Beneficial effects of metoprolol on myocardial sympathetic function: Evidence from a randomized, placebo-controlled study in patients with congestive heart failure☆☆☆★

Article Outline

• Abstract
• Methods
  • Study patients
  • Study design
  • Baseline parameters
  • Statistical methods
• Results
• Discussion
  • Mechanisms of action
  • Study design
  • Nonischemic versus ischemic cardiomyopathy
  • Dose related effects
• Conclusions
• References
• Copyright

Abstract 

Background We sought to investigate whether β-blockers exert a presynaptic effect in the myocardium as measured by ¹²³I-metaiodobenzylguanidine. Methods The study comprised 59 patients with congestive heart failure, New York Heart Association class II or III, and left ventricular ejection fraction <35%. After an open label titration phase, patients were randomized to their maximal tolerable dose of metoprolol or placebo. Myocardial MIBG uptake was measured before the titration phase and after 6 months of treatment. Other parameters were maximal oxygen consumption, 6-minute walking test, plasma neurohormones, and echocardiographic parameters. Results We found a 21.9% increase in mean myocardial MIBG uptake after 6 months of treatment with metoprolol. In contrast, MIBG uptake decreased by 7.8% in the placebo group (P = 0.03 compared with metoprolol). Left ventricular end-diastolic diameter decreased from 74 ± 11 mm to 67 ± 10 mm (P < .05, within-group comparison) and LVEF increased from 25.3% ± 7.4% to 32.6% ± 9.6% (P < .05, within-group comparison) in the metoprolol group. Placebo-treated patients showed no significant changes. Comparison of changes in left ventricular end-diastolic diameter and LVEF between metoprolol and placebo did not reach statistical significance (P = 0.2). Conclusions This randomized, placebo-controlled study demonstrates that metoprolol has a presynaptic effect as measured by myocardial MIBG scintigraphy in both ischemic and nonischemic cardiomyopathy. (Am Heart J 2002;144:e3.)

Sympathetic activation plays a pivotal role in heart failure (HF) and leads to an increase of circulating norepinephrine (NE) levels,¹, ² as well as to depletion of intraneuronal myocardial NE content.³, ⁴, ⁵, ⁶, ⁷ Sympathetic activation increases the level of NE in the synaptic cleft and consequently down-regulates the myocardial β₁-adrenoceptors. Initially, this activation of the sympathetic function can be considered as compensation, but with progression of the disease it becomes pathologic and may even aggravate the disease. The clinical benefits of β-blockers in terms of reduced mortality and morbidity were recently demonstrated.⁸, ⁹ However, the exact mechanisms of action are only partly explained.

Aside from the effects of β-blockers at the myocyte receptor level,¹⁰ on calcium homeostasis,¹¹, ¹² on the metabolic state, their interaction with the renin-angiotensin aldosterone system, and the beneficial effects of negative chronotropism, β-blockers probably have an effect at the presynaptic level (as recently demonstrated in patients with dilated cardiomyopathy¹³, ¹⁴, ¹⁵, ¹⁶).

Presynaptic myocardial sympathetic function can be studied by means of ¹²³I-metaiodobenzylguanidine (MIBG), a catecholamine analog, which is competitively taken up into the presynaptic neuron via uptake-1 (NE transporter) in a manner similar to that for NE. ¹²³I-MIBG is not metabolized and thus is a marker of the functional integrity of sympathetic nerve terminals.¹⁷, ¹⁸, ¹⁹ Reduced ¹²³I-MIBG sequestering has been demonstrated in chronic HF²⁰, ²¹ and shown to be related to mortality.²²

It was the aim of our randomized, placebo-controlled study to explore the presynaptic effects of a β₁-blocker in patients with both ischemic and nonischemic cardiomyopathy. Myocardial ¹²³I-MIBG uptake was measured before treatment and after 6 months of metoprolol. In addition, a possible relationship between MIBG uptake, metoprolol dosage, and several clinical parameters was studied.

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Methods 

Study patients 

The study was approved by the review board and the medical ethical committees of both participating institutions. Written informed consent was obtained from all patients before entering the study. The study population consisted of patients from the outpatient clinic.

Eligible for enrollment were patients with a history of chronic symptomatic HF, a left ventricular ejection fraction (LVEF) <35% at radionuclide ventriculography, stable disease for at least 2 months before entering the study, and no major change in medical therapy over the past month. Exclusion criteria included obstructive airway disease, known hypersensitivity to β-blockers, and signs of ischemia in the month preceding the study. Patients were classified as “ischemic cardiomyopathy” if a myocardial infarction had been documented in the past or coronary angiography showed significant obstructions. All other patients were classified as “nonischemic.” The study was conducted between 1996 and 1999.

Study design 

The study was designed as a double-blind, placebo-controlled trial (Figure 1).

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• Fig. 1. 

  Study design and flow chart.

Baseline parameters were obtained including a 6-minute walking test, maximal oxygen consumption, plasma catecholamines, atrial natriuretic peptide (ANP), echocardiographic measurements, MIBG scintigraphy, and quality of life assessment. Next, the patients entered the open label titration phase and initially received 25 mg sustained release metoprolol once daily (AstraZeneca, Zoetermeer, the Netherlands). Tablets were taken in the evening. After 2 weeks, the dose was increased to 50 mg, and every 2 weeks thereafter was increased by 50 mg up to a maximum dose of 150 mg once daily. Up-titration was stopped for one of the following reasons: cumbersome side effects, heart rate <50 beats per minute and/or systolic blood pressure <100 mm Hg. In case of side effects or a significant drop in heart rate or blood pressure, medication was de-escalated to the earlier tolerated dosage. After 2 weeks on a maximally tolerated dose, the patients continued with 50 mg metoprolol daily for another 2 weeks before starting randomization medication.

Patients who tolerated at least 50 mg metoprolol were assigned to 1 of 3 dosing groups: 50 mg, 100 mg, or 150 mg daily, depending on their maximally tolerated dose. Within each dosing group we randomized the patients to metoprolol or placebo (ratio 4:1). After 6 months of treatment (or earlier in case of premature discontinuation), the baseline parameters were reassessed. To prevent potentially hazardous effects of the sudden cessation of metoprolol, all patients continued to receive 50 mg metoprolol after the end of the study.

Baseline parameters 

The 6-minute walking test was conducted with a predefined course in the corridors of our hospital with small distance markers on the wall, which were not visible to the patients. Patients walked at their own pace and were allowed to stop during the test but were instructed to resume walking as soon as they were able to do so. A study nurse accompanied the patients but did not attempt to influence them. After 6 minutes patients stopped walking and the total distance was measured.

Blood samples for plasma catecholamines and ANP were drawn after 30 minutes of rest in the supine position. An indwelling catheter was inserted in the antecubital vein before the resting period. Blood samples were transferred immediately to ice-chilled tubes. The plasma was separated by centrifugation at 4°C and stored at −70°C up to the time of assay. Laboratory personnel not aware of treatment status performed the analysis. After purification on BioRex 70 (Bio-Rad Laboratories, Hercules, Calif) and concentration by solvent extraction, plasma NE concentrations were determined by high-performance liquid chromatography and electrochemical detection. ANP was determined by radioimmunoassay (Nichols Institute Diagnostics, Wychen, the Netherlands). Normal values are plasma NE <3.25 nmol/L, epinephrine <.55 nmol/L, and ANP concentrations ranging from 22 ng/L to 65 ng/L.

Quality of life was assessed with the Minnesota Living with Heart Failure questionnaire.²³ Peak oxygen consumption was measured on a bicycle ergometer according to previously defined standards. Echocardiographic measurements were performed by one of the investigators who was unaware of the treatment status of the patients.

The ¹²³I-MIBG SPECT imaging was performed in the morning, 1 hour after oral administration of 100 mg potassium iodide to block thyroid uptake of free ¹²³I. The 185 MBq MIBG (Cygne BV, Technical University Eindhoven, the Netherlands) was injected intravenously; SPECT images were obtained 15 minutes and 4 hours after injection (Siemens MultiSPECT3, medium-energy collimators). We used a 20% energy window centered on the 159 keV photopeak of ¹²³I. Data were collected with 60 frames over 360° for 60 seconds per frame (64 × 64 pixel matrix, zoomfactor 1.23) with the camera autocontour facility. Attenuation correction was not applied. Myocardial MIBG uptake was quantitated with short-axis slice elliptic regions of interest, which were semiautomatically drawn over the left ventricular myocardium. Volumes of interest were constructed and quantified with the Cardiac SPECT Analysis tool package (CASPAN version 1.0). At the time of image acquisition, a venous blood sample was drawn, and ¹²³I activity was measured in duplicate with a gamma counter (Auto-gamma 5000, Packard Instruments Company, Downers Grove, Ill). Myocardial MIBG uptake was calculated in mean counts/voxel and corrected for blood activity as measured in venous blood samples, injected radioactivity and radioactive decay.

Because all patients served as their own control, no attempt was made to account for variations in attenuation or scatter secondary to varying body habitus. The effect of metoprolol on myocardial MIBG uptake in a patient with HF is shown in Figure 2.

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• Fig. 2. 

  Reconstruction of cardiac MIBG SPECT acquisition in a patient with congestive heart failure. Myocardial uptake (A) before and (B) after 6 months of treatment with metoprolol. Red areas (low), yellow areas (high), and white areas (very high) denote MIBG uptake. SA, Short axis; HLA, horizontal long axis; VLA, vertical long axis; C, left ventricular cavity; M, myocardium; L, liver.

Two experienced investigators, both unaware of treatment assignments, analyzed all of the images.

Statistical methods 

Outcomes are presented as mean ± SD unless stated otherwise. Changes in myocardial MIBG uptake and clinical and neurohormonal parameters are expressed as percent change from baseline after 6 months of treatment. Between-group comparison was made by use of an unpaired t test with equal variances, except in cases for which this assumption could not be made (P < .01, Levene's test). In those cases, a t test for unequal variances was used. A paired t test was used to allow within-group comparison. We prefer percent change to absolute change because the use of percent change allows standardized units for comparing change between the treatment groups. However, we also performed the same statistical analyses for absolute change. The corresponding P values were virtually the same.

Placebo comparisons for subgroups were not performed because of the small sample size.

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Results 

The study population included 59 consecutive patients who met the inclusion criteria and entered the titration phase. Five patients did not proceed to the randomization phase: 1 died of progressive HF, and 4 did not tolerate the low dose of 50 mg of metoprolol. There were no significant differences between these 5 patients and the randomized patients (Table I).

Table I. Baseline characteristics

A total of 54 patients were randomized after the titration phase. There were no significant differences in baseline characteristics between the placebo group and the 3 treatment groups (50 mg, 100 mg and 150 mg metoprolol). Coronary artery disease (CAD) was confirmed by coronary angiography in 13 out of 30 randomized patients with ischemic etiology. The remaining 17 patients had a previous myocardial infarction. CAD was not seen at angiography in 8 out of 24 randomized patients with a nonischemic etiology. In the remaining 16 patients, the nonischemic etiology was established on the basis of clinical information. However, we cannot exclude the possibility that some of these patients may have had CAD.

Five patients died during the 6-month randomization phase. Four of them were assigned to metoprolol (2 died suddenly outside the hospital, 1 died of progressive HF, and 1 died of colon carcinoma). In the placebo group, 1 patient died suddenly. Baseline characteristics, including MIBG uptake from those 5 patients, did not differ from the other patients. However, because follow-up parameters could not be obtained, those 5 patients were excluded from analysis. The mean dose for patients assigned to metoprolol was 126 mg ± 35 mg daily.

Baseline myocardial MIBG uptake was similar for the treatment group and the placebo group. Compared with baseline, myocardial MIBG uptake increased by 21.9% after 6 months of treatment with metoprolol, whereas MIBG uptake in the placebo group decreased by 7.8%, a significant difference in response (P = .03). The difference in absolute changes in MIBG uptake between metoprolol and placebo was also statistically significant (P = .04). Table II and Figure 3 summarize these results.

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• Fig. 3. 

  Box and whiskers plot of changes in mean myocardial MIBG uptake (percentage of baseline) in patients treated with placebo and patients treated with metoprolol. Mean MIBG uptake increased 21.9% in the metoprolol group as opposed to placebo with a decrease of 7.8% (P = .03, between-group comparison).

Table II. Efficacy parameters at baseline and after 6 months of treatment with a maximal tolerated dose of metoprolol or placebo

SBP, Systolic blood pressure; EF, left ventricular ejection fraction; EDD, left ventricular end-diastolic diameter. Quality of life assessed with the Minnesota Living with Heart Failure questionnaire. Heart rate measured as mean heart rate over 24 hours during Holter monitoring.

Stratification according to HF etiology showed no significant differences in baseline myocardial MIBG uptake between the nonischemic group and the ischemic group (96.3 ± 55.3 vs 80.2 ± 38.1 counts/voxel, P = NS). The effect of metoprolol treatment on MIBG uptake was the same in both groups (Table III).

Table III. Efficacy parameters for metoprolol treated patients divided by etiology

No significant differences in baseline parameters between ischemic and nonischemic etiology.

Patients in New York Heart Association class II had a slightly higher initial MIBG uptake than those in class III (95.5 ± 51.6 vs 78.8 ± 42.6 counts/voxel, P = NS). By use of within-group comparison, MIBG uptake increased significantly more in patients in class II than those in class III after 6 months of treatment with metoprolol. However, when changes in MIBG uptake were expressed as percent changes from baseline, the difference in MIBG uptake was not statistically significant (Table IV).

Table IV. Efficacy parameters for metoprolol treated patients in NYHA class II and III

Baseline VO₂ max and Quality of life assessment significantly different between NYHA class II and III.

There were no significant differences in baseline MIBG uptake and metoprolol-induced changes between the 3 dosing groups (Figure 4).

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• Fig. 4. 

  Mean myocardial MIBG uptake (counts/voxel) in the 3 groups of patients treated with metoprolol (50 mg, 100 mg, 150 mg) and the patients treated with placebo at baseline and after 6 months of treatment. There were no significant differences in MIBG uptake between the 3 metoprolol groups. Results expressed as mean ± SEM. MIBG, ¹²³I-metaiodobenzylguanidine.

The negative chronotropic effect of metoprolol was reflected by a significant decrease in heart rate from 91 ± 12 to 74 ± 12 beats per minute after 6 months of treatment (P = .0001); systolic and diastolic blood pressure did not change. LVEF and left ventricular end-diastolic diameter (LVEDD) changed over time. The placebo treatment group showed negligible changes in LVEF and LVEDD. For patients treated with metoprolol, LVEF increased from 25.3% ± 7.4% to 32.6% ± 9.6% and LVEDD decreased from 74.2 mm ± 11 mm to 66.9 mm ± 10 mm after 6 months of treatment. Both parameters changed significantly within-group comparison (P < .05) was made. When expressed as percent change compared with placebo, the differences were not significant (P = .2 for EF and EDD).

The neurohormonal parameters, plasma epinephrine, NE, and ANP did not change during the 6 months of treatment (Table II).

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Discussion 

The major finding of our randomized, placebo-controlled study of patients with HF is that long-term metoprolol treatment significantly increased myocardial MIBG uptake when compared with placebo. This indicates an effect of metoprolol at the presynaptic level in the myocardium. During the 6-month treatment period, LVEF increased in metoprolol treated patients, whereas EDD decreased.

Results of this study extend the findings of recently published studies¹³, ¹⁴, ¹⁵, ¹⁶, ²⁴ and add new aspects: (1) the findings were demonstrated in a randomized, placebo-controlled study, (2) the increase in MIBG uptake was observed in both nonischemic and ischemic cardiomyopathy but somewhat more pronounced in the latter, and (3) changes in MIBG uptake were not dose related.

Mechanisms of action 

The mechanisms of action of β-blockers in HF can be attributed, in part, to effects at the level of the myocytes by protecting the β-receptor from high concentrations of NE in the synaptic cleft. This prevents the toxic effects of NE and probably also the down-regulation of β-receptors. In addition, there may be an influence on post-receptor events²⁵ and on calcium homeostasis.¹¹, ¹²

However, results from our study suggest an effect of metoprolol at the presynaptic level because MIBG is taken up into the neuron via the NE transporter (in a manner similar to that for NE). The observed increase in myocardial MIBG uptake must reflect changes either in sympathetic nerve ending density, the nerve firing rate, or the NE transporter (uptake-1).

In HF, density and functional integrity of sympathetic nerve endings are reduced.²⁶ It can be postulated that metoprolol treatment increases sympathetic nervous innervation density. This effect of metoprolol can be mediated through its negative chronotropic properties resulting in improved blood-flow and oxygen and nutrition delivery to the myocardium. In addition, anti-ischemic effects of metoprolol can restore sympathetic nervous innervation. Improved MIBG uptake thus reflects an increased density and an improved functional integrity of sympathetic nervous innervation.

Neuronal release of NE is increased in HF and contributes to depletion of myocardial NE stores and increased NE levels in the synaptic cleft.⁵, ⁶, ⁷, ²⁷ Adrenergic firing rate is modulated by presynaptic β₂, α₂, and angiotensin II receptors. It can be postulated that metoprolol modulates NE release by interacting either directly or indirectly in the complex interplay among these facilitating receptors (β₂, angiotensin II) and inhibitory receptors (α₂) for NE release. In this conceptual framework, a metoprolol-induced decrease in neuronal release of NE leads to lower levels of NE in the synaptic cleft. Because MIBG follows the same uptake mechanism as NE, competition in uptake between the 2 from the synaptic cleft into the presynaptic neuron by the NE transporter will change in favor of MIBG.

Another potential mechanism by which metoprolol can exert a presynaptic effect is related to a decreased efficiency of presynaptic NE uptake (uptake-1, NE transporter) from the synaptic cleft in HF.²⁸, ²⁹, ³⁰, ³¹ This reuptake is the main mechanism to remove NE from the synaptic cleft. Metoprolol might influence these uptake-1 sites, thereby improving MIBG (and thus NE) uptake in the presynaptic nerve endings.

Finally, it has been suggested that ventricular dilatation may cause underestimation of myocardial sympathetic activity.³² An increased MIBG uptake during metoprolol treatment might thus be related to the observed decrease in LVEDD. However, we found no correlation between a decrease in LVEDD and change in MIBG uptake (Figure 5).

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• Fig. 5. 

  Correlation between changes in EDD and MIBG uptake during 6 months of treatment with metoprolol (R = 0.15). EDD, left ventricular end-diastolic diameter.

Study design 

An effect of β-blockers on myocardial ¹²³I-MIBG uptake was recently demonstrated in several studies.¹³, ¹⁴, ¹⁵, ¹⁶ None of these studies included a placebo group, although Merlet¹⁴ showed that in healthy volunteers there was no change in MIBG uptake after 1 month of treatment with metoprolol. Among other reasons, we included a placebo group to correct for potential changes in MIBG uptake over time related to disease progress. Especially in patients with idiopathic dilated cardiomyopathy, it can be speculated that spontaneous improvement occurs with better hemodynamics and decrease of sympathetic activation, leading to improved MIBG uptake. The fact that no changes in MIBG uptake were seen in the placebo group over time suggests that the observed increase in MIBG uptake in patients treated with metoprolol is a direct result of this treatment.

Nonischemic versus ischemic cardiomyopathy 

This study included patients with symptomatic systolic dysfunction irrespective of etiology. Earlier studies on the effect of β-blockers on MIBG uptake restricted inclusion to patients with idiopathic dilated cardiomyopathy. The observed improvement in myocardial MIBG uptake was seen in both ischemic and nonischemic cardiomyopathy, though it was somewhat more pronounced in the ischemic group. Our observations extend the results from these earlier studies but provide initial evidence that improved MIBG uptake as a result of β-blocker therapy is not restricted to the nonischemic cardiomyopathies.

Although patients were excluded if they had objective signs of ischemia, we cannot exclude the possibility that some patients in the ischemic group had silent ischemia, with neuronal damage as a consequence, at the beginning of the study. This neuronal damage can lead to decreased MIBG uptake.³³, ³⁴ Therefor, the observed improvement in MIBG uptake after treatment with metoprolol can partly be explained by restoration of sympathetic nerve endings as a result of the anti-ischemic effects of metoprolol and improved hemodynamics.

Dose related effects 

Contrary to other authors,³⁵, ³⁶ we could not demonstrate a dose-related response to metoprolol. The observed improvement in MIBG uptake after 6 months of treatment showed no difference between the 3 dosing groups (50 mg, 100 mg, 150 mg). Similarly, the LVEF increase and the LVEDD decrease were the same for all groups (data not shown). Studies with bucindolol³⁵ and carvedilol³⁶ showed dose-related improvements in left ventricular function. In addition, carvedilol showed a dose-related reduction in mortality and hospitalization rate.³⁶ An essential difference between these 2 studies and ours is the titration phase. We randomized our patients after a titration phase to either their maximal tolerated dose or placebo. In contrast, in the studies with bucindolol and carvedilol, patients were directly randomized to 1 of 3 dosing groups of active treatment or placebo. It might well be possible that the degree of β-blockade was insufficient in the lower dosing group. Moreover, bucindolol and carvedilol are nonselective β-blockers with weak vasodilating properties, whereas metoprolol is a selective β₁-blocker devoid of vasodilator activity.

Although the factors that determine the optimal degree of β-blockade are not yet known, there is accumulating evidence that treatment with a β-blocker should be directed to the maximally tolerated dose.

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Conclusions 

Our randomized, placebo-controlled study of 59 patients with congestive HF irrespective of etiology demonstrated an increased myocardial MIBG uptake after long-term treatment with a maximal tolerated dose of metoprolol. An increase in LVEF and decrease in LVEDD accompanied this increased MIBG uptake.

Whether this increased MIBG uptake was the result of a direct effect of metoprolol on the presynaptic neuron, a consequence of hemodynamic improvement, or both, is unknown. In addition, it remains to be elucidated whether the different mechanisms that are operative are dependent on the etiology of HF.

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