Skip Navigation

European Journal of Heart Failure 2003 5(5):679-691; doi:10.1016/S1388-9842(03)00105-3
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Waagstein, F.
Right arrow Articles by Wahlqvist, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Waagstein, F.
Right arrow Articles by Wahlqvist, I.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2003 European Society of Cardiology

Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy

F. Waagsteina,*, O. Strömblada, B. Anderssona, M. Böhmb, M. Dariusc, W. Deliusd, F. Gosse, K.J. Osterzielf, M. Sigmundg, S.-P. Trenkwalderh and I. Wahlqvisti

a Wallenberg Laboratory and Department of Cardiology, Sahlgrenska University Hospital Göteborg SE-413 45, Sweden
b Klinik und Poliklinik für Innere Medizin III, Universität des Saarlandes Homburg/Saar, Germany
c Department of Medicine II, Johannes Gutenberg-University Mainz, Germany
d Städt Krankenhaus München-Bogenhausen, I Med. Abteilg/Kardiol Ambulanz Munich, Germany
e Private Cardiologist Marienplatz 1 Munich, Germany
f Charité Campus Berlin-Buch Franz Volhard Klinik Humboldt University Berlin, Germany
g Department of Cardiology, Dr-Horst-Schmidt-Kliniken GmbH Wiesbaden, Germany
h Department of Medicine, University of Munich, Starnberg Hospital Germany
i R&D AstraZeneca Mölndahl, Sweden

* Corresponding author. Tel.: +46-31-3423014; fax: +46-31-823762. E-mail address: Waagstein{at}wlab.gu.se


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
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<0.001) and 0.078 during submaximal exercise (P<0.001). LV end-diastolic volume decreased by 22 ml at rest (P=0.006) and by 15 ml during exercise (P=0.006). LV end-systolic volume decreased by 23 ml both at rest (P=0.001) and during exercise (P=0.004). Exercise time increased by 39 s (P=0.08). In the metoprolol group, mitral regurgitation decreased (P=0.0026) and only one patient developed atrial fibrillation vs. eight in the placebo group (P=0.01).

Conclusion: metoprolol improves EF both at rest and during submaximal exercise and prevents LV dilatation in mild to moderate CHF due to IHD or DCM.

Key Words: Drugs • Heart failure • Exercise • Cardiomyopathy • Ischemia

Received February 13, 2003; Revised April 2, 2003; Accepted June 16, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Pharmacological prevention of LV dilatation was first demonstrated more than a decade ago by Sharpe and coworkers, who used captopril to treat patients with asymptomatic left ventricular dysfunction after transmural myocardial infarction [1]. This beneficial effect on remodeling has been considered an important mechanism to explain the positive long-term outcome in heart failure treated with ACE inhibitors [2]. Beta-blockers are now generally accepted for treatment of both ischemic and non-ischemic heart failure after having convincingly proved to reduce cardiovascular morbidity and mortality [3–5]. A consistent finding in many small and medium sized studies is the long-term improvement of systolic function and reversed or prevented remodeling of the left ventricle [6–15]. Most of these studies, with a few exceptions [14,15], have used echocardiography, making volume estimation less accurate. None of these studies have tested whether the beneficial effect of long-term beta-blockade on systolic function and ventricular volumes were sustained during exercise. Such an effect may better predict the effect of beta-blockade on exercise performance and heart failure symptoms.

The present study was, therefore, designed to measure volumes not only at rest but also during steady state submaximal exercise using radionuclide angiography instead of echocardiography. The study population was patients with mild to moderate heart failure stratified by etiology (IHD or DCM).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients
Symptomatic patients of either sex, 18- to 80-years old, with stable CHF (NYHA class II–III) were considered for inclusion. Patients were prospectively stratified into an IHD group and a DCM group. DCM was diagnosed based on the presence of LV dilatation and EF≤0.40 without significant coronary artery obstruction. IHD was diagnosed based on LV dilatation, EF≤0.40, and the presences or a history of at least one significant coronary obstruction.

Patients who had undergone coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) within the previous 6 months or who were scheduled for or expected to require these treatments during the 6-month study, were excluded. Also, excluded were patients who had a major ischemic event (acute MI or unstable angina) within the previous 6 months and those with large anterior aneurysms, acute myocarditis, primary valvular heart disease, exercise-limiting angina pectoris or severe systemic disease. Additional exclusion criteria were excessive consumption of alcohol (≥100 g of pure alcohol/day or ≥700 g/week), resting systolic blood pressure >190 mmHg or diastolic >100 mmHg, systolic blood pressure <95 mmHg (unless considered occasional), heart rate <50 beats/min, second- or third-degree atrioventricular (AV) block, sick sinus syndrome, sinoatrial block or atrial fibrillation (which makes equilibrium radionuclide angiography difficult to perform). Patients with a pacemaker for third-degree AV block or a ventricular inhibited (VVI) pacemaker programmed with a fixed heart rate above the spontaneous heart rate were also excluded.

Other treatment for heart failure was allowed. Patients with overt heart failure who were stabilized on ACE inhibitors, diuretics and digitalis were enrolled at the discretion of the investigator. ACE inhibitors and digoxin could be used, as long as the dosage remained unchanged for at least 2 weeks before the study period; diuretic doses could be altered as clinically indicated. Chronic treatment with β-blockers (including sotalol), amiodarone, calcium-channel blockers other than dihydropyridines and antidepressants was not allowed. To be included, IHD patients had to be able to exercise for at least 3 min with ≤2 mm of ST depression. Written informed consent was obtained from all patients, and the protocol was approved by local ethics committees before the enrollment began.

One hundred seventy-two patients at 19 hospitals in Germany, Finland and Sweden who met the inclusion and exclusion criteria were challenged with a test dose of metoprolol (5 mg b.i.d). All patients tolerated the test dose, but three were not randomized for non-cardiac reasons. Thus, 169 patients were randomized to double-blind treatment. Two patients randomized to placebo and one to metoprolol never took study medication; one patient was withdrawn from the study before any measurements were performed, and it is unclear whether the patient took any study medication. These four patients are not included in the intention-to-treat analysis. Thus, 165 patients started double-blind medication (86 metoprolol, 79 placebo); 70 had DCM and 93 IHD.

2.2. Equilibrium radionuclide angiography
LV volumes and EF were measured by equilibrium radionuclide angiography. Red blood cells were labeled with 99Tc (25 mCi) by the in vivo–in vitro technique. Images were acquired with the patient supine; the left anterior oblique projection was used for optimal separation of left and right ventricles. Exercise began at 25 W, increasing 25 W every 4 min. To maintain high image quality and comparable images throughout the study, the submaximal load (acquisition period before the maximal load) was used. Studies with poor image quality were excluded. If reliable data transformation could be obtained (55% of studies), central analysis with a closed-line integral for edge detection developed at the Sahlgrenska university hospital [16] was used. EF was calculated by using end-diastolic and end-systolic regions of interest (ROIs). When data transformation was not possible, commercially available software was used for edge detection at each center. All volumes were obtained by using end-systolic and end-diastolic ROIs and the count ratio between the hottest pixels and total LV count [17].

2.3. Mitral regurgitation
In a subset of patients (n=128), mitral regurgitation was semi quantitatively assessed from the mitral Doppler signal as follows: none, mild, moderate, large and severe. Doppler registrations were evaluated blindly at each study site.

2.4. Bicycle exercise
Maximal exercise capacity was assessed at baseline and at 6 months by bicycle tests. The initial load was 20 W, increasing 10 W/min.

2.5. Self assessment and NYHA classification
Self assessment of CHF symptoms and a modified NYHA classification were performed at baseline and at follow-up. NYHA subclasses were defined as follows: I, no chest discomfort; IIa, slight chest discomfort during very heavy exercise; IIb, moderate chest discomfort during heavy exercise; IIIa, marked chest discomfort after walking >200 m on flat ground; IIIb, marked chest discomfort after walking ≤200 m on flat ground; and IV, chest discomfort at rest. None of the patients were in NYHA class IV at randomization.

2.6. Drug titration
Double-blind treatment with metoprolol or placebo was initiated by titration over 6 weeks as follows: week 1, 5 mg b.i.d.; week 2, 5 mg t.i.d.; week 3, 10 mg t.i.d.; week 4, 25 mg b.i.d.; week 5, 25 mg t.i.d.; week 6, 50 mg b.i.d. Thereafter, the dose was 50 mg t.i.d. (target dose). A slower titration was allowed. The final dose was the highest tolerated or target dose.

2.7. Statistical analysis
Datas were analyzed on an intention-to-treat basis: all randomized patients who had taken at least one dose of study medication were included. Analysis of covariance (ANCOVA) was applied to the main efficacy variables, LV volumes and EF. The factors in the ANCOVA were center, etiology (IHD or DCM) and treatment (randomization code); the baseline value of the efficacy variable was analyzed as a covariate. Data from the centers with fewer than eight patients were pooled. The differences between the treatment groups, adjusted for all the factors in the model are presented with 95% confidence intervals. The main efficacy variables were also analyzed separately for the IHD and DCM groups. P<0.05 (two-sided) was considered significant.

A Mann–Whitney test was performed to determine if the distribution of changes in mitral regurgitation was identical in the two treatment groups. In a post-hoc analysis (log–rank), the number of patients that changed from sinus rhythm to atrial fibrillation during follow-up was analyzed.

Net differences were defined as the difference from baseline to 6 months in the metoprolol group minus the difference in the placebo group.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
Of the 169 randomized patients, 138 took the study drug for 6 months; 15 metoprolol patients and 16 placebo patients discontinued treatment prematurely and had no follow-up investigations. Most of those who remained on the study drug reached the target dose of 150 mg/day (64% in the metoprolol group [mean daily dose, 125 mg] and 73% in the placebo group [mean, 130 mg]). In the IHD group, the mean daily dose was 118 mg of metoprolol and 122 mg of placebo; in the DCM group, it was 133 mg and 139 mg, respectively.

3.1. Clinical characteristics
At randomization, the two treatment groups were well matched for age, weight, height, heart rate and blood pressure (Table 1). As expected, the mean age was somewhat higher in the IHD than in the DCM group. The groups were also well matched in terms of functional class, concomitant treatment for heart failure, EF, exercise duration, previous MI and previous interventions such as CABG and PTCA (Table 2). All patients were in sinus rhythm at randomization.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline anthropomorphic data in all randomized patients and in the IHD and DCM subgroups

 


View this table:
[in this window]
[in a new window]

  		Table 2 Baseline clinical characteristics in all randomized patients and in the IHD and DCM subgroups

 
3.2. EF
At 6 months, the mean resting EF was significantly higher in the metoprolol group than in the placebo group (Fig. 1); the net difference was 0.069 (P<0.001). The net differences in the IHD and DCM groups were 0.080 (P<0.001) and 0.057 (P=0.004), respectively.


Figure 1
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 (left panels) Mean resting LVEF at baseline (white bars) and at 6 months (black bars). (right panels) The 95% confidence intervals for net differences between groups.

 
During sub-maximal exercise, EF was significantly higher in the metoprolol group (Fig. 2); the net difference was 0.078 (P<0.001). The net differences in the IHD and DCM groups were 0.077 (P=0.004) and 0.075 (P=0.003), respectively.


Figure 2
View larger version (11K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 (left panels) Mean LVEF during submaximal exercise at baseline (white bars) and at 6 months (black bars). (right panels) The 95% confidence intervals for net differences between groups.

 
3.3. LV Volumes
Resting LVEDV was significantly reduced in the metoprolol group and unchanged in the placebo group (Fig. 3); the net difference was 22 ml (P=0.006). The net differences in the IHD and DCM groups were 22 ml (P=0.03) and 21 ml (P=0.09), respectively. Metoprolol significantly reduced resting LVESV as well (Fig. 4); the net difference was 23 ml (P<0.001). In the IHD and DCM group, the net differences were 25 ml (P=0.006) and 21 ml (P=0.05), respectively.


Figure 3
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 (left panels) Mean resting LVEDVs at baseline (white bars) and at 6 months (black bars). (right panels) The 95% confidence intervals for net differences between groups.

 


Figure 4
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 (left panels) Mean resting LVESVs at baseline (white bars) and at 6 months (black bars). (right panels). The 95% confidence intervals for net differences between groups.

 
During submaximal exercise, the net difference in LVEDV between the metoprolol and placebo groups was not statistically significant (Fig. 5) (15 ml; P=0.06). The net differences were 23 ml (P=0.06) and 4 ml (P>0.20) in the IHD and DCM groups, respectively. Exercise LVESV was significantly reduced in the metoprolol group but was unchanged in the placebo group (Fig. 6); the net difference was 23 ml (P=0.004). The net differences in the IHD and DCM groups were 32 ml (P=0.006) and 13 ml (P>0.20), respectively.


Figure 5
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 (right panels) Mean LVEDV during submaximal exercise at baseline (white bars) and at 6 months (black bars). (right panels). The 95% confidence intervals for net differences between groups.

 


Figure 6
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 6 (left panels) Mean LVESV during submaximal exercise at baseline (white bars) and at 6 months (black bars). (right panels) The 95% confidence intervals for net differences between groups.

 
3.4. Mitral regurgitation
Doppler recordings showed that significantly more patients were free of mitral regurgitation or had a lesser degree of mitral regurgitation at follow-up in the metoprolol group than in the placebo group (P=0.0023 (Fig. 7).


Figure 7
View larger version (7K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 7 Changes in mitral regurgitation during follow-up in the two randomization groups.

 
3.5. Bicycle exercise
There was no significant difference in maximal exercise capacity assessed with bicycle test. The net difference was 39 s (P<0.20) in favor of the metoprolol group.

3.6. Adverse events
Ten patients in each group were withdrawn because of adverse events. Three patients in the metoprolol group and seven in the placebo group had adverse cardiovascular events. Seven patients (four on metoprolol and three on placebo) died during the study or within 3 weeks after discontinuing study medication. The most common adverse events were dizziness and fatigue in the metoprolol group and dyspnea and atrial fibrillation in the placebo group. A change from sinus rhythm to atrial fibrillation was observed during follow-up in one metoprolol patient and eight placebo patients (P<0.01). There was no difference in the number of patients that were admitted to the hospital or emergency room for cardiovascular reasons (CHF, arrhythmias or ischemic event) during follow-up.

NYHA class improved in 42% of the patients in the metoprolol group and 33% in the placebo group; 49 and 56% were stable and 8% and 11% deteriorated, respectively. These differences were not statistically significant.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
In this study, metoprolol increased EF and decreased LV volumes in patients with CHF. It has been known for some years that β-blockers can increase EF at rest [6–15], but to our knowledge, this is the first time that effects of similar size have been demonstrated during exercise in patients with IHD as well as in those with DCM. Our findings are at variance with the findings of a previous study of bucindolol in patients with severe IHD showing no effect on myocardial function [18] but agree with those of studies in mild to moderate IHD [7,8,11–15,23]. The volume reduction may reflect reduced loading conditions, as reported previously [8,9] and corroborates other reports on the use of long-term treatment with carvedilol and bisoprolol and metoprolol in heart failure, showing reversed remodeling [7,8,10,12–14,20,22]. Reduced loading conditions alone may, however, not explain volume reduction [8,9]. Other mechanisms as discussed below, may play a bigger role.

In some of the previous studies, the net increase in EF was somewhat smaller compared to the present study [7,8,11] (5.1, 4.9 and 4.0 EF units), but similar to another study with metoprolol [14] (7.0 EF units). Different patient selection criteria may account for this difference. The absence of marked ST depression, angina and decreased EF during exercise in our patients indicated that no major coronary obstructions were present (or had been successfully eliminated by revascularization). Also, patients with extensive myocardial necrosis or anterior wall aneurysm were excluded. Thus, factors that may reduce the potential for improvement were absent in our patients.

In contrast to the positive effect of placebo on EF, indicating spontaneous improvement reported in some previous studies [9,19], EF did not increase in either placebo subgroup in the present study. This difference reflects the inclusion of clinically unstable patients in those studies. All patients in our study had been clinically stable for at least 6 months and had a baseline ejection fraction ≤0.40.

Submaximal exercise was used rather than maximal exercise. We assumed that the patients were still in the aerobic phase because they were able to sustain a steady-state load for 4 min without severe dyspnea or fatigue. Submaximal exercise is more representative of exercise during daily activity. Metoprolol significantly reduced LVEDVs at rest, but not during submaximal exercise, where only a trend was observed (P=0.06). LVESVs were significantly reduced both at rest and during exercise.

Although 6 months of metroprolol did not significantly prolong maximal exercise time, the mean difference (39 s) was similar to that observed at 6 months in the MDC trial, which showed a significant difference after 12 months of treatment [9]. Thus, longer-term metoprolol therapy may improve or prevent deterioration in exercise performance in patients with CHF.

Metoprolol was well tolerated, since adverse events and discontinuations were not more frequent in the treatment group than in the placebo group. Our withdrawal rate is similar to the rates from other trials with similar study populations [7]. The incidence of atrial fibrillation was significantly reduced by metoprolol. In a recent double-blind placebo-controlled study [21], metoprolol prevented relapse to atrial fibrillation after cardioversion to sinus rhythm.

Most of our patients were on stable chronic treatment with ACE inhibitors. The unchanged EF during exercise in all patients before therapy may indicate that a beneficial effect of ACE inhibitors and revascularization on remodeling was already present before randomization. Nevertheless, metoprolol significantly increased EF. Likewise, in the MDC trial, the drug combination was more effective than single-drug therapy [9]. Three comparative studies have shown that β-blockers is equal to or even better than ACE-inhibitors with regard to effects on LV function and volumes [23,24,26]. These observations have lead to the question whether a beta-blocker should be first-line therapy in mild heart failure, which has recently been tested in the carvedilol and ACE-inhibitor remodeling mild heart failure evaluation trial (CARMEN) [25,26]. In this study, carvedilol showed a trend towards a greater reduction of left ventricular end-systolic volume compared to the ACE-inhibitor alone. The combination therapy, however, had the best effect. One study, however, showed somewhat more attenuation of left ventricular remodeling with captopril than with metoprolol [27] and another study only showed an attenuating effect on left ventricular remodeling with the ACE-inhibitor [28]. Thus, β-adrenoceptor-antagonism seems to be a promising treatment both as monotherapy and in combination with ACE-inhibitors in patients with CHF.

A retrospective analysis of the SAVE trial showed that survival was significantly prolonged only in patients treated with both an ACE inhibitor and a β-blocker [23]. Improvement in survival and morbidity was shown recently in patients with CHF of mixed etiology when treated with a combination of ACE-inhibitors and metoprolol, bisoprolol or carvedilol [3–5].

Our data do not permit us to draw definite conclusions concerning the mechanism of action of β-blockers, but suggest several possibilities. Ischemia might be the common cause for LV dysfunction in both IHD and IDC [29].

β-blockers improves the endocardial/epicardial flow ratio, mainly by reducing heart rate and prolonging diastole [30–32]. Metoprolol reduced the rate-pressure product both at rest and during maximal exercise, which may explain the preserved increase in EF during exercise. β-blockers may also improve microcirculation by reducing release of vasoconstricting substances, by increasing nitric oxide production or by some other rheological effect [33,34]. Metoprolol also increases the energy supply/demand ratio and improves energy utilization [35–37] Recently, metoprolol was shown to down-regulate Gi proteins in patients with CHF due to IHD and DCM [38]. This effect improves the compromised receptor-effect coupling and may improve LV function in both IHD and DCM. Finally, our finding that the increase in EF was sustained during submaximal exercise may explain why cardiac index and exercise tolerance increases and pulmonary capillary wedge pressure decreases after long-term metoprolol treatment in patients with DCM [9,39].

One limitation of this study is that we did not include patients in atrial fibrillation, for technical reasons (see Section 2). Nor did we include patients with extensive myocardial damage such as those with saccular LV aneurysm, since these patients would be less likely to have a considerable amount of hibernating myocardium, which could respond to β-blockade [40]. Some patients with severely compromised systolic function and with a considerable amount of hibernating myocardium may, however, also have a favorable outcome on a beta-blocker, like those in the CHRISTMAS study with mild to moderate heart failure due to coronary artery disease [40–42].


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Treatment with metoprolol for 6 months in addition to conventional treatment, including ACE inhibitors, markedly improved both resting and exercise EF in patients with mild to moderate CHF. The effect was similar in patients with IHD and in those with DCM. Metoprolol also significantly reduced mitral regurgitation. The decreases in LVEDVs at rest were of the same magnitude as those achieved with enalapril alone [43], however, this effect was seen on top of ACE-inhibitor treatment.


   Acknowledgements
 
The study was supported by the Medical Research Council (project 02529), the Swedish Heart-Lung Foundation and AstraZeneca, Mölndal, Sweden. Thanks to technician Margareta Taeng-Scharin for excellent technical assistance.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

  1. Sharpe N., Murphy J., Smith H., Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet (1988) 1:255–259.[Web of Science][Medline]
  2. Sutton M., St J., Pfeffer M.A., Plappert T., Rouleau J.-L., Moyé L.A., et al. For the SAVE Investigators. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effect of captopril. Circulation (1994) 89:68–75.[Abstract/Free Full Text]
  3. CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomized trial. Lancet 1999;353:9–13.
  4. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001–2007.
  5. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 22 October, 2002;106(17):2194–9.
  6. Waagstein F., Caidahl K., Wallentin I., Bergh C.H., Hjalmarson Å. Long-term beta blockade in dilated cardiomyopathy. Effects of short-and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol. Circulation (1989) 80:551–563.[Abstract/Free Full Text]
  7. Australia-New Zealand Heart Failure Research Collaborative Group. Effect of carvedilol, a vasodilator-beta-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation (1995) 92:212–218.[Abstract/Free Full Text]
  8. Doughty R.N., Whalley G.A., Gamble G., MacMahon S., Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Am Coll Cardiol (1997) 29:1060–1066.[Abstract]
  9. Waagstein F., Bristow M.R., Swedberg K. Beneficial effects of the metoprolol in idiopathic dilated cardiomyopathy (MDC) trial. A randomised, double-blind, placebo-controlled multicentre trial. Lancet (1993) 342:1441–1446.[CrossRef][Web of Science][Medline]
  10. Hall S.A., Cigarroa C.G., Marcoux L., Risser R.C., Grayburn P.A., Eichhorn E.J. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol (1995) 25:1154–1161.[Abstract]
  11. Fisher M.L., Gottlieb S.S., Plotnick G.D., Greenberg N.L., Patten R.D., Benneth S.K., et al. Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol (1994) 23:943–950.[Abstract]
  12. Senior R., Basu S., Kinsey C., Schaeffer S., Lahiri A. Carvedilol prevents remodeling in patients with left ventricular dysfunction after acute myocardial infarction. Am Heart J (1999) 137:646–652.[CrossRef][Web of Science][Medline]
  13. Khattar RS, Senior R, Soman R, van der Does R, Lahiri A. Regression of left ventricular remodeling in chronic heart failure: Comparative and combined effects of captopril and carvedilol. Am Heart J;142:704–713.
  14. Groenning B.A., Nilsson J.C., Sondergaard L., Fritz-Hansen T., Larsson H.B.W., Hildebrandt P.R. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol (2000) 36:2072–2080.[Abstract/Free Full Text]
  15. Dubach P., Myers J., Bonetti P., Schertler T., Froelicher V., Wagner D., et al. Effects of bisoprolol fumarate on left ventricular size, function and exercise capacity in patients with heart failure: Analysis with magnetic resonance myocardial tagging. Am Heart J (2002) 143:676–683.[CrossRef][Web of Science][Medline]
  16. Ekman M., Lomsky M., Strömblad G.O., Carlsson S. Closed-line integral optimization edge detection algorithm and its application in equilibrium radionuclide angiography. J Nucl Med (1995) 36:1014–1018.[Abstract/Free Full Text]
  17. Massardo T., Gal R.A., Grenier R.P., Schmidt D.H., Port S.C. Left ventricular volume calculation using a count-based ratio method applied to multigated radionuclide angiography. J Nucl Med (1990) 31:450–456.[Abstract/Free Full Text]
  18. Woodley S.L., Gilbert E.M., Anderson J.L., O'Connell J.B., Detitchman D., Yanowitz F.G., et al. Beta-blockade with bucindolol in heart failure due to ischemic versus idiopathic dilated cardiomyopthy. Circulation (1991) 84:2426–2441.[Abstract/Free Full Text]
  19. Figulla H.R., Rahlf G., Nieger M., Luig H., Kreuzer H. Spontaneous hemodynamic improvement or stabilization and associated biopsy findings in patients with congestive cardiomyopathy. Circulation (1985) 71:1095–1104.[Abstract/Free Full Text]
  20. Palazzouli A., Bruni F., Pouccetti L., Pastorelli M., Angori P., Pasqui A.L., et al. Effects of carvedilol on left ventricular remodelling and systolic function in elderly patients with heart failure. Eur J Heart Fail (2002) 4:765–770.[Abstract/Free Full Text]
  21. Kuhlkamp V., Schirdewan A., Stangl K., Homberg M., Ploch M., Beck O.A. Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol (2000) 36:139–146.[Abstract/Free Full Text]
  22. Regitz-Zagrosek V., Leuchs B., Krulls-Munch J., Fleck E. Angiotensin-converting enzyme inhibitors and beta-blockers in long-term treatment of dilated cardiomyopathy. Am Heart J (1985) 129:754–761.[CrossRef]
  23. Vantrimpont P., Rouleau J.L., Wun C.C., Ciampi A., Klein M., Sussex B., et al. Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the survival and ventricular enlargement (SAVE) study. Save investigators. J Am Coll Cardiol (1997) 29:229–236.[Abstract]
  24. Khattar S.R., Senior R., Soman P., van der Does R., Lahiri A. Regression of left ventricular remodelling in chronic heart failure:comparative and combined effects of captopril and carvedilol. Am Heart J (2001) 142:704–713.[CrossRef][Web of Science][Medline]
  25. Remme W.J. Carmen Steering Committee and Investigators. The Carvedilol and ACE-inhibitor remodelling mild heart failure evaluation trial (CARMEN)—rationale and design. Cardiovasc Drugs Ther (2001) 15:9–10.[CrossRef][Web of Science][Medline]
  26. Coletta A.P., Louis A.A., Clark A., Nikitin N., Cleland J.G.F. Clinical trials update from the European Society of Cardiology: CARMEN, EARTH, OPTIMAAL, ACE,TEN-HMS, MAGIC, SOLVD-X and PATH-CHF II. Eur J Heart Fail (2002) 4:661–666.[Abstract/Free Full Text]
  27. Yoshitomi Y., Kojima S., Michiko Y., Toshihiko S., Matsumotu Y., Kuramochi M. Long-term effects of bisoprolol com pared with imidapril on left ventricular remodeling after reperfusion in acute myocardial infarction: an angiographic study in patients with maintained vessel patency. Am Heart J (2000) 140:e27.[CrossRef][Medline]
  28. Ricci R., Colletta C., Ceci V., Pajes G., Lucia R., Salustri A., et al. On behalf of RIMA Researchers. Effect of early treatment with capotopril and metoprolol singly and together on postinfarction left ventricular remodeling. Am Heart J (2001) 142(4):E5.[CrossRef][Medline]
  29. Neglia D., Parodi O., Galoppin M., Sambuceti G., Giorgetti A., Pratali L., et al. Myocardial blood flow response to pacing tachycardia and to dipyridamole infusion in patients with dilated cardiomyopathy without overt heart failure. A quantitative assessment by positron emission tomography. Circulation (1995) 92:796–804.[Abstract/Free Full Text]
  30. Buck J.D., Hardman H.F., Warltier D.C., Garett J.G. Changes in ischemic blood flow distribution and dynamic severity of coronary stenosis induced by beta blockade in canine heart. Circulation (1981) 64:708–715.[Abstract/Free Full Text]
  31. Åblad B., Abrahamsson T., Adler G., Björkman J.-A., Bjurö T., Ek L., et al. Cardiac anti-ischemic effects of metoprolol: role of beta-blockade within the ischemic region. J Cardiovasc Pharm (1987) 10(suppl):S117–S125.[CrossRef]
  32. Gross D.J., Lamping K.G., Warltier D.C., Hardman H.F. Effects of three bradycardic drugs on regional myocardial flow and function in areas to a total or partial coronary occlusion in dogs. Circulation (1984) 69:391–399.[Abstract/Free Full Text]
  33. Garlichs C.D.E., Zhang H., Mugge A., Daniel W.G. Beta blockers reduce the release and synthesis of endothelin-1 in human endothelial cells. Eur J Clin Invest (1999) 29:12.[Web of Science][Medline]
  34. Boogaerts M.A., Roelant C., Temmerman J., Goossens W., Verwilghen R.L. Effect of beta-blocking drugs on red cell adhesive and rheological properties. J Lab Clin Med (1983) 102:899–908.[Web of Science][Medline]
  35. Eichhorn E.J., Bedotto J.B., Malloy C.R., Hatfiled B.A., Deichman D., Brown M., et al. Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure. Circulation (1990) 82:473–483.[Abstract/Free Full Text]
  36. Andersson B., Blomström-Lundquist C., Hedner T., Waagstein F. Exercise hemodynamics and myocardial metabolism during long-term betablockade in severe heart failure. J Am Coll Cardiol (1991) 18:1059–1066.[Abstract]
  37. Omerovic E., Bollano, Mobini R., Basetti M., Kujacic V., Soussi B., et al. Selective beta-1-blockade improves cardiac bioenergetics and function and decreases neuroendocrine activation in rats during early postinfarct remodeling. Biochem Biophys Res Commun (2001) 281:491–498.[CrossRef][Web of Science][Medline]
  38. Sigmund M., Jakob H., Becker H., Hanrath P., Schumacher T., Eschenhagen T., et al. Effects of metoprolol on myocardial β-adrenoceptors and Gia-proteins in patients with congestive heart failure. Eur J Clin Pharmacol (1996) 51:127–132.[CrossRef][Web of Science][Medline]
  39. Andersson B., Hamm C., Persson S., Wikstrom G., Sinagra G., Hjalmarsson A., et al. Improved exercise hemodynamic status in dilated cardiomyopathy after beta-adrenergic blockade treatment. J Am Coll Cardiol (1994) 23:1397–1404.[Abstract]
  40. Cleland J.G.F., Penell D., Ray S., Coats A., Lahiri A., Dalle Mule J., et al. Effect of carvedilol on myocardial ischaemia, hibernation and viability in patients with left ventricular dysfunction due to CAD. Eur Heart J (2002) 23(Suppl. 81):517.[Free Full Text]
  41. Packer M., Coats J.S., Fowler M.B., Katus H.A., Krum H., Mohacsi P., et al. For the Carvedilol prospective randomized cumulative study group. N Eng J Med (2001) 344:1651–1658.[Abstract/Free Full Text]
  42. Goldstein S., Fagerberg B., Hjalmarson A., Kjekshus J., Waagstein F., Wedel H., et al. Metoprolol controlled release/extended release in patients with severe heart failure:analysis of the experience in the MERIT HF study. J Am Coll Cardiol (2001) 38:932–938.[Abstract/Free Full Text]
  43. Konstam M.A., Rousseau M.F., Kronenberg M.W., Udelson J.E., Melin J., Stewart D., et al. Effects of ACE inhibitor enalapril on long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD Investigators. Circulation (1992) 86:431–438.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
G. Casaclang-Verzosa, B. J. Gersh, and T. S.M. Tsang
Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation.
J. Am. Coll. Cardiol., January 1, 2008; 51(1): 1 - 11.
[Abstract] [Full Text] [PDF]

Home page
 Card Surg AdultHome page
M. Enriquez-Sarano, V. T. Nkomo, and H. Michelena
Principles and Practice of Echocardiography in Cardiac Surgery
Card. Surg. Adult, January 1, 2008; 3(2008): 315 - 348.
[Full Text]

Home page
 Eur J Heart FailHome page
L. Fauchier, B. Pierre, A. de Labriolle, and D. Babuty
Comparison of the beneficial effect of beta-blockers on mortality in patients with ischaemic or non-ischaemic systolic heart failure: A meta-analysis of randomised controlled trials
Eur J Heart Fail, November 1, 2007; 9(11): 1136 - 1139.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
B. G. Svealv, M. S. Tang, F. Waagstein, and B. Andersson
Pronounced improvement in systolic and diastolic ventricular long axis function after treatment with metoprolol
Eur J Heart Fail, June 1, 2007; 9(6-7): 678 - 683.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
P. J. Hauptman and H. N. Sabbah
Reversal of ventricular remodeling: Important to establish and difficult to define
Eur J Heart Fail, April 1, 2007; 9(4): 325 - 328.
[Full Text] [PDF]

Home page
 Eur Heart JHome page
I. A. Nasr, A. Bouzamondo, J.-S. Hulot, O. Dubourg, J.-Y. Le Heuzey, and P. Lechat
Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis
Eur. Heart J., February 8, 2007; (2007) ehl484v1.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart J SupplHome page
B. Silke
Beta-blockade in CHF: pathophysiological considerations
Eur. Heart J. Suppl., June 1, 2006; 8(suppl_C): C13 - C18.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
T. V. Salukhe, M. Y. Henein, and R. Sutton
Ischemic Mitral Regurgitation and Its Related Risk After Myocardial Infarction
Circulation, January 25, 2005; 111(3): 254 - 256.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Waagstein, F.
Right arrow Articles by Wahlqvist, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Waagstein, F.
Right arrow Articles by Wahlqvist, I.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?