Although β-adrenoreceptor agonists, such as pirbuterol, and phosphodiesterase (PDE) inhibitors, such as milrinone, initially improve left ventricular (LV) performance in patients with congestive heart failure (1,2), β-adrenoreceptor agonists can cause desensitization and arrhythmia (3), and PDE inhibitors increase the risk of mortality (4). These adverse effects have limited the clinical usefulness of cyclic adenosine monophosphate-dependent inotropic agents. However, many patients with chronic heart failure experience persistent symptoms and an impaired quality of life despite optimal treatment with diuretics, digitalis, and angiotensinconverting enzyme inhibitors. Therefore, the intensive search for a safe, orally active inotropic agent continues.
Agents that increase the calcium sensitivity of myocardial cells have been a focus of recent studies. Pimobendan (UD-CG115 BS) is a recently developed inotropic and vasodilating agent (inodilator) that mediates positive inotropy by inhibiting PDE III and sensitizing myocardial contractile proteins to calcium (5,6). In vitro experiments (7) have shown that PDE inhibition is a less important mediator of the inotropic activity of pimobendan than of other pure PDE inhibitors, such as milrinone. Pimobendan increases the calcium affinity of troponin C (5). This calcium-sensitizing effect increases the force of contraction without causing a significant increase in the intracellular calcium concentration (6), and thus calcium-sensitizing drugs may not increase the energy demand. Indeed, pimobendan has been shown to increase myocardial force more economically than milrinone (8). However, calcium sensitizers have one major potential drawback in that they may slow the process of myocardial relaxation.
Several studies (9-11) have shown that pimobendan improves short-term hemodynamics in patients with congestive heart failure. However, these studies evaluated inotropic activity in terms of the maximal rate of the LV pressure increase or the velocity of circumferential fractional shortening. Because these parameters are load dependent, they may not accurately estimate the inotropic effect of inodilators (12,13). In our study, we used the slope of the end-systolic pressure-volume relation (end-systolic elastance), which is relatively independent of load, to assess inotropic activity (14). To date, no data are available concerning the effects of pimobendan on systolic and diastolic pressure-volume relations in humans. Previous studies evaluating the hemodynamic effects of pimobendan used relatively high doses. A recent multicenter trial (15) has shown that pimobendan is more effective when administered in low doses (2.5 mg twice a day), emphasizing that there may be a difference between the dose that provides the maximal initial hemodynamic response and that which produces long-term clinical improvement. We evaluated the effects of a single low dose of oral pimobendan on systolic and diastolic hemodynamics in patients with cardiomyopathy and congestive heart failure.
We studied 10 male Japanese patients with congestive heart failure resulting from idiopathic dilated cardiomyopathy (mean age, 50 ± 2 years; range, 39-61 years). Idiopathic dilated cardiomyopathy was defined as a decrease in the LV ejection fraction (<50%, as determined by contrast ventriculography) and a dilated LV cavity in the absence of coronary or valvular heart disease, arterial hypertension, and cardiac muscle disease caused by any known systemic disease. The mean LV ejection fraction was 32 ± 3%, and the mean LV end-diastolic volume index was 126 ± 11 ml/m2. All patients had experienced at least one episode of cardiac failure, and they had been treated with angiotensin-converting enzyme inhibitors (5 mg/day of enalapril or 4 mg/day of temocapril), four patients with methyldigoxin, and four patients with diuretics. Despite therapy, they complained of dyspnea at rest or on exertion. All patients were in normal sinus rhythm and were clinically stable for ≥1 week before the study. They had New York Heart Association functional class II or III congestive heart failure. The study protocol was reviewed and approved by the appropriate institutional review committee, and all patients provided written informed consent before participating in the study.
Patients underwent cardiac catheterization in the morning in the fasting state. All medications were withheld for ≥48 h. Left and right heart catheterization was performed by the femoral approach. A 7F Swan-Ganz thermodilution catheter was advanced to the pulmonary artery to measure pulmonary artery pressure, pulmonary artery wedge pressure, right atrial pressure, and cardiac output. At least 20 min after left ventriculography, when LV end-diastolic pressure returned to the baseline values, a 7F or 8F pigtail dual-field conductance catheter (Leycom, Oegstgeest, The Netherlands) with a 2F micromanometer tip (Millar Instruments, Houston, TX, U.S.A.) was inserted into the LV to measure volume and pressure. A Fogarty catheter (model 62-080-8/22F; Edwards Laboratories, Santa Ana, CA, U.S.A.) was placed in the inferior vena cava and transiently inflated to determine the LV end-systolic and end-diastolic pressure-volume relations.
After control measurements were obtained, patients received a single oral dose of 2.5 mg of pimobendan. Measurements were obtained at 45 and 90 min after drug administration. After completion of the study protocol, selective coronary angiography was performed, and a right ventricular biopsy was obtained to confirm the diagnosis of dilated cardiomyopathy. The histologic findings including myocyte degeneration and interstitial fibrosis were graded by pathologists according to the severity.
The volume-conductance catheter was connected to a volumetric system (model Sigma 5; Leycom) to measure LV volume conductance and to convert the result to the LV volume. A real-time pressure-volume diagram was generated, and eight-channel analog/digital conversion (at 200 Hz) was performed using a 16-bit microcomputer system (PC-9801 VX; NEC Co., Tokyo, Japan). The catheter had eight electrodes spaced at 1-cm intervals and was excited by an alternating current (30 μA, 20 kHz) across the distal and the proximal electrodes. The LV volume obtained by the conductance method was calibrated by biplane ventriculography (the area-length method) (16), which was performed before drug administration, as described previously (17).
The LV pressure and volume signals were digitized at 3-ms intervals and analyzed with software developed in our laboratory with a 32-bit microcomputer system (PC-9821; NEC Co.). Hemodynamic analysis was subdivided into chronotropy, preload, arterial vascular load, ventricular systolic function, ventricular diastolic relaxation and compliance, and ventricular-arterial coupling and energetics.
Ventricular preload was defined as end-diastolic volume. Arterial characteristics were assessed in terms of the systemic vascular resistance and the effective arterial elastance, as proposed by Sunagawa et al. (18). We defined the effective arterial elastance as the ratio of the LV end-systolic pressure to the stroke volume.
Systolic pump function parameters included cardiac index, stroke volume, ejection fraction, and end-systolic volume. The ejection fraction was calculated as the ratio of the stroke volume to the LV end-diastolic volume. The first derivative (dP/dt) of LV pressure was obtained by digital differentiation of the pressure data. An end-systolic pressure-volume line was drawn on the upper left corner of the pressure-volume loops during the transient decrease in preload caused by inflation of the Fogarty catheter in the inferior vena cava. The end-systolic elastance was defined as the slope of the end-systolic pressure-volume line. We assessed contractility change by the ratio of maximal dP/dt to end-diastolic volume and the end-systolic elastance.
Diastolic parameters included the time constant of isovolumic relaxation and the end-diastolic pressure-volume relation. We used two methods to calculate the time constant of the diastolic LV pressure decay from the digitized data obtained during the isovolumic relaxation period, that is, from the point of the peak negative dP/dt to a point 5 mm Hg above the LV end-diastolic pressure: T1/2 was obtained by direct measurement of the pressure half-time, as described by Mirsky (19), and TD was determined using a derivative model with a variable pressure asymptote, according to the method of Raff and Glantz (20). The end-diastolic pressure-volume relation was also determined from the set of pressure-volume points obtained at end diastole in multiple cardiac cycles measured at various filling volumes during mechanical obstruction of the inferior vena cava (21). The end-diastolic data were then analyzed by exponential regression analysis to obtain the following equation: p = b × exp(k × v), where p is the LV end-diastolic pressure (mm Hg), b is the LV end-diastolic pressure at zero volume, and v is the simultaneous LV end-diastolic volume (ml). We defined the constant 'k' (mm Hg/ml) in the equation as the passive diastolic chamber stiffness constant.
We used the ratio of end-systolic to arterial elastance (18) as an index of ventriculoarterial coupling. This ratio reflects the matching of cardiac systolic properties with the arterial system. As proposed by Feldman et al. (22), myocardial oxygen consumption was estimated by the pressure-work index of Rooke and Feigl (23) and calculated by the following equation: EQUATION (1) where PWI is the pressure-work index, sAoP and dAoP are the systolic and diastolic arterial pressure, respectively, HR is the heart rate, SV is the stroke volume, and BW is the body weight in kilograms. Schipke et al. (24) showed that this parameter is reasonably well correlated with the directly measured myocardial oxygen consumption. External work was defined as the area within the pressure-volume diagrams calculated with a 32-bit microcomputer (PC-9821; NEC Co.) using our original system of analysis. Mechanical efficiency was defined as the ratio of external work to myocardial oxygen consumption.
Blood samples for determinations of the plasma levels of pimobendan (UD-CG115) and its active metabolite, UD-CG212, were collected before drug administration and at 45, 90, and 120 min after drug administration.
Data are expressed as the mean ± SEM. Changes in hemodynamic indices and the plasma drug concentration from baseline were evaluated by two-way analysis of variance for repeated measures followed by Scheffé's test. Correlations between hemodynamic indices and plasma drug concentrations were determined by least-squares linear regression analysis. A value of p < 0.05 was considered statistically significant.
Baseline hemodynamic characteristics and right ventricular biopsy findings are shown in Table 1. The biopsy samples from all patients showed interstitial fibrosis and myocyte degeneration.
Plasma levels of pimobendan and UD-CG212
The plasma concentration of pimobendan fitted a one-compartment model. The time to maximal plasma concentration (Tmax) was 1.3 ± 0.2 h, and the maximal plasma concentration (Cmax) was 14.3 ± 1.9 ng/ml. In eight patients, the plasma concentration of UD-CG212 also fit a one-compartment model. Tmax was 1.6 ± 0.1 h, and Cmax was 11.8 ± 1.5 ng/ml. The mean plasma levels of pimobendan were similar at 45, 90, and 120 min (Table 2), whereas the mean plasma levels of UD-CG212 were higher at 90 than at 45 min (p < 0.01).
Systemic hemodynamic effects
The LV minimal and end-diastolic pressure decreased significantly at 90 min after oral administration of pimobendan (p < 0.01; Table 3). Systemic vascular resistance, effective arterial elastance, and LV end-diastolic volume index also decreased significantly (p < 0.01), suggesting the drug had a vasorelaxant effect. Heart rate tended to increase slightly. There was no change in right atrial pressure after pimobendan administration.
Effect on systolic indices
Pimobendan significantly increased the cardiac index, the stroke volume, and the ejection fraction (all p <0.01), and the LV end-systolic volume was significantly decreased at 90 min after administration (p < 0.01; Table 3). Fig. 1 displays pressure-volume loops and relations recorded at baseline and 45 and 90 min. At 45 min, only the end-systolic elastance significantly increased by 25% (p < 0.05) without any significant hemodynamic changes. The end-systolic elastance increased significantly by 55% (p < 0.01), and the ratio of peak positive dP/dt to end-diastolic volume increased by 45% (p < 0.05) at 90 min. The inotropic effects of pimobendan at 90 min were accompanied by reductions in LV end-diastolic volume (an index of preload) and in systemic vascular resistance (an index of afterload). The inotropic effect was reduced in patients with severely impaired myocardial contractility (Fig. 2). This attenuated inotropic response was not associated with any difference in the plasma concentration of pimobendan or UD-CG212.
Effect on diastolic indices
The time constant of diastolic LV pressure decay decreased significantly, suggesting that pimobendan accelerated the LV pressure decay at 90 min (p < 0.01). The decrease in T1/2 after drug administration was accompanied by an increase in end-systolic elastance, and there was a weak correlation between the absolute changes in T1/2 and changes in the end-systolic volume (r = 0.45; p < 0.05; Fig. 3).
Pimobendan concomitantly reduced the LV end-diastolic pressure and volume at 90 min. The diastolic pressure-volume curves then showed a leftward and downward shift, maintaining a similar shape, in all patients (Fig. 4). However, the passive diastolic chamber stiffness constant 'k' did not differ before and after the administration of pimobendan (Table 3).
Effects on ventriculoarterial coupling and mechanical efficiency
The ratio of end-systolic to arterial elastance was low at baseline and increased significantly at 90 min (p < 0.01; Table 4). Myocardial oxygen consumption did not change after administration of pimobendan. Mechanical efficiency tended to increase, but the changes were not significant.
Recent multicenter trials (15,25) have shown that pimobendan exerts maximal effects when administered in low doses and have suggested that the therapeutic range of this drug is 2.5-5 mg/day. Therefore we investigated the effects of a low dose of oral pimobendan in patients with heart failure. In this study, a single oral dose of 2.5 mg of pimobendan significantly increased myocardial contractility without an increase in myocardial oxygen consumption, and reduced LV preload and afterload, and accelerated LV relaxation.
Pharmacokinetics of pimobendan and UD-CG212
Table 2 shows plasma concentrations of pimobendan and its active metabolite. Berger et al. (7) reported that UD-CG212 was about 34 times more potent than pimobendan on inotropic effects. Van Meel (26) and Brunkhorst et al. (27) have shown that the calcium-sensitizing effects and the PDE-inhibiting effects of UD-CG212 are apparent at concentrations higher than 10−10 and 10−8M, respectively, whereas those of pimobendan are apparent at concentrations higher than 10−6M. In our study, Cmax of pimobendan and UD-CG212 were 14.3 ± 1.9 ng/ml (4.3 × 10−8M) and 11.8 ± 1.5 ng/ml (3.6 × 10−8M), respectively. Our data were similar to those reported in a previous study (28), including that the elimination half-life was 1.4 h in pimobendan and 3.2 h in UD-CG212, respectively. These data suggest that hemodynamic changes in our study were largely due to the calcium-sensitizing effects of UD-CG212 and partly due to the PDE-inhibiting effects of it.
Effect on LV systolic function
In this study low-dose pimobendan exerted significant inotropic effects. The end-systolic elastance increased by 55% at 90 min after administration of pimobendan. Most important, this inotropic effect was associated with no increase in myocardial oxygen consumption. These results are consistent with the study (29) that showed that pimobendan reduced myocardial oxygen consumption for a single cardiac cycle, whereas our previous study (17) reported that dobutamine and pure PDE-III inhibitor increased myocardial oxygen consumption. Enhanced energy turnover may have detrimental effects on the failing human heart, especially in patients with coronary heart disease, and may also be harmful in patients with idiopathic dilated cardiomyopathy (30,31). This energy-saving effect of a low dose of pimobendan is favorable as a treatment for heart failure. In our study, this inotropic effect occurred in association with an average 5% increase in the heart rate, although this positive chronotropic effect was not significant. In previous studies (9-11), higher doses of pimobendan were associated with a >10% increase in the heart rate. Theoretically, a positive chronotropic effect would increase myocardial oxygen consumption; thus higher doses of pimobendan would disturb the energy-saving effect of this drug. In our study, 2.5 mg of oral pimobendan exerted an inotropic effect without significantly increasing the heart rate or myocardial oxygen consumption, which should favorably influence myocardial energetics. The chronotropic effect of pimobendan, which is not significant, may reflect its PDE-inhibiting properties. Previous experiments (26,27) have shown that the calcium-sensitizing effects of UD-CG212 are apparent even at concentrations lower than the concentration that has PDE-inhibiting effects. In our study, pimobendan significantly increased the endsystolic elastance by 25% at 45 min without increasing the heart rate. It is possible that an even lower dose of pimobendan (1.25 mg) would have an inotropic effect without causing an increase in heart rate. Daily doses of both 2.5 and 5 mg of pimobendan have been found to improve exercise duration to a similar extent (25). Further studies are needed to evaluate the hemodynamic and long-term effects of 1.25 mg of oral pimobendan.
The inotropic effect of pimobendan was significantly correlated with the baseline end-systolic elastance in this study, indicating that the positive inotropic response was lessened in the presence of severe heart failure. Our results in patients with cardiomyopathy are consistent with data obtained in dogs with pacing-induced heart failure compared with normal dogs (32). There are several possible explanations for the depressed response to pimobendan in patients with severe heart failure. First, interstitial fibrosis and myocardial cell degeneration are present, and myocardial cells are decreased in the LV of patients with idiopathic dilated cardiomyopathy (33). These myocardial structural abnormalities may have contributed to the decrease in contractility and the depressed inotropic response to pimobendan. In our study, the biopsy samples from three patients whose end-systolic elastance (Ees) was <1.0 mm Hg/ml showed severe interstitial fibrosis. Second, a previous study (5) has shown that pimobendan affects only myofibrillar calcium sensitivity and not the maximal calcium-activated tension. Generally, calcium responsiveness of myofilaments is modulated by two primary determinants, calcium sensitivity and the maximal calcium-activated tension (34). Perreault et al. (35) reported that the maximal calcium-activated tension was reduced in the failing myocardium. In a recent study (36) on pacing-induced heart failure, another calcium sensitizer, MCI-154, which has been shown to increase both of these determinants (37), caused a similar improvement in LV contractility in heart failure and in the control state. Thus a reduced maximal calcium-activated tension in the failing myocardium may contribute to the decreased inotropic response to pimobendan.
Effect on LV diastolic function
In theory, calcium sensitizers prolong relaxation by shifting the relation between the calcium concentration and force to the left on the calcium concentration axis. However, Asanoi et al. (32) found that pimobendan had lusitropic effects in conscious dogs with tachycardia-induced heart failure. There are limited data on the effect of pimobendan on LV isovolumic relaxation and LV distensibility in patients with dilated cardiomyopathy.
Pimobendan significantly shortened LV relaxation, as assessed by the time constant. There are several possible explanations for this effect. Several studies (38,39) have suggested that energy stored in the myocardium during systole is released during diastole, and this elastic recoil may contribute to LV pressure decay. In the present study, the decrease in T1/2 after drug administration was accompanied by the increase in end-systolic elastance, and the absolute changes in T1/2 were correlated with changes in the end-systolic volume. This finding suggests that the inotropic effect of pimobendan increased elastic recoil, which may induce an improvement in relaxation. In addition, pimobendan is also a PDE inhibitor, and this property improves LV relaxation (40). However, the decrease in time constant may be, in part, due to the decrease in LV end-systolic pressure (41). These effects may counterbalance the negative lusitropic effect of a calcium sensitizer.
Pimobendan caused leftward and downward shifts in the diastolic pressure-volume curves in all patients in this study. However, the passive diastolic chamber stiffness constant 'k' was unchanged. The LV diastolic pressure-volume relations are influenced by a number of factors. The extent of relaxation and ventricular interaction modulated by the pericardium are important during late to end diastole (42). We evaluated end-diastolic pressure-volume relations during inferior vena cava occlusion, which essentially eliminates the effect of the positive pressure from the right heart and the pericardium (21). Therefore our data suggest that pimobendan has little influence on the extent of relaxation. These findings are consistent with the results of Kass et al. (21), who showed that short-term pharmacologic interventions had little effect on the end-diastolic pressure-volume relation. Carroll et al. (43) have shown that the vasodilator nitroprusside causes a leftward and downward shift in the diastolic pressure-volume curves in patients with a normal mean right atrial pressure. In our study, the mean baseline right atrial pressure was within the normal range (6.6 ± 1.1 mm Hg). Vasodilation induced by pimobendan may have been responsible for reductions in diastolic pressure and chamber size and a leftward and downward shift in the diastolic pressure-volume curve.
Effect on ventriculoarterial coupling and energetics
The evaluation of LV contractility and vascular loading conditions and their interaction is important for quantifying the effects of inotropic agents. Sunagawa et al. (18,44) first proposed that this interaction between the heart and the arterial system should be assessed by the ratio of end-systolic to arterial elastance. Under normal conditions, this ratio ranges from 1 to 2, and cardiac work and efficiency are nearly optimal (45). In failing human hearts, however, this ratio declines, and work and efficiency are compromised (46). In our study, the baseline ratio of end-systolic to arterial elastance was low, suggesting that this ventriculoarterial mismatch resulted in depressed energetics. Pimobendan significantly increased this ratio and tended to enhance mechanical efficiency. These data suggest that a low dose of oral pimobendan favorably influenced ventriculoarterial coupling, and tended to improve myocardial energetics.
One limitation of this study is that data were not obtained in a placebo group to test the short-term effects of catheterization itself on LV pressure-volume dynamics during the first 90 min. Packer et al. (47) observed significant hemodynamic changes mimicking vasodilator effects after right heart catheterization in the absence of drug therapy. However, after 2 h, many of these changes were small and were much smaller than the responses observed after oral pimobendan. More substantial changes in filling pressure and cardiac output have been observed after 6-24 h of right heart catheter placement, but these effects are not relevant to our short-term investigation.
Because the volume-conductance catheter method of measuring LV volume does not provide an absolute volume signal, the results must be calibrated to other standard volumes. The conductance catheter may underestimate the real volume when calibrated by blood conductivity and measurement of the parallel conductance by injection of a hypertonic solution. To minimize this error, we calibrated the LV volume by biplane contrast ventriculography, which was performed immediately before control measurement were obtained in the steady-state condition. After calibration, the catheter method provides more consistent results than many other methods of measurement (48). Thus we assume that the conductance catheter method provided reliable estimates of LV volume under steady-state conditions and during a transient reduction in preload.
Because of the invasive nature of the protocol, we excluded patients with very severe congestive heart failure. Whether the effects of pimobendan on hemodynamics may differ in a more severely ill population requires further investigation.
We demonstrated that low-dose oral pimobendan exerted favorable short-term inotropic and lusitropic effects in patients with mild to moderate congestive heart failure due to idiopathic dilated cardiomyopathy. Pimobendan also reduced preload and afterload. Its inotropic effects were accompanied by improved ventriculoarterial coupling, but not accompanied by an increase in myocardial oxygen consumption. Additional clinical trials are needed to evaluate the long-term efficacy of low-dose pimobendan. These data indicate that low-dose oral pimobendan may have beneficial effects in patients with chronic heart failure, and may be a useful alternative to more traditional agents. It would merit further study in a larger trial.
Acknowledgment: This work has supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan to Dr. Yokota. Financial support from the Ichihara International Foundation to Dr. Yokota is gratefully acknowledged. We are grateful to Drs. Toshikazu Sobue, Mitsunori Iwase, Ryozo Kato, Hirofumi Kanda, Takeshi Machii, Takaharu Fujimura, Sahoko Ichihara, Masafumi Inagaki, Yasushi Takeichi, Fuji Somura, and Kazushige Shigemura for their cooperation; Mrs. Nobuyuki Kitagawa, Kohsei Takahashi, and Akihiro Mita for their valuable technical advice; Mr. Norio Sugimoto for his valuable statistical advice; and secretarial assistance of Kiyoko Tekeuchi for manuscript preparation.
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