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J Am Coll Cardiol, 2000; 36:2072-2080
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDY: HEART FAILURE

Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure

Bjoern A. Groenning, MD* {dagger}, Jens C. Nilsson, MD*, Lars Sondergaard, MD* {dagger}, Thomas Fritz-Hansen, MD*, Henrik B. W. Larsson, MD, DMSc* and Per R. Hildebrandt, MD, DMSc{dagger}

* Danish Research Center of Magnetic Resonance, Department of Magnetic Resonance, H:S Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
{dagger} Department of Cardiology and Endocrinology, H:S Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark

Manuscript received January 14, 2000; revised manuscript received June 23, 2000, accepted August 11, 2000.

Reprint requests and correspondence: Dr. Bjoern A. Groenning, Danish Research Center of Magnetic Resonance, Department of Magnetic Resonance, Section 340, H:S Hvidovre Hospital, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark
bjoerng{at}dadlnet.dk


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

The purpose of the study was to investigate the effects of beta1-blockade on left ventricular (LV) size and function for patients with chronic heart failure.

BACKGROUND

Large-scale trials have shown that a marked decrease in mortality can be obtained by treatment of chronic heart failure with beta-adrenergic blocking agents. Possible mechanisms behind this effect remain yet to be fully elucidated, and previous studies have presented insignificant results regarding suspected LV antiremodeling effects.

METHODS

In this randomized, placebo-controlled and double-blind substudy to the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF), 41 patients were examined with magnetic resonance imaging three times in a six-month period, assessing LV dimensions and function.

RESULTS

Decreases in both LV end-diastolic volume index (150 ml/m2 at baseline to 126 ml/m2 after six months, p = 0.007) and LV end-systolic volume index (107 ml/m2 to 81 ml/m2, p = 0.001) were found, whereas LV ejection fraction increased in the metoprolol CR/XL group (29% to 37%, p = 0.005). No significant changes were seen in the placebo group regarding these variables. Left ventricular stroke volume index remained unchanged, whereas LV mass index decreased in both groups (175 g/m2 to 160 g/m2 in the placebo group [p = 0.005] and 179 g/m2 to 164 g/m2 in the metoprolol CR/XL group [p = 0.01]).

CONCLUSIONS

This study is the first randomized study to demonstrate that the beta1-blocker metoprolol CR/XL has antiremodeling effects on the LV in patients with chronic heart failure and consequently provides an explanation for the highly significant decrease in mortality from worsening heart failure found in the MERIT-HF trial.

Abbreviations and Acronyms
  CI = cardiac index
  HR = heart rate
  LV = left ventricle or ventricular
  LVEDV = left ventricular end-diastolic volume
  LVEDVI = left ventricular end-diastolic volume index
  LVEF = left ventricular ejection fraction
  LVESV = left ventricular end-systolic volume
  LVESVI = left ventricular end-systolic volume index
  LVmassI = left ventricular mass index
  LVSI = left ventricular stroke volume index
  LVSV = left ventricular stroke volume
  MERIT-HF = metoprolol CR/XL randomized intervention trial in heart failure
  MRI = magnetic resonance imaging
  NYHA = New York Heart Association

Treatment of heart failure with beta-adrenergic blocking agents has been intensely investigated during the past 20 years (1–9). Recently, it has been shown that a substantial benefit on survival can be obtained by beta-blocker treatment of patients with ischemic and nonischemic chronic heart failure (10–13). The largest and most recently published mortality trial is the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure study (MERIT-HF), in which 3,991 patients with symptomatic heart failure in New York Heart Association (NYHA) functional classes II to IV were randomized to either placebo or metoprolol CR/XL (controlled release/extended release), which is a beta1-selective receptor antagonist with no intrinsic activity in a slow release formulation. The beta-blocker was given in addition to conventional heart failure treatment. In the MERIT-HF trial, a reduction in total mortality of 34% in the metoprolol CR/XL group compared with the placebo group was found. However, the mechanism behind the marked effect of beta-blocker treatment on survival in heart failure is not yet fully understood (14–17). When examined in detail, the data from the MERIT-HF trial revealed a significant reduction in the number of deaths from worsening heart failure of 49% as well as a significant reduction in mortality from sudden death of 40% (12,18). A number of studies into the hemodynamic effects of chronic heart failure treatment with beta-blockers have been performed to provide information on the mechanism of action. All studies have shown that an improvement in left ventricular (LV) ejection fraction (LVEF) can be obtained with beta-blocker treatment. However, no randomized studies have been able to demonstrate a significant antiremodeling effect of metoprolol on either LV dimensions or LV mass. The negative or inconclusive findings in previous studies might have been caused by inaccurate hemodynamic measurements since they have all been performed with M-mode echocardiography, two-dimensional echocardiography or LV angiography. These methods are all associated with unsolved problems with methodology, observer-dependency and precision, especially in a setting of patients with abnormally shaped LVs. This study was performed as a substudy to the MERIT-HF trial and was conducted with magnetic resonance imaging (MRI), which offers an unsurpassed precision in the measurement of heart volumes and function. The aim was to investigate potential antiremodeling effects of metoprolol CR/XL on the LV for patients with chronic heart failure.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   In this study patients from the MERIT-HF study were consecutively included in the period from October 1997 to April 1998. The inclusion took place at seven Danish cardiology centers that participated in the MERIT-HF trial, and all MRI examinations and other measurements were performed at the Danish Research Center of Magnetic Resonance at H:S Hvidovre Hospital. The inclusion of patients in the study was terminated concomitantly with the inclusion-termination in the MERIT-HF trial in April 1998 (12).

The inclusion and exclusion criteria in this study were identical to the criteria in the MERIT-HF trial, in which the most important inclusion criteria were: patients with symptoms of heart failure in NYHA functional classes II to IV on optimal treatment for heart failure, LVEF ≤40% and age between 40 and 80 years (18). Additional exclusion criteria in this study with respect to the MRI examination were atrial fibrillation, implanted pacemaker, implanted mechanical heart valves, implanted insulin pump and claustrophobia.

Study design.   The first MRI examination took place after the inclusion in the MERIT-HF trial, but before the randomization. At this point the patients had not yet received the blinded study medication. The second examination took place five weeks after randomization if the patients had received 25 mg of metoprolol CR/XL/placebo as an initial dose of study medication or, alternatively, seven weeks after randomization if the patients had received 12.5 mg of metoprolol CR/XL/placebo as an initial dose. An initial dose of 25 mg metoprolol CR/XL/placebo per day was recommended for patients in NYHA class II, and an initial dose of 12.5 mg metoprolol CR/XL/placebo was recommended for patients in NYHA classes III and IV. In the MERIT-HF trial, the target dose of study medication was 200 mg, and the recommended up-titration period was six to eight weeks. Thus, the patients examined in this study at five or seven weeks after randomization were on a daily dose of 100 mg metoprolol CR/XL. The third examination took place six months after randomization. At this point the patients had been on the target dose of metoprolol CR/XL for four months.

The study was approved by the Copenhagen Committee on Scientific Ethics and, after written informed consent, a total of 48 patients were included in the study. Of these, 41 patients were examined at all three examinations, and 7 patients were examined only once. The reasons for the withdrawal of the seven patients who were examined only at baseline before the metoprolol CR/XL/placebo treatment were that one patient died (before the first dose of study medication); three patients were withdrawn early from the MERIT-HF trial because of suspected side effects (two patients randomized to placebo and one patient randomized to metoprolol CR/XL), and three patients were withdrawn from this study because of claustrophobia (two patients randomized to placebo and one patient randomized to metoprolol CR/XL).

In order to obtain comparable measurements regarding hormonal circadian rhythm, all examinations were performed between 1 PM and 4 PM. At each examination, an MRI study was performed, and heart rate was measured continuously during the MRI-investigation and determined as the average heart rate (HR) during the volume measurement of the LV. Blood pressure was measured before the MRI-examination after 20 min of rest in a sitting position. In addition, body weight and height were measured, and body surface area was calculated (19).

MRI investigation.   The study was carried out on a whole-body MR scanner (Siemens Impact Magnetom, Siemens, Erlangen, Germany) operating at 1.0 tesla with a phased array chest coil as receiver coil. Each slice of the LV was obtained over 15 heartbeats with an electrocardiogram-triggered breath-hold fast low-angle shot cinematographic sequence in the true short axis plane with a temporal resolution of 55 ms. Slice thickness was 10 mm; field of view was 263 x 350 mm, and matrix size was 126 x 256. The LV was encircled using a stack of 10 to 15 slices (20–22).

MRI postprocessing.   The images were analyzed using the computer program RGBwin developed at the Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, London, England. The MRI-examinations were all analyzed in one batch in a blinded manner, and the analysis was completed before the treatment-code was broken in the MERIT-HF trial. In each examination the number of slices to include in the covering of the LV in end-diastole and end-systole were decided, and, typically, one slice less in end-systole than in end-diastole was included due to systolic shortening of the LV. End-systole was chosen at the point where the total LV blood pool was smallest. On each end-diastolic frame, both inner and outer circumferences of the LV myocardium were defined for volume and mass determination. On each systolic frame, the inner circumference of the myocardium was defined for volume determination. The papillary muscles were included as part of the muscle mass and not as part of the chamber volume (23). The borders marked for each of the three volumes over the stack of contiguous slices were used to calculate the relevant volumes by simple addition of the individual slice-volumes since there were no interslice gaps.

In this manner the following volumes were determined: LV end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and LVEDV at the outer circumference of the myocardium. From these measurements the following variables were calculated: LV mass (LVmass) was determined as the difference between the LVEDV at the inner and outer circumferences of the myocardium multiplied by a density-factor of 1.05 (21). Left ventricular stroke volume (LVSV) was determined as the difference between LVEDV and LVESV. Left ventricular ejection fraction was determined as LVSV divided by LVEDV, cardiac output was determined as LVSV multiplied by the heart rate. Subsequently, all MRI variables, apart from LVEF, were indexed by division with body surface area.

Variables for subsequent statistical analysis.   For the subsequent statistical analysis the following variables were selected: LVEDV index (LVEDVI), LVESV index (LVESVI), left ventricular stroke volume index (LVSI), LVEF, cardiac index (CI), LVmass index (LVmassI), HR, systolic blood pressure and diastolic blood pressure.

It was decided not to include the seven patients who were examined only at baseline into the analysis, thus leaving 22 patients in the placebo group and 19 patients in the metoprolol CR/XL group at all three examination points.

Statistics.   Two-sample t tests between groups were performed at baseline. Verification of normal distribution of data was accomplished using histograms. The statistical approach in the study was to fit a linear regression of each subject’s data on time, which is often named "stochastic regression analysis." The slope of the lines (each representing one subject at all examination times) represented the rate of change of the measurement per unit of time. Subsequently, the mean slope of each of the two treatment groups (calculated as the mean value of all slopes in each group) was tested against 0, and the mean slopes of the two treatment groups were tested against each other using t tests. Thus, analysis of all data from the repeated measurements was performed in one step. Before the stochastic regression analysis, data were evaluated on scatter plots for linearity control. After the stochastic regression analysis procedure, a model control consisting of residual column plots, standardized residuals versus predicted value plots and normal plots was applied, which showed that all conditions for the statistical procedure had been fulfilled. All data fit a normal distribution model, and no transformation of data has been made. Data from all three examinations were included in the analysis. In all tests a significance level of 5% has been used. All tests were performed in the SAS system (SAS Institute Inc., Cary, North Carolina).


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The entry characteristics of the patients in this study compared with the entry characteristics in the MERIT-HF trial are given in Table 1. No major differences between patients in this study and patients in the MERIT-HF trial were found. The results of this study are summarized in Table 2 and Figures 1 to 4. For all variables, no differences were found between the two groups at baseline. During the study period, LVEDVI and LVESVI decreased, and LVEF increased significantly in the metoprolol CR/XL group versus baseline and versus placebo. No changes were seen in the placebo group with regard to these variables. At five or seven weeks after the baseline examination, an average decrease in LVEDVI of 7%, an average decrease in LVESVI of 10% and an average increase in LVEF of 10% were found. The data at six months after baseline revealed a similar, but more marked, decrease in LVEDVI and LVESVI of 16% and 24%, respectively, as well as an average increase in LVEF of 28% (Fig. 1 to 3). No change was seen in LVSI, but a significant decrease in CI versus baseline of 18% at six months after baseline was found in the metoprolol CR/XL group. A significant decrease in HR of 24% after six months of treatment was found in the metoprolol CR/XL group. For LVEDVI, LVESVI, LVEF, LVSI, CI and HR, no significant changes were seen in the placebo group. Left ventricular mass index decreased significantly and uniformly in the two groups versus baseline (9% and 8% in the placebo and metoprolol groups, respectively, after six months), and no significant difference was found between the groups (Fig. 4). A significant decrease in systolic blood pressure was found in the placebo group versus baseline, whereas no change was seen in the metoprolol CR/XL group. A significant decrease in diastolic blood pressure was found in the metoprolol CR/XL group versus baseline, while no change was seen in the placebo group. Body surface area was unchanged in both groups.


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  		Table 1 Baseline Characteristics in this Study and in the MERIT-HF Trial

 

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  		Table 2 Results

 


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  		Figure 1 LVEDVI over time. Mean LVEDVI is shown in the metoprolol CR/XL group and in the placebo group at baseline, five or seven weeks and six months after randomization. *The metoprolol CR/XL group versus the placebo group. CI = confidence interval; LVEDVI = left ventricular end-diastolic volume index.

 


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  		Figure 2 LVESVI over time. Mean LVESVI is shown in the metoprolol CR/XL group and in the placebo group at baseline, five or seven weeks and six months after randomization. *The metoprolol CR/XL group versus the placebo group. CI = confidence interval; LVESVI = left ventricular end-systolic volume index.

 


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  		Figure 3 LVEF over time. Mean LVEF is shown in the metoprolol CR/XL group and in the placebo group at baseline, 5 or 7 weeks and six months after randomization. *The metoprolol CR/XL group versus the placebo group. CI = confidence interval; LVEF = left ventricular ejection fraction.

 


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  		Figure 4 LVmassI over time. Mean LVmassI is shown in the metoprolol CR/XL group and in the placebo group at baseline, five or seven weeks and six months after randomization. *The metoprolol CR/XL group versus the placebo group. Metoprolol CR/XL group versus baseline: p = 0.01; placebo group versus baseline: p = 0.005. CI = confidence interval; LVmassI = left ventricular mass index.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Main findings.   In this study we found a significant reduction in LVEDVI and LVESVI as well as a significant increase in LVEF after six months of treatment with metoprolol CR/XL. The net effect was an unaltered LVSI with the LV at a better hemodynamic set point on the Frank-Starling curve than before the metoprolol CR/XL treatment. This is the first randomized study to demonstrate this very important antiremodeling effect of metoprolol in the treatment of chronic heart failure, which might be one of the key explanations for the highly significant 49% reduction in the total number of deaths from worsening heart failure found in the MERIT-HF trial (12). Previous hemodynamic metoprolol studies have found significant improvements in LVEF after the active treatment, but no randomized study has been able to detect any significant antiremodeling effect (7,24–32).

In addition to the MERIT-HF trial, several large mortality trials with other beta-receptor antagonists of patients with chronic heart failure have recently been performed. Two trials have been conducted with the combined alpha1beta1&2-receptor antagonist, carvedilol, in which decreases in mortality of 65% after 12 months of treatment (13) and 21% after 19 months of treatment (10) were found. Furthermore, one trial has been carried out with the beta1-selective receptor antagonist with no intrinsic activity, bisoprolol, in which a reduction in mortality of 32% after 16 months of treatment was found (11).

The exact mechanism behind the mortality reduction in chronic heart failure after beta-blocker treatment is not yet fully elucidated but is expected to arise from a combination of an antiarrhythmic effect and an improvement in the hemodynamic function of the LV caused by a combination of HR reduction and inhibition of the detrimental neurohormonal activation virtually always present in patients with chronic heart failure (17). The two carvedilol studies have not attempted to stratify the reduction in mortality with regard to these causes. In the bisoprolol trial a significant decrease in mortality from sudden death of 42% and an insignificant reduction in mortality from worsening heart failure were demonstrated after stratification of total mortality. Thus, the MERIT-HF trial is the only beta-blocker mortality trial to have confirmed a significant benefit on mortality from hemodynamic causes. No clinical studies on the effects of bisoprolol on LV dimensions or function have been published, but several carvedilol studies have been published in which hemodynamic effects comparable with the findings in the present metoprolol study have been demonstrated (30,33–36). The view that metoprolol and carvedilol seem to exert similar effects on LV dimensions and function is supported by results from two comparative studies on the hemodynamic effects of metoprolol and carvedilol in patients with chronic heart failure, in which no significant hemodynamic differences were found between the two agents (30,34).

Cardiac index.   As a natural consequence of a stable LVSI and a marked decrease in HR found in this study and by all previous investigators, a significant decrease in CI versus baseline was seen after metoprolol CR/XL treatment. Previous studies have found insignificant effects on (7,24,28,34) or small increases in (29,32,37) CI at rest. From a clinical point of view, this hemodynamic variable is more interesting in an exercise situation than in a resting state. We have not addressed this issue in our study, but others have found beneficial hemodynamic exercise effects of metoprolol, indicating that the improvement in LV function in an exercise situation overrides the decrease in maximum HR (7,25,29,31,37,38).

LV mass.   We found significant decreases in LV mass in both the placebo group and the metoprolol CR/XL group without any difference between the groups. Previously, one randomized study found no effect on LV mass after three months of metoprolol treatment, whereas, in an uncontrolled 18-month continuation of the same trial, a significant 18% decrease in LV mass was found (27). A possible explanation for the reduction in LV mass in both groups in this study might be found in the design of the MERIT-HF trial with its run-in period immediately preceding the randomization in which the patients were optimized in conventional heart failure treatment (18). This treatment-optimization of both groups, in which the patients typically had an angiotensin-converting enzyme inhibitor added or adjusted or had their diuretic medication attuned, might explain the improvement in both groups in this study. We found no evidence that the metoprolol CR/XL treatment in itself had any impact on this variable. However, in the metoprolol CR/XL group, the concomitant decrease in LV size and mass suggests that wall thickness remained about the same, and, because systolic blood pressure did not change, average systolic wall stress may consequently have decreased during the study period. Although we do not have wall stress data, this possible effect may constitute another beneficial effect of metoprolol CR/XL for patients with chronic heart failure.

Investigation method.   This study was performed as an MRI study and differs, as such, from previously published beta-blocker heart failure studies. Compared with conventional methods such as M-mode echocardiography, two-dimensional echocardiography and LV angiography, MRI offers several advantages since no geometrical assumptions are applied in the determination of LV volumes and mass (39). This is mainly of importance for patients with an abnormally shaped LV, as is frequently the case for patients with chronic heart failure. Furthermore, MRI is totally independent of lung cover and disposition of the heart (40) and finally, MRI offers a reproducibility in the determination of all LV volumes of 2% to 5%, which is markedly lower than that offered by other methods (40–42). This considerably reduces the number of patients required to detect intergroup differences in LV dimensions and function and may explain why this study is the first to demonstrate a significant antiremodeling effect from metoprolol in chronic heart failure.

Drug safety.   With regard to hemodynamic parameters, metoprolol CR/XL seemed to be a hemodynamically safe drug in the treatment of chronic heart failure. Even though one patient died and three patients were withdrawn because of suspected side effects from the metoprolol CR/XL/placebo treatment, their withdrawal from this study had no impact on the conclusions since these patients were equally distributed in the placebo and metoprolol CR/XL groups. Furthermore, it is evident from the data at the second examination at five to seven weeks after randomization that LV function did not deteriorate at this point during the run-in period of metoprolol CR/XL. In other studies performed with short acting metoprolol, a potential decrease in LVEF during the very early phase of beta-blocker up-titration has been reported (43,44). In this study a slow release compound of metoprolol was up-titrated very cautiously over a protracted period, which might have been a critical factor for the positive outcomes of this study and the MERIT-HF trial (18).

Conclusions.   This substudy to the MERIT-HF trial is the first randomized study to demonstrate that the beta1-blocker metoprolol CR/XL has antiremodeling effects on LV dimensions and function in patients with chronic heart failure and consequently provides an explanation for the highly significant decrease in mortality from worsening heart failure found in the MERIT-HF trial.


   Acknowledgments
 
The authors are indebted to the laboratory technicians and radiographers of the Department of Magnetic Resonance at H:S Hvidovre Hospital and, in particular, to laboratory technician Sussi Larsen for her invaluable assistance during the course of this study. We are also grateful to the cardiology departments at Herlev County Hospital, H:S Rigshospitalet, Hilleroed Hospital, Glostrup County Hospital, Frederikssund Hospital and Hoersholm Hospital for the referral of patients to this study.


   Footnotes
 
Supported by AstraZeneca Denmark and by the Research Fund of the Copenhagen Hospital Corporation.


   References
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 Discussion
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