). View this table: Abstract 22 Table 1 Assessment of LV systolic function View this table: Abstract 22 Table 2 Prescribing of eplerenone in eligible patients Conclusions This audit indicates that national and international guidelines for the assessment and management of LV systolic function post-STEMI are not being adhered to within this region. Identifying those with LV systolic dysfunction post-STEMI is not only of importance for the optimisation of drug therapy, but also for patient selection for implantable defibrillators. The wider implications of LV systolic dysfunction include DVLA-imposed restrictions on driving and critical illness policies. Potential barriers to compliance with guidelines include time-constraints, training and shorter inpatient stay since the adoption of PPCI. These factors may explain the low prescribing rate of eplerenone in eligible patients. [1]: #T1 [2]: #T2

Structural Heart Disease and ST2: Cross-Sectional and Longitudinal Associations With Echocardiography

To further explore the potential role of sST2 in the progression of cardiac disease, this section reviews both the associations with cross-sectional findings and longitudinal changes in cardiac structure and function measured by echocardiography and cardiac magnetic resonance imaging with sST2 levels in a variety of patient populations with or at-risk for cardiovascular disease. In a Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department substudy in patients with acute dyspnea, sST2 levels were found associated with left ventricular ejection fraction (LVEF), and both estimated right ventricular (RV) systolic pressure and RV hypokinesis. In a large cohort of ambulatory patients referred for echocardiograms, sST2 was predominantly associated with RV and not LV structural findings. In contrast, in the Framingham Heart Study, a community cohort of >3,300 participants, sST2 was not associated with either echocardiographic finding, although in the Cardiovascular Health Study, sST2 appeared strongly associated with the presence of diastolic dysfunction. Little evidence exists on the relation of sST2 levels with longitudinal change in cardiac structure and function. A substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) evaluated the association among LV remodeling (defined as an increase in LV end-systolic and -diastolic volumes), sST2, and the benefit of eplerenone and found that sST2 levels were good surrogates of left ventricular remodeling. In the same line, the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study found that more time spent with an sST2 level less than the cutoff of 35ng/L identified patients with a greater probability of a decrease in LV diastolic index over 1 year.

Mineralocorticoid receptor antagonists and therapeutic strategies of cardiovascular damage

In recent years, much attention has focused on the role of aldosterone and mineralocorticoid receptors (MRs) in the pathophysiology of hypertension and cardiovascular disease. Patients with primary aldosteronism, in whom angiotensin II levels are low, have a higher incidence of cardiovascular complications than patients with essential hypertension. The Randomized Aldactone Evaluation Study (RALES) demonstrated that adding a non-specific MR antagonist, spironolactone, to a standard therapy that included angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, and digoxin, significantly reduced morbidity and mortality in patients with moderate to severe heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) showed that the addition of a selective MR antagonist (ARM), eplerenone, to an optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. These data suggest that aldosterone induces cardiac injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent cardiac injury, through mechanisms that cannot be simply explained by hemodynamic changes. Although, MRA are highly effective in patients with heart failure, the risk of hyperkalemia should not be overlooked. Serious hyperkalemia events were reported in some MRA clinical trials; however these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up.

Mineralocorticoid Receptor, the Main Player in Aldosterone-Induced Large Artery Stiffness

See related article, p 520–526 Aldosterone, a key hormone in the control of sodium and potassium balance, regulates extracellular volume and blood pressure. In the kidney, aldosterone, released by adrenal glomerulosa in response to angiotensin II, high potassium levels, and adrenocorticotropic hormone, classically acts through the mineralocorticoid receptor (MR), a ligand-activated transcription factor. The extensive expression of the MR in the cardiovascular system, including in the heart, endothelial cells, vascular smooth muscle cells, and mesangial cells, provides supportive evidence for a role of aldosterone in renal and cardiovascular injuries. Excess mineralocorticoid, in the context of inappropriate salt status, is a mediator of cardiac fibrosis, left ventricular hypertrophy, and hypertension, in a blood pressure–independent manner.1 The role of aldosterone in cardiovascular remodeling is emphasized in patients with primary hyperaldosteronism type 1 (also called glucocorticoid remediable hyperaldosteronism) where cardiac and vascular damages precede the development of hypertension.2 MR blockers have been shown to prevent vascular fibrosis, hypertrophic remodeling, inflammation, and impaired vascular reactivity in a blood pressure–independent manner in animal models of hypertension1 and vascular fibrosis in hypertensive patients stage 1.3 The demonstration of the benefits of MR blockade in chronic heart failure and hypertension emphasizes the importance of MR signaling pathways in cardiac and hypertensive diseases. Indeed, in patients with severe chronic heart failure, in addition to standard care, which included angiotensin-converting enzyme blockers or angiotensin II receptor blockers, spironolactone has been associated with a 30% improvement in survival (RALES [Randomized ALdactone Evaluation Study]).1 Similar observation has been made with eplerenone added to standard care in heart failure after myocardial infarction (EPHESUS [Eplerenone post-Acute Myocardial Infarction heart failure Efficacy and Survival …

Mineralocorticoid receptor and cardiac arrhythmia

Mineralocorticoid receptor (MR) activation has been shown to play a deleterious role in the development of heart disease in studies using specific MR antagonists (spironolactone, eplerenone) in both experimental models and patients. Pharmacological MR blockade attenuates the transition to heart failure (HF) in models of systolic left ventricular dysfunction and myocardial infarction, as well as diastolic dysfunction, in rats and mice. In humans, MR antagonism is highly beneficial in patients with mild or advanced HF and postinfarct HF. The consequences of aldosterone and MR activation for cardiac arrhythmia and its prevention and/or correction by MR antagonists are often underestimated. Activation of MR modulates cardiac electrical activity, causing atrial and ventricular arrhythmias. A pro-arrhythmogenic effect of aldosterone (possibly partly dependent on fibrosis) has been suggested by several studies. Cardiac MR activation has important consequences for the control of cellular calcium homeostasis, action potential lengthening, modulation of calcium transients and sarcoplasmic reticulum diastolic leaks, resulting in the promotion of rhythm disorders. Aldosterone and/or MR activation (in both cardiomyocytes and coronary vessels) result in vascular dysfunction and also contribute to pro-arrhythmogenic conditions. Together, the pro-arrhythmic effects of aldosterone and/or MR may explain the highly beneficial effect of MR antagonism, namely a decrease in the incidence of sudden death, observed in the Randomized Aldactone Evaluation Study (RALES) and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) studies.

Mineralocorticoid Receptor Antagonists and Mortality in Heart Failure With Concurrent Atrial Fibrillation

Aldosterone is the major mineralocorticoid in the human body and is produced in the zona glomerulosa of the cortex in the adrenal glands, and its secretion is stimulated by angiotensin II, adrenocorticotrophic hormone, catecholamines, and local potassium levels. Its levels in plasma are elevated 4-fold in heart failure (HF).1 Through a variety of mechanisms, aldosterone is believed to play a role in the pathogenesis and progression of left ventricular dysfunction.2 The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have consistently demonstrated a 20% reduction in mortality and 21% reduction in sudden death, which has been counterbalanced by a 6% to 12% risk of hyperkalemia (potassium >6.0 mEq/L) depending on the baseline estimated glomerular filtration rate.3,4,5 Article see p 586 In this issue of Circulation: Heart Failure , O’Meara and colleagues report on a retrospective analysis from …

Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are Independent From its Diuretic and Potassium-Sparing Effects: Insights From an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) Substudy

Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are Independent From its Diuretic and Potassium-Sparing Effects: Insights From an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) Substudy

Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are Independent From its Diuretic and Potassium-Sparing Effects: Insights From an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) Substudy

Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are Independent From its Diuretic and Potassium-Sparing Effects: Insights From an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) Substudy

Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are Independent From its Diuretic and Potassium-Sparing Effects: Insights From an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) Substudy

The purpose of this study was to determine whether a diuretic effect may be detectable in patients treated with eplerenone, a mineralocorticoid receptor antagonist, as compared with placebo during the first month of EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival study) (n = 6,080) and whether this was associated with eplerenone's beneficial effects on cardiovascular outcomes. The mechanism of the survival benefit of eplerenone in patients with heart failure post-myocardial infarction remains uncertain. A diuretic effect was indirectly estimated by changes at 1 month that was superior to the median changes in the placebo group in body weight (-0.05 kg) and in the estimated plasma volume reduction (+1.4%). A potassium-sparing effect was defined as a serum potassium increase greater than the median change in the placebo group: +0.11 mmol/l. In the eplerenone group, body weight (p < 0.0001) and plasma volume (p = 0.047) decreased, whereas blood protein and serum potassium increased (both, p < 0.0001), as compared with the placebo group, suggesting a diuretic effect induced by eplerenone, associated with a potassium-sparing effect. A diuretic effect, as defined by an estimated plasma volume reduction, was independently associated with 11% to 19% better outcomes (lower all-cause death, cardiovascular death or cardiovascular hospitalization, all-cause death or hospitalization, hospitalization for heart failure). Potassium sparing was also independently associated with 12% to 34% better outcomes. There was no statistically significant interaction between the observed beneficial effects of eplerenone (9% to 17%) on cardiovascular outcomes and potassium-sparing or diuretic effects. Eplerenone's beneficial effects on long-term survival and cardiovascular outcomes are independent from early potassium-sparing or diuretic effects, suggesting that mineralocorticoid receptor antagonism provides cardiovascular protection beyond its diuretic and potassium-sparing properties.

Double-Barreled Assault by Aldosterone and Salt on the Heart

Aldosterone, a mineralocorticoid hormone secreted by the adrenal zona glomerulosa, is generally regarded as the end product of the renin-angiotensin-aldosterone system. Aldosterone is a major regulator of body fluid and electrolyte homeostasis by virtue of its classic actions at renal collecting duct principal cells, mediated by mineralocorticoid receptors (MR), to induce sodium (Na ) and water reabsorption and potassium (K ) excretion. In addition to these classic effects, aldosterone induces nonclassical actions in both epithelial and nonepithelial tissues, including inflammation and fibrosis that lead to cardiac, vascular, and renal target organ damage. Indeed, a large body of evidence supports the concept that aldosterone induces deleterious effects on the cardiovascular system independently of both angiotensin II and blood pressure (1, 2). The detrimental effects of MR activation in patients with heart failure have been amply demonstrated in large clinical outcome trials. The Randomized Aldactone Evaluation Study showed that adding MR antagonist spironolactone to usual therapy in patients with moderate-severe symptoms decreased the rate of death from any cause and the risk of hospitalization for cardiovascular reasons (3). The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy Survival Study showed that the selective MR antagonist eplerenone, added to conventional therapy, reduced the rates of death from any cause and hospitalization for cardiovascular reasons in patients with acute myocardial infarction complicated by left ventricular (LV) systolic dysfunction and heart failure (4). This year, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure reported that eplerenone significantly reduced the risks of death and hospitalization in patients with systolic heart failure and mild symptoms (5). Impressively, in that study the number of patients with heart failure needed to treat to prevent one primary outcome was only 19, placing MR antagonist therapy at the forefront of choices for heart failure with mild symptoms (5). Recent studies have convincingly demonstrated that MR can be activated by both cortisol and aldosterone (6, 7). Cardiac MR activation contributes to infarct size after experimental myocardial infarction in rodents (7). Spironolactone not only reversed the resultant tissue damage but acted as an inverse protective agonist in the absence of the steroid receptor ligand (aldosterone or cortisol). These results encourage the initiation of human clinical trials aimed to determine whether starting MR antagonist therapy early after myocardial infarction can limit tissue damage. Taken together, the results of the animal and human studies discussed above emphasize the importance of MR in the pathophysiology of cardiac structural damage. MR are overexpressed in the failing heart and contribute to cardiac inflammation and fibrosis, and patients with even mild heart failure may have increased aldosterone and cortisol levels in spite of angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and -blocker therapy. Both dietary Na intake and aldosterone secretion have been linked to the pathogenesis of hypertension and related cardiovascular disease. A core issue in the pathophysiology of target organ damage is the relationship of salt to aldosterone. It is clear that elevated levels of aldosterone inappropriate for Na status (high salt intake) can induce cardiovascular hypertrophy and fibrosis in a variety of experimental animal models. However, during

Impact of diabetes mellitus on outcomes in patients with acute myocardial infarction and systolic heart failure

To determine independent associations of diabetes mellitus with outcomes in a propensity-matched cohort of patients with acute myocardial infarction (AMI) and systolic heart failure (HF). In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial, hospitalized AMI patients complicated by left ventricular ejection fraction ≤40% and symptoms of HF receiving standard therapy were randomized 3-14 days post-AMI to receive eplerenone 25-50 mg/day (n = 3319) or placebo (n = 3313). Of the 6632 patients, 2142 (32%) had a history of diabetes, who were older and sicker. Using propensity scores for diabetes, we assembled a cohort of 1119 pairs of patients with and without diabetes who were balanced on 64 baseline characteristics. Incident fatal or nonfatal recurrent AMI occurred in 136 (12%) and 87 (8%) of matched patients with and without diabetes, respectively, during 2.5 years of follow-up [hazard ratio (HR) when diabetes was compared with no-diabetes, 1.61; 95% confidence interval (CI), 1.23-2.10; P = 0.001]. Diabetes was associated with nonfatal AMI (HR, 1.68; 95% CI, 1.23-2.31; P = 0.001) but not with fatal AMI (HR, 1.42; 95% CI, 0.88-2.28; P = 0.146). Hazard ratios (95% CIs) for the association of diabetes with all-cause mortality, cardiovascular mortality, all-cause hospitalization, and cardiovascular hospitalization were 1.12 (0.93-1.37; P = 0.224), 1.11 (0.90-1.37; P = 0.318), 1.13 (1.00-1.27; P = 0.054), and 1.20 (1.01-1.44; P = 0.042), respectively. In post-AMI patients with systolic HF, diabetes mellitus is a significant independent risk factor for recurrent short-term nonfatal AMI, but had no association with fatal AMI.

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

Oxidative stress and inflammation are involved in cardiac remodeling after acute myocardial infarction (AMI). We have found that pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, effects of PEDF on cardiac remodeling after AMI remain unknown. We investigated whether PEDF could inhibit left ventricular remodeling and improve cardiac function in rats with AMI. AMI was induced in 8-week-old Sprague-Dawley rats by ligation of the left ascending coronary artery. Rats were treated intravenously with vehicle or 10 μg PEDF/100 g b.wt. every day for up to 2 weeks after AMI. Each rat was followed until 16 weeks of age. PEDF levels in infarcted areas and serum were significantly decreased at 1 week after AMI and remained low during the observational periods. PEDF administration inhibited apoptotic cell death and oxidative stress generation around the infarcted areas at 2 and 8 weeks after AMI. Further, PEDF injection suppressed cardiac fibrosis by reducing transforming growth factor-β and type III collagen expression, improved left ventricular ejection fraction, ameliorated diastolic dysfunction, and inhibited the increase in left ventricular mass index at 8 weeks after AMI. The present study demonstrated that PEDF could inhibit tissue remodeling and improve cardiac function in AMI rats. Substitution of PEDF may be a novel therapeutic strategy for cardiac remodeling after AMI.

Diabetes mellitus in patients with myocardial infarction complicated by heart failure: a ‘low ejection fraction’ equivalent?

Diabetes mellitus in patients with myocardial infarction complicated by heart failure: a ‘low ejection fraction’ equivalent?

Is a blood pressure rise the only deleterious off-target effect of cholesterol ester transfer protein inhibitors?

Is a blood pressure rise the only deleterious off-target effect of cholesterol ester transfer protein inhibitors?

Association of obesity and survival in systolic heart failure after acute myocardial infarction: potential confounding by age

To determine the association between obesity and outcomes in post-acute myocardial infarction (AMI) patients with systolic heart failure (HF). Of the 6632 Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) participants, 6611 had data on baseline body mass index (BMI) and 6561 had BMI > or = 18.5 kg/m(2). Of these, 1573 were obese (BMI > or = 30 kg/m(2)) and 4988 were non-obese (BMI 18.5-29.9 kg/m(2)). Propensity scores for obesity, estimated for each patient, were used to assemble a cohort of 1519 pairs of obese and non-obese patients who were balanced on 65 baseline characteristics. All-cause mortality occurred in 13.7 and 13.8% of matched obese and non-obese patients, respectively, during 16 months of median follow-up [matched hazard ratio (HR) for obesity 0.98; 95% confidence interval (CI) 0.79-1.21; P = 0.831]. Before matching, the obese group was younger (mean age, 62 vs. 64 years; P < 0.0001) and had more women (37 vs. 26%; P < 0.0001). The paradoxical pre-match association between obesity and reduced mortality (unadjusted HR 0.82; 95% CI 0.70-0.95; P = 0.008) disappeared when adjusted for age alone (age-adjusted HR 0.91; 95% CI 0.78-1.06; P = 0.206) but not for gender alone (gender-adjusted HR 0.79; 95% CI 0.68-0.92; P = 0.003). Obesity had no association with mortality in 1573 pairs of age-matched obese and non-obese patients (age-adjusted HR 0.94; 95% CI 0.77-1.13; P = 0.484). In post-AMI patients with systolic HF, obesity provides no independent intrinsic survival benefit. The paradoxical unadjusted survival associated with obesity is largely explained by the younger age of obese patients.