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Background The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. Objectives The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. Methods Of the 11,900 hospitalized patients with HFrEF (EF ≤45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. Results Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). Conclusions Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes.

Aim: We investigated if the baseline value of mid-regional pro-atrial natriuretic peptide (NP), N-terminal pro-B-type NP and copeptin may be helpful in optimizing β-blocker uptitration in elderly patients with heart failure. Patients & methods: According to the biomarkers’ levels, 457 patients were divided into three subgroups and compared with each other at baseline and 3 months after. Results: All mid-regional pro-atrial NP and N-terminal pro-B-type NP subgroups had significant amelioration of left ventricle ejection fraction and New York Heart Association (NYHA) class after 3 months of β-blocker uptitration (p

BACKGROUND: Digoxin use has been associated with a lower risk of 30‐day all‐cause admission and readmission in patients with heart failure and reduced ejection fraction (HFrEF). HYPOTHESIS: Digoxin use will be associated with improved outcomes in patients with HFrEF receiving β‐blockers. METHODS: Of the 3076 hospitalized Medicare beneficiaries with HFrEF (EF

Finn Waagstein was born in Copenhagen in 1938. He graduated from Aarhus University Medical School in 1964. He received his cardiology training in the Sahlgrenska University Hospital at the University of Gothenburg, Sweden. He was appointed Associate Professor in 1980, and he assisted in establishing and directing the first Swedish heart transplant program. From 1990 he directed the heart failure and cardiomyopathy research programs. He is currently Professor of Cardiology and senior physician at Wallenberg Laboratory. In 2002, he was awarded the King Faisal International Prize for Medicine.

Chronic viral infections of the heart are considered one antecedent event leading to progressive dysfunction of the myocardium, often with an impaired prognosis due to a virus- or immune-mediated myocardial injury. Symptomatic treatment does not influence the viral cause of heart failure, and the effect of antiviral treatment has not been determined, yet.In this phase II study 143 patients with symptoms of heart failure and biopsy-based confirmation of the enterovirus (EV), adenovirus, and/or parvovirus B19 genomes in their myocardial tissue were randomly assigned to double-blind treatment, and received either placebo (n = 48) or 4 × 10(6) (n = 49) and 8 × 10(6) IU (n = 46) interferon beta-1b (IFN-β-1b) for 24 weeks, in addition to standard heart failure treatment. Patients with active myocarditis or other specific causes of heart failure were excluded. Compared to placebo, virus elimination and/or virus load reduction was higher in the IFN-β-1b groups (odds ratio 2.33, p = 0.048), similarly in both interferon groups and both strata. IFN-β-1b treatment was associated with favourable effects on NYHA functional class (p = 0.013 at follow-up week 12), improvement in quality of life (Minnesota Heart Failure score; p = 0.032 at follow-up week 24) and patient global assessment (follow-up week 12 to follow-up week 24; p = 0.039). The frequency of adverse cardiac events was not higher in the IFN-β-1b groups compared to the placebo group.Immunomodulatory IFN-β-1b treatment is a well-tolerated and safe treatment option, leading to effective virus clearance or reduction of the virus load in patients with chronic viral cardiomyopathy. Favourable clinical effects assess quality of life, NYHA functional class, and patient global assessment. ClinicalTrials.gov identifier: NCT001185250.

Aim We aimed to study the relationships of loop diuretic dose with renal function and clinical outcomes in patients with chronic heart failure (HF). Methods and results Loop diuretic dose at baseline was recorded in patients included in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). The relationship to change in estimated glomerular filtration rate (eGFR) over time and to the first occurrence of the composite outcome of cardiovascular (CV) death or hospitalization owing to HF was examined in propensity score matched cohorts. Of the 5011 patients, 2550, 745, and 449 were receiving >80 mg (high), 41–80 mg (medium) and ≤40 mg (low) of loop diuretics in furosemide equivalent daily dosages, respectively, which were used to assemble 229, 385, and 1045 pairs of propensity-matched high, medium, and low dose cohorts. Compared with matched no loop diuretic groups, eGFR declined 0.3 ± 0.2, 0.3 ± 0.3 and 1.2 ± 0.5 mL/min/1.73 m2/year in the low-, medium-, and high-dose groups, respectively. Compared with matched no loop diuretic groups, hazard ratios (HR) (95% confidence intervals) for outcome associated with low-, medium- and high-dose groups were 1.71 (1.41–2.06), 1.99 (1.50–2.64), and 2.94 (1.95–4.41), respectively. Higher loop diuretic dose was particularly associated with increased risk for hospitalization owing to HF: HR 4.80 (2.75–8.37), P

BACKGROUND: Beta-blockers improve outcomes in patients with systolic heart failure. However, it is unknown whether their initial negative inotropic effect may increase 30-day all-cause readmission, a target outcome for Medicare cost reduction and financial penalty for hospitals under the Affordable Care Act. METHODS: Of the 3067 Medicare beneficiaries discharged alive from 106 Alabama hospitals (1998-2001) with a primary discharge diagnosis of heart failure and ejection fraction (EF)

Background: The aim of our study was to examine regional differences in the demographics, etiology, risk factors, comorbidities and treatment of female patients with heart failure (HF) in the Cardiac Insufficiency BI soprolol Study in ELDerly (CIBIS-ELD) clinical trial. Methods and results: One hundred and fifty-nine female patients from Germany and 169 from Southeastern (SE) Europe (Serbia, Slovenia and Montenegro) were included in this subanalysis of the CIBIS-ELD trial. Women comprised 54% of the study population in Germany and 29% in SE Europe. German patients were significantly older. The leading cause of HF was arterial hypertension in German patients, 71.7% of whom had a preserved ejection fraction. The leading etiology in SE Europe was the coronary artery disease; 67.6% of these patients had a reduced left ventricular ejection fraction (34.64 ± 7.75%). No significant differences were found in the prevalence of traditional cardiovascular risk factors between the two regions (hypertension, diabetes, hypercholesterolemia, smoking and family history of myocardial infarction). Depression, chronic obstructive pulmonary disease and malignancies were the comorbidities that were noted more frequently in the German patients, while the patients from SE Europe had a lower glomerular filtration rate. Compared with the German HF patients, the females in SE Europe received significantly more angiotensin converting enzyme inhibitors, loop diuretics and less frequently angiotensin receptor blockers and mineralocorticoid receptor antagonists. Conclusions: Significant regional differences were noted in the etiology, comorbidities and treatment of female patients with HF despite similar risk factors. Such differences should be considered in the design and implementation of future clinical trials, especially as women remain underrepresented in large trial populations.

To explore the pharmacogenetic effects of the cytochrome P450 (CYP) 2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional * 4 allele (1846G> A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6* 4 allele (EM: * 1* 1, 60.4%; IM: * 1* 4, 35.8%; and PM: * 4* 4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P

This pharmacogenetic substudy of the prospective, double-blind, randomized CIBIS-ELD trial determined the impact of the β1-adrenoceptor Arg189Gly polymorphism on heart-rate responses to bisoprolol or carvedilol in elderly patients with heart failure (421 with sinus rhythm, 107 with atrial fibrillation). Patients were randomized 1:1 to bisoprolol or carvedilol with a fortnightly dose-doubling scheme and guideline target doses. Patients with sinus rhythm responded essentially identically to bisoprolol and carvedilol, independent of genotype. Atrial fibrillation patients homozygous for Arg389 had a much smaller response to carvedilol than carriers of at least one Gly389 allele (mean difference 12 bpm, P < 0.00001). Carvedilol up to 2 × 12.5 mg did not reduce heart rate in Arg389Arg homozygotes at all. Interestingly, the immediate response to carvedilol did not differ between genotypes. The Arg389Gly polymorphism has a major impact on the heart-rate response to carvedilol (but not bisoprolol) in patients with heart failure plus atrial fibrillation.

Objectives The purpose of this study was to determine whether coenzyme Q10 is an independent predictor of prognosis in heart failure. Background Blood and tissue concentrations of the essential cofactor coenzyme Q10 are decreased by statins, and this could be harmful in patients with heart failure. Methods We measured serum coenzyme Q10 in 1,191 patients with ischemic systolic heart failure enrolled in CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and related this to clinical outcomes. Results Patients with lower coenzyme Q10 concentrations were older and had more advanced heart failure. Mortality was significantly higher among patients in the lowest compared to the highest coenzyme Q10 tertile in a univariate analysis (hazard ratio: 1.50, 95% confidence interval: 1.04 to 2.6, p = 0.03) but not in a multivariable analysis. Coenzyme Q10 was not an independent predictor of any other clinical outcome. Rosuvastatin reduced coenzyme Q10 but there was no interaction between coenzyme Q10 and the effect of rosuvastatin. Conclusions Coenzyme Q10 is not an independent prognostic variable in heart failure. Rosuvastatin reduced coenzyme Q10, but even in patients with a low baseline coenzyme Q10, rosuvastatin treatment was not associated with a significantly worse outcome. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310 )

To estimate the cost-effectiveness of 10 mg rosuvastatin daily for older patients with systolic heart failure in the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) trial.This within trial analysis of CORONA used major cardiovascular (CV) events as the outcome measure. Resource use was valued and the costs of hospitalizations, procedures, and statin use compared. Cost-effectiveness was estimated as cost per major CV event avoided. There were significantly fewer major CV events in the rosuvastatin group compared with the placebo group (1.04 vs. 1.20 per patient; difference 0.164; 95% CI: 0.075-0.254, P This economic analysis showed that a significant reduction in major CV events with rosuvastatin led to significantly reduced costs of CV hospitalizations and procedures. The reduction in associated costs for major CV events was found to offset partially (by 44%) the cost of rosuvastatin treatment in patients with systolic heart failure.

Objectives We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective. Background Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile. Methods In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke. Results Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin. Conclusions Patients with heart failure due to ischemic heart disease who have NT-proBNP values

Background: Limited information is available on the risk and impact of renal dysfunction on the response to beta-blockade and mode of death in systolic heart failure (HF).Methods and Results: Renal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR(MDRD) > 60 (n = 2496), eGFR(MDRD) 45 to 60 (n = 976), and eGFR(MDRD) 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR 60; corresponding data for the combined end point was HR. 0.44 (95% CI, 0.31 to 0.63; P Conclusions: Renal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR 60. (J Cardiac Fail 2009;15:310-318)

A double-blind trial with the beta 1-selective blocker metoprolol in suspected acute myocardial infarction and during 3 months' follow-up included 1395 patients, aged 40-74 years, 698 on metoprolol and 697 on placebo. In order to further evaluate the tolerability to beta-blockade in the elderly, the total series was divided into 2 groups according to median age (61 years) and into quartiles, the lowest quartile (40-57 years) being compared with the highest (67-74 years). The decrease in heart rate and systolic blood pressure after intravenous metoprolol in the acute phase was similar in the elderly and the younger patients. Hypotension was observed more often in the metoprolol-treated than in the placebo-treated younger patients, while no difference was observed in the elderly. Bradycardia was observed more often in the metoprolol group in both age groups, while there was no difference regarding the incidence of congestive heart failure in either the younger or in the elderly patients. The effect on mortality, serious ventricular arrhythmias and chest pain seemed to be similar in different age groups. From the present series we conclude that hemodynamic reactions and tolerability to beta-blockade can be expected to be similar in elderly and younger patients.

A double-blind study including three different cardioselective beta-blockers, practolol, H 87/07 and metoprolol, was performed in 54 patients with acute myocardial infarction and chest pain shortly after onset of symptoms. Transmural infarctions were found in 42 patients while 12 patients had nontransmural infarctions. Chest pain and the product of heart rate and systolic blood pressure were significantly reduced in the beta-blocker groups whereas no changes were seen after saline. All patients with nontransmural infarctions and 14 out of 29 with transmural infarctions got pain relief lasting for at least 30 min. None of the patients developed signs of left ventricular backward failure, shock, or bradycardia. A decrease in ST segment elevation was observed in all the transmural infarctions after beta-blockade. No changes in ST segment elevation were found after analgesics when given after saline, but in some cases an increase was seen in this parameter when analgesics were given due to insufficient pain relief after beta-blockers or due to return of chest pain. It is suggested that pain relief by beta-blockers indicates decrease of myocardial ischemia.

Hemodynamic changes were studied in ten patients with uncomplicated transmural myocardial infection during 24 hours on beta-blockade. The cardioselective beta-adrenergic blocking drug metoprolol was injected (15 mg i.v.) within the first 24 hours after onset of chest pain and was followed by oral therapy (25-50 mg at 6-hour intervals). There was a decrease in heart rate, systolic BP, and cardiac output, which was most marked after the injection. The stroke volume and diastolic BP for the whole group of patients remained unchanged. The pulmonary artery end diastolic pressure did not change significantly after the injection but a continuous fall was obtained in three out of four patients with initially elevated values. The preejection period, measured from the ECG and carotid pressure curve, as initially short and was prolonged in all patients after administration of the beta-blocking drug. It is concluded that the cardioselective beta-blocking drug metoprolol may be used in selected patients in the acute phase of myocardial infarction without danger of hemodynamic deterioration during the first 24 hours of therapy. The selection of patients can be based on clinical criteria. In this study signs of left heart failure, hypotension, poor peripheral circulation, bradycardia, and AV block were regarded as contraindications.

Aims Few prognostic models in heart failure have been developed in typically elderly patients treated with modern pharmacological therapy and even fewer included simple biochemical tests (such as creatinine), new biomarkers (such as natriuretic peptides), or, especially, both. In addition, most models have been developed for the single outcome of all-cause mortality. Methods and results We built a series of models for nine different fatal and non-fatal outcomes. For each outcome, a model was first built using demographic and clinical variables (Step 1), then with the addition of biochemical measures (serum creatinine, alanine aminotransferase, creatine kinase, thyrotrophin, apolipoproteins A-1 and B, and triglycerides) (Step 2) and finally with the incorporation of high-sensitivity C-reactive protein (hsCRP) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Ranked according to the Wald χ2 value, age (56), ejection fraction (44), and body mass index (42) were most predictive of all-cause mortality in Step 1 (total model χ2 343). Creatinine was the most powerful predictor at Step 2 (48) and ApoA-1 ranked fifth (25), with the overall χ2 increasing to 440. Log NT-proBNP (167) was the most powerful of the 14 independently predictive variables identified at Step 3 and the overall χ2 increased to 600. NT-proBNP was the most powerful predictor of each other outcome. hsCRP was not a predictor of all-cause mortality but did predict the composite atherothrombotic outcome. Conclusion Of the two new biomarkers studied in prognostic models in heart failure, NT-proBNP, but not hsCRP, added substantial and independent predictive information, for a range of clinical outcomes, to that provided by simple demographic, clinical, and biochemical measures. ApoA-1 was more predictive than LDL or HDL.

Background: Although it is well known that left ventricular (LV) function improves after treatment with beta-blockers in heart failure, little attention has been paid to the effects on LV long axis (LAX) function. Aims: To evaluate LV LAX function after treatment with metoprolol, and to assess whether LV LAX contractile reserve could predict future long-term improvement. Methods: Twenty-four heart failure patients were randomised to metoprolol or placebo for 6 months, followed by 6 months of open treatment with metoprolol. Rest and dobutamine stress echocardiography (DSE) was performed before and after each treatment period. Results: After treatment with metoprolol, LV LAX function improved significantly, systolic velocity from 29±8 to 32±15 mm/s, p

The interaction between the heart and the arterial system (ventricular-arterial coupling - VA) is an important determinant of cardiovascular performance. Vascular stiffness (Ea) and left ventricular (LV) endsystolic stiffness (Elv) augment with age and in heart failure (HF). Beta blockers (BB) are recommended therapy for patients with HF. However, data about the effects of BB on VA coupling are scarce.TO ASSESS: 1) changes in VA after BB therapy; 2) interactions between VA and LV functions, 3) predictive factors influencing VA change.Eight hundred seventy-seven elderly patients with HF (aged ≥ 65, NYHA ≥ II, LV ejection fraction (LVEF) ≤ 45%), treated with BB according to the CIBIS-ELD protocol of up-titration, underwent Doppler echocardiography with clinical and laboratory assessment before and after 12 weeks of BB. VA coupling was calculated as Ea/Elv ratio.Ventriculo-arterial interaction improved after 12 weeks of BB in elderly patients with HF. Values of Ea significantly decreased from 2.73 ± 1.16 to 2.40 ± 1.01, p0.001, resulting in a VA level close to the optimal range i.e. from 1.70 ± 1.05 (1.46) to 1.50 ± 0.94 (1.29), p0.001. A similar degree of VA change was found in the patients with ischemic and non-ischemic HF after the treatment. Improvement in the clinical stage of HF closely correlated with VA coupling change after BB (p = 0.006). The strongest predictor of VA coupling alteration during BB was the improvement in global LVEF (p0.001) followed by the age of patients (p = 0.014).The beneficial effect of BB in elderly patients with HF was achieved by optimizing VA coupling close to recommended range, associated with an improvement in LVEF and contractility.

To investigate the association between hyperinsulinemia and cardiac hypertrophy, we treated rats with insulin for 7 wk and assessed effects on myocardial growth, vascularization, and fibrosis in relation to the expression of angiotensin II receptors (AT-R). We also characterized insulin signaling pathways believed to promote myocyte growth and interact with proliferative responses mediated by G protein-coupled receptors, and we assessed myocardial insulin receptor substrate-1 (IRS-1) and p110α catalytic and p85 regulatory subunits of phospatidylinositol 3 kinase (PI3K), Akt, MEK, ERK1/2, and S6 kinase-1 (S6K1). Left ventricular (LV) geometry and performance were evaluated echocardiographically. Insulin decreased AT1a-R mRNA expression but increased protein levels and increased AT2-R mRNA and protein levels and phosphorylation of IRS-1 (Ser374/Tyr989), MEK1/2 (Ser218/Ser222), ERK1/2 (Thr202/Tyr204), S6K1 (Thr421/Ser424/Thr389), Akt (Thr308/Thr308), and PI3K p110α but not of p85 (Tyr508). Insulin increased LV mass and relative wall thickness and reduced stroke volume and cardiac output. Histochemical examination demonstrated myocyte hypertrophy and increases in interstitial fibrosis. Metoprolol plus insulin prevented the increase in relative wall thickness, decreased fibrosis, increased LV mass, and improved function seen with insulin alone. Thus our data demonstrate that chronic hyperinsulinemia decreases AT1a-to-AT2 ratio and increases MEK-ERK1/2 and S6K1 pathway activity related to hypertrophy. These changes might be crucial for increased cardiovascular growth and fibrosis and signs of impaired LV function.

Introduction Immunoadsorption has been shown to improve cardiac performance and reduce mortality in patients with dilated cardiomyopathy. In this study, the underlying mechanism for these beneficial effects was investigated in cultured rat cardiomyocytes. Methods and results Immunoadsorption was performed in patients with dilated cardiomyopathy (n=7). Antibody-induced complement-dependent cytotoxicity was investigated by colorimetric MTT. Autoantibodies against the β1-adrenoceptor were detected by ELISA and purified. Column eluent from six patients exhibited a cytotoxic effect, three patients were positive for the β1-adrenoceptor autoantibodies. The purified autoantibodies were able to visualize the β1-adrenoceptors by immunocytofluorescence on rat cardiomyocytes, and also displayed partial agonist properties and induced a positive chronotropic effect, which were blocked by the β1-selective antagonist bisoprolol and the peptide corresponding to the β1-adrenoceptor. Column eluent from one patient induced apoptosis in nick end labelling test (8.1±1.7% vs. 2.9±1.2% in control, p

Although β-adrenergic blockade is beneficial in heart failure, inhibition of central sympathetic outflow using moxonidine has been associated with increased mortality. In the present study, we studied the acute effects of the imidazoline-receptor agonist moxonidine on haemodynamics, NA (noradrenaline) kinetics and myocardial metabolism. Fifteen patients with CHF (chronic heart failure) were randomized to a single dose of 0.6 mg of sustained-release moxonidine or matching placebo. Haemodynamics, NA kinetics and myocardial metabolism were studied over a 2.5 h time period. There was a significant reduction in pulmonary and systemic arterial pressures, together with a decrease in cardiac index in the moxonidine group. Furthermore, there was a simultaneous reduction in systemic and cardiac net spillover of NA in the moxonidine group. Analysis of myocardial consumption of substrates in the moxonidine group showed a significant increase in non-esterified fatty acid consumption and a possible trend towards an increase in myocardial oxygen consumption compared with the placebo group (P=0.16). We conclude that a single dose of moxonidine (0.6 mg) in patients already treated with a β-blocker reduced cardiac and overall sympathetic activity. The finding of increased lipid consumption without decreased myocardial oxygen consumption indicates a lack of positive effects on myocardial metabolism under these conditions. We suggest this might be a reason for the failure of moxonidine to prevent deaths in long-term studies in CHF.

Background: Previous prospective outcome studies of statins have not provided any guidance on benefit-risk in patients with heart failure. Aim: The primary objective is to determine whether rosuvastatin (10 mg) reduces the combined endpoint of cardiovascular mortality, nonfatal myocardial infarction or non-fatal stroke (time to first event). The first secondary endpoint is all-cause mortality. Methods: CORONA is a randomized, double-blind, placebo-controlled trial. Briefly, men and women, aged 60 years with chronic symptomatic systolic heart failure of ischemic aetiology and ejection fraction 0.40 (NYHA class III and IV) or 0.35 (NYHA class II) were eligible if they were not using or in need of cholesterol lowering drugs. Results: Mean age was 73 years (n=5016; 24% women), with 37% in NYHA II and 62% in NYHA III, ejection fraction 0.31, total cholesterol 5.2 mmol/L. Sixty percent have a history of myocardial infarction, 63% hypertension, and 30% diabetes. Patients are well treated for heart failure with 90% on loop or thiazide diuretics, 42% aldosterone antagonists, 91% ACE inhibitor or AT-I blocker, 75% beta-blockers, and 32% digitalis. Conclusion: CORONA is important for three main reasons: (1) A positive result is very important because of the high risk of the population studied, the increasing prevalence of elderly patients with chronic symptomatic systolic heart failure in our society, and the health economic issues involved. (2) If negative, new mechanistic questions about heart failure have to be raised. (3) If neutral we can avoid unnecessary polypharmacy.

[Expert Consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease]

Background: the effects of long-term administration of β-blockers on left ventricular (LV) function during exercise in patients with ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM) are controversial. Patients and methods: patients with stable congestive heart failure (CHF) (New York heart association [NYHA] class II and III) and ejection fraction (EF) ≤0.40 were randomized to metoprolol, 50 mg t.i.d. or placebo for 6 months. Patients were divided into two groups: ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM). The mean EF was 0.29 in both groups and 92% were taking angiotensin-converting enzyme (ACE) inhibitors. In the IHD group, 84% had suffered a myocardial infarction (MI) and 64% had undergone revascularization at least 6 months before the study. LV volumes were measured by equilibrium radionuclide angiography. Mitral regurgitation was assessed by Doppler echocardiography. All values are changes for metoprolol subtracted by changes for placebo. Results: metoprolol improved LV function markedly both at rest and during sub-maximal exercise in both groups. The mean increase in EF was 0.069 at rest (P

Context: The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization in patients with heart failure. While none of these trials are large enough to provide definitive results in any particular subgroup, it is of interest for physicians to examine the consistency of results as regards efficacy and safety for various subgroups or risk groups. Objective: To summarize results from both predefined as well as post-hoc subgroup analyses performed in the MERIT-HF trial, and to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. For some subgroups we performed metaanalyses with data from the CIBIS II and COPERNICUS trials in order to obtain more robust data on mortality in subgroups with a small number of deaths (e.g. for women). Setting: MERIT-HF was run in 14 countries, and randomized a total of 3,991 patients with symptomatic systolic heart failure (NYHA class II to IV with ejection fraction ≤0.40). Treatment was initiated with a very low dose with careful titration to a maximum target dose of 200 mg metoprolol succinate controlled release/extended release (CR/XL), or highest tolerated dose. Main outcome measures: Total mortality (first primary endpoint), total mortality plus all-cause hospitalization (second primary endpoint), and total mortality plus hospitalization for heart failure (first secondary endpoint) analyzed on a time to first event basis. Results: Overall, MERIT-HF demonstrated a 34% reduction in total mortality (p = 0.00009 nominal) and a 19% reduction for mortality plus all-cause hospitalization (p = 0.00012). The first secondary endpoint of mortality plus hospitalization for heart failure was reduced by 31% (p = 0.0000008). The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as nearly all post-hoc subgroups. Metoprolol CR/XL has been very well tolerated, overall as well as in all subgroups analyzed. Overall 87% of the patients reached a dose of 100 mg or more of metoprolol CR/XL once daily, and 64% reached the target dose of 200 mg once daily. Conclusion: Our results show that when carefully titrated, metoprolol CR/XL can safely be instituted for the overwhelming majority of outpatients with clinically stable systolic heart failure, with minimal side effects or deterioration. The time has come to overcome the barriers that physicians perceive to beta-blocker treatment, and to provide it to the large number of patients with heart failure in need of this therapy, including also high risk patients like elderly patients, patients with severe heart failure, and patients with diabetes. Because of the increased risk, these are the patients in whom treatment will have the greatest impact as shown by number of lives saved and number of hospitalizations avoided. The target dose should be strived for in all patients who tolerate this dose. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups due to small sample size in subgroups and due to chance. However, we believe that the best estimate of treatment effect for any particular subgroup should be the overall effect observed in the trial.

Objective: To determine whether patients with congestive heart failure on different β adrenoreceptor blocking drugs have similar haemodynamic responses to dobutamine. Design: Single centre, single blind, randomised, two period crossover study comparing carvedilol with metoprolol CR/XL. Patients: Ten patients with stable chronic congestive heart failure (ejection fraction < 40%) on chronic treatment with metoprolol CR/XL. Methods: Patients were treated with carvedilol or metoprolol CR/XL (target dose 50 mg twice daily and 200 mg once daily, respectively) for eight weeks. Stress echocardiography was undertaken at the end of each maintenance period, using dobutamine 5 and 15 µg/kg/min. Results: No significant haemodynamic differences were seen at rest on the two treatments. There was a more pronounced increase in heart rate and cardiac output during dobutamine infusion when the patients were on metoprolol than when they were on carvedilol. Mean arterial pressure increased significantly when the patients were on carvedilol, and cardiac output increased during low dose dobutamine, without further change during high dose dobutamine. During the dobutamine infusion, there was no significant difference in ejection fraction between carvedilol and metoprolol treatment. Conclusions: Patients with congestive heart failure on a non-selective β adrenoreceptor blocker or β1 selective blocker responded differently to the inotropic drug dobutamine: the β1 blockade caused by metoprolol could be counteracted by dobutamine, whereas with carvedilol a low dose of dobutamine increased cardiac output, and a higher dose of dobutamine caused a pressor effect. These findings may be clinically relevant when choosing an inotropic drug.

Objectives We performed a post-hoc subgroup analysis in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) with the aim of reporting on the heart rate (HR) response during the titration phase and clinical outcomes from the three-month follow-up visit to end of study in two dosage subgroups: one that had reached more than 100 mg of metoprolol CR/XL once daily (high-dose group; n = 1,202; mean 192 mg) and one that had reached 100 mg or less (low-dose group; n = 412; mean 76 mg). Background Clinicians have questioned whether patients need to reach the target beta-blocker dose to receive benefit. Methods Outcome (Cox-adjusted) was compared with all placebo patients with dose available at the three-month visit (n = 1,845). Results Data indicated somewhat higher risk in the low-dose group compared with the high-dose group. Heart rate was reduced to a similar degree in the two dose groups, indicating higher sensitivity for beta-blockade in the low-dose group. The reduction in total mortality with metoprolol CR/XL compared with placebo was similar: 38% (95% confidence interval [CI], 16 to 55) in high-dose group (p = 0.0022) and also 38% (95% CI, 11 to 57) in the low-dose group (p = 0.010). Conclusions Risk reduction was similar in the high- and low-dose subgroups, which, at least partly, may be the result of similar beta-blockade as judged from the HR response. The results support the idea of an individualized dose-titration regimen, which is guided by patient tolerability and the HR response. Further research is needed to shed light on why some patients respond with a marked HR reduction and reduced mortality risk on a relatively small dose of a beta-blocker.

OBJECTIVES This study analyzed the effect of the beta1-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure. BACKGROUND There continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure. METHODS A subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction

Background International placebo-controlled survival trials (Metoprolol Controlled-Release Randomised Intervention Trial in Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS-II], and Carvedilol Prospective Randomized Cumulative Survival trial [COPERNICUS]) evaluating the effects of β-blockade in patients with heart failure have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization. Also, the analysis of the US Carvedilol Program indicated an effect on these end points. Although none of these trials are large enough to provide definitive results in any particular subgroup, it is natural for physicians to examine the consistency of results across various subgroups or risk groups. Our purpose was to examine both predefined and post hoc subgroups in the MERIT-HF trial to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. Methods The study was conducted at 313 clinical sites in 16 randomization regions across 14 countries, with a total of 3991 patients. Total mortality (first primary end point) and total mortality plus all-cause hospitalization (second primary end point) were analyzed on a time to first event. The first secondary end point was total mortality plus hospitalization for heart failure. Results Overall, MERIT-HF demonstrated a hazard ratio of 0.66 for total mortality and 0.81 for mortality plus all-cause hospitalization. The hazard ratio of the first secondary end point of mortality plus hospitalization for heart failure was 0.69. The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as for nearly all post hoc subgroups. The results of the post hoc US subgroup showed a mortality hazard ratio of 1.05. However, the US results regarding both the second primary combined outcome of total mortality plus all-cause hospitalization and of the first secondary combined outcome of total mortality plus heart failure hospitalization were in concordance with the overall results of MERIT-HF. Tests of country by treatment interaction (14 countries) revealed a nonsignificant P value of .22 for total mortality. The mortality hazard ratio for US patients in New York Heart Association (NYHA) class III/IV was 0.80, and it was 2.24 for patients in NYHA class II, which is not consistent with causality by biologic gradient. We have not been able to identify any confounding factor in baseline characteristics, baseline treatment, or treatment during follow-up that could account for any treatment by country interaction. Thus we attribute the US subgroup mortality hazard ratio to be due to chance. Conclusions Just as we must be extremely cautious in overinterpreting positive effects in subgroups, even those that are predefined, we must also be cautious in focusing on subgroups with an apparent neutral or negative trend. We should examine subgroups to obtain a general sense of consistency, which is clearly the case in MERIT-HF. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups because of small sample size in subgroups and chance. Thus the best estimate of the treatment effect on total mortality for any subgroup is the estimate of the hazard ratio for the overall trial. (Am Heart J 2001;142:502-11.)

OBJECTIVE—Contraction of longitudinal and subendocardial myocardial muscle fibres is reflected in descent of the atrioventricular (AV) plane. The aim was therefore to determine whether β blocker treatment with prolongation of diastole might result in improved function as reflected by AV plane movements in patients with chronic heart failure. DESIGN—Double blind, randomised, placebo controlled and open intervention study. SETTING—University hospital. PATIENTS—Patients with congestive heart failure: placebo controlled (n = 26) and an open protocol (n = 15). INTERVENTIONS—12 months of metoprolol treatment. MAIN OUTCOME MEASURES—Short axis and long axis echocardiography, invasive haemodynamics, radionuclide angiography. RESULTS—Recovery of systolic and diastolic function during metoprolol treatment was reflected by early changes in mean (SD) AV plane amplitude, from 5.3 (2.0)% to 7.1 (3.2)% and 7.8 (3.1)% (at 3 and 12 months, respectively; p

Beta-blocker therapy results in a functional benefit in patients with heart failure (CHF) due to idiopathic dilated cardiomyopathy (DCM). This study assessed if similar effects were observed in patients with ischemic heart disease (CAD), NYHA II–III after 6 months of therapy with metoprolol. Methods and results: Fifty-two patients with CHF secondary to DCM (26 patients) and CAD (26 patients) and a left ventricular ejection fraction (EF) < 40% were enrolled in the placebo-controlled study. The study medication was titrated over 6 weeks, the mean final dosage was 135 mg/day. Three patients died due to cardiogenic shock, two received placebo and one metoprolol. Eight patients did not complete the study due to non-compliance. Metoprolol significantly reduced heart rate at rest and after submaximal and maximal exercise. Vo2-max and Vo2-AT as well as the 6-min walk test improved significantly after metoprolol treatment. There was a significant increase in EF at rest (27.3–35.2%), submaximal (28.5–37.7%) and maximal exercise (28.7–40.9%) in the metoprolol-treated patients. No differences were found between patients with CAD and DCM. We also observed reduced left ventricular volumes. Conclusion: The additional therapy with metoprolol improved cardiac function and the cardiopulmonary exercise capacity in patients with CHF.

Over a 9-yr period, heart transplantation was performed in 200 patients at Sahlgrenska University Hospital. Of these 200 patients, 151 were followed for 1 to 9 yr with regard to renal function, hemodynamics, cyclosporin A concentrations, and complications. Patients with a preoperative serum creatinine130 micromol/L received inotropic drugs to test for reversibility of renal dysfunction. The end point was graft failure. The average preoperative GFR of 66 +/- 17 ml/min per 1.73 m(2) declined to 52 +/- 19, 44 +/- 16, and 37 +/- 17 at 1, 5, and 9 yr after heart transplantation, respectively. Altogether, the average GFR declined by 44%. There was no significant correlation between the preoperative GFR and postoperative renal function or survival. Recipient age was a predictor of renal function during the entire follow-up. Severe renal dysfunction (GFR20 ml/min per 1.73 m(2)) developed in 20% of the patients, which was predicted by the recipient age at transplantation together with the GFR 1 yr after transplantation. A nomogram that shows the risk of developing severe renal dysfunction after heart transplantation is presented. Cyclosporin A concentrations and treatment with statins, calcium channel blockers, or angiotensin-converting enzyme inhibitors did not correlate with the evolution of renal function. Patients with a preoperative depressed renal function who improved on inotropic treatment seemed to have a poorer outcome compared with the other study patients.

To elucidate potential mechanisms for insulin resistance occurring early in the development of type 2 diabetes, we studied 10 young healthy individuals, each with two first-degree relatives with type 2 diabetes, and 10 control subjects without known type 2 diabetic relatives. They were pairwise matched for age (35 +/- 1 vs. 35 +/- 1 years), BMI (23.6 +/- 0.6 vs. 23.1 +/- 0.4 kg/m2), and sex (four men, six women). Glucose turnover was assessed during a euglycemic clamp at two insulin levels (low approximately 20 mU/l; high approximately 90 mU/l), and abdominal subcutaneous adipose tissue (SAT) lipolysis and blood flow were concomitantly studied with microdialysis and 133Xe clearance. HbA1c was higher in patients with type 2 diabetic relatives than in control subjects (4.8 +/- 0.1 vs. 4.5 +/- 0.1%, P < 0.02), but fasting glucose, insulin, and C-peptide levels were similar. During the clamp, the insulin sensitivity index for glucose disposal was lower (P < 0.03) in relatives than in control subjects (low 12.0 +/- 1.6 vs. 18.1 +/- 1.4; high 9.4 +/- 0.8 vs. 12.9 +/- 0.6 [100 x mg x l x kg(-1) x mU(-1) x min(-1)]). This difference was partially attributed to slightly higher clamp insulin levels in the relatives (P < 0.03), suggesting an impaired rate for insulin clearance. SAT lipolysis measured as in situ glycerol release did not differ under basal conditions (2.0 +/- 0.2 vs. 2.1 +/- 0.2 micromol x kg(-1) x min(-1)), but the suppression during the insulin infusion was less marked in relatives than in control subjects (glycerol release: low 0.92 +/- 0.09 vs. 0.68 +/- 0.16; high 0.71 +/- 0.10 vs. 0.34 +/- 0.10 micromol x kg(-1) x min(-1); P < 0.03). Plasma nonesterified fatty acids also tended to be higher in relatives than in control subjects during the insulin infusion (NS). In contrast, in vitro experiments with isolated subcutaneous adipocytes displayed similar effects of insulin in relatives and control subjects with respect to both glucose uptake and antilipolysis. In conclusion, insulin action in vivo on both lipolysis and glucose uptake is impaired early in the development of type 2 diabetes. Since this impairment was not found in isolated adipocytes, it may be suggested that neural or hormonal perturbations precede cellular insulin resistance in type 2 diabetes.

BACKGROUND: Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure. METHODS: We enrolled 3991 patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV and with ejection fraction of 0.40 or less, stabilised with optimum standard therapy, in a double-blind randomised controlled study. Randomisation was preceded by a 2-week single-blind placebo run-in period. 1990 patients were randomly assigned metoprolol CR/XL 12.5 mg (NYHA III-IV) or 25.0 mg once daily (NYHA II) and 2001 were assigned placebo. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat. FINDINGS: The study was stopped early on the recommendation of the independent safety committee. Mean follow-up time was 1 year. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7.2%, per patient-year of follow-up]) vs 217 deaths [11.0%], relative risk 0.66 [95% CI 0.53-0.81]; p=0.00009 or adjusted for interim analyses p=0.0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0.59 [0.45-0.78]; p=0.0002) and deaths from worsening heart failure (30 vs 58, 0.51 [0.33-0.79]; p=0.0023). INTERPRETATION: Metoprolol CR/XL once daily in addition to optimum standard therapy improved survival. The drug was well tolerated.

β-Blockers reduce mortality in patients with congestive heart failure and a proposed mechanism has been changes of autonomic tone. Heart rate variability is a non-invasive tool to estimate cardiac autonomic tone. The aim was to study changes of heart rate variability in patients with congestive heart failure on placebo, on the β 1 -selective antagonist metoprolol or 24 h after metoprolol withdrawal. Forty-five patients with congestive heart failure were studied with Holter recordings. Heart rate variability measurements were performed before, after 6–12 months of treatment with 150 mg metoprolol/placebo, or 24 h after discontinued metoprolol. After treatment, patients on β-blockade had a significantly longer mean RR interval and changes of heart rate variability, suggesting elevated vagal tone. Patients monitored in the rebound phase of β-blocker withdrawal had a significant vagal reduction to the level of the placebo group. There was also a nonsignificant trend towards increased sympathetic tone (LF/HF over 24 h), compared with the β-blockade group. Heart rate variability indicates an elevated vagal tone during treatment with metoprolol but β-blockade withdrawal shifts the autonomic balance towards lower vagal and higher sympathetic tone within 24 h. These results could imply a potential risk when abruptly discontinuing β-blockade medication in these patients.

Earlier studies have shown that spinal cord stimulation (SCS) has antianginal and anti-ischemic effects in severe coronary artery disease. In the present study, 14 patients were subjected to right-sided atrial catheterization and atrial pacing. The patients were paced to angina during a control session and during spinal cord stimulation. Myocardial extraction of β-endorphin (BE) during control pacing (8 ± 22%) changed to release at the maximum pacing rate during treatment (–21 ± 47%, a negative value representing release). Furthermore, the results indicate local myocardial turnover of leuenkephalin, BE and calcitonin-gene-related peptide. In addition, it is implied that SCS may induce myocardial release of BE which could explain the beneficial effects in myocardial ischemia.

Aims Spinal cord stimulation has been used in the treatment of intractable angina pectoris since the beginning of the 1980s. This study was designed to investigate whether the documented anti-ischaemic effects of spinal cord stimulation are mediated through a decrease in sympathetic activity. Methods and Results Ten patients with a spinal cord stimulator implanted as anti-anginal treatment were included in the study. Atrial pacing until the patient experienced moderate angina was performed and after 50 min rest the procedure was repeated during spinal cord stimulation. Total body and cardiac norepinephrine spillover was calculated and the former was found to have increased during pacing (47%, P =0·02). When spinal cord stimulation was applied, total body norepinephrine spillover decreased at a comparable pacing rate (18%, P =0·02). Cardiac norepinephrine spillover was not affected during the procedure. Conclusion The results of this study indicate that the anti-ischaemic effect of spinal cord stimulation is not due to reduced cardiac sympathetic activity. However, spinal cord stimulation decreases overall sympathetic activity which may benefit the heart, possibly by reducing oxygen demand.

Despite the well-documented benefits of beta blockade in a variety of cardiovascular conditions, the value of beta blockade in congestive heart failure (CHF) is still in question. The concept of neurohormonal blockade in heart failure has, however, brought beta blockade into focus. There is experimental evidence for the value of blocking sympathetic activation in CHF, and increased sympathetic activation may be an etiologic factor for development of CHF. Clinical studies have shown that long-term beta blockade improves both systolic and diastolic function. The effects on exercise tolerance and quality of life seem to differ between beta1-selective and nonselective beta blockers in favor of the beta1-selective blockers. To date, results of all trials reveal a consistent pattern of decreased cardiovascular morbidity. In one trial of metoprolol, fewer heart transplantations were required; such a reduction may have a great impact on healthcare costs associated with heart failure. Improved long-term survival found by one study must be confirmed in additional trials: 3 such survival trials (with metoprolol, bisoprolol, and bucindolol) are now in progress.

The aim of this study is to describe the impact of early treatment with metoprolol on prognosis during 1 year of follow-up in patients with suspected acute myocardial infarction (AMI) and indirect signs of congestive heart failure (CHF). Patients aged 40-74 years who presented within 48 hours of onset of symptoms raising suspicion of AMI were assessed for inclusion. All patients participated in the Goteborg Metoprolol Trial and had indirect indices of CHF according to various clinical criteria. As soon as possible after hospital admission, patients received either placebo or metoprolol (15 mg) divided into 3 intravenous injections, then oral treatment, 200 mg daily for 3 months. Thereafter, most patients in both treatment groups received metoprolol in an open manner. Among the 1,395 randomized patients, 262 (19%) had signs of mild-to-moderate CHF before randomization. Of these, 131 were randomized to metoprolol and 131 to placebo. During the first 3 months, mortality was 10% among patients randomized to metoprolol versus 19% among patients randomized to placebo (p = 0.036). The corresponding figures for the first year were 14% and 27%, respectively (p = 0.0099). Patients randomized to placebo who showed signs of CHF had a 1-year mortality rate of 28% compared with 10% among patients without such signs (p

Experience accumulated from several large trials strongly suggests that beta-blockers should be used for the management of chronic heart failure[87]. It is appropriate to add beta-blockade to conventional therapy such as diuretics, ACE inhibitors and digoxin, as this was the approach used in the major trials. It is appropriate to treat patients with mild, moderate and, when stable, severe chronic heart failure. The benefits obtained include improvements in left ventricular function, reductions in symptoms and morbidity, improvement of quality of life, and delay of clinical progression, reflected in a reduced need for cardiac transplantation and, probably, a reduction in mortality. beta-blockers are much better tolerated, when used appropriately in selected patients, than was previously supposed. To confirm the improvement in survival recently reported with carvedilol, further prospective trials using different beta-blockers are warranted. No major comparative trials have been carried out between beta-blockers in chronic heart failure, therefore it is not known whether the differences between them are clinically significant. The optimal dose of beta-blocker and the effect in patient groups excluded from or poorly represented in the clinical trials (e.g. elderly patients) have yet to be determined. Placebo-controlled mortality trials with bucindolol (BEST) and bisoprolol (CIBIS-II) are under way[89,90]. A large study of carvedilol versus metoprolol (COMET), added to conventional treatment, is planned.

The primary myocardial disease idiopathic dilated cardiomyopathy (IDCM) is not clearly defined in the literature. The description is both morphologic and etiologic. We examined consecutive patients with congestive heart failure (CHF) of unknown cause to identify possible cases of IDCM and to give a detailed description of echocardiographic data and possible diastolic dysfunction in this group. The hospital records of patients aged 16 to 65 years hospitalized due to CHF or IDCM during a 6-year period (N = 2,711) were evaluated in a defined region of western Sweden. Twenty-two percent (584/2,711) of these records contained no plausible cause of CHF or IDCM, and among patients being alive, obvious cause was lacking in 411 of 1,516 (27%). These 411 patients were offered a diagnostic investigation, including echocardiography, and they were compared with a randomly selected control group (n = 103) from the general population. Of 411 patients, 293 accepted investigation. From the control group, we defined the reference level for left ventricular (LV) dilatation to be32 mm/m2, and reduced ejection fraction according to Teichholz formula to be50%. Applying these borderlines, we identified LV dilatation and systolic dysfunction to be present in 30%, either dilatation or systolic dysfunction in 36%, and neither in 34%. In patients without any signs of systolic dysfunction 44% (26/59) showed signs of diastolic dysfunction. In a multivariate analysis, LV dimension was not independently correlated to disease, although LV dimension was univariately correlated to ejection fraction (EF) (r = -0.59; p0.0001). However, EF (p0.0001), left atrial dimension (p0.0001), and the first third filling fraction (p0.0001) were the constellation of parameters that most accurately separated patients from controls. By using these three parameters, a positive and negative predictive accuracy of 98% and 61%, respectively, was achieved. Thus, in a consecutive group of patients with idiopathic CHF recruited from a nonselected group of hospitalized patients with CHF, all grades of ventricular function were found. In this group, 30% were identified as having IDCM. We give reference values for the diagnosis of idiopathic IDCM and a simple tool to identify patients with systolic and diastolic dysfunction.

beta 1 and beta 2 adrenoceptor ligand activity has been shown to be down-regulated in failing myocardium. It is the aim of this study to test the hypothesis that also mRNA levels are down-regulated in dilated cardiomyopathy. beta 1 and beta 2 adrenoceptor ligand activities and mRNA expressions were analyzed in left ventricular biopsies from six organ donor hearts, in papillary muscles from seven patients operated on for mitral regurgitation, and in six explanted hearts as the result of dilated cardiomyophathy. mRNA levels were determined by solution hybridization. beta 1 ligand activity was decreased in the cases of mitral regurgitation (p0.01) and dilated cardiomyopathy (p0.001). beta 2 ligand activity did not differ between the three groups. mRNA expression was depressed in mitral regurgitation regarding both beta 1 (p0.001) and beta 2 (p0.01), while no differences were observed in dilated cardiomyopathy as compared to the donor hearts. The regulation of beta 1 and beta 2 adrenoceptor ligand activity and mRNA expression appears to follow a specific pattern in dilated cardiomyopathy. The specific down-regulation of beta 1 ligand activity seems to occur at a posttranslational level.

BACKGROUND Autoantibodies against the beta 1-adrenoceptor have been detected in the sera of patients with idiopathic dilated cardiomyopathy (DCM). The mechanisms by which these autoantibodies can alter normal receptor function are investigated, and the results are interpreted in the light of the beneficial effects of beta 1-blockade in some of these patients. METHODS AND RESULTS Autoantibodies against the beta 1-adrenoceptor, affinity purified from sera of patients with idiopathic DCM, were analyzed in a functional test system of spontaneously beating neonatal rat heart myocytes. Antibodies from rabbits immunized with peptides derived from the amino acid sequence of this receptor were also analyzed. Autoantibodies, against the second extracellular loop increased the beating frequency of isolated myocytes in a concentration-dependent manner, to approximately 80% of maximal isoproterenol stimulation. Rabbit anti-peptide antibodies against the second extracellular loop increased the beating frequency correspondingly. Autoantibodies and rabbit anti-peptide antibodies against the second extracellular loop were able to immunoprecipitate the unliganded receptor but not the antagonist-occupied receptor. In contrast, rabbit antibodies against the extracellular N-terminal sequence 34-57 of the beta 1-adrenoceptor were able to immunoprecipitate both the unliganded and the antagonist-occupied receptor although with no effect on the beating frequency of myocytes. The positive chronotropic effect of the antibodies was completely neutralized both by the addition of increasing concentrations of the beta 1-selective antagonist bisoprolol and by preincubation with the peptide corresponding to the second extracellular loop. The antibody-induced increase in beating frequency remained unchanged for more than 6 hours. This should be compared with the isoproterenol-stimulated beating frequency, which undergoes desensitization within 60 minutes. Addition of isoproterenol to autoantibody-stimulated myocytes resulted in only a small increase in beating frequency and did not cause desensitization. Antibodies had only a marginal effect on cyclic AMP production of stimulated cardiomyocytes compared with the 10-fold increase obtained after stimulation with isoproterenol. CONCLUSIONS The second extracellular loop of the beta 1-adrenoceptor is a specific target for antibodies with stimulatory activity detected in patients with idiopathic DCM. The antibodies have a positive chronotropic effect on isolated rat heart myocytes. Autoantibody stimulation does not cause the normal agonist-induced desensitization phenomena of the effector system. These findings could contribute to our understanding of the pathophysiological mechanisms of the autoantibodies and of the beneficial effect of beta 1-blocking agents in the treatment of patients with idiopathic DCM.

Objectives. This study was performed to investigate exercise hemodynamic status in a double-blind, placebo-controlled trial and was a substudy in the Metoprolol in Dilated Cardiomyopathy Trial.Background. Previous open studies have shown beneficial effects on exercise hemodynamic status after beta-adrenergic blocking agent therapy in patients with congestive heart failure.Methods. The study included 41 patients with idiopathic dilated cardiomyopathy with ejection fraction

OBJECTIVE--To measure plasma concentrations of noradrenaline and neuropeptide Y-like immunoreactivity in relation to cardiac function in patients with congestive heart failure. DESIGN--Retrospective analysis of plasma noradrenaline concentrations and neuropeptide Y-like immunoreactivity in the arterial and coronary circulations, in patients with a high or low ejection fraction (31.3% (1.3%) or 17.7% (1.1%) respectively) and in healthy volunteers. SETTING--Cardiology department of a university hospital. PATIENTS--41 patients with congestive heart failure with various aetiologies. Ten healthy volunteers served as a reference group. MAIN OUTCOME MEASURES--Concentrations of noradrenaline measured by high performance liquid chromatography and of neuropeptide Y-like immunoreactivity measured by radioimmunoassay. Cardiac index, pulmonary capillary wedge pressure, pulmonary vascular resistance, and systemic vascular resistance were derived by catheterisation of the right heart. Ejection fraction was measured by radionuclide angiography, cineangiography, or M mode echocardiography. RESULTS--There were pronounced and significant increases in circulating arterial concentrations of neuropeptide Y-like immunoreactivity and noradrenaline in both the high and low ejection fraction groups compared with the healthy subjects. In the patients myocardial release of neuropeptide Y-like immunoreactivity tended to be greater compared with normal subjects, but not significantly so. While normal subjects showed myocardial noradrenaline uptake, patients with congestive heart failure showed significant and progressive myocardial noradrenaline release. Arterial as well as coronary sinus concentrations of neuropeptide Y-like immunoreactivity correlated significantly with plasma noradrenaline concentrations from the respective sites. Plasma noradrenaline concentrations in the artery and coronary sinus were negatively correlated with ejection fraction and cardiac index; no such relations were found for concentrations of neuropeptide Y-like immunoreactivity. CONCLUSIONS--Both circulating concentrations of neuropeptide Y-like immunoreactivity and noradrenaline are significantly increased in moderate to severe forms of congestive heart failure. Plasma concentrations of neuropeptide Y-like immunoreactivity correlated with plasma noradrenaline concentrations, but plasma noradrenaline concentrations alone correlated with ejection fraction and cardiac index. Thus plasma noradrenaline concentration seems to be a more sensitive index of cardiac dysfunction than the concentration of neuropeptide Y-like immunoreactivity in congestive heart failure.

It has been suggested that long-term beta blockade treatment in congestive heart failure might be less effective in patients with ischemic cardiomyopathy as compared with patients having idiopathic dilated cardiomyopathy. This study was performed to evaluate the effect of long-term adrenergic beta blockade treatment on regional myocardial function in patients with ischemic cardiomyopathy. The regional wall motion (RWM) was evaluated in 12 patients with ischemic cardiomyopathy before and after long-term open treatment with metoprolol. On average, the patients were treated over 11 months (range 6-36 months). The regional left ventricular function was assessed using two-dimensional echocardiographic recordings by two independent blinded observers. The RWM score was evaluated in 16 segments of the left ventricle on a scale from 0 (hypercontractility) to 5 (dyskinesia). Following treatment, there was an improvement in general ventricular function (ejection fraction 0.24-0.31; p = 0.01) as well as in RWM (86 improved segments, 48 deteriorated, 49 unchanged; p0.002). Ventricular segments with poor contractility (RWM scoreor = 3.5) tended to improve (53 improved segments, 16 deteriorated, 13 unchanged; p0.0001), whereas less severely impaired segments (RWM score3.5) did not improve (33 improved segments, 32 deteriorated, 36 unchanged; NS). It is suggested that poorly contracting myocardial segments might improve following beta blockade treatment, while an effect on less impaired segments might be lacking. An improvement in overall myocardial function would then be harder to detect.

As first reported by our group in 1975, severe heart failure due to idiopathic dilated cardiomyopathy could be improved in patients receiving β-blocker therapy starting at a very low dose and followed by a stepwise increase. Since then, these results have been confirmed by our own group and by others, and similar results were also obtained in patients with other forms of cardiomyopathy, including ischaemic cardiomyopathy. In 13 separate studies involving a total of 651 patients with idiopathic dilated cardiomyopathy, β-blockade for 2 to 19 months (in addition to conventional treatment of heart failure, including angiotensin converting enzyme inhibitor therapy), significantly improved cardiac function. These studies were performed using metoprolol, bucindolol, labetalol and practolol. Eight studies investigated the effects of long term β-blocker treatment in patients with heart failure and cardiomyopathy due to coronary artery disease, valvular heart disease, diabetes and doxorubicin therapy. A total of 128 patients were treated with metoprolol, carvedilol or bucindolol for periods of 2 to 12 months. All studies reported a significant improvement in cardiac function. Three studies reported results on survival and the need for cardiac transplantation. The first study published by our group reported improved survival in patients with idiopathic dilated cardiomyopathy treated with metoprolol plus digitalis and diuretics compared with a matched control group. In the more recent Metoprolol in Dilated Cardiomyopathy trial, metoprolol treatment in patients with idiopathic dilated cardiomyopathy resulted in an estimated 34% reduction in the number of primary end-points, total number of deaths, and the need for cardiac transplantation compared with placebo treatment. Recently, it was reported that bisoprolol in patients with heart failure due to various forms of cardiomyopathy caused a nonsignificant 21% reduction in mortality compared with placebo. However, larger studies are needed to further study the effects of β-blockers on the prognosis for patients with various forms of cardiomyopathy.