© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing β2-adrenergic receptors in the heart
Baker Medical Research Institute and the Alfred Heart Centre, Alfred Hospital, Melbourne, Victoria, Australia
* Corresponding author. Tel.: +61-39-522-4333; fax: +61-39-521-1362 xiaojun.du{at}baker.edu.au
Received 26 May 2000; accepted 18 July 2000
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Abstract |
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Objective: To explore long-term cardiac phenotype in transgenic (TG) mice with 300-fold overexpression of β2-adrenergic receptors (AR). Methods: Echocardiography was performed serially on a cohort of wild-type and TG mice (n = 26 each) between 4 and 15 months of age. Survival was monitored and autopsy and histological examinations were performed. Results: Heart rate was higher in TG than in wild-type mice throughout the study period. The left ventricular dimensions and fractional shortening were similar between TG and wild-type groups during 4–6 months. Starting at 9 months, however, TG mice showed progressive reduction in fractional shortening and systolic wall thickening, and increase in left ventricular dimensions and left ventricular mass, indicating onset of heart failure, left ventricular hypertrophy and remodeling. Abnormal waveforms in the electrocardigram and episodes of ventricular ectopic beats were also observed in TG mice. Death of TG mice started at 8.5 months, and the cumulative mortality was 81% by 15 months (P<0.0001 vs. 4% in wild-type mice). The majority of deaths were due to severe heart failure, indicated by cardiac dilatation, lung congestion, pleural effusion and atrial thrombus. Left ventricular sections showed widespread interstitial fibrosis, loss of myocytes and myocyte hypertrophy in TG mice. Conclusions: A high level of β2AR overexpression results in cardiomyopathy and heart failure. The onset was slower and the expression levels of receptors required are much higher than previously described for the β1AR overexpression.
KEYWORDS Cardiomyopathy; Heart failure; Autonomic nervous system; Receptors; Ultrasound
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The role of the β-adrenergic system in heart failure has been intensively studied in recent decades. A large number of clinical and experimental studies have documented detrimental effect of chronically elevated stimulation of the cardiac β-adrenergic system [1,2]. However, there are controversial findings which suggest the functional enhancement by elevation of β-adrenergic signaling and its potential use in heart failure gene therapy [3–12].
Information has been generated recently from transgenic (TG) lines with cardiac specific expression, by the use of 
-myosin heavy chain promoter, of β1- and β2-adrenergic receptors (AR) [5,13] and down-stream signaling proteins such as Gs [14,15], subtypes of adenylyl cyclase [7–9] and a peptide inhibitor for βAR kinase [4]. Mice that express 15-fold β1AR developed, at 2 months of age, fibrosis, dropout of myocytes, myocardial hypertrophy and functional decline [13]. Similar changes have been observed in mice expressing stimulatory G-proteins (Gs) but at about 15 months of age [14,15]. A very recent study by Liggett et al. has demonstrated the development of cardiomyopathy and heart failure in TG lines with 150- and 350-fold increase in β2AR but not the line with 60-fold expression [16]. These findings strongly indicate that chronic and uncontrolled activation of the cardiac β-adrenergic system is deleterious.
Milano et al. developed a TG line (TG4) with approximately 200-fold increase in cardiac β2AR [5]. Recent studies on these mice at 12 months of age showed minor morphological abnormalities in the ventricular myocardium with maintained supernormal ventricular contractility [17]. However, prospective study is required to explore the potential age-dependency in the development of cardiac phenotype in the TG4 mice. We have studied TG4 and wild-type mice from 4 to 15 months of age by monitoring cardiac function using echocardiography. The results from this prospective study showed that TG4 developed severe cardiomyopathy, ventricular dysfunction and a poor survival during 8.5–15 months of age. These findings were very similar to the recent paper by Liggett et al. that appeared when we were finalizing this article [16].
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Animals, transgene screening and β2-AR binding
Parent TG4 mice were generated at the Howard Hughes Medical Institute, Duke University Medical Center [5] and bred at the Baker Institute. The tail biopsy of offspring was screened by Southern blot hybridization to detect expression of the transgene using a 32P-labeled Hinc II fragment of the transgene construct [5]. Both male and female mice of 4 months old were studied for 11 months and animals were inspected at least twice daily. A local animal experimentation and ethics committee approved experimental procedures.
β2AR density in the left ventricle (LV) was measured in a separate group of TG and wild-type mice (4 months old, n = 6 each) from the same batch as used for echocardiographic study. The binding assay was done by incubating myocardial membrane proteins with 100 pmol/l [125I]-(–) iodocyanopindalol (125I-CYP, NEN, 2200 Ci/mmol) for 1 h in the presence of ICI 118,551 (Sigma) at 10–11–10–5 mol/l. Saturation curves were generated to determine the affinity of receptors for 125I-CYP at 12 to 400 pmol/l. Non-specific binding was determined by the presence of L-isoproterenol at 20 µmol/l. β2AR density was 300-fold higher in TG than in wild-type hearts (1506±274 vs. 5±2 fmol/mg protein).
2.2 Echocardiography
Transthoracic echocardiography was performed using a Hewlett–Packard Sonos 5500 ultrasound machine with a 12 MHz transducer (0.5–0.7 cm standoff), as described previously [18]. Mice were anesthetized (mixture 6 mg/100 g ketamine, 1.2 mg/100 g xylazine, 0.06 mg/100 g atropine) and placed on a heating pad. A standard lead II electrocardiogram (ECG) was routinely recorded for a few seconds. After a short axis two-dimensional (2 D) image of the LV was obtained at a level close to the papillary muscles, a 2-D guided M-mode trace crossing the anterior and posterior wall was recorded at sweep speed of 100 mm/s. The following parameters were measured on the M-mode tracings using the leading-edge technique: LV internal dimensions of diastole and systole (LVIDd, LVIDs), LV external dimension of diastole (LVEDd) and wall thickness at diastole and systole. Fractional shortening (FS%) was calculated as (LVIDd–LVIDs)/LVIDd. Wall-thickening index (WTI%) was the net increase in LV wall thickness in systole vs. diastole. Measurements were taken from two cardiac cycles and the averages were used. The reproducibility of this method has been documented previously [18].
2.3 Morphological examination
Animals were examined either after being found dead or after being killed at the end of the 15-month study period. Under a surgical microscope, the chest was opened via the diaphragm to determine whether pleural effusion in the chest was present before isolation of the heart. Hearts were weighed after removal of blood clots. The presence of organic thrombi in the left atrium was determined by their yellowish color and tight adhesion to the atrial wall [19]. When an atrial thrombus was present, the weight of thrombus was subtracted from heart weight. The lungs and liver were weighed and the tibia length was measured. Hearts were then fixed in 10% formalin in PBS for sectioning.
2.4 Histological examination
Hearts of TG and wild-type mice were embedded in paraffin and serially cut from the apex to the base. A 5-µm transverse section was collected every 0.8 mm with six–seven sections obtained from each heart. One set of sections was stained with hematoxylin and eosin and another set with 0.1% picrosirius red for determining collagen content and myocyte cross-sectional area. Images of LV sections were gathered with a CCD video camera (Optimas, BioScan, Edmonds, WA, USA), digitized and quantified with polarized light using OPTIMAS 6.5 program. Interstitial collagen content in the LV was determined following the method described previously [19]. The sections were sampled in a systematic fashion and ten fields in each LV were analyzed. Fields containing blood vessels, epicardial layer or artifacts were replaced by an adjacent field [19]. The area stained was calculated as a percentage of the total area within a field and presented as averaged percentage per field. One section collected at the ventricular equator and stained with picrosirus red was used for measuring myocyte transverse cross-sectional area. Five–seven fields were randomly chosen and eight–ten cells per field were measured and the average of 40–70 cells was used.
2.5 Statistics
Results are expressed as mean±S.E.M or as percentages. For parametric data, between-group comparison was made using unpaired Student t-test. Chi-squire test or Fisher's exact test was used to compare percentages between groups. P<0.05 was considered significant.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Survival and body weight
In wild-type group (n = 26), one mouse died at 9 months and all others survived till 15 months of age. In the TG group (n = 26), however, loss of animals started at 8.5 months with a cumulative mortality of 62% by 12 months and 81% by 15 months (both P<0.001 vs. wild-type, Fig. 1). There was no gender-related difference in the mortality. The body weight was similar between wild-type and TG groups during 4 to 9 months of age indicating that β2AR overexpression does not affect the body weight gain (Table 1). However, TG mice that were either found dead or killed at 15 months of age had lower body weight compared to wild-type mice at 15 months of age.
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3.2 Echocardiographic changes
In the wild-type group, all echo parameters were stable during 6 to 15 months of age. Heart rate remained higher in TG than in wild-type mice during the 11-month study period (Fig. 2). There was no significant difference between the two groups in any of the echo parameters measured at 4 and 6 months of age. In TG mice, starting at 9 months, a progressive LV dilatation occurred as indicated by increases in internal and external LV dimensions of diastole (Fig. 2). This remodeling of LV was accompanied by a significant reduction in FS. WTI of both anterior and posterior walls was significantly lower compared to wild-type group at 12–15 months (Fig. 2), suggesting weakened muscle contraction. The LV mass was increased in TG than wild-type mice indicating LV hypertrophy. Despite the continuous loss of TG mice during the study period, the progressive worsening in all these changes observed by echocardiography was evident (Fig. 2).
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wild-type, 
transgenic.3.3 ECG abnormalities
Except markedly increased HR, we observed that TG mice had altered configuration of standard lead II ECG waves and development of ectopic beats. The majority of TG mice had suppressed S-T segment and a large ‘Q’ wave (Fig. 3A). Although ECG was recorded only for a few seconds at each echo test, episodes of ectopic beats were recorded in eight TG mice. Ectopic beats mainly occurred as singles but occasionally appeared as salvos and appeared from the ventricle in origin (Fig. 3B).
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3.4 Morphometry
The initial body weights were similar between TG and wild-type groups. At the end of the 15-month period, wild-type mice had a 30% increase in body weight whereas TG mice had no gain in body weight (Table 1). Organ weights and incidence of pathological events were compared between wild-type mice killed at 15 months of age and TG mice that either died during the study (8–14.5 months, n = 21) or were killed at 15 months (n = 5). TG mice had greater wet weights of heart and lungs (Table 1), higher incidences of pleural effusion (0.2–0.8 ml in volume) and chronic thrombus (15–90 mg in weight) in the left atrium (Fig. 4A, Table 1). In contrast, none of the wild-type mice had atrial thrombus and only one mouse had pleural effusion.
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The reason for death of TG mice was estimated by findings at autopsy and the most recent echo test. Deaths were assigned to heart failure when all the following were observed: LV dilatation, FS below the lower-limit in wild-type mice (27%), increase in heart weight, pleural effusion, increase in lung weight (above the upper limit of 217 mg in wild-type mice) and no gain in body weight. By these criteria, 17/21 TG mice died of HF. The other four mice that did not fall into this category probably died of fatal arrhythmias. In the five TG mice killed at 15 months of age, four satisfied the heart failure criteria.
3.5 Histological features
The major histological abnormalities in the heart of TG mice were dropout of myocytes, hypertrophy of remaining myocytes and widespread interstitial fibrosis (Fig. 4B–D). Death of cardiac myocytes was indicated by the absence of myocytes in large fibrotic areas. The average transverse cross-sectional area of remaining myocytes was three times greater in TG than in wild-type mice (Table 1). In some areas of the LV, myocyte cross-sectional area was measured at 2000–2500 µm2. Polymorphism of nuclei of myocytes was frequently observed (Fig. 4C, right panel). Interstitial fibrosis was mostly severe in LV free wall, the apex, the atrio-ventricular junction and perivascular regions (Fig. 4B–D). In some cases, certain regions of LV wall were largely replaced by scar tissues (Fig. 4C, left panel). There was an eight-fold increase in collagen content in LVs of TG compared with wild-type mice (P<0.001, Table 1). Lungs from TG mice were congested with thickening of alveolar walls and increase in cellular components (Fig. 4E).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The TG4 strain with a few hundred-fold increase in β2AR density is characterized by markedly increased ventricular contractility and heart rate [5,19]. The long-term impact of β2AR overexpression on cardiac phenotype has not been reported until recently [16,17]. In the present study, we observed a poor survival in the TG mice between 8.5 to 15 months of age with a total mortality of 81%. The presence of congestive left heart failure in these TG mice was indicated by LV dilatation, decline in ventricular contraction, increase in LV mass, pulmonary congestion, pleural effusion and atrial thrombus. The onset of cardiac dysfunction and mortality occurred at around 9 months, indicating the importance of age in determining cardiac phenotype in this TG model. Furthermore, loss of myocytes, myocardial hypertrophy and widespread interstitial fibrosis were notable in almost all TG hearts. Thus, our results showed that TG4 mice had a phenotype of cardiomyopathy and heart failure that developed with aging. These findings are also similar to that by Liggett et al. who reported cardiomyopathy in TG lines that express β2AR at 150- and 350-fold [16]. Importantly their study demonstrated that the extent of deleterious effect of β2AR activation is the factor of expression levels.
Koch et al. reported very recently that TG4 mice of 12–14 months of age had only slight fibrosis and collagen replacement in areas of hearts affecting no more than 
10% of total myocardium, and that TG mice have significantly higher level of LV dP/dtmax than wild-type controls [17]. The reasons for the different findings at the two locations in regard to morphological and functional alterations in the old TG4 mice are not clear but may be due to differences in the experimental design and the parameters examined. The prospective design, as described in this article, would be more appropriate to address the question on the chronic effect of β2AR overexpression. Whilst previous studies on TG4 line have consistently shown an enhanced LV contractility based on dP/dtmax, other and the present studies did not find a increased FS in TG4 mice at young age [20,21]. In TG strains with cardiac expression of adenylyl cyclase, FS was unchanged although LV dP/dtmax was markedly enhanced [7–9]. However, Liggett et al. reported an increased FS in three β2AR TG lines at 15 weeks of age, but not in the mice with 350-fold increase in β2AR [16].
TG strains with cardiac specific expression of β1AR, β2AR and Gs have, at younger age, the common phenotype of an enhanced ventricular contractility at baseline and during β-agonist stimulation [4,5,14,16]. These strains all developed interstitial fibrosis, dropout of myocytes, myocardial hypertrophy, ventricular remodeling, heart failure and immature death [13–16]. Thus the cardiomyopathic phenotype appears to be similar, except that cardiac damage occurs much earlier in the mice that express 15-fold β1AR or 350-fold β2AR [13,16]. Compared with β1AR TG mice [13], the cardiomyopathy in TG4 mice requires overexpression over 15-fold higher levels and occurs much later. Further, β2AR expression at lower levels might actually provide inotropic support to the heart with minimal adverse consequence. This has been suggested by the beneficial effect of a 30-fold β2AR expression in mice with a genetic cardiomyopathy [6] and by the lack of major cardiac abnormalities in the 12-month old mice with 60-fold rise in β2AR [16]. These differences in the cardiac phenotypes seen in the TG lines indicate that the chronic impact of cardiac overexpression of β1AR and β2AR are not entirely the same. Both receptors activate adenylyl cyclase via stimulation of Gs, but stimulation of β2AR induces localized and cAMP- independent activation of protein kinase A [22]. Further, β2AR, but not β1AR, couples to inhibitory G-protein, Gi, and activation of Gi can antagonize Gs-mediated signaling [22].
The precise mechanism responsible for the cardiomyopathy in β2AR TG mice is not clear but is likely due to long-term unrestrained β-adrenergic overdrive to the heart. βAR stimulation may activate certain growth factors or transcriptional factors [23,24] and cross-talk with other signaling pathways [25,26], thereby facilitating interstitial fibrosis and myocardial hypertrophy. The apparent loss of cardiac myocytes in TG mice suggests an important role of cell death, either by necrosis or apoptosis, in the development of cardiomyopathy and heart failure. Recent studies have shown that β1AR stimulation or Gs expression facilitates, but β2AR activation inhibits, myocyte apoptosis [27,28]. It is known that β2AR TG mice have enhanced susceptibility to myocardial ischemia [29], most likely due to markedly increased myocardial contractility and heart rate thereby increasing energy consumption. A high heart rate will also limit the energy supply by shortening the diastolic period. Occurrence of arrhythmias can be attributable to the presence of documented arrhythmogenic substrates, such as interstitial fibrosis, myocardial hypertrophy, tachycardia and probably β-adrenergic activation.
In conclusion, the present study demonstrates that mice with transgenic overexpression of β2AR at a high level develop cardiac morphological and functional abnormalities. Most experiments on gene-targeted mice are conducted in young adults. However, several recent studies on TG mice targeting on β-adrenergic signaling pathway have confirmed the importance of studying the TG lines with age [2,14–16]. Our findings indicate the necessity in determination of cardiac phenotype by examining genetically engineered animals over a wide age scope.
Time for primary review 31 days.
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Acknowledgements |
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This work was supported by an institute block grant from Australia National Health and Medical Research Council. X.M. Gao is a recipient of a scholarship from ACIS Heart Foundation via Professor Y.L. Lim, Director of ACIS Heart Foundation and National Heart Centre of Singapore. We are grateful to Dr R.J. Lefkowitz, Duke University Medical Center, for providing the transgenic line. We thank the technical help from Elodie Percy and the staff at the Biological Research Unit, Baker Institute.
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