© 2008 European Society of Cardiology
Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats
a Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine Suita, Japan
b Genome Information Research Center, Osaka University Suita, Japan
c Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine Nishinomiya, Japan
d Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama Toyama, Japan
e The Center for Advanced Medical Engineering and Informatics, Osaka University Suita, Japan
* Corresponding author. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan. Tel.: +81 6 6879 6612; fax: +81 6 6879 6613. E-mail address: kazuhiro{at}medone.med.osaka-u.ac.jp (K. Yamamoto).
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Background: β-blocker therapy is an established therapeutic strategy for systolic heart failure. However, its benefits in diastolic heart failure (DHF) are controversial.
Aims: This study was designed to investigate the effects of bisoprolol on DHF.
Methods and results: Dahl salt-sensitive rats fed on 8% NaCl diet from age 6weeks, DHF model rats, were divided into three groups at age 13 weeks. One group was treated with bisoprolol 12.5 mg/kg/day (Low dose group, n=18), one group was treated with bisoprolol 250 mg/kg/day (High dose group, n=18), and there was also an untreated group (Untreated group, n=18). The survival rate was best in the High dose group. Left ventricular hypertrophy and the expression of proinflammatory cytokines in the myocardium were significantly attenuated in the High dose group, but not in the Low dose group, and oxidative stress was most suppressed in the High dose group. Measurement with electron spin resonance revealed that bisoprolol had a potent scavenging ability, and bisoprolol attenuated the down-regulation of peroxisome proliferation-activated receptor coactivator-1
, an important element in the mitochondrial reactive oxygen species detoxification system.
Conclusion: β-blocker administration, particularly at high dose, improved the survival rate of the DHF model, at least partly through the attenuation of inflammatory changes and oxidative stress.
Key Words: Diastole • Heart failure • β-blocker • Inflammation • Oxidative stress
Received August 29, 2007; Revised December 24, 2007; Accepted March 4, 2008
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Left ventricular (LV) ejection fraction is preserved or only minimally depressed in 40% of patients with heart failure [1]. Hypertension is a major underlying cardiovascular disease, and diastolic dysfunction is one of the principal causes of this phenotype of heart failure [2]. Diastolic heart failure (DHF) is pathophysiologically distinct from systolic heart failure (SHF) [3]. Over the past two decades, the number of DHF patients has increased but there has been no improvement in prognosis [4], because a therapeutic strategy has not been established.
β-blocker therapy improves the prognosis of SHF [5-7], by inducing reverse remodelling and improvement in LV ejection fraction. However, these effects are unlikely to be beneficial in DHF where there is no LV dilatation or reduced ejection fraction; previous clinical studies have not produced conclusive findings about the effects of β-blocker therapy in DHF [8,9].
The current study was designed to examine the therapeutic effects of the β-blocker, bisoprolol, in hypertensive DHF model rats [10]. The effects of bisoprolol on inflammatory changes and oxidative stress in cardiac tissues which play crucial roles in the development of DHF [11,12] were also assessed.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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This study consisted of two protocols, and different rats were used in each protocol. The study schedule was determined based on our previous studies [10,13].
Male Dahl salt-sensitive rats (SLC Japan, Shizuoka, Japan) fed on 8% NaCl from age 6 weeks served as the hypertensive DHF model [10,13]. We have previously demonstrated that this model shows signs of overt heart failure, such as tachypnoea, laboured respiration and loss of activity with elevated LV end-diastolic pressure and pulmonary congestion around age 19 weeks [10]. LV myocardial stiffness constant is increased at this age, but there are no changes in LV dimension or midwall fractional shortening [14]. This model has been used as a DHF model by our group and by others [13-17].
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and with the guiding principles of Osaka University Graduate School of Medicine with regard to animal care.
2.1. Protocol 1: survival study
To evaluate the effects of bisoprolol (Tanabe Co. Ltd, Osaka, Japan) on survival rate, 54 rats were randomly assigned at age 13 weeks, a compensatory hypertrophic stage, into three groups. One group was treated with bisoprolol 12.5 mg/kg/day (Low dose group, n=18), one group was treated with bisoprolol 250 mg/kg/day (High dose group, n=18), and there was also an untreated group (Untreated group, n=18). For each dose, bisoprolol was dissolved in drinking water on the basis of preliminary data about the volume of daily water consumption in each group, water was provided ad libitum throughout the experiment. Deaths were recorded daily and systolic blood pressure was measured at age 6, 10, 13, 16, 18, and 20 weeks with a tail cuff system (BP-98A, Softrin, Tokyo, Japan).
2.2. Protocol 2: echocardiographic and pathophysiological studies
2.2.1. Experimental procedure
In this second protocol, 41 DHF model rats were arbitrarily divided at age 13 weeks into Low dose group (n=12), High dose group (n=11), and Untreated group (n=18). Ten male Dahl salt-sensitive rats continuously fed on 0.3% NaCl diet served as a Control group.
At age 19 weeks, the rats were anesthetized with ketamine HCl (50 mg/kg) and xylazine HCl (10 mg/kg), and echocardiographic and LV pressure recordings were obtained to determine LV geometry, LV midwall fractional shortening, LV filling time, LV end-diastolic pressure, dP/dt, time constant of LV relaxation and myocardial stiffness constant as previously described [11]. LV filling time was evaluated as the duration from the onset of early diastolic filling wave to the end of diastolic filling wave at atrial contraction on pulsed Doppler transmitral flow velocity curves. The values of peak +dP/dt and peak –dP/dt were corrected for instantaneous LV pressure to avoid the overestimation of LV contractility and relaxation. Following the haemodynamic study and adequate anesthesia, the lung and the heart were rapidly harvested and weighed. The tibial length was measured to correct the LV and lung weight. For the measurement of mRNA levels and NADPH oxidase activity, the LV myocardium was immediately placed in liquid nitrogen and stored at –80 °C. Samples for immunohistochemistry were embedded in Tissue-Tek O.C.T. compound (Sakura Finetechnical Co., Tokyo, Japan) and frozen on dry ice. The remainder of the left ventricle was fixed with a phosphate-buffered 10% formalin solution for 48 h, and 2-
m thick transverse sections were stained with Azan Mallory stain to determine the percent area of fibrosis as previously described [10]. Briefly, myocardial cells were stained red and areas of interstitial fibrosis were stained blue. The number of pixels for myocardial cells and interstitial fibrosis was determined from a histogram on Scion image (Scion Co., Maryland, USA). The area of fibrosis was determined as follows:
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2.2.2. Quantitative real-time RT-PCR
The cardiac gene expression for interleukin-1β (IL-1β), transforming growth factor (TGF)-β1, monocyte chemoattractant protein-1 (MCP-1), peroxisome proliferation-activated receptor coactivator-1 (PGC-1) and GAPDH was assessed by real-time TaqMan reverse transcription-polymerase chain reaction (RT-PCR). The sequences of oligonucleotides used as forward primers, reverse primers and TaqMan probes for IL-1β, TGF- β1, MCP-1 and GAPDH have been reported previously [11,18,19]. Primers and TaqMan probes for PGC-1 (assay ID Rn00580241_m1), which play important roles in the mitochondrial reactive oxygen species (ROS) detoxification system [20,21], were assays-on-demand gene expression products (Applied Biosystems, Foster City, CA). To correct the efficacy of cDNA synthesis, the expression level of the target gene was normalized by the GAPDH level in each sample.
2.2.3. Immunohistochemistry
Cryostat transverse sections were stained using mouse monoclonal anti-4-hydroxy-2-nonenal (HNE) antibody (1:50 dilution, NOF Medical Department, Tokyo, Japan) as previously described [11].
2.2.4. Assessment of cardiac NADPH oxidase activity by lucigenin chemiluminescence
NADPH oxidase activity in LV myocardium was determined by lucigenin-enhanced chemiluminescence as previously described [12].
2.2.5. Electron spin resonance (ESR) measurement
The free radical scavenging ability of bisoprolol was estimated from the reduction of electron spin resonance (ESR) signal intensity of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)-OH adducts which was induced by X-irradiation as previously described [22]. Briefly, aqueous DMPO solutions (10 mM) saturated with air containing various concentrations of bisoprolol were exposed to X-rays (150 Gy). The ESR spectra of X-irradiated samples were measured with an ESR spectrometer (RFR-30 Radical Analyzer System, Radical Research, Tokyo, Japan). The concentration at which the DMPO-OH adducts yield was decreased by 50% of the maximum yield was defined as C1/2 value. A comparison of C1/2 value and a rate constant for reactions of OH radicals was performed based on our previously reported data [22].
2.3. Statistical analysis
Results are expressed as mean±SD. Data were analyzed using statistical software (STATVIEW version 5.0, SAS Institute Inc.). Differences between groups were assessed using one-way ANOVA followed by Fisher's protected least significant difference test. Survival was depicted graphically using Kaplan-Meier survival curves and compared using log-rank test. A value of p<0.05 was considered statistically significant.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. Protocol 1: survival study
The survival rate was improved by the administration of bisoprolol and was better in the High dose group than in the Low dose group (Fig. 1). Although blood pressure significantly decreased in the bisoprolol-treated groups compared to the Untreated group (Fig. 2), there was no significant diference between the treated groups. Heart rate decreased with the increase in the dose of bisoprolol in the treated groups (Fig. 2).
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p<0.05 vs. Untreated group. 
p<0.05 vs. Low dose group.3.2. Protocol 2: echocardiographic and pathophysiological studies
In the Untreated group, 5 of 18 rats died before age 19 weeks with a significant increase in the ratio of lung weight to tibial length (64±19 mg/mm). No rats died before age 19 weeks in the other groups.
The ratio of lung weight to tibial length at age 19 weeks was above the mean+2SD of the Control group in 7 rats of the Untreated group, 4 rats of the Low dose group and 3 rats of the High dose group, indicating the presence of pulmonary congestion. We excluded these rats from the data analysis because some of the findings derived from these rats may result from, rather than be responsible for, the haemodynamic deterioration. Therefore, data from 6 rats in the Untreated group, 8 rats in the Low dose group, 8 rats in the High dose group and 10 rats in the Control group were analyzed.
3.2.1. Effects of bisoprolol on LV geometry, structure and function
All echocardiographic and haemodynamic data at age 19 weeks are summarized in Table 1. The Untreated group had higher systolic blood pressure, LV posterior thickness, ratio of LV mass to tibial length, area of fibrosis, LV end-diastolic pressure, and myocardial stiffness constant than the Control group, but there was no difference in LV midwall fractional shortening or LV end-diastolic dimension between the two groups. The ratio of lung weight to tibial length was slightly, but significantly higher in the Untreated group than in the Control group.
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The ratio of lung weight to tibial length and LV end-diastolic pressure were not different among the bisoprolol-treated and Untreated groups. Systolic blood pressure and heart rate decreased and LV filling time was prolonged in the Low and High dose groups compared to the Untreated group. Systolic blood pressure was not different between the bisoprolol-treated groups. Heart rate was significantly lower in the High dose group than in the Low dose group, but LV filling time was not significantly different. The ratio of LV mass to tibial length and LV posterior wall thickness at end-diastole were not different between the Low dose and Untreated groups, however they were both significantly decreased in the High dose group. Area of fibrosis and myocardial stiffness constant significantly decreased in the Low and High dose groups compared to the Untreated group, but there was no significant difference between the bisoprolol-treated groups. The time constant of LV relaxation and peak –dP/dt/LV pressure were not affected by the administration of bisoprolol at low dose, but the high dose prolonged the time constant and decreased peak –dP/dt/LV pressure. LV midwall fractional shortening and end-diastolic dimension were not different between the Untreated, Low dose and High dose groups.
3.2.2. Effects of bisoprolol on cardiac cytokine generation
In the untreated rats, gene expression of IL-1β, TGF-β1 and MCP-1 was significantly enhanced as compared with the control rats (Fig. 3). The administration of low-dose bisoprolol did not change the mRNA levels of IL-1β and TGF-β1, but the high-dose administration significantly lowered their gene expression. The treatment with bisoprolol did not affect MCP-1 mRNA level.
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3.2.3. Effects of bisoprolol on ROS and the related systems
Immunohistochemical stains of HNE in the LV myocardium revealed an increase in ROS production in the untreated rats (Fig. 4), and an increase in NADPH oxidase activity was associated (Fig. 5). The administration of bisoprolol attenuated the HNE staining with the increase in the dose (Fig. 4), but did not significantly affect NADPH oxidase activity (Fig. 5).
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The mRNA level of PGC-1
, which has a protective role against the mitochondrial production of oxidative stress [20,21], was significantly decreased in the Untreated group compared to the Control group (Fig. 3). The administration of high-dose, but not low-dose, bisoprolol significantly attenuated the down-regulation of PGC-1. To assess the scavenging ability of bisoprolol itself, the C1/2 value was measured using ESR. The C1/2 value of bisoprolol was 2.52±0.37x10–3 mol/L and an estimated rate constant for reactions of OH radicals was 3.5x109 L/mol/s (Fig. 6). The values were similar to those of sodium formate, indicating that bisoprolol has a potent activity to scavenge radiation-induced OH radicals.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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β-blocker therapy induces LV reverse remodelling and improves LV ejection fraction in SHF, resulting in prognostic improvement [23]. However, DHF is not associated with LV dilatation or depressed ejection fraction, and therefore these effects of β-blockers in SHF are not expected to provide benefits in DHF. Although SHF is associated with the down-regulation of β1-adrenergic receptor and the translocation of G protein-coupled receptor kinase 2 to the plasma membrane in the heart [24,25], these phenomena were not observed in the DHF model rats (data not shown). Thus, pathophysiological characteristics are distinctly different between SHF and DHF, and it remains unclear whether β-blocker therapy is effective in DHF.
We have shown that the long-term administration of bisoprolol improved the survival rate in the hypertensive DHF model rats. Kobayashi et al. previously reported that the β-blocker, metoprolol, improved survival in the same DHF model [16], our results expand the findings of this previous study by demonstrating that a high dose of bisoprolol is more effective in DHF than a low dose, this dose related effect has been shown previously in SHF patients [26]. The administration of bisoprolol significantly decreased systolic blood pressure, but systolic blood pressure was not significantly different between the bisoprolol-treated groups (Table 1). Thus, the anti-hypertensive effects cannot explain the different survival rates between the Low and High dose groups.
The High dose group showed significant decreases in the IL-1β and TGF-β1 mRNA levels compared to the Untreated group (Fig. 3). HNE immunohistochemical staining revealed that the administration of bisoprolol, particularly at high dose, attenuated oxidative stress (Fig. 4). These data indicate that bisoprolol possesses anti-inflammatory and anti-oxidative effects.
Oxidative stress and inflammatory changes contribute to the development of ventricular hypertrophy [11,27-29], and LV hypertrophy has prognostic impact. The significant decrease in the ratio of LV mass to tibial length in the High dose group, but not in the Low dose group, may be at least partly attributed to the greater attenuation of oxidative stress and inflammatory changes, and may have contributed to the better survival rate.
Oxidative stress and inflammatory changes promote ventricular fibrosis as well as hypertrophy [30,31], and ventricular fibrosis also plays a crucial role in the development of DHF through myocardial stiffening [14,32]. However, there was no significant difference in the area of fibrosis or myocardial stiffness constant between the bisoprolol-treated groups. This may be partly explained by the fact that the data in Protocol 2 were collected when the rats were at the pre-heart failure stage. Our additional experiment showed that the type I collagen mRNA level in the LV tissue was decreased by 40% at this stage in the High dose group compared to the Low dose group. If the data were collected at a more advanced stage, the attenuation of ventricular fibrosis and myocardial stiffening might be different between the bisoprolol-treated groups.
The activation of NADPH oxidase may be at least partly responsible for the enhancement of oxidative stress in the untreated rats. However, the attenuation of oxidative stress in the bisoprolol-treated rats was not associated with the decrease in NADPH oxidase activity (Fig. 5). The current study suggests two mechanisms for the anti-oxidative effects of bisoprolol. First, the C1/2 value of bisoprolol was low compared to mannitol and was similar to that of sodium formate. This result indicates that bisoprolol itself has a potent OH radical scavenging ability independent of bisoprolol-induced heart rate reduction or intracellular anti-oxidation mechanism. Second, the untreated rats had a down-regulation of PGC-1 in the heart, which plays an important role in the mitochondrial ROS detoxification system [20,21], the administration of bisoprolol at high dose attenuated this down-regulation. This may also explain the anti-oxidative effects of bisoprolol and the better survival in the High dose group.
The bisoprolol-induced reduction of heart rate prolonged LV filling time compared to the Untreated group. This prolongation of diastolic filling time may well exert beneficial effects in DHF; however, LV filling time was not significantly different between the High and Low dose groups. Yamamoto et al. demonstrated that tachycardia itself enhanced cardiac oxidative stress through activation of NADPH oxidase [31]; however, the bisoprolol-induced reduction of heart rate was not associated with changes in NADPH oxidase activity. The CIBIS II trial demonstrated that for a given heart rate reduction, bisoprolol treatment further reduced mortality to a similar extent in SHF patients whatever the amplitude of heart rate reduction [33]. Mulder et al. showed that heart rate reduction by the selective If-current inhibitor, ivabradine, did not improve diastolic function in rats with myocardial infarction [34]. Ciobotaru et al. recently demonstrated that heart rate reduction with ivabradine increased LV filling pressure and promoted LV hypertrophy and fibrosis in rats with pressure overload [35]. These results suggest that the prolongation of filling time or the reduction of heart rate cannot completely explain the superior survival rate of the High dose group, although the effects of heart rate reduction in DHF should be investigated in future studies.
4.1. Study limitations
There are several limitations in this study. First, the administered doses of bisoprolol were much higher than those in clinical usage, and we did not investigate the effects of lower doses. This is because the bioavailability of the β-blocker is much lower in rats than in humans [36]. The 20-fold increase in the dose of bisoprolol further reduced heart rate, but did not provide additive depressor effects in this study. We previously observed a lack of dose-dependent depressor effects during treatment with angiotensin II and endothelin receptor blockers in the same rat model [19]. Thus, the findings in this study should be confirmed in future clinical studies.
Second, the improved survival rate in the High dose group was associated with an exacerbation of LV relaxation. We previously reported a limited contribution of abnormal LV relaxation to the development of DHF [14], the current findings indicate that such negative lucitropic effects can be overcome by the benefits of bisoprolol.
Third, we did not conduct the post-mortem measurement of lung weight in Protocol 1 (survival study), and the cause of death was not identified. In Protocol 2, we confirmed that 5 of 18 untreated rats died with a significant increase in the ratio of lung weight to tibial length before age 19 weeks. In another 7 of the 18 untreated rats, the ratio was increased at age 19 weeks. Thus, the bisoprolol-induced improvement in the survival may be attributed to the prevention of DHF.
Finally, evaluation of blood markers of inflammation or oxidative stress may have helped in understanding the effects of bisoprolol; however, these data were not available in this study.
4.2. Conclusions
The survival rate of the hypertensive DHF model rats was improved by the long-term administration of bisoprolol, particularly at high dose, and the beneficial effects were provided, at least partly, through the attenuation of inflammatory changes and oxidative stress. The anti-oxidative effects of bisoprolol were likely due to its potent scavenging ability and inhibition of the down-regulation of PGC-1. These results suggest that β-blocker therapy is effective in the treatment of DHF, and future clinical trials are awaited to address this issue.
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Acknowledgements |
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This study was supported by grants from the Japan Society for the Promotion of Science, the Ministry of Health, Labour and Welfare, Japan, and Osaka University Graduate School of Medicine. The authors are grateful to Ms. Saori Nanbu for the excellent technical assistance of the experiment.
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