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European Journal of Heart Failure 2007 9(6-7):678-683; doi:10.1016/j.ejheart.2007.02.007
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© 2007 European Society of Cardiology

Pronounced improvement in systolic and diastolic ventricular long axis function after treatment with metoprolol

Bente Grüner Sveälv, Margareta Scharin Täng, Finn Waagstein and Bert Andersson*

Department of Molecular and Clinical Medicine/Cardiology, Wallenberg Laboratory, Sahlgrenska Academy at Göteborg University, SE-413 45 Göteborg, Sweden

* Corresponding author. Tel: +46 31 342 75 37, +46 0340 62 15 65 (Home); fax: +46 31 82 37 62. E-mail address: bert.andersson{at}wlab.gu.se


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Although it is well known that left ventricular (LV) function improves after treatment with beta-blockers in heart failure, little attention has been paid to the effects on LV long axis (LAX) function.

Aims: To evaluate LV LAX function after treatment with metoprolol, and to assess whether LV LAX contractile reserve could predict future long-term improvement.

Methods: Twenty-four heart failure patients were randomised to metoprolol or placebo for 6 months, followed by 6 months of open treatment with metoprolol. Rest and dobutamine stress echocardiography (DSE) was performed before and after each treatment period.

Results: After treatment with metoprolol, LV LAX function improved significantly, systolic velocity from 29±8 to 32±15 mm/s, p<0.01 (metoprolol) vs. 28±7 to 28±11 mm/s, ns (placebo); atrioventricular plane fractional shortening (AVP-FS) from 5.4±2.1 to 7.4±2.7%, p< 0.001 (metoprolol) vs. 5.9±2.1 to 5.8±2.9%, ns (placebo). The improvement in function was maintained during DSE. LV LAX contractile reserve could not predict treatment response; the treatment effect on LV LAX function was significantly greater than the contractile reserve at baseline. The relative improvement in LV LAX function after metoprolol was 38%, compared with a 20% improvement in LV ejection fraction (EF).

Conclusion: A significant improvement in LV LAX function was observed after treatment with metoprolol. AVP-FS and systolic velocities increased significantly, and to a greater extent than LVEF.

Key Words: Echocardiography • Heart failure • Longitudinal function • Prediction • Recovery • Beta-blockade

Received October 4, 2006; Revised January 4, 2007; Accepted February 26, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
There is conclusive evidence that in patients with chronic heart failure (CHF) left ventricular (LV) function improves after treatment with beta-adrenergic blocking agents [1,2]. This improvement has mostly been focused on myocardial function, expressed as LV ejection fraction (EF), reflecting function of the foremost epicardial circumferential middle layer fibres of the LV wall. However, little attention has been paid to the improvement of subendocardial longitudinal muscle fibres, located in the deep layer [3,4], which contribute to shortening of the long axis (LAX). The movement of the mitral annulus (atrioventricular plane, AVP) towards the apex, plays a major role in the pumping mechanism of the left ventricle [5]. Although AVP movement has been recorded for many years [6,7], the introduction of Doppler tissue imaging (DTI) has renewed interest in this measurement [8-10]. Evaluation of LV LAX function with dobutamine stress echocardiography (DSE) has been performed using both AVP [11] and DTI recordings [12]. Even though longitudinal myocardial velocities are considered to be sensitive to changes in myocardial function, there are only a few studies that have used this technique to study the effects of treatment [13].

The aim of the present study was to evaluate the effect of long term treatment with the beta-blocker metoprolol on systolic and diastolic LV LAX function. Further, we wanted to investigate if assessment of systolic LV LAX function with DSE at baseline could be used as a tool to evaluate contractile reserve, and if it could be used to predict long-term improvement in global LV function after treatment with metoprolol.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study group
This study was a substudy of a prospective, double blind, randomised, placebo controlled, international multicenter trial [14]. Patients were recruited at Sahlgrenska University hospital. Twenty-four patients with stable CHF, in New York Heart Association functional class II or III and with LVEF <50%, as measured by equilibrium radionuclide angiography, were included in the study. Exclusion criteria were chronic treatment with beta-blockers, patients waiting for revascularization, pacemaker, myocardial infarction within 6 months, significant valve disease, severe systemic disease or atrial fibrillation. All patients were investigated with coronary angiography. Six patients had ischaemic aetiology and 18 patients had dilated cardiomyopathy. Baseline characteristics are presented in Table 1. The study was approved by the Ethics Committee of Göteborg University and informed consent was obtained from all patients.


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  		Table 1 Baseline characteristics

 
2.2. Treatment protocol
Eleven patients were randomised to placebo and 13 to metoprolol tartrate treatment. The dose of study medication was titrated from 5 mg twice daily to the maximal tolerated dose or 50 mg three times daily. Echocardiographic investigations were performed as previously described [13,15] at baseline before starting treatment, then after 6 months of metoprolol/placebo treatment and after an additional 6 months of open treatment when all patients received metoprolol. Data for the first 6 months of metoprolol treatment for the treatment group was combined with data for the second six month period for the placebo group when open metoprolol treatment was administered (combined group).

2.3. Echocardiography
Echocardiography was performed with the patient in the left lateral position, all recordings were obtained during relaxed end-expiratory apnoea and recorded on videotape and on strip-charts at 50-100 mm/s. ECG and phonocardiographic recording was continued throughout the study.

From an optimal apical four- and two-chamber view, the cursor was positioned from the apex to the insertion of the mitral valve. With zoom function the M-mode beam recorded the movement of the AVP in four different regions, septal, lateral, anterior and inferior region.

The systolic AVP amplitude was measured from the onset of systole, after the isovolumic contraction time, until the point that coincides with aortic closure [16].

A minimum of three cardiac cycles, from each region, were analysed and averaged. The curves were traced on a digitizing table and processed using a computer software program, Cardiac Analysis Software (CAS), Sahlgrenska University Hospital, Göteborg. Maximal velocities were calculated from the steepest parts of systolic and diastolic movements. Amplitudes, time intervals and velocities were analysed as described earlier [17]. In order to normalise function to the size of the heart, the AVP-fractional shortening (FS) was calculated by dividing the systolic amplitude with the length of the long-axis. The long axis was measured from the epicardial apex to the end of diastasis in the AVP recording [13,15]. LVEF was calculated using the method of discs (modified Simpson's rule) and in accordance with the recommendations of the American Society of Echocardiography [18]. Treatment response was defined as the long-term treatment effect at rest, from baseline to the six month investigation, in the metoprolol treated group. Contractile reserve was defined as the response of dobutamine from rest to stress. Contractile reserve and long-term treatment response of AVP-FS was normalised for mean AVP-FS at baseline and expressed as percentage ({Delta}AVP-FS/mean AVP-FS at baseline*100). Evaluations of echocardiographic recordings were evaluated blindly by same investigators, LV LAX function (BGS) and LVEF (MST).

2.4. Dobutamine stress echocardiography
After recording at rest, dobutamine was infused intravenously. Initially 5 µg/kg/min were given, followed by dose increments of 5 µg/kg/min every 5 min, until an increase in heart rate of 20 beats/min was reached, then a complete recording was performed.

2.5. Statistical methods
Data was analysed using SPSS 11 for Windows (Chicago, IL). Paired data were analysed with the Wilcoxon signed rank test and Mann-Whitney U test was used to compare data between independent groups. To analyse the relation between two variables, Spearman's rank correlation coefficient rs was applied. Data are expressed as mean±SEM in graphs and mean±SD in tables. A p value <0.05 was considered as statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Contractile reserve
Mean dobutamine dose was 12±4 µg/kg/min at baseline, and 23±9 µg/kg/min after 6 months of metoprolol treatment (p=0.001). In the combined group (n=24) we observed a significant contractile reserve before treatment with metoprolol, AVP-FS responded significantly to dobutamine (5.6±2.4 vs. 6.7±2.9%, rest vs. stress, p<0.001). After 6 months of treatment with metoprolol, the DSE did not induce a significant contractile reserve (7.7±2.6 vs. 8.4±3.2%, p=0.076), Table 4.

Nevertheless, maximal systolic velocity responded significantly during DSE, both before (28±9 vs. 44±17 mm/s, p<0.001) and after 6 months of treatment (33±13 vs. 50±21 mm/s, p<0.001).

The relation between AVP-FS and systolic velocities was significant at rest (r=0.92, p<0.001) as well as during DSE (r=0.72, p<0.01).

3.2. Response to metoprolol treatment
The mean dose of metoprolol at the end of the study was 136±26 mg. At rest and during DSE, we observed a significant treatment response to metoprolol after 6 months in the treated group. Improvements in mean AVP-FS (%) (Table 2), as well as in systolic velocities (Table 3) were observed. There were no improvements in the placebo group. During the open metoprolol treatment period from 6 to 12 months, a significant increase was also observed in the former placebo group. The improvement was seen at rest and during DSE. There was no further improvement in the metoprolol group from 6 to 12 months. Also for the combined group (all patients treated with metoprolol) similar findings were observed (Table 4). Positive effects on diastolic function, observed as an increase in atrial filling velocity and diastasis, were also evident during DSE. Despite an expected decrease in heart rate during metoprolol treatment, systolic velocities were significantly higher during comparable heart rates (Fig. 1).


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  		Table 2 AVP-FS at rest and during dobutamine stress in patients treated with metoprolol or placebo

 


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  		Table 3 Maximal systolic velocity (mm/s) at rest and during dobutamine stress in patients treated with metoprolol or placebo

 


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  		Table 4 Systolic and diastolic function in long-axis recording in the combined group (n=24)

 


Figure 01
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  		Fig. 1 Myocardial systolic velocity in relation to heart rate at baseline and after treatment with metoprolol, at rest and during dobutamine stress.

 
3.3. Contractile reserve and treatment effect
Contractile reserve and its ability to predict global LV improvement was analysed in the combined group. Assessment of contractile reserve in mean AVP function (average of the four regions) at baseline was not able to predict long-term treatment response to metoprolol. Contractile reserve at baseline (Fig. 2) was lower than the long-term treatment response to metoprolol (Fig. 3). The relative improvement in LV LAX function was 38% after 6 months beta-blockade, as compared with only 20% improvement in LVEF (Fig. 3)


Figure 02
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  		Fig. 2 The response of dobutamine, (contractile reserve), in AVP-FS and global LVEF before treatment with metoprolol.

 


Figure 03
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  		Fig. 3 The treatment response, at rest, in AVP-FS and global LVEF after 6 months treatment with metoprolol.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The present study provides new information regarding improvement in LV LAX function after treatment with metoprolol in patients with CHF. AVP-FS and systolic velocities increased significantly both at rest and during DSE and to a greater extent than LVEF.

4.1. Systolic LV LAX function
Metoprolol improved systolic function significantly both at rest and during DSE. We believe that this is the first study to report increased myocardial velocities during beta-blocker treatment. This observation is of interest, as HR and systolic velocities were not positively related, i.e., velocities increased in spite of a decrease in HR. Lack of relationship between HR and peak systolic velocities has been reported previously using colour myocardial Doppler [19]. Of interest, the treatment effect on LV LAX function was substantially larger than the increase in LVEF. There was a 38% increase in AVP-FS, compared to only a 20% increase in LVEF. A similar degree of improvement, 24% increase in LVEF, was observed in the main (multicenter) study [14].

Several authors have shown that the long-term effect of beta-blockers on global LVEF can be predicted by assessment of contractile reserve using DSE [20,21]. We were not able to predict future treatment outcome by evaluating contractile reserve of the LV LAX function. The treatment effect of metoprolol on LV LAX function was significantly higher than the response to dobutamine at baseline.

4.2. Diastolic LV LAX function
We observed prolongation of the diastolic time periods, which could improve myocardial perfusion. The subendocardial layers would probably benefit most from improved coronary perfusion and decrease in wall stress; this would help to explain the greater improvement in AVP-FS as compared to LVEF. Improved systolic and diastolic LV function would facilitate left atrial filling as expressed by the decrease in filling fraction. Further, on metoprolol treatment, a significant increase in diastolic time was also observed during DSE which might be a sign of increased resistance towards catecholamines during stress.

4.3. The role of subendocardial function
Beau and co-workers reported that the distribution of beta-receptors in the longitudinal subendocardial fibres was different to that in the circumferential muscle fibres of the epicardial fibres [22]. Despite a significant reduction in total beta-receptor density, no significant reduction was observed in the subepicardium, whereas beta-receptors were significantly reduced in the subendocardium. Likewise, cAMP and phosphodiesterase are significantly decreased in endocardial but not in epicardial layers [23]. Long-term metoprolol therapy has been shown to be associated with an increase in myocardial beta-receptor density [24] and the beta1:beta2 ratio in the failing human myocardium is about 60:40 compared to the normal ratio of 80:20 [25]. Assuming that beta-receptor density in the subendocardium is significantly reduced compared with the epicardium, it is likely that restoration after beta-blockade is more prominent in the deep layers. This might be the reason for the differences in contractile reserve and long-term recovery that we observed. Interestingly, it has been shown that decreased tissue Doppler velocity is significantly related to decreased beta-receptor density [26].

4.4. Limitation
We chose to maintain treatment during follow-up investigations because acute withdrawal of beta-blocker therapy can be dangerous. Thus, the effect of dobutamine via beta-receptor stimulation was partially blocked by metoprolol, which may have influenced the interpretation of inotropic reserve. It has been shown that AVP motion displays a biphasic response during DSE (an increase followed by a decrease during peak dobutamine-atropine infusion) [11]. The dose of dobutamine in our study was low leading to a predominant contractile response. We used M-mode echocardiography to measure velocities of AVP motion. DTI was not available at the time of investigation but is probably a more convenient method. Velocities derived from M-mode excursion are approximately 30% lower compared to DTI velocities. However, a linear correlation between velocity recorded by M-mode and by DTI has been shown [27]. On the other hand it has been observed, in a phantom study, that velocities by DTI are overestimated [28]. Nevertheless, DTI has so far not been used for testing of cardiac reserve and treatment effects. This study included patients with both ischaemic and non-ischaemic cardiomyopathy. Due to the limited number of patients it was not possible to separate the beta-blocker effects between the two different aetiologies. No patients had signs of angina pectoris or exercise induced ischaemia.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
The significant improvement in systolic LV LAX function after treatment with metoprolol may be due to restoration of subendocardial beta-receptors, facilitated by the prolongation of diastolic time periods and improved myocardial perfusion. The beneficial effect of metoprolol on myocardial function seems to be due to improvement in LV LAX function.


   Acknowledgements
 
The authors are grateful to Ronny Wiik for developing the Cardiac Analyse System.

This study was supported by the Medical Research Council (project 02529), the Swedish Heart-Lung Foundation, and AstraZeneca R&D, Mölndal, Sweden.


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

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