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European Journal of Heart Failure 2008 10(6):534-539; doi:10.1016/j.ejheart.2008.03.016
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© 2008 European Society of Cardiology

Exercise training prevents β-adrenergic hyperactivity-induced myocardial hypertrophy and lesions

Andrey J. Serraa, Maria L. Higuchib, Silvia S.M. Iharac, Ednei L. Antôniod, Marília H.H. Santosb, Maria T.N.M. Bombiga and Paulo J.F. Tuccia,d,*

a Department of Medicine, Cardiology Division, Federal University of São Paulo, (UNIFESP) Brazil
b Heart Institute (INCOR), University of São Paulo Brazil
c Department of Pathology, Federal University of São Paulo (UNIFESP) Brazil
d Department of Physiology, Cardiovascular Division, Federal University of São Paulo (UNIFESP) Brazil

* Corresponding author. R. Estado de Israel 181 / 94 CEP:04022-000, São Paulo, Brazil. Tel./fax: +55 11 5573 7820. E-mail address: tucci{at}fcr.epm.br


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Sustained β-adrenoreceptor activation promotes cardiac hypertrophy and cellular injury.

Aims: To evaluate the cardioprotective effect of exercise on damage induced by β-adrenergic hyperactivity.

Methods: Male Wistar rats were randomised into four groups (n=8 per group): sedentary non-treated control (C), sedentary treated with isoproterenol 0.3 mg/kg/day administered subcutaneously for 8 days (I), exercised non-treated (E) and exercised plus isoproterenol administered during the last eight days of exercise (IE). Exercised animals ran on a treadmill for 1 h daily 6 times a week for 13 weeks.

Results: Isoproterenol caused increases in left ventricle (LV) wet and dry weight/body weight ratio, LV water content and cardiomyocyte transverse diameter. Additionally, isoproterenol induced severe cellular lesions, necrosis, and apoptosis, increased collagen content and reduced capillary and fibre fractional areas. Notably, all of these abnormalities were completely prevented by exercise.

Conclusion: Our data have demonstrated that complete cardioprotection is possible through exercise training; by preventing β-adrenergic hyperactivity-induced cardiac hypertrophy and structural injury.

Key Words: Myocardial hypertrophy • Isoproterenol • Exercise training • Cardioprotection

Received September 30, 2007; Revised February 5, 2008; Accepted March 25, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Pronounced activation of the sympathetic nervous system in heart failure (HF) is inversely correlated with survival [1] and the clinical use of beta-adrenoreceptor antagonists is now recommended as a part of the gold-standard treatment for heart failure [2]. Accordingly, experimental models of adrenergic hyperactivity have gained interest. Isoproterenol (ISO), a synthetic non-selective β-adrenergic agonist, causes severe cardiac injury by promoting myocardial hypertrophy [3] and a necrosis-like infarction [4] of the heart muscle through inflammation [5], cytosolic Ca2+ overload [3,6], and oxygen-derived free radicals generation [7]. Hence, several treatment schemes with potential for preventing the structural myocardial modifications induced by the β-adrenergic actions of ISO have been evaluated: including calcium channel blockers [8], angiotensin-converting enzyme inhibitors [9], AT1 angiotensin II receptors blockers [8], β-adrenergic receptor antagonists [10], and antioxidants [11].

Although the cardioprotective effects of exercise training have been extensively described [12,13], only a few studies have investigated the possible benefits of exercise training prior to ISO administration. Riggs et al. [14], and Brodowicz and Lamb [15] studied serum and myocardial creatine kinase activity 24 h after a single injection of isoproterenol. Darrah et al. [16] examined the electrocardiographic changes associated with myocardial necrosis induced by two subcutaneous injections of ISO. These authors reported that exercise only attenuates myocardial lesions caused by very large doses of ISO.

In spite of the known beneficial cardiovascular effects of exercise, there is no data on myocardial structural characteristics in animals undergoing exercise training prior to β-adrenergic hyperactivity induced by ISO. The aim of this study was therefore to describe the structural myocardial changes following ISO administration, and to evaluate the effect of previous exercise training on these changes. A more detailed morphological characterization of ISO-induced myocardial lesions in animal models, and an evaluation of the effect of exercise training preceding ISO administration, may help in the understanding of HF pathogenesis in terms of β-adrenergic receptor hyperactivity and its treatment.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Animals and administration of ISO
Thirty-two male Wistar rats weighing 150-180 g were randomly assigned to four treatment groups (n=8 per group): 1) non-trained control rats that received only olive oil (Control group: C); 2) non-trained rats that received subcutaneous injections of ISO (0.3 mg/kg/day) diluted in 1 ml of olive oil (ISO group: I); 3) trained rats that received only olive oil (exercise group: E); and 4) trained rats that received ISO injections (ISO plus E group: IE). Animals were cared for in compliance with the "Principles of Laboratory Animal Care" formulated by the National Institutes of Health (National Institutes of Health publication no. 96-23, revised, 1996), according to a protocol approved by the Ethics Research Committee at the Federal University of São Paulo, Brazil.

2.2. Exercise protocol
Animals were made to run on a treadmill for 1 h per day, 6 days per week. This exercise protocol lasted for 13 weeks. The treadmill speed was set at 18 m/min for the first 30 min and was increased to 22 m/min for the remaining 30 min of exercise. Before the start of the formal exercise protocol, rats were preconditioned to treadmill running for 12 consecutive days; during this time the treadmill speed was progressively increased by 3 m/min every 2 days until the final speed of 18 m/min was reached. The sessions initially lasted for 5 min and were increased by 5 min each day to reach 60 min on day 12. ISO or olive oil was administered on the last day of week 12 and on all seven days of week 13 of the exercise protocol, to achieve 8 days of treatment. Twenty-four hours after the last training session the rats were anesthetized (urethane: 1.2 g/kg) and sacrificed. Eight rats in each group were studied for evaluation of myocardial mass and LV water content. Left ventricular wet weight (WW) and dry weight (DW) were determined before and after samples were dried at 70 °C until they achieved constant weight in order to determine myocardial water content (H2O), which was estimated using the formula:

H2O (%)=[(WW–DW)/WW]x100.

2.3. Histomorphometric analysis
After anesthesia, the right carotid artery was cannulated and 1 ml of KCL 19% was injected to promote cardiac arrest. The thorax was opened, the aorta was occluded just beyond the right carotid artery and the heart was removed. Thereafter, the right atrium was opened and the heart was perfused with phosphate buffer (0.01 mM; pH 7.4) for 2 min, and then with 10% formalin buffered solution with 2% glutaraldehyde for another 10 min under 90 mmHg of perfusion pressure. The heart was transversally sectioned at the mid-ventricular level; the basal portion was utilized for electron microscopy studies and the apical portion was used for optical microscopic examination. Small LV fragments were sampled for electron microscopy study, after fixing in 2% glutaraldehyde at pH 7.2. The apical portion was fixed in a mixture of buffered formalin 10% and glutaraldehyde 2% and processed for embedding in paraffin and optical microscopic examination.

For optical microscopic examination, 7 {varepsilon}m thickness sections were obtained from the left ventricular equator and haematoxylin-eosin stained. LV diameter and free wall thickness were determined in these transverse cardiac sections. Nuclear length (major diameter) and width (minor diameter) were then measured. Fifty nuclei from each animal (n=3 per group) were measured. The nuclear volume (V) was estimated from the formula for a prolate ellipsoid [17]: V={pi}AB2/6; where A is the major diameter and B is the minor diameter. Collagen content was determined by picrosirius red staining of sections of myocardium and analyzed using polarized light observation [18]. Histological images were visualized using an Olympus microscope at 40x magnification, and analyzed using Image Tool software 3.0.

Ultrastructural evaluation was performed in three rats from each group by electron microscopy. Fragments were cut into small 1 mm thick pieces, post-fixed in 1% OsO4 solution for 2 h at 4 °C, and then dehydrated and embedded in araldite. Silver or grey thin sections were cut on a Porter-Blum MT-B ultra microtome, mounted on copper grids and stained with uranyl acetate and lead citrate. Preparations were examined through a Philips EM-301 electron microscope and photographed at 1.650x or 8.900x the original magnification. For each rat, cardiomyocyte transverse diameter was measured at the nucleus level in five longitudinally oriented cells. A 1.056 point-reticule was superimposed on five representative microphotographs from each rat; and capillary and fibre fractional areas were calculated according to the method described by Gundersen et al. [19]. Means of the five measurements were considered representative for each rat.

2.4. TUNEL staining
In order to detect apoptotic cells, a fluorescent TUNEL assay was performed in 2-cm long, 5-µm thick paraffin embedded, formalin-fixed myocardial sections from the medial poles of the resected fragments. In brief, sections were dewaxed in xylene and rehydrated. Sections were pretreated with proteinase K (Gibco, Gaithensburg, MD) at a dilution of 20 µg mL–1 in 10 mM Tris/HCL, pH 7.5 for 15 min at 32-35 °C. Sections were rinsed in 0 1 M phosphate buffered saline (PBS), pH 7.3, and incubated in a humid atmosphere at 37 °C for 60 min in 50 µL of TUNEL reaction mixture coupled with fluorescein (Boehringer, Mannheim, Germany). Positive-stained controls were prepared through incubation of serial sections of each paraffin block with 10 U/ml DNase I for 20 min at 37 °C before treatment with terminal transferase. Negative controls were prepared by staining serial slides without terminal deoxynucleotide transferase. The number of TUNEL-positive myocardial cells was counted using 200x microscopic enlargement in 5 randomly chosen fields (1 mm2) of each rat and expressed as the number of apoptotic cells/10,000 cardiomyocytes. The actual area of myocardium studied was measured using a Leica Q Win (Leica, Bensheim, Germany) image analysis system coupled with a Zeiss SV6 stereomicroscope. The mean area studied was 179±34 mm2. The cardiomyocyte origin of the TUNEL-labelled cells was confirmed by staining of muscular elements with phalloidin conjugated to TRITC. For this purpose, TUNEL-stained sections were incubated for 40 min with a TRITC conjugated phalloidin solution (Sigma) at a dilution of 1 mg mL–1 in PBS containing 0.1% Triton-X-100. Double-stained sections were analyzed by confocal microscopy using a Noran confocal microscope.

2.5. Statistical analysis
One way ANOVA complemented by Newman-Keuls test was used to detect differences between groups. A p value<0.05 was considered significant and results are presented as means±standard deviation (SD).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Myocardial mass
Results are summarized in Table 1. Non-trained ISO-treated rats (Group I) had significantly higher values of heart weight/body weight, LV wet weight/body weight and LV dry weight/body weight compared to the other groups. The tissue weight increase was accompanied by oedema as LV water content was significantly higher. Exercise did not affect myocardial mass or water content. Exercise combined with ISO prevented the changes in mass and water content observed in Group I.


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  		Table 1 Structural data (mean±SD) for control rats (C), non-trained rats that received ISO (I), trained rats that received only olive oil (E) and trained rats that received ISO injections (IE)

 
3.2. Optical microscopy
Non-trained ISO-treated rats (Group I) had significantly smaller LV chamber diameter and increased free wall thickness (Table 1) characterizing the occurrence of LV concentric hypertrophy, which corroborates previous findings in our lab [20]. The ISO-treated rats showed significantly increased nuclear volume in LV (Table 1), multiple foci of subendocardial necrosis, subendocardial fibrosis, and increased myocardial collagen. Subendocardial necrosis foci were represented by granulation tissue with lymphomononuclear inflammatory infiltrate. As expected, these changes were not present in Groups C or E, and importantly, the rats in Group IE had a normal histological appearance (Fig. 1).


Figure 01
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  		Fig. 1 Optical micrographs (n=8 per group). Panel (A-D): haematoxylin-eosin staining. Panel (E) picrosirius red. Panels A, C and D: show normal morphology of the LV myocardium in groups C, E and IE, respectively. Panel B: Granulation tissue, lymphomononuclear inflammatory infiltrate and diffuse myocardial necrosis, as well as subendocardial fibrosis (panel E) and increase in collagen content (Panel F) were seen in group I. All changes were suppressed by exercise training. Same letters indicate values not different in ANOVA. Different letters indicate significant difference between means.

 
3.3. Transmission electronic microscopy
Electron microscopy (Fig. 2) showed that Group I had important changes in myocardial fibres, as represented by myofilament lysis, sarcolemmal rupture and intracellular and extracellular oedema. Histomorphometric analysis (Table 1) of sedentary treated rats revealed significantly larger cardiomyocyte diameter, and reduction in capillary and myocardial fibre fractional areas. In all evaluations, the cardioprotective effect of exercise was characterized. Indeed, ultra structural evaluation of the myocardium of ISO trained rats (Group IE) was essentially normal, as was the case in Group C and Group E rats.


Figure 02
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  		Fig. 2 Electron micrographs (magnification: 8900x; n=3 per group). Group C (Panel A) and Group E (Panel C) rats showed normal myocardium. ISO rats (Panel: B) showed severe cellular injury, including myofilament lysis, sarcolemmal rupture, and intracellular and extracellular oedema. Exercise trained ISO rats (Panel: D) showed totally preserved ultrastructure.

 
3.4. TUNEL staining
ISO treatment significantly increased (p=0.01) the number of apoptotic cells (C: 15.0±8.6; I: 46.1±24.5; E: 12.5±10.0; IE: 9.7±5.4) normalized per 10,000 cardiomyocytes (Fig. 3). This increase in apoptotic cardiomyocytes was prevented by exercise training.


Figure 03
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  		Fig. 3 Apoptotic cardiomyocytes in experimental animals (n=8 per group) estimated from positive control slides of serial sections (per 10,000 cardiomyocyte nuclei). Same letters indicate values not different in ANOVA. Different letters indicate significant difference between means.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
Our data showed that non-trained ISO animals had heavier hearts, higher LV dry weight, LV water content and cardiomyocyte transverse diameter when compared to the control group; indicating that ISO caused myocardial oedema, increased protein content and cardiomyocyte hypertrophy. Since nuclear enlargement is associated with cellular hypertrophy [17], cardiomyocyte growth was confirmed by the increase in nuclear volume. Additionally, our results on myocardial mass, LV chamber transverse diameter and free wall thickness, indicate that ISO-induced cardiac hypertrophy was of the concentric type, which corroborates previous findings in our lab [20]. Taking into account the myofilament lysis in association with the sarcolemmal rupture, indicating ISO-induced myocardial necrosis, it can be proposed that collagen content increase (Fig. 1F) occurs as reparative fibrosis [21]. In addition, apoptosis has been shown to coexist with necrosis in the heart following ISO, and increases cardiomyocyte loss. Marked myocardial necrosis and apoptosis, coexisting with increased collagen content in these animals, explains the impaired ability of the myocardium to generate force in combination with more marked elastic stiffness, as described previously [9,20].

Chronic β-adrenergic activation is thought [3] to promote cardiomyocyte hypertrophy via local stimulation of myocardial growth factors such as angiotensin II, transforming growth factor β1 and insulin-like growth factor-1. The pathogenesis of catecholamine-induced myocardial injury has yet to be fully defined. Mechanisms previously proposed [11,22-24] include: ischaemia-reperfusion injury, free radical generation, cAMP-dependent calcium overload of cardiac myocytes, and activation of the renin-angiotensin-aldosterone system. It can be supposed that the significant reduction in myocardial capillary fractional area in sedentary ISO-treated rats could cause reduced oxygen delivery to cardiomyocytes due to capillary deficiency, thus contributing to myocardial necrosis and apoptosis in these animals. In contrast, in the IE rats, the exercise regime was able to inhibit the reduction in capillary fractional area, which may have maintained oxygen delivery to the cardiomyocytes during ISO administration in the exercised rats, thus preventing tissue ischaemia.

Calcium channel blockers [8], angiotensin-converting enzyme inhibitors [9], AT1 angiotensin II receptors blockers [8], β-adrenergic receptors antagonists [10], and antioxidants [11] have been shown to prevent the cardiac hypertrophy and structural injury caused by β-adrenergic agonists. In our study, we demonstrated complete protection from cardiac hypertrophy and myocardial lesions in rats that received ISO after exercise training. To the best of our knowledge, this is the first demonstration of full protection against cardiac lesions secondary to β-adrenergic stimulation by exercise training. Previous studies have shown that exercise training only attenuates ISO-induced myocardial necrosis [14-16], rather than completely abolishing the lesions as occurred in our study. It is possible that the very high doses of ISO used in these previous studies (20 mg/kg, 70 mg/kg and 250 mg/kg, respectively) may have made full cardioprotection impossible. Indeed, taking into account the fact that the cardiac effects observed at the dose used in our study were clearly toxicological and never having been seen in physiological β-adrenergic stimulation, we consider that the amount of ISO used by these authors is clearly non-physiological. This is particularly important because β-adrenergic stimulation is known [25] to cause dose-dependent cardiac injury. In light of these facts, we conclude that these previous studies were unlikely to demonstrate exercise induced cardioprotection against physiological β-adrenergic hyperactivity. In addition, assuming that the ISO dose used in our study is also excessive in terms of usual physiological β-adrenergic stimulation, for clinical purposes, exercise training can be considered as very effective in promoting heart protection against β-adrenergic hyperactivity.

In conclusion, the cardioprotective effect of exercise against lesions due to β-adrenergic stimulation was complete: that is to say it included prevention of myocardial hypertrophy, myocardial necrosis and apoptosis, inflammation, cardiac oedema, subendocardial fibrosis, increased collagen content, and reduction in myocardial fibre and capillary fractional area. These results strongly suggest that regular exercise is a very effective non-pharmacological intervention for protecting the heart against β-adrenergic injury.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
Special acknowledgements to Dr. Regina H. E. Alfarano, PhD, for her help in advising on language correction and style.


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

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