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European Journal of Heart Failure 2001 3(6):651-660; doi:10.1016/S1388-9842(01)00180-5
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© 2001 European Society of Cardiology

Growth hormone alone or combined with metoprolol preserves cardiac function after myocardial infarction in rats

Entela Bollanoa, Claes-Håkan Bergha,b, Christer Kjellströmc, Elmir Omerovica, Vuk Kujacicd, Kenneth Caidahld, Bengt-Åke Bengtssone, Finn Waagsteina,b and Jörgen Isgaarde,*

a Wallenberg Laboratory, Sahlgrenska University Hospital SE-41345 Göteborg, Sweden
b Department of Cardiology, Sahlgrenska University Hospital SE-41345 Göteborg, Sweden
c Department of Pathology, Sahlgrenska University Hospital SE-41345 Göteborg, Sweden
d Department of Clinical Physiology, Sahlgrenska University Hospital SE-41345 Göteborg, Sweden
e Department of Internal Medicine, Research Center for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital SE-41345 Göteborg, Sweden

* Corresponding author. Tel.: +46-31-342-4972; fax: +46-31-82-1524. E-mail address: entela.bollano{at}wlab.wall.gu.se (J. Isgaard).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background and objective: Beta-adrenoreceptor blocking agents are important for the treatment of myocardial infarction (MI). Accumulating evidence also indicates that growth hormone (GH) improves cardiac function after MI in rats. We aimed to investigate the cardiovascular effects of combined treatment in an animal model of MI.

Methods: MI was induced in rats by ligation of the left coronary artery. Three days after MI, animals were randomly assigned to one of four groups: controls (C) (n=19); GH (n=19) receiving s.c. 2 mg/kg per day rhGH; metoprolol (M) group (n=19) receiving 24 mg/kg per day and combined group (GHM) (n=20) treated with both GH (2 mg/kg per day s.c.) and M (24 mg/kg per day) for 9 days. Transthoracic echocardiography was performed before and after treatment.

Results: Serum levels of insulin-like growth factor I were significantly elevated in the GH-group but not in the GHM group compared to controls. Left ventricular volumes, cardiac index, systolic blood pressure, were similar in all groups. Percent changes in ejection fraction compared to baseline were; GH (6.1±5.0%) and GHM (6.1±4.2%) vs. C (–12.5±3.0%), P<0.01, M (–7.3±4.2%). The occurrence of aneurysms was not significantly different between the various treatment regimes.

Conclusion: Treatment with growth hormone alone or in combination with metoprolol preserved left ventricular function after MI.

Key Words: Left ventricular remodeling • Growth hormone • Metoprolol • Aneurysm

Received December 15, 2000; Revised February 13, 2001; Accepted April 26, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Despite significant advances in therapy, coronary artery disease is still the leading cause of mortality in the Western world [1]. Since the Göteborg metoprolol trial [2,3], several others have confirmed the beneficial effects of beta-blockers in acute MI. These range from a 13% reduction in mortality in the first 24 h after early intravenous beta-blockade to substantial reduction in mortality and morbidity after chronic therapy in post myocardial infarction patients and patients with chronic heart failure (CHF) [4].

Recent experimental data have demonstrated beneficial effects of growth hormone (GH) in the treatment of postinfarct remodeling and heart failure [5–8]. Early start of GH treatment after MI has been shown to prevent pathologic remodeling and to improve left ventricle (LV) function [5]. Decreased peripheral resistance [9], induction of a ‘physiologic hypertrophy’ [5], improvement of intra-cellular Ca2+ handling [10] and increased force of contraction without increased energy expenditure [11], are some of the proposed mechanisms of GH action on the cardiovascular system. Small uncontroled clinical studies have demonstrated beneficial effects of GH on hemodynamics and clinical function in patients with CHF [12,13] although these findings have so far not been confirmed in placebo-controled trials [14,15].

The therapy of the acute myocardial infarction and post MI remodeling is complex. Data from randomized trials in patients with postinfarct heart failure have shown that the use of ACE inhibitors decreases mortality and attenuates the remodeling process without reversing it [16]. However, long-term therapy with beta-blockers has been shown to reverse remodeling and increases survival in patients with CHF [16].

However, introduction of GH into the therapeutic armamentarium of CHF needs to be explored since little is known about the possible interactions with GH and the sympathetic nervous system. An early report from Castagnini et al. [17], showed a negative impact of the combined treatment with regard to the prevalence of LV aneurysms after MI in an experimental rat model.

In our study we aimed to evaluate the effects of short-term combined treatment of GH and metoprolol in a model of acute MI, and compare to individual treatment with GH or metoprolol alone. We hypothesized that this combination would offer beneficial synergistic effects: acceleration of the healing process after MI and protection from the effects of sympathetic activation. Moreover GH could oppose the decrement of systolic function often following the introduction of beta blocking.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animals
The experiments were conducted on male Sprague–Dawley rats (B&K Universal, Sollentuna, Sweden) weighing 200–240 g. All animals were fed with standard rat pellets and tap water ad libitum and housed in cages in groups of five animals, at 26°C with 60% humidity and a 05.00–19.00-h light regimen. The study protocol was approved by the ethics committee for animal experiments at the University of Göteborg (Göteborg, Sweden). The investigation conformed with the Guide for Care and Use of Laboratory Animals published by the US National Institute for Health (NIH Publication No. 85-23, revised 1996).

2.2. Induction of myocardial infarction
Myocardial infarction was induced according to previously described methods [18]. Animals were anesthetized with a mixture of ketamine hydrochloride (Ketalar®, Parke–Davis, Barcelona, Spain; 60 mg/kg body wt.) and xylazine hydrochloride (Rompun® Vet, Bayer Corp., Leverkusen, Germany; 10 mg/kg) intraperitoneally (i.p). The rats were orally intubated and artificially ventilated (10 ml/kg, 70 strokes/min) using a rodent respirator (Carlsson ventilator, Astra-Zeneca, Mölndal, Sweden). Rectal temperature was maintained at 37–38°C. The heart was exposed via a left-sided thoracotomy, and the anterior descending branch of the left coronary artery was ligated between the pulmonary outflow tract and the left atrium. The lungs were thereafter hyperinflated, positive end-expiratory pressure was applied and the thorax was immediately closed. All animals received postoperative analgesia with buprenorphine (Temgesic®, Reckitt & Colman, Hull, England; 0.05 mg/kg s.c.).

On the third day after surgery, all surviving animals were screened by transthoracic echocardiography (as below). According to infarct size, only rats with MI/s involving at least 30% of the left ventricle were included. Animals with small MI/s were excluded. The animals were then randomized to different treatment groups, receiving either recombinant human GH (GH-group, 2 mg/kg per day; n=19), control group (C-group, 0.9% NaCl n=21), metoprolol (M-group; 24 mg/kg per day; n=20) and combined treatment group: GHM group, metoprolol (1 mg/kg per h) and rhGH (2 mg/kg per day n=24). GH and NaCl were injected s.c. once daily and metoprolol was given via osmotic mini-pumps implanted on the same day (Alzet® 2ml2, ALZA Corp., Palo Alto, CA, USA). This dose of metoprolol was chosen to correspond to a pharmacologically effective myocardial β1-adrenergic receptor blockade according to information provided by manufacturer (Astra-Zeneca, Mölndal, Sweden). The dose of growth hormone was chosen based on previous data of Isgaard et al. [7] and other groups [8]. The short-term treatment also avoided the formation of the antibodies against human GH. Recombinant GH was supplied by Pharmacia & Upjohn, Inc (Stockholm, Sweden).

After a 9-day treatment period the rats were anaesthetized and echocardiography was performed (as below), blinded for treatment. After completion of the second echocardiographical examination, blood was sampled from the inferior caval vein and the rats were killed by rapid excision of the heart. Hearts were then perfused with 4% formaldehyde. The atria were dissected and both ventricles were weighed. Blood samples were centrifuged, serum or plasma was kept at –20°C for subsequent analysis.

2.3. Echocardiography
Transthoracic echocardiography was performed before treatment, i.e. 3 days after surgery and at the end of the treatment period, using validated two-dimensional (2D), M-mode and Doppler techniques [5,7,18]. Rats were anaesthetized with a half dose of the anaesthetic mixture used for open-chest surgery to maintain light anaesthesia and spontaneous breath. Their chest was shaved and rats were placed on a heating pad in a shallow left lateral position. Electrocardiographic electrodes were placed and a standard lead II was recorded for heart rate measurements. Two-dimensional images were obtained at frame rate of 150–197 Hz, using a commercially available ultrasound system equipped with a 10-MHz linear transducer (Vingmed System Five®, GE Medical System, Milwaukee, WI, USA). The two-dimensional recording allowed direct measurement of LV diastolic and systolic volumes and ejection fraction in a cine-loop picture using the single plane area length method. Infarct size was measured by observing the hypo and akinetic region in real time at both long and short axis as previously described [19].

Short axis two-dimensional views of the left ventricle at the papillary muscle level were used to obtain M-mode targeted recordings. Anterior and posterior end-diastolic and end-systolic wall thickness and LV internal dimensions in diastole and systole were measured using the leading edge method of the American Society of Echocardiography [20]. Doppler measurements included peak early (E) and late (A) mitral valve inflow velocities, filling ratio (E/A), deceleration slope, and ejection time as well as peak aortic flow.

Cardiac output and stroke volumes were calculated using pulmonary artery Doppler flow and diameter as previously described [18]. Cine-loop pictures, M-mode tracings and Doppler spectra were stored for off-line analysis. All measurements were averaged at least on three consecutive cardiac cycles and were performed by an observer blinded to the treatment group using an imaging analysis system (EchoPacTM, GE Vingmed Ultrasound A/S, Horten, Norway) with digitally acquired data. Left ventricular wall-stress was calculated from two-dimensional measurements according to the formula: WS=1.33xPx(Ac/Am)x103 dynes/cm2 [21], where P is the systolic blood pressure, Am is the myocardial area determined by subtraction of the LV cavity area (Ac) from the total LV area at perpendicular mid ventricular level (1.33x103 is the conversion constant from millimeters of mercury to dynes/cm2). This formula allows a calculation of an average systolic wall stress assuming a rather spherical LV, not taking into account the regional difference on wall-stress in infarcted hearts.

2.4. Blood pressure measurement
Systolic blood pressure was measured by the cuff-tail method using an indirect rat tail blood pressure monitor (RTBP Monitor, Harvard Apparatus, Inc. South Natick, MA, USA) in connection with the echocardiographic investigations. After warming the tail for approximately 10 min the recording of the pulse and pressure curves were obtained. The average of at least four consecutive recordings was used to calculate the systolic blood pressure.

2.5. Histological analysis
The formaldehyde-treated hearts were cut into six transversal slices from the apex to the base. From each paraffin block a section 2–3 µm in thickness was cut, stained with Masson's trichrome and mounted. All stereological measurements were carried out in an IBAS® system (Interaktives Bild-Analysen System, Kontron Elektronik, Eching, Germany).

All images used for measuring were captured with a high-resolution digital camera ProgRes 3012 (Kontron Elektronik, Eching, Germany).

For quantification of diffuse fibrosis, measurements were carried out on the non-infarcted ventricular septum. Briefly, in 15 systematically randomly selected high power fields the colormetric spectrum of blue stained fibrous tissue was defined and its area fraction was calculated in the IBAS®. Vascular profiles and the subendocardial fibrous zone were excluded in the sampling procedures. The area fraction of diffuse fibrosis was expressed as a percent of sampled myocardium.

For scar tissue, the area fraction of the scarred infarcted surfaces was measured in low power images of the heart profile. The same three slices used for calculation of diffuse fibrosis were then measured. On the image of the heart presented in the IBAS® system, a line was drawn around the LV chamber, through the middle of the LV myocardium and ventricular septum. The fraction of the length of the line passing through scar tissues was expressed in percent and thus reflects the area fraction of scared tissue on a cut surface paralleling the endocardium. The same slices were also used to determine the presence of aneurysms defined as a convex protrusion of the full thickness of the LV wall [22].

2.6. Analytical methods
The serum concentration of insulin-like growth factor I (IGF-I) was determined by a hydrochloride acid–ethanol extraction radioimmunoassay using human IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). The assay was performed according to the manufacturer's protocol and after centrifugation of precipitated serum proteins at +4°C followed by neutralization with Tris base and another centrifugation at +4°C. Plasma insulin was analyzed with a rat insulin RIA kit (Linco research, St. Charles, MO, USA) and for corticosteron measurement a radioimmunoassay was used (RSL 125 I corticosterone RIA; ICN Biomedicals, Casta Mesa, CA, USA).

2.7. Plasma brain natriuretic peptide (BNP)
The blood sample was collected into ice cold tubes containing aprotinin [1000 KIU (ml) and Na2EDTA (1 mg/ml)] and centrifuged at +4°C. Plasma samples were stored at –20°C until assay. The plasma concentration of BNP was measured in 250 µl plasma using radioimmunoassay according to the manufacturer's protocol (Peninsula Laboratories Inc., San Carlos, CA, USA).

2.8. Statistical analysis
Mortality rate and distribution of aneurysms were analyzed using the Chi-squared test. The distribution of the continuous variables was checked for normality. Intergroup comparisons of echocardiographic indexes were analyzed (StatView, SAS Insitute Inc. Cary, NC, USA) using analysis of variance (ANOVA) for repeated measurements followed by Student–Newman–Keuls post-hoc test. One-way ANOVA was used for the other comparisons, also followed by the Student–Newman–Keuls test. Paired t-tests were performed to compare the data before and after treatment within the groups. A value of P<0.05 was considered statistically significant. Data are given as means±S.E.M.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Total mortality at 48 h after induction of myocardial infarction was 53%. Over the study period two rats in the C group and M group, respectively, and three in the GHM group died 24 h after the echo examination and implantation of the mini-pumps. Echocardiography showed the presence of large MI/s in these rats and probably the use of anesthesia and/or the trauma from the implantation procedure could have influenced the outcome. One rat from the GHM group died after 5 days of treatment. All the baseline data from these animals were excluded from further analysis.

3.1. Baseline data
Echocardiographic and hemodynamic data obtained at 2 days after MI are shown in Tables 1–3. Animals in all groups had similar body weight (BW), hemodynamic variables, infarct size, LV dimensions and volumes. Mean ejection fraction was <40% in all treatment groups, indicating impaired systolic function in all animals.


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  		Table 1 Effects of treatment on somatic, cardiac growth and hormone levels

 


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  		Table 2 Basal hemodynamics in rats with MI before and after 9 days treatment

 


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  		Table 3 LV volumes and dimensions before and after treatment

 
3.2. End of treatment period
At the end of the experiment all animals had increased their BW significantly compared to baseline (Table 1). Compared to baseline values, heart rate was decreased in M, GH and GHM groups but was unchanged in the C-group (Table 2). Blood pressure tended to be lower compared to the baseline values but this difference was not significant. Systolic wall stress was increased significantly vs. baseline in all animals. LV dimensions and volumes were significantly increased in all groups compared to baseline. Stroke volumes were higher at the end of the treatment period in all groups, whereas stroke volume index (SV/BW) and cardiac index (CO/BW) decreased significantly in group-C during follow-up. Cardiac index was slightly increased at the end of the study (Table 2) in the M, GH and GHM groups, without reaching significance.

Ejection fraction decreased significantly in controls compared to baseline and there was a tendency for lower EF even for the M group compared to baseline (P<0.06). In the GH and GHM treated rats EF did not change from baseline. The same pattern was observed for posterior wall thickening (PW%), an index of regional systolic function, which significantly deteriorated in untreated rats compared to baseline (27.2±1.3 vs. 33.6±1.2%, P<0.01), and did not change significantly in the M group (30.3±1.7 vs. 33.7±1.1%, NS), GH group (30.9±1.9 vs. 29.3±2.3%, NS) or GHM group (33.2±2.1 vs. 35.2±1.8%, NS).

Mitral inflow Doppler variables did not change significantly in any group during the study period (data not shown).

3.3. Comparisons between different treatments
Body weight gain was higher in GH-treated rats compared to the M group (84.2±2.1 vs. 69.9±4.0 g, P<0.01) but not compared to saline-treated MI rats. There was no significant effect of any treatment regimen on cardiac mass; either in absolute weights or heart weight/BW. Levels of IGF-I were significantly increased in the GH group compared to all other groups (Table 1), whereas insulin and corticosteron levels were similar among the four groups.

Systemic hemodynamics in controls and treated animals at baseline and 9 days after initiation of treatment are shown in Table 2. There was no significant effect of GH, metoprolol or their combination on blood pressure. Regarding heart rate change, the treatment effect was seen in the M group as compared to controls (Table 2).

Stroke volumes and cardiac indexes were not significantly altered by the different treatments and the plasma BNP was at a similar level in all four groups (Table 1).

Ejection fraction, expressed as percent of change from baseline was preserved in animals receiving GH alone or in combination with metoprolol (Fig. 1a). A similar pattern was observed regarding the thickening of the non-infarcted wall (Fig. 1b).


Figure 1
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  		Fig. 1 Ejection fraction (A) and posterior wall thickening (B) as a percentage of change from baseline. C, control group; GH, GH treated group; M, metoprolol group; GHM, GH+metoprolol treated group. Values are means±S.E.M. *P<0.05 vs. controls.

 
3.4. Effect of treatment on infarct size, diffuse fibrosis and aneurysm formation (Table 4)


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  		Table 4 Effects of treatments on infarct size, interstitial fibrosis and presence of aneurysms

 
The mean infarct size measured as percentage of scar tissue of left ventricle in treated and untreated groups was similar. GH treatment was not associated with a significant increase of the area fraction of collagen, which is a marker of interstitial fibrillar collagen, compared to controls. The location of aneurysms was mainly anteroapical and there was no significant difference regarding the presence of aneurysms between the different treatment groups.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study demonstrates that GH alone and in combination with metoprolol preserves systolic function in rats after experimental MI. GH treatment was not associated with a significant increase in interstitial fibrillar collagen compared to controls. The incidence of aneurysms was not affected by either treatment, alone or in combination.

4.1. Treatment effects on hemodynamic parameters and cardiac function
Use of GH in MI or post MI remodeled hearts has been studied during recent years. Experimental data have demonstrated positive effects of GH and/or IGF-I treatment starting early after MI [5,6] or later after ischemic injury [7,8]. In the present study, GH alone or combined with metoprolol prevented the decline in cardiac function after myocardial infarction. The comparatively modest beneficial effects in our study could probably in part be explained by a relatively short duration of treatment compared with previous studies reporting beneficial effects of longer term GH treatment and in a chronic state after MI [8,23]. However, experimental data using GH or IGF-I in the setting of MI or heart failure are not consistent. Several groups have reported beneficial effects of GH treatment on remodeling [5–8], with or without induction of hypertrophy, whereas others did not show the same effect [24,25]. It is obvious that experimental conditions such as infarct size, onset and duration of treatment, dosing of GH and methodology to monitor treatment effects influence the outcome of these studies. In the present study, GH treatment alone increased the circulating levels of IGF-I, but this stimulating effect was not observed in the group receiving the combination with metoprolol. The reason for this is not clear, but this could be due to an interplay between beta blockers and IGF-I production. In a study using an experimental model of hypertension, it was reported that treatment with propanolol reduced both LV content and circulating IGF-I [26]. Nevertheless, a comparable effect on ejection fraction was observed in both the GH and combined group despite different levels of circulating IGF-I, suggesting a direct effect of GH through the GH receptors present in the heart. However, we did not measure the content of myocardial IGF-I, which may be of importance, although previous studies failed to show a GH-mediated increase of heart IGF-I mRNA in MI rats [7,27].

The interaction between the GH/IGF-I axis and the sympathetic nervous system in normal conditions and in the setting of acute MI is incompletely investigated and poorly understood at the present time. Adult patients with GH deficiency have been reported to have an increased activity of the sympathetic nervous system [28]. A small study performed in patients with heart failure showed that GH administration reduced the sympathetic activity in these patients [29]. Our group has reported that treatment with GH in a rat model of myocardial infarction markedly decreased noradrenaline levels in the non-infarcted area without changing the number of beta receptors [30]. However, the expected negative chronotropic effect of metoprolol was blunted when it was given together with GH, possibly because of a compensatory increase in heart rate due to the vasodilating effect of GH. This apparently paradoxical effect of the combined treatment could be of interest adding more on the complexity of this interaction that needs further exploration.

Short-term treatment with metoprolol after the acute MI did not prevent the deterioration of cardiac performance, which is consistent with prior animal studies of post infarct remodeling [31,32]. Using beta-1 selective blockade, Hu et al. have shown that infarct size and timing of the start of therapy have an impact on its effect on LV remodeling [33]. Deterioration of cardiac function related to the negative inotropic effect of metoprolol, was prevented in the combined group. This could be of interest during initiation of beta-blockers after MI or in the setting of heart failure. It is well known that the long-term effects of β-blockade on myocardial function are opposite to the short-term negative inotropic effect [4].

4.2. Effect of treatment on LV aneurysms and fibrosis
It has previously been reported that GH and atenolol in combination increases the frequency of aneurysms in rats after experimental MI [17]. When given alone GH prevented the formation of aneurysms [17,34]. The authors proposed that the explanation for the increased incidence of aneurysms in the combined group was that administration of both drugs produced a chemical pancreatectomy with a secondary adrenal hyperfunction. In our study we could not find any significant difference in the incidence of aneurysms in the left ventricle in either treatment group compared to controls. Analysis of plasma levels of insulin and corticosteron at the end of the study did not reveal any difference between the groups. However, there are important differences in study design between the Castagnino et al. study and ours, especially regarding dose and timing of treatment, that are likely to contribute to the differences. Our main aim was to study the effects of short-term treatment with GH, metoprolol and their combination on hemodymanics and cardiac function after myocardial infarction in a rat model. Therefore, our histological analysis was performed 12 days after MI. Although, the healing process is completed at day 21 after MI, it is reported that the aneurysms develop as early as within 2 weeks after MI in rats [22]. Whether a histological analysis at 3 weeks after MI could have modified our results regarding the presence of aneuryms, will be the object of a future study.

There was no significant effect of either treatment on interstitial fibrillar collagen in the present study. It has previously been reported that GH induced cardiac hypertrophy without increasing fibrosis [5] and even reduced collagen I accumulation along with effect on cardiac remodeling after MI in rats [35]. The fibrosis content measured is an adaptive fibrosis located in the interstitial space of the non-infarcted area where increased wall stress is one of the stimuli [36]. In our study a remaining increased wall stress in all animals could partly explain the difference between our data and others regarding GH effect on fibrosis content after MI.

In conclusion, short-term treatment with growth hormone alone and in combination with metoprolol preserved cardiac function in rats with experimentally induced MI.


   Acknowledgements
 
We are grateful to Monika Remmefors, Department of Pathology, Britt-Mari Larsson, Ewa Angwald, Wallenberg Laboratory, Sahlgrenska University Hospital for excellent technical assistance and to Per-Årne Lundberg, Clinical chemistry, Sahlgrenska University Hospital, for valuable expertise regarding IGF-I and BNP measurements. The study was supported by the Swedish Heart and Lung Foundation (67519), the Swedish Medical Research Council (11022) and Pharmacia & Upjohn, Stockholm, Sweden.


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

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