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CARDIOVASCULAR
Institut National de la Santé et de la Recherche Médicale U698, Groupe Hospitalier Bichat-Claude Bernard, Paris, France (V.C., M.H., L.L., J.-B.M., J.-J.M., D.L.); Institut National de la Santé et de la Recherche Médicale U689, Hôpital Lariboisière, Paris, France (C.H.); Institut National de la Santé et de la Recherche Médicale U769, Chatenay-Malabry, France (R.V.-C.); Pathology Department, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8149, Assistance Publique-Hôpitaux de Paris, Beaujon Hospital, Clichy, France (P.B.); Institut Nationale de la Sante et de la Recherche Médicale U772, Groupe Hospitalier Bichat-Claude Bernard, Paris, France (B.E.); Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Bichat-Claude Bernard, Service de Physiologie-Explorations Fonctionnelles, Paris, France (B.E., J.-J.M.); and Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Cardiology Department, Paris, France (D.L.)
Received August 15, 2007; accepted September 26, 2007.
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Abstract |
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). The precise role of the heart rate in the pathophysiology of chronic heart failure is poorly understood, but heart rate reduction (HRR) is considered a specific therapeutic target in patients with heart failure (Laperche et al., 1999). Indeed, HRR increases the duration of both left ventricular (LV) filling and diastolic coronary perfusion, which are altered in heart failure. HRR also reduces myocardial O2 consumption. However, the effects of long-term HRR on chronic heart failure are largely unknown. In patients with heart failure and cardiac pacing, reversal of β-blocker-induced bradycardia worsened ventricular function (Thackray et al., 2006). Clinical trials of β-blockers in chronic heart failure do not allow to conclude definitely regarding the intrinsic effect of the associated HRR (Lechat et al., 2001; Gullestad et al., 2005). Indeed, β-blockers have additional properties, including inhibition of catecholamine-induced myocardial toxicity and decreased renin secretion, and they are likely to favorably influence cardiac remodeling.
The class of pure heart rate-lowering agents—inhibitors of the cardiac pacemaker If current—provides an opportunity to study the direct effects of HRR in heart failure. Ivabradine is a selective If current inhibitor that induces HRR in a dose-dependent manner, with no direct hemodynamic effects (Simon et al., 1995; Vilaine, 2006). In a rat model of myocardial infarction, ivabradine was beneficial by improving LV systolic function, reducing collagen density in the noninfarcted myocardium, and improving myocardial perfusion and the coronary reserve (Mulder et al., 2004; Dedkov et al., 2007).
The effect of pure HRR on pressure overload-induced heart failure, a clinically relevant situation, has not been investigated. Accordingly, the aim of our study was to examine the effects of ivabradine-induced pure HRR in a rat model of pressure overload-induced heart failure to assess the impact of long-term pure HRR itself on LV remodeling and function.
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Materials and Methods |
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). Ninety-two rats survived surgery, and they were included in the study. The control group included 16 sham-operated rats. The animals were given free access to standard powder rodent chow (A04-C10; UAR, Epinay-sur-Orge, France) and tap water ad libitum.
Two weeks after surgery, the rats were randomized to receive ivabradine (n = 44) or no treatment (n = 36) for the following 3 months. Ivabradine was mixed with the diet to obtain a dose of approximately 10 mg/kg/day and a 15 to 20% HRR as described by Mulder et al. (2004). The dose was adjusted weekly on the basis of body weight and food intake. The amount of ivabradine in the diet was controlled monthly.
Electrocardiographic Monitoring. Two months after aortic banding, 24 conscious rats (12 rats receiving ivabradine and 12 controls) underwent a 12-h continuous-lead II electrocardiographic recording to assess the heart rate. Under light isoflurane anesthesia, the rats were implanted with a transmitter and electrodes (TA 10ETA-F20; Data Sciences International, Warwick, RI) placed under the abdominal skin. The animals were housed individually and given the same treatment regimen described above. The ECG signal was recorded during the dark period of the standardized light/dark cycle and stored for off-line analysis (PowerLab/16SP; ADInstruments Pty Ltd. (Castle Hill, Australia). The mean heart rate was calculated, and ventricular arrhythmias were identified and quantified manually.
Echocardiographic Studies. Rats underwent echocardiography under isoflurane anesthesia (1.0–1.5% in oxygen), just before and then after 30 and 90 days of ivabradine treatment, using a PowerVision 6000, SSA 370A apparatus (Toshiba, Tokyo, Japan) equipped with a phase array 7.5-MHz transducer. The left ventricle was imaged as described previously (Prunier et al., 2002; Chen et al., 2004). Data were transferred to a computer (Ultrasound Image Workstation-300A; Toshiba) for off-line analysis. The following parameters were measured or calculated: left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter; thickness of the interventricular septum and posterior wall; LV shortening fraction [(LVEDD–left ventricular end-systolic diameter)/LVEDD]; stroke volume (SV) as aortic velocity-time integral x [
x (diameter of LV outflow)2/4]; LV ejection fraction (SV/LVEDD3); cardiac output (SV x heart rate); and peak velocity of early diastolic mitral filling (E), E wave deceleration time, and isovolumic relaxation time. Peak velocities of systolic (Sa) and early diastolic (Ea) LV motion were measured by pulsed wave TDI, with the sample volume placed at the lateral corner of the mitral annulus, to assess global LV function in the longitudinal axis. E/Ea was calculated to estimate LV end-diastolic pressure (Prunier et al., 2002; Slama et al., 2005). The strain rate of the LV posterolateral wall was derived from time-movement color TDI, and it was measured in the parasternal short-axis view, as described previously (Chen et al., 2004).
Hemodynamic Measurements. The hemodynamic study was performed after the last echographic examination, just before euthanasia (after 90 days of treatment) as described previously (Prunier et al., 2002; Chen et al., 2004). In brief, rats were sedated with 50 mg/g ketamine and 10 mg/g xylazine, and then they were ventilated. After left thoracotomy, a 2-French micromanometer-tipped catheter (Millar Instruments Inc., Houston, TX) was placed in the LV cavity through the apex. The LV pressure (peak systolic, end-diastolic and developed pressures), and its maximal and minimal derivatives (dP/dtmax and dP/dtmin) were recorded with a MacLab software. All data are reported as the means for 15 steady-state cardiac cycles.
Cardiac Morphometry and Molecular Remodeling. Before and after the hemodynamic measurements, the rats were carefully inspected for pleural and abdominal effusion. Then, blood was removed by aortic puncture, and organs were immediately rinsed by infusion with cold saline. The lungs, atria, and right and left ventricles were dissected and weighed. Then, cross sections of the LV were made at the level of the papillary muscles, frozen in liquid nitrogen, and stored at –80°C for analysis.
Cardiac fibrosis was assessed by semiquantitative measurement of cardiac collagen density. Eight-micrometer-thick LV cryosections were stained with Sirius red, and then they were analyzed microscopically (500x) by a trained operator blinded to the treatment arm. Fibrosis was scored from 0 to 9 as follows: 0 to 3 for expansion across the whole LV section, 0 to 3 for transmural expansion, 0 or 1 for myocytes necrosis, and 0 or 1 for perivascular fibrosis.
Frozen LV tissue samples were homogenized in ice-cold buffer, and total creatinine kinase, cytochrome c oxidase, and citrate synthase activities were assayed after extraction, by using coupled enzyme systems as described previously (De Sousa et al., 1999). Other samples were used for mRNA quantification of type 2a sarco(endo)-plasmic reticulum Ca2+ ATPase (SERCA2a), phospholamban, type 2 ryanodine receptor (RyR2), and atrial natriuretic peptide (ANP). After reverse transcription with random primers, the level of mRNA expression was assessed by real-time reverse transcription-polymerase chain reaction using a LightCycler device and the FastStart DNA Master SYBR Green kit (Roche Diagnostics, Meylan, France). For quantification, a standard curve was generated with six different amounts of cDNA. The following oligonucleotide primers were used: SERCA2a, 5'-ATGGACGAGACGCTCAAGTT-3' and 5'-CAAACTGTACAGGGCCAAT-3'; phospholamban, 5'-TGTGACGATCACAGAAGCC-3' and 5'-GCAGCAGACATATCAAGATGAG-3'; RyR2, 5'-GTGTTTGGATCCTCTGCAGTTCAT-3' and 5'-AGAGGCACAAAGAGGAATTCGG-3'; and ANP, 5'-CCTGCTAGACCACCTGGAG-3' and 5'-GGATCTTTTGCGATCTGCT-3'. Messenger RNA expression was normalized to that of the housekeeping gene β-actin, amplified with primers 5'-TGGAATCCTGTGGCATCCATGAAAC-3' and 5'-TAAAACGCAGCTCAGTAACAGTCCG-3'.
Statistical Analysis. Continuous data are expressed as means ± S.E.M., and categorical data are expressed as percentages. Comparison of means among groups was based on analysis of variance and the Newman-Keuls test. Group-to-group comparisons were done using the Bonferroni correction. Linear regression analysis was based on the least-squares method. p < 0.05 was considered to denote a significant difference.
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Results |
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Effect of Aortic Banding and HRR on LV Hypertrophy. Echographic examination revealed a marked LV hypertrophy as early as 14 days after aortic banding (i.e., before ivabradine treatment) in the two banded groups (Fig. 2). At sacrifice, LV hypertrophy in the untreated group averaged 55% (Table 2).
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Ivabradine treatment was associated with more marked LV hypertrophy (70 ± 10% versus untreated rats; p < 0.05), but not with an increase in LV diastolic diameter (11.5 ± 0.1 versus 11.1 ± 0.2 mm; p = 0.09) (Table 1).
Effect of Aortic Banding and HRR on LV Systolic Function. Aortic banding was associated with a gradual decrease in LV stroke volume, LV shortening fraction, and cardiac output that averaged, respectively 41, 34, and 38% at 3 months (Fig. 2). TDI parameters (Sa peak velocity and systolic peak strain rate) were also reduced, whereas dP/dtmax was unchanged (Table 1). HRR was associated with a 19% increase in stroke volume (p < 0.01) but no change in cardiac output or in other parameters of LV systolic function. Because HRR was associated with a proportional increase in the ejection time, the stroke volume/ejection time ratio did not change.
Effect of Aortic Banding and HRR on LV Diastolic Function and Filling Pressure. Aortic banding was associated with a gradual alteration of LV filling, as shown by an increased E/Ea at echo and by hemodynamic data at 3 months, characterized by a marked increase in LV filling pressure (Fig. 2; Table 1). The increased E/Ea and almost unchanged LV end-diastolic volume suggested a decrease in LV compliance in banded rats compared with sham-operated controls.
In ivabradine-treated rats, LV filling pressure increased further, as shown by increased E/Ea and LVEDP values compared with untreated rats. Increased atrial weight, lung weight, and right ventricle weight in rats treated with ivabradine for 3 months (38, 30, and 54%, respectively, versus untreated rats; p < 0.01) were consistent with increased LV filling pressure. This was further supported by the increased prevalence of pleural or peritoneal effusion in these rats (36 versus 19%; p < 0.05) (Table 2).
Effect of Aortic Banding and HRR on Tissue and Molecular LV Remodeling. Marked LV perivascular and subendocardial fibrosis was seen in banded rats at 3 months. This fibrosis further increased in ivabradine-treated rats (fibrosis score, 6.4 ± 0.3 versus 5.2 ± 0.2 in treated and untreated rats, respectively; p < 0.05) and was essentially located in the subendocardium (Fig. 3).
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Effect of Treatment Cessation at the End of the Study. After 3 months, treatment with ivabradine was stopped for 3 days in a subgroup of eight rats, and echographic analyses were repeated after ivabradine washout. On treatment cessation, the heart rate returned to the level of untreated rats, LV stroke volume decreased, and cardiac output was unchanged (Table 4). In addition, E/Ea and LV end-diastolic diameter decreased. Together, these data indicated that some HRR-related effects were rapidly reversible.
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Discussion |
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; Litwin et al., 1995). Several studies have shown beneficial effects of angiotensin-converting enzyme inhibitors, β-blockers, and statins in aortic banding-induced heart failure (Weinberg et al., 1994; Kagaya et al., 1996; Grimm et al., 2001; Indolfi et al., 2002; Marano et al., 2002; Pape et al., 2002). Several reasons led us to postulate that HRR itself could also be beneficial. First, hypertrophy impairs relaxation, which shortens the duration of LV filling (Leite-Moreira et al., 1999). Accordingly, we postulated that HRR would improve LV filling. In addition, ivabradine-mediated HRR has no negative lusitropic effect and further increases the LV filling duration compared with β-blockers (Colin et al., 2002). Second, because the force-frequency relationship is altered in heart failure (Mulieri et al., 1992), we suspected that HRR might allow the heart to operate on the ascending limb of this relation. Third, myocardial perfusion, which is altered in hypertrophied ventricles (Hittinger et al., 1995), occurs mainly during diastole. Accordingly, we postulated that HRR, by extending the diastole, would improve myocardial perfusion and thus myocardial metabolism. In addition, angiogenic effects and an increase in coronary reserve were demonstrated using alinidine-mediated HRR (Lei et al., 2004). Finally, because the heart rate is a major determinant of myocardial O2 consumption (Colin et al., 2003), we thought that HRR could be beneficial in heart failure, as in coronary artery disease (Shinke et al., 1999; Borer et al., 2003).
In our model, chronic HRR increased LV filling pressure, as demonstrated by echographic and hemodynamic findings and by a marked increase in atrium and lung weight. An HRR-induced worsening of LV diastolic dysfunction was suggested by a markedly increased LVEDP, with no significant increase in LV end-diastolic volume. Such an effect might be explained as follows. First, HRR per se increased LV filling, but aortic banding physically precluded any resulting increase in LV stroke volume and therefore led to a major rise in LVEDP because of the poor LV compliance characteristic of pressure overload-induced LVH. Second, elevated LVEDP further increased LV hypertrophy and fibrosis, which further reduced LV compliance. In this type of maladaptive LV hypertrophy, the main mechanism leading to LV hypertrophy and fibrosis is considered to be the increase in wall stress, although neurohumoral alterations are also likely to play a role (Mercadier, 2007). Regarding LV systolic wall stress, we could not directly measure the systolic pressure gradient through the aortic clip. However, the mean pressure gradient would probably have been little altered by HRR, because the stroke volume/ejection time ratio did not change (Dangas and Gorlin, 1997). The HRR-related increase in LV ejection duration clearly increased the duration of systolic LV wall stress, a phenomenon that might worsen LV hypertrophy. LV diastolic wall stress also was most probably increased by HHR, because of the marked increase in both LV filling pressure and filling duration, associated with a slight increase in LV volume. In addition, hypertrophy and high diastolic and systolic LV wall stress favor myocardial ischemia and subsequent fibrosis, especially in the subendocardium (Hittinger et al., 1989).
To determine whether the HRR-associated structural and functional changes observed were reversible, we withdrew ivabradine treatment in 8 rats. Three days after treatment cessation the heart rate returned to the values observed in untreated rats, whereas LV diastolic diameter fell and a major decrease in E/Ea occurred, indicating a marked decrease in LV filling pressure. These results, which are consistent with a downward shift of the operating point along the same diastolic pressure-volume relationship, strongly suggest that HRR was directly responsible for the high LV filling pressure in these ventricles characterized by low compliance.
Regarding LV systolic function, pressure overload resulted in a depressed LV ejection fraction, which is related more to afterload mismatch than to decreased LV contractility (Ross et al., 1976). Indeed, LV fractional shortening was markedly decreased whereas LV dP/dtmax, which is less load-dependent than the ejectional parameter, was unchanged. Importantly, HRR was not associated with significant changes in isovolumic or ejectional parameters of LV systolic function, in keeping with ivabradine's lack of a negative inotropic effect. At the subcellular level, however, HRR was associated with increased ANP mRNA and decreased SERCA2a mRNA levels compared with untreated rats, and this latter decrease has been shown to correlate with the transition to cardiac failure in this model (Feldman et al., 1993). As reported previously (De Sousa et al., 1999), aortic banding resulted in decreased activity of creatine kinase, an enzyme involved in energy transfer within cardiac myocytes. No further decrease in this activity was observed in ivabradine-treated rats, at a time when both LV hypertrophy and dysfunction were more severe than in untreated rats, indicating some degree of preservation of energy metabolism by HRR.
Previous studies have shown beneficial effects of If current inhibitors in the myocardial infarction-induced heart failure model. Mulder et al. (2004) demonstrated that a 16% ivabradine-mediated HRR maintained for 90 days increased the LV shortening fraction without LV dilation and that this effect persisted after treatment cessation. Using isolated Langendorff-perfused hearts, Mulder et al. (2004) also observed a leftward shift of the developed pressure-volume relationship in ivabradine-treated rats compared with controls. Interestingly, this was associated with a decrease in collagen density and in the plasma noradrenaline concentration. Recently, Dedkov et al. (2007) showed that a 25% ivabradine-induced HRR after myocardial infarction improved maximal myocardial perfusion and the coronary reserve, an effect that was related to reduced periarteriolar collagen content. Using an 8-week 25% zatebradine-mediated HRR, Hu et al. (2004) observed mitigated results. In large myocardial infarctions, HRR enhanced LV performance with no change in LV remodeling. In contrast, in small myocardial infarctions, HRR favored LV dilation and increased LV filling pressures (Hu et al., 2004). The difference between our results and those obtained in other models may be explained by different patterns of LV remodeling. Indeed, postmyocardial infarction remodeling is characterized by eccentric LV hypertrophy, a lesser decrease in LV chamber compliance (Pfeffer, 1991; Hu et al., 2004), and a profound decrease in LV systolic function. Moreover, it is likely that HRR also alters ventriculoarterial coupling. In heart failure, HRR has been shown to improve ventriculoarterial coupling, in part by decreasing arterial elastance (Yamakawa et al., 1996; Albaladejo et al., 2003). Our model of fixed aortic banding may not permit HRR to alter arterial elastance, precluding one possible benefit of HRR. Regarding myocardial O2 consumption, potential HRR-related benefits may have been blunted in our model because myocardial O2 consumption is poorly determined by the heart rate when afterload is high. Finally, β-blockers could be more effective than pure bradycardic agents in this model, because of their negative inotropic effect and the subsequent decrease in LV load. In this respect, although some studies have shown positive effects (Grimm et al., 2001; Marano et al., 2002; Pape et al., 2002), the impact of β-blocker-induced HRR on LV hypertrophy remains uncertain (Marano et al., 2002). Together, our results suggest that HRR itself may not be beneficial in all types of heart failure. If HRR is beneficial in heart failure associated with LV dilation, such as ischemic and dilated cardiomyopathy, it may not be so in case of aortic stenosis and hypertrophic cardiomyopathy associated with a major decrease in LV compliance. In this latter clinical setting, prolonged diastolic filling induced by HRR might also greatly increase LV filling pressure in stiff ventricles that are less prone to dilate. Moreover, impaired sinus node function and arrhythmogenic ion channel remodeling during heart failure needs also to be taken into account (Nattel et al., 2007).
Our study has some limitations. Our measurement of LVEDP in vivo clearly yielded underestimated values due to the direct LV puncture in open-chest rats. LVEDP indirect assessment using Doppler E/Ea probably better reflected actual pressures. Because we tested only one dosage of ivabradine, the effects of other dosages are unknown. Similarly, we cannot directly extrapolate the results of our study to situations in which ivabradine treatment starts later after aortic banding.
In summary, long-term HRR showed no beneficial effects in pressure overload-induced LV hypertrophy in the rat. On the contrary, it favored LV hypertrophy, fibrosis, diastolic pressure increases, and their congestive consequences. Taken together, these results indicate that pure HHR should not be considered as a pertinent therapeutic approach in patients unable to increase their stroke volume because of severe LV outflow track obstruction, and/or patients with severe alteration in LV compliance. Additional studies of HRR produced by different dosages of ivabradine or other pharmacological agents in different models of cardiac diseases are needed to refine the conditions in which pure HRR exerts its most beneficial effects.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: HRR, heart rate reduction; LV, left ventricular; LVEDD, left ventricular end-diastolic diameter; SV, stroke volume; E, early diastolic transmitral maximal velocity; Ea, early diastolic maximal velocity at the mitral annulus; Sa, peak velocity of systolic left ventricular motion; LVEDP, left ventricular end diastolic pressure; TDI, Tissue Doppler imaging; dP/dt, rate of change on pressure; SERCA2a, type 2a sarco(endo-) plasmic reticulum Ca2+ ATPase; RyR2, type 2 ryanodine receptor; ANP, atrial natriuretic peptide; IVS, interventricular septum; BW, body weight; prot, protein.
Address correspondence to: Dr. Damien Logeart, Cardiology Department, Lariboisiere Hospital, 2 rue Ambroise Pare, 75010 Paris, France. E-mail: damien.logeart{at}lrb.aphp.fr
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, untreated group; 
, ivabradine treated group).
, untreated banded rats; and 
, ivabradine-treated banded rats). p < 0.01.