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Article, see p 1320 Potassium is the dominant cation in all cells and intimately involved in generation of the cardiac action potential. Disturbances of potassium levels increase susceptibility to cardiac arrhythmia, drug toxicities, and sudden cardiac death. These abnormalities are of particular concern in the patient with heart failure (HF). The triad of diuretic use, renal abnormalities, and neurohormonal blocking agents, found in >33% of patients with HF,1,2 makes potassium monitoring a fact of life for both patients with HF and their providers. The impressive impact of aldosterone-blocking agents such as spironolactone and eplerenone in patients with HF and reduced ejection fraction, coupled with their predictable dose-dependent effect to increase serum potassium levels by impairing sodium reabsorption (and thus potassium excretion) in the collecting duct, has made potassium management more challenging and more important than ever in HF clinics. Additionally, in cases of severe congestive HF, when renal perfusion becomes reduced, proximal sodium reabsorption can become so avid that little sodium is present in the distal nephron, and thus renal potassium excretion is further impaired.3 The presence of comorbidities such as diabetes mellitus, which occurs in ≈40% of those hospitalized with acute HF, further complicates this picture …

Background— Eplerenone is known to reduce time to first hospitalization for heart failure or cardiovascular death in patients with heart failure and mild symptoms. In chronic diseases such as heart failure, characterized by repeat hospitalizations, analyzing all heart failure hospitalizations, not just the first, should give a more complete picture of treatment benefits. Methods and Results— The Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF) trial compared eplerenone with placebo in 2737 patients with mild heart failure, followed for a median 2.08 years (interquartile range, 1.08–3.10 years). Data were collected on all hospitalizations, with a focus on those due to heart failure. Heart failure hospitalization rates in the eplerenone and placebo groups were 10.70 and 16.99 per 100 patient-years, respectively. Allowing for skewness in the frequency of hospitalizations by using the negative binomial generalized linear model, the rate ratio (eplerenone versus placebo) was 0.53 (95% confidence interval, 0.42–0.66; P Conclusions— Eplerenone markedly reduces the risk of heart failure hospitalizations in patients with heart failure and mild symptoms to a greater extent than is captured by only studying the time to first hospitalization. Future clinical trials in heart failure would gain from incorporating repeat hospitalizations into their primary evaluation of treatment effects. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00232180.

Background— 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). Methods and Results— 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 −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 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. Conclusions— 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.

A 63-year-old woman is evaluated after a recent hospitalization for an acute myocardial infarction. She reports fatigue and exertional dyspnea after ambulating 25 m. Her left ventricular (LV) ejection fraction is 38%, and her medications include aspirin, clopidogrel, a loop diuretic, an angiotensin-converting enzyme inhibitor (ACE-I), and a β-adrenergic receptor antagonist. On physical examination, her blood pressure is 144/92 mm Hg, and her heart rate is 72 bpm. Her jugular venous pressure is 9 cm water, and bilateral inspiratory rales and 1+ peripheral edema are noted. The patient’s serum K+ is 4.5 mEq/L and creatinine is 1.2 mg/dL. She is diagnosed with hypertension and moderate congestive heart failure (CHF) with LV systolic dysfunction. Despite evidence from clinical trials demonstrating a morbidity and mortality advantage for selected patients treated with aldosterone receptor antagonists, these drugs are underused in clinical practice. The Randomized Aldactone Evaluation Study (RALES) and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) established that spironolactone and eplerenone, respectively, increased survival in patients with severe CHF symptoms from LV systolic dysfunction occurring with minimal exertion or at rest (New York Heart Association [NYHA] class III or IV) or CHF after an acute myocardial infarction.1–3 As a result of these studies, aldosterone receptor antagonists were given an American Heart Association/American College of Cardiology class I recommendation for use, yet only 32% of eligible patients are routinely prescribed these drugs.4,5 This trend likely reflects clinicians’ persisting concerns over reports linking increased community-based spironolactone use with drug-induced deaths and hospitalizations.6 This association is drawn largely from population-based observational data demonstrating a temporal (and not causal) relationship between increased prescription rates of spironolactone and increased rates of hospital admission for the treatment of hyperkalemia and subsequent in-hospital deaths. Given that aldosterone receptor antagonists are often used …

Background— 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. Methods and Results— 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. Conclusions— 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.

Background— In obesity, decreases in adiponectin and increases in proinflammatory adipokines are associated with heart disease. Because adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of proinflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice. Methods and Results— We determined the effect of MR blockade (eplerenone, 100 mg/kg per day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db / db mice (n=8) compared with untreated obese, diabetic db / db mice (n=10) and lean, nondiabetic db /+ littermates (n=11). Expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, plasminogen activator inhibitor type 1, and macrophage protein CD68 increased, and expression of adiponectin and peroxisome proliferator-activated receptor-γ decreased in retroperitoneal adipose tissue from obese versus lean mice. In addition, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Furthermore, treatment of undifferentiated preadipocytes with aldosterone (10 −8 mol/L for 24 hours) increased mRNA levels of tumor necrosis factor-α and monocyte chemoattractant protein-1 and reduced mRNA and protein levels of peroxisome proliferator-activated receptor-γ and adiponectin, supporting a direct aldosterone effect on gene expression. Conclusions— MR blockade reduced expression of proinflammatory and prothrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade.

Background— 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. Methods and Results— 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 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 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 per life-year gained with Framingham (96.7% under $50 000 per life-year gained), $21 876 with Saskatchewan, and $10 402 with Worcester. Conclusions— 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.

Background— Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload. Methods and Results— We used the mineralocorticoid receptor–selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4±0.1 versus 3.7±0.1 mm) and end-systolic (2.0±0.1 versus 2.5±0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42±2% versus 34±4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages. Conclusions— Mineralocorticoid receptors play an important role in mediating the transition from LV hypertrophy to failure with chronic pressure overload. The effects of mineralocorticoid receptor stimulation are associated with alterations in the interstitial matrix and myocyte apoptosis and may be mediated, at least in part, by oxidative stress and inflammation.

Background— Disease-specific health status instruments such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) can quantify symptoms, functional limitations, and quality of life in patients with heart failure. Understanding the relationship between KCCQ scores and prognosis may assist clinicians in both interpreting KCCQ scores and stratifying risk in patients. Methods and Results— We examined the prognostic value of the KCCQ in a prospective, international cohort of 1516 patients with heart failure after a recent acute myocardial infarction. We focused on the relationship between the KCCQ overall score (KCCQ-os), measured at the first outpatient visit (4 weeks after enrollment), and subsequent 1-year cardiovascular mortality or hospitalization (n=258, 20.3%). KCCQ-os was strongly associated with subsequent cardiovascular events in that those with a score ≥75 had an 84% 1-year event-free survival compared with 59% for those with a score P P Conclusions— In outpatients with heart failure complicating an acute myocardial infarction, KCCQ-os is strongly associated with subsequent 1-year cardiovascular mortality and hospitalization. Use of the KCCQ in outpatient clinical practice can both quantify patients’ health status and provide insight into their prognosis. (Circulation. 2004;110:546-551.)

Background—The renin-angiotensin-aldosterone system is involved in the pathogenesis of atherosclerosis, partially because of its pro-oxidative properties. We questioned the effect and mechanisms of action of administration of aldosterone to apolipoprotein E–deficient (E0) mice on their macrophages and aorta oxidative status and the ability of pharmacological agents to block this effect.Methods and Results—Aldosterone (0.2 to 6 μg · mouse−1· d−1) was administered to E0mice alone or in combination with eplerenone (200 mg · kg−1· d−1), ramipril (5 mg · kg−1· d−1), or losartan (25 mg · kg−1· d−1). Mouse aortic atherosclerotic lesion area and macrophage and aortic oxidative status were evaluated. Aldosterone administration enhanced the mouse atherosclerotic lesion area by 32%. Mouse peritoneal macrophages and aortic segments from aldosterone-treated mice exhibited increased superoxide anion formation by up to 155% and 69%, respectively, and this effect was probably mediated by NADPH oxidase activation, because increased translocation of its cytosolic component p47phoxto the macrophage plasma membrane was observed. THP-1 macrophages incubated in vitro with aldosterone (10 μmol/L) exhibited a higher capacity to release superoxide ions by 110% and increased ability to oxidize LDL by 74% compared with control cells. Aldosterone administration enhanced mouse peritoneal macrophage ACE activity and mRNA expression by 2.3-fold and 2.4-fold, respectively. Only cotreatment of eplerenone with ramipril or losartan completely blocked the oxidative effects of aldosterone.Conclusions—Aldosterone administration to E0mice increased macrophage oxidative stress and atherosclerotic lesion development. Blocking of the mineralocorticoid receptor and inhibition of tissue ACE and/or the angiotensin receptor-1 reduced aldosterone deleterious pro-oxidative and proatherogenic effects.

Data from animal studies and clinical trials indicate that aldosterone causes cardiovascular and renal injury through mineralocorticoid receptor–dependent mechanisms. However, although aldosterone receptor antagonism reduces mortality in patients with congestive heart failure, the progestational and antiandrogenic side effects of the nonspecific aldosterone receptor antagonist, spironolactone, have limited its usefulness in the treatment of hypertension. This review provides an overview of the pharmacology, efficacy, and safety of a new, more selective aldosterone receptor antagonist, eplerenone, in the context of emerging concepts of the role of aldosterone in cardiovascular toxicity.

Background— 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. Methods and Results— 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 P P Conclusions— Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Background— Previous studies have demonstrated the development of cardiac fibrosis in aldosterone (Aldo)–salt hypertensive rats. Our aim was to determine the effects of Aldo and the Aldo receptor antagonist eplerenone (Epl) on in vivo mechanical properties of the carotid artery using echo-tracking system. Methods and Results— Aldo was administered (1 μg/h) in uninephrectomized Sprague-Dawley rats (SD) receiving a high-salt diet from 8 to 12 weeks of age. Uninephrectomized control SD rats received a normal salt diet without Aldo. Three groups of Aldo-salt rats were treated with 1, 10, or 30 mg/kg −1 · d −1 of Epl by gavage. Elasticity was measured by elastic modulus (Einc)-wall stress curves using medial cross-sectional area (MCSA). The structure of the arterial wall was analyzed by histomorphometry (elastin and collagen), immunohistochemistry (EIIIA fibronectin, Fn), and Northern blot (collagens I and III). Aldo produced increased systolic arterial pressure, pulse pressure, Einc, MCSA, and EIIIA Fn with no change in wall stress or elastin and collagen densities compared with controls without Aldo. No differences in collagen mRNA levels were detected between groups. Epl blunted the increase in pulse pressure in Aldo rats and normalized Einc-wall stress curves, MCSA, and EIIIA Fn. These effects were dose dependent and not accompanied by a reduction in wall stress. Conclusions— Aldo is able to increase arterial stiffness associated with Fn accumulation, independently of wall stress. The preventive effects of Epl suggest a direct role for mineralocorticoid receptors in mechanical and structural alterations of large vessels in rat hyperaldosteronism.

Introduction: Cardiomyopathy has become a leading cause of death in Duchenne muscular dystrophy (DMD). We previously showed that early mineralocorticoid receptor antagonist therapy reduces myocardial damage in a preclinical model of DMD. The Eplerenone for Subclinical Cardiomyopathy in DMD (E-SCAR DMD, NCT01521546) is a multicenter randomized placebo-controlled clinical trial evaluating eplerenone in boys with preserved left ventricular ejection fraction (LVEF) and evident myocardial injury by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Hypothesis: To better define biomarkers of early disease, we hypothesized that LGE has greater sensitivity vs. serum biomarkers for myocardial injury in DMD cardiomyopathy. Methods: Boys with DMD age ≥ 7 years were enrolled across 3 centers. LGE-CMR images were acquired using comparable techniques across 3T scanners, and core laboratory LGE quantification was performed blinded to laboratory findings as a percentage of LV mass using software based on the full-width half-maximum technique. Troponin-I, creatine kinase (CK) and CK isoenzymes were measured from blood samples obtained at the time of CMR examination using standardized clinical assays. Results: 42 boys age 16 ± 7 years had preserved LVEF (57 ± 6%), and LGE-positive regions averaged 5.0 ± 2.6% of LV myocardium. While 100% had evident myocardial injury by LGE, 43% had measurable CK-MB and only 18% had detectable troponin-I in serum (Figure). %LGE was higher (5.4 ± 2.7 vs. 3.3 ± 1.8%, p Conclusion: DMD patients with abnormal myocardium by LGE-CMR may have no detectable abnormalities by serum biomarkers, underscoring the importance of myocardial injury imaging in identifying patients with subclinical cardiomyopathy who may benefit from early treatment.

Background Coronary artery angioplasty triggers healing that causes constrictive remodeling. Because collagen accumulation correlates with constrictive remodeling and aldosterone has been implicated in collagen accumulation, we examined how aldosterone and the mineralocorticoid receptor antagonists spironolactone and eplerenone affect remodeling and collagen in porcine coronary and iliac arteries after angioplasty. Methods and Results Twenty-four pigs were allocated into 4 treatment groups: oral eplerenone (100 mg/d), oral spironolactone (200 mg/d), subcutaneous aldosterone (400 μg/d), or no treatment. Twenty-eight days after angioplasty of the coronary arteries, eplerenone increased total vessel area by 30% ( P P P Conclusions Eplerenone attenuates constrictive remodeling after coronary artery angioplasty by mechanisms involving reduction in collagen accumulation, which thus appears to be an important contributor to constrictive remodeling of angioplastied coronary arteries.

of over 6600 patients with acutemyocardial infarction complicated by evidence of systolic leftventricular dysfunction (left ventricular ejection fraction 40%) and signs of heart failure showed that the selectiveAB with eplerenone, when administered at a dose of up to 50mg daily (mean dose 42 mg daily) between days 3 and 14after infarction (mean 7.3 days) in addition to standardtherapy which could include reperfusion, aspirin, statins,angiotensin-converting enzyme inhibitor (ACE-I)/angioten-sin receptor blocker (ARB), and a -blocker, resulted in a15% reduction in total mortality (P 0.008) and a 17%reduction in cardiovascular mortality (P 0.005), mainly dueto a 21% reduction in sudden cardiac death (P 0.03). Therewas also a 13% (P 0.002) reduction in the co-primaryendpoint of cardiovascular mortality/cardiovascular hospital-ization (including hospitalization for non-fatal myocardialinfarction, non-fatal stroke, heart failure, and ventriculararrhythmias). The reduction in cardiovascular hospitaliza-tions was mainly attributable to a 15% (P 0.03) reduction inpatients hospitalized for heart failure and a 23% (P 0.002)reduction in episodes of hospitalization for heart failure.There was also an 8% (P 0.02) reduction in total mortality/total hospitalizations. These beneficial effects were associ-ated with a 1.6% (P 0.002) excess incidence in serioushypokalemia (K 6.0 mEq/L) but a 4.9% (P 0.001) decreasein the incidence of hypokalemia (K 3.5 mEq/L). In contrastto the previous experience with the use of spironolactone,there was no increase in the incidence of gynecomastia, breastpain, or impotence in males or menstrual irregularities infemales.Of interest was the finding that the reduction in mortalityassociated with AB, especially sudden cardiac death, seemedto occur relatively early after AB and was sustained over themean 16-month follow-up period. At the time EPHESUS wasplanned, there was little experience with the use of AB duringthe early hours after infarction. Given the uncertainty at thattime as to the effectiveness of AB in patients with acutemyocardial infarction, the necessity of both starting anACE-I/ARB, -blocker, aspirin, and a statins and of assuringthe most timely and effective means of reperfusion, and thepotential for hypotension when adding an AB to standardtherapy, it was decided to delay the administration of ABuntil patients were hemodynamically stable between day 3 to14 after myocardial infarction. Given the beneficial results ofAB in EPHESUS

Large-scale clinical trials have established that mineralocorticoid receptor (MR) blockade with spironolactone or eplerenone decreases morbidity and mortality in patients with chronic severe congestive heart failure and left ventricular systolic dysfunction (ejection fraction ≤35%),1 heart failure and left ventricular systolic dysfunction after an acute myocardial infarction,2 and chronic systolic heart failure with New York Heart Association class II (mild) symptoms.3 Although it was initially suggested that MR blockade with spironolactone improved outcomes in part by altering renal sodium or potassium handling or both, it was recognized that the mean dosage (26 mg/d) used in the Randomized Aldactone Evaluate Study (RALES) was not natriuretic, which indicates that other extrarenal effects of MR antagonism were more likely to prevent adverse cardiovascular events.1,4 Aldosterone and MR activation may also lead to dysregulation of local sodium, potassium, and water balance; promote autonomic dysfunction; impair vascular reactivity; and importantly, increase extracellular matrix turnover and fibrosis.5 In fact, there is now evidence to show that the hyperaldosteronism or enhanced MR activation contributes to (mal)adaptive ventricular structural and electric remodeling by stimulating extracellular matrix deposition and turnover. The association between aldosterone and left ventricular remodeling has been shown previously in a community-based sample. In 2119 participants in the Framingham Offspring Study, the aldosterone-renin ratio was positively associated with both concentric (odds ratio per SD increment 1.29; 95% confidence interval, 1.06–1.58) and eccentric (odds ratio per SD increment 1.20; 95% confidence interval, 1.05–1.37) left ventricular hypertrophy.6 Although the study did not measure circulating markers of extracellular matrix turnover, a follow-up study performed in the same community-based sample related elevated levels of procollagen type …

Background— 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. Methods and Results— 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 P P =0.0002). Conclusion— Health status assessment predicts resource use and costs over the next year in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction.

Maintenance of normal potassium homeostasis is increasingly an important limiting factor in the therapy of cardiovascular disease. Many pharmacological agents that reduce morbidity and mortality in patients with complicated myocardial infarction and chronic heart failure, including β-blockers, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers (ARBs), and aldosterone receptor antagonists, are also known to raise serum potassium and augment the risk of life-threatening hyperkalemia. Conversely, loop diuretics, a mainstay of heart failure treatment, tend to enhance the risk of hypokalemia and ventricular arrhythmias, which may in part account for their consistent dose-related association with increased mortality in observational studies. Because combination drug therapy may simultaneously improve clinical outcomes and enhance the risk of potassium-related adverse events, an appropriate balance of benefit and risk depends heavily on careful patient selection and adequate surveillance of serum potassium and renal function. Article p 1643 The ability of the kidney to maintain potassium homeostasis even as the glomerular filtration rate declines depends critically on adequate sodium delivery to the distal nephron, normal production of aldosterone, and adequate sodium/potassium exchange in the cortical collecting duct.1 Reduction in the filtered sodium load (as a consequence of decreased renal perfusion or reduced cardiac output), diminished aldosterone production, or impaired potassium secretion by the cortical collecting duct (related, for example, to tubulointerstitial disease or use of potassium-sparing diuretics) may attenuate tubular compensatory mechanisms and precipitate hyperkalemia in the vulnerable patient. Aldosterone production is decreased in the elderly, in diabetic patients, and in those receiving drugs that block the production or action of renin (eg, β-blockers, nonsteroidal antiinflammatory drugs, and plasma renin inhibitors) and angiotensin II (angiotensin-converting enzyme inhibitors and ARBs); as a result, these groups, as well as those with already impaired potassium excretion due to progressive age or disease-related decline in glomerular filtration rate, are particularly vulnerable to the …

Background— 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). Methods and Results— Hospitalized patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction (left ventricular ejection fraction ≤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 + ≥6.0 mEq/L, and a 4.7% absolute decrease in hypokalemia (K + + greater than the median; 4.3 mEq/L), estimated glomerular filtration rate (≤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. Conclusions— 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 (≥6.0 mEq/L) when periodic monitoring of serum K + is instituted.

To the Editor: An economic analysis of a treatment contributes greatly to decisions about its use in individuals and large populations. However, the analysis performed on the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) trial1 would be more relevant if eplerenone had been compared with spironolactone …

The patient, W.L., is a 62-year-old white man with a history of hypertension, hypercholesterolemia, and an anterior Q-wave myocardial infarction 3 years ago. He has had 2 admissions for heart failure in the past 6 months. He was last discharged 2 months ago on aspirin 325 mg daily, simvastatin 40 mg daily, enalapril 10 mg BID, metoprolol XL 100 mg daily, digoxin 0.25 mg daily, and furosemide 120 mg BID. Over the past month, he has noted some increasing dyspnea on exertion and occasional episodes of paroxysmal nocturnal dyspnea but has not had any increase in peripheral edema or body weight. His left ventricular ejection fraction on discharge from the hospital 2 months ago was 26%, with evidence of a large anterior akinetic area but without evidence of inducible myocardial ischemia on dobutamine echocardiography. His laboratory data today included a hematocrit of 41%, serum creatinine 1.1 mg%, potassium 4.1 meq/L, fasting blood sugar 108 mg%, LDL cholesterol 92 mg/dL, HDL cholesterol 45 mg/dL, triglycerides 188 mg/dL, serum digoxin level 1.2, and brain natriuretic peptide (BNP) (Biosite) 508. ECG revealed evidence of an old anterior myocardial infarction, and chest x-ray showed cardiomegaly with some increase in pulmonary vascularity. At this time, would you suggest any change in his medical regimen? Angiotensin-converting enzyme (ACE) inhibition and β-blockade have been shown effective in improving survival in patients with systolic left ventricular dysfunction (SLVD) resulting from both ischemic and nonischemic cardiomyopathy; they are indicated in all patients with heart failure (HF) caused by SLVD unless contraindicated or not tolerated. Although they improve the symptoms of HF, loop diuretics and digoxin have not been shown to reduce mortality rate. There is, however, increasing evidence that aldosterone blockade is effective in reducing mortality and morbidity rates in patients with HF caused by SLVD that is associated …

Background— Elevated renin-angiotensin-aldosterone system activity correlates with left ventricular hypertrophy (LVH) and cardiovascular risk, but the relative contributions of angiotensin II and aldosterone remain unclear. This study compared LVH regression during treatment with the selective aldosterone blocker eplerenone, enalapril, and their combination in patients with hypertension. Methods and Results— A 9-month, double-blind, randomized study was performed in 202 patients with LVH and hypertension who received eplerenone 200 mg daily, enalapril 40 mg daily, or eplerenone 200 mg and enalapril 10 mg daily. At week 8, hydrochlorothiazide 12.5 to 25 mg and/or amlodipine 10 mg was added if diastolic blood pressure was >90 mm Hg. Change in left ventricular (LV) mass as assessed by MRI was the primary end point. Change in blood pressure, renin-angiotensin-aldosterone system hormones, albuminuria, and safety were also assessed. Eplerenone significantly reduced LV mass from baseline (−14.5±3.36 g; n=50) similarly to enalapril (−19.7±3.20 g; n=54; P =0.258), but eplerenone/enalapril (−27.2±3.39 g; n=49) was more effective than eplerenone alone ( P =0.007). All treatments reduced systolic blood pressure and diastolic blood pressure from baseline (eplerenone, −23.8 and −11.9 mm Hg; enalapril, −24.7 and −13.4 mm Hg; and eplerenone/enalapril, −28.7 and −14.4 mm Hg, P =0.048, in systolic blood pressure compared with eplerenone alone). Cough was more common with enalapril than with eplerenone ( P =0.033), and elevated potassium was more common with eplerenone. Conclusions— Eplerenone was as effective as enalapril in LVH regression and blood pressure control. The combination of eplerenone and enalapril was more effective in reducing LV mass and systolic blood pressure than eplerenone alone.

The following studies were presented at the 51st Annual Scientific Sessions of the American College of Cardiology in Atlanta, Ga, March 17–20, 2002. ### LIFE (Losartan Intervention For Endpoint Reduction in Hypertension Study) #### The Presenter: Bjorn Dahlof, MD, Goteborg University, Sweden #### The Study: A randomized, double-blind, parallel group study of losartan (a selective angiotensin I receptor blocker)–based versus atenolol-based therapy in 9193 patients with essential hypertension and ECG evidence of left ventricular hypertrophy (LVH).1 To base therapy (both up to a maximum of 100 mg), diuretics and other antihypertensive agents (excluding angiotensin-converting enzyme inhibitors, other angiotensin receptor blockers, or β-blockers) could be added. Study therapy was continued for ≤4 years; the primary end point was the composite of cardiovascular mortality, stroke, and myocardial infarction. #### The Results: The degree of blood pressure control was similar between groups. There were significantly fewer cardiovascular events in the losartan group (11% versus 13%, P =0.021), and the primary difference was a reduction in the number of strokes (5% versus 7%, P =0.001). Regression of LVH on the ECG was also significantly more frequent with losartan. Intriguingly, with losartan, there was a 25% reduction in the number of patients who developed diabetes, and in the subgroup of patients with diabetes, total mortality was reduced by 39%. #### Summary: In hypertensive patients with ECG evidence of LVH, outcomes with losartan are significantly better than with atenolol. This benefit is particularly manifested in patients with diabetes. It is also worth noting that the likelihood of developing diabetes was also reduced with losartan. ### 4E (Epleronone, Enalapril, and Eplerenone/Enalapril Combination Therapy in Patients With Left Ventricular Hypertrophy) #### The Presenter: Bertram Pitt, MD, University of Michigan, Ann Arbor #### The Study: A double-blind, randomized parallel group trial comparing eplerenone (a selective aldosterone blocker, 200 mg/d), enalapril (an angiotensin-converting enzyme inhibitor, 40 mg/d), and eplerenone (200 mg/d) plus enalapril (10 mg/d) in 202 patients with essential hypertension and left ventricular hypertrophy on ECG. Additional add-on antihypertensive therapy with hydrochlorothiazide and/or amlodipine was permitted. Study drug therapy …

Background — Aldosterone has been implicated in the effects of angiotensin II in the vasculature. We hypothesized that there is local expression of the mineralocorticoid receptor (MR) in the vasculature and that the use of a selective aldosterone receptor antagonist (SARA) improves endothelial function in early atherosclerosis. Methods and Results — New Zealand rabbits were placed on normal chow or 1% cholesterol diets, randomized to placebo or SARA (eplerenone, 50 mg/kg twice daily), and killed at the end of 6 weeks for various studies. In the hyperlipidemic (HL) chow group, there was a 2.3-fold increase in superoxide (O 2 ·− ) generation. SARA normalized O 2 · − generation in intact aortas and reduced NADH and NADPH oxidase activity to basal levels (0.31±0.04 and 0.27±0.02 in HL versus 0.16±0.05 and 0.07±0.02 in HL-SARA, respectively; P P 50 6.8×10 −8 mol/L in HL-SARA and 1.2×10 −7 mol/L in HL; P =NS) to near-normal levels. Vessels from the HL group demonstrated hyperreactivity to angiotensin II that could not be corrected with SARA. Plasma aldosterone levels by radioimmunoassay demonstrated a 4- to 5-fold increase in response to SARA but no differences with lipid feeding. Real-time reverse transcriptase–polymerase chain reaction studies revealed expression of MR in the aorta of HL rabbits and those of controls. Conclusions — MR antagonism improves endothelial function and reduces O 2 ·− generation in diet-induced atherosclerosis. Targeting aldosterone by blocking its receptor has potential antiatherosclerotic effects.