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To assess the effects of a calcium sensitizer, pimobendan, in patients with mild to moderate chronic heart failure.
Pimobendan was administered at a dose of 2.5 mg/day for 12 months to 34 patients with chronic heart failure (New York Heart Association functional class IIm to III) after treatment with diuretics and angiotensin-converting enzyme inhibitors. The etiologies of heart failure were dilated cardiomyopathy (DCM), old myocardial infarction (OMI) and other heart disease (Others). The effects of pimobendan were assessed by echocardiography, blood pool scintigraphy, Holter monitoring, 123I-meta-iodobenzylguanidine (MIBG) imaging and 123I-β-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) imaging.
Pimobendan produced improvement of symptoms in the majority of patients. Improvement was more common in the DCM group than in the OMI group. Left ventricular internal diameter measured by echocardiography was significantly decreased. Left ventricular ejection fraction was significantly increased in the DCM and Others groups. The heart to mediastinum ratio on MIBG imaging was significantly increased in the DCM and Others groups, and the heart to mediastinum ratio on BMIPP imaging was significantly increased in the DCM group.
Pimobendan is effective in patients with chronic heart failure but is less effective in patients with OMI than in patients with DCM or other heart diseases.
In addition to digitalis and diuretics, angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blockers have recently been introduced for the treatment of heart failure, but even combination therapy with these drugs is sometimes insufficient to obtain good results in patients with chronic heart failure. Therefore, new drugs are being developed for the treatment of heart failure (1,2). Pimobendan is a new calcium sensitizer that shows both inotropic and peripheral vasodilating effects, which are attributable to the sensitization of cardiac myofilaments to intracellular calcium and inhibition of phosphodiesterase III (3,4). This agent is distinctive in that it enhances myocardial contractility without increasing cytosolic calcium release, and it should therefore not increase energy demand (5). Since the intracellular calcium concentration is decreased in the failing myocardium (6), pimobendan is expected to be beneficial in the treatment of heart failure. In this study, the effect of long term administration of pimobendan was evaluated in patients with mild to moderate chronic heart failure. The effects of pimobendan in this study were assessed by blood pool scintigraphy, which allows cardiac function to be accurately estimated without being influenced by cardiac geometry, and 123I-meta-iodobenzylguanidine (MIBG) imaging, which can be used to estimate effects of treatment of heart failure (7).
The patient population consisted of out-patients with either low left ventricular ejection fraction (≤45%) or wide left ventricular internal diameter at diastole (≥55 mm), both measured by echocardiography, who had symptoms corresponding to New York Heart Association (NYHA) functional class IIm to III heart failure after more than two months’ treatment with loop diuretics and ACE inhibitors. The etiologies of heart failure were dilated cardiomyopathy (DCM), old myocardial infarction (OMI) and other heart disease (Others). No patients experienced worsening of symptoms after treatment with these two drugs, but the effects of drug treatment were not deemed sufficient. These patients were treated additionally with pimobendan at a daily dose of 2.5 mg (1.25 mg twice a day) for 12 months. The dose of 2.5 mg/day was determined according to a previous clinical trial (8). The treatment was not changed during the 12 month period.
Standard M mode echocardiography was performed before and after 12 months of treatment using the Toshiba SSH-140A ultrasound system (Toshiba Medical Systems, Japan). To avoid the influence of variability, echocardiography was performed by the same examiner. Cardiac geometry and functions were measured in the supine position and standard parasternal view with a 5 MHz probe in the M mode.
Holter monitoring was recorded for 24 h to investigate arrhythmia.
A rotating digital scintillation camera (Gamma-camera GCA-901A, Toshiba Co, Ltd, Japan) equipped with a collimator dedicated to 123I was used. 123I-MIBG (111 MBq) (Dai-ichi Radio Isotope Inc, Japan) was injected intravenously into patients who had been fasting since the previous night. Early and delayed single photon emission computed tomography of the myocardium was performed 15 min and 4 h after injection. 123I-β-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) (111 MBq) was injected and the same procedure as for MIBG was used to estimate myocardial fatty acid metabolism. Blood pool scintigraphy was performed using technetium-99m-human serum albumin (740 MBq).
Values are expressed as mean ± SD. The paired t test was used to assess differences between data at baseline and at 12 months. P<0.05 was considered significant.
Patient profiles are shown in Table 1. None of the DCM group had coronary stenosis and their left ventricular biopsy samples showed histological changes consistent with DCM. The Others group consisted of four patients with hypertension, two with myocarditis and two with valvular heart disease. All patients had been administered loop diuretics and ACE inhibitors for more than two months before pimobendan treatment. Four patients in the OMI group and one in the Others group had diabetes mellitus. All diabetic patients were treated with glibenclamide.
As shown in Figure 1, pimobendan improved the symptoms of heart failure in 12 of 14 patients with DCM, seven of 12 with OMI and six of eight with other heart diseases.
Table 2 compares total heart beats measured by Holter monitoring, systolic and diastolic blood pressures, and cardiothoracic ratio on the chest radiograph between baseline and after 12 months’ treatment. The number of premature ventricular contractions did not increase with pimobendan (Figure 2). In three patients in the DCM group, one in the OMI group and one in the Others group, arrhythmia was improved from Lown class II to class I.
Left ventricular internal diameter at diastole assessed by echocardiography decreased significantly in the DCM and OMI groups, and tended to decrease in the Others group (Figure 3). Left ventricular ejection fraction measured by the radioisotope method was significantly increased in the DCM and Others groups (Figure 4).
Figures 5 and and66 show the effects of pimobendan on the heart to mediastinum (H:M) ratio and the washout rate on MIBG and BMIPP images, respectively. The H:M ratio on MIBG imaging was significantly increased in the DCM and Others groups, but the wash-out rate was not significantly increased. The H:M ratio on BMIPP imaging was significantly increased in the DCM group.
A decrease of myocardial intracellular calcium concentration has been reported in the failing myocardium (6). Reports that alteration of calcium regulation may play an important part in the pathogenesis of heart failure are accumulating (9). Therefore, pimobendan should be useful for heart failure because it increases the calcium sensitivity of cardiac troponin C without increasing energy demand. Another mechanism of pimobendan is its effect on cytokines. Various phosphodiesterase III inhibitors, including pimobendan, inhibit the production of cytokines (10) and nitrite accumulation by inhibiting inducible nitric oxide synthase (11). Our results, showing improvement of the symptoms of heart failure with pimobendan, coincide with other reports (8,12). Intravenous administration of pimobendan was reported to increase the incidence of ventricular arrhythmia because it enhances atrioventricular conduction and shortens myocardial refractoriness (13). Our study showed that pimobendan did not aggravate arrhythmia and even improved it in some patients. Arrhythmia may simply be a sign of severe ventricular dysfunction because recent trials showed that antiarrhythmic treatment does not improve the survival of patients with heart failure (14,15). If so, the decrease in premature ventricular contractions in some of our patients must be a result of improvement in heart failure.
Recent studies have shown that neurohormonal activation, such as activation of the sympathetic nervous system, occurs early in congestive heart failure (16). Cardiac MIBG imaging is a useful technique to assess early alterations in cardiac sympathetic activity in patients with mild to moderate heart failure (17). A characteristic of MIBG imaging in patients with heart failure is the enhanced washout rate of 123I-MIBG from the early to the delayed image and a decrease of the H:M ratio in the delayed image.
Myocardial BMIPP imaging is a potent tool in assessing myocardial fatty acid metabolism. Reduced uptake of 123I-BMIPP reflects sarcolemmal and mitochondrial functional abnormalities, and the image is useful for predicting prognosis (18,19). In our study, improvement of the H:M ratio in both the MIBG and BMIPP images was slight but significant in the DCM group. This may reflect the significant improvement of the left ventricular ejection fraction in the DCM group, but not in the OMI group, after pimobendan treatment.
Five patients in the OMI group and one in the Others group also had diabetes mellitus. In two of the five in the OMI group, diabetes had been well controlled (fasting plasma glucose ≤8 mmol/L and hemoglobin A1c ≤7.0%) and NYHA class was improved by 12 months of treatment with pimobendan. In the other patients with diabetes in whom it was poorly controlled, NYHA class was not improved. Although the number of patients with diabetes was small, it may be postulated that diabetes should be well controlled to obtain the beneficial effects of pimobendan.
Digitalis is useful for congestive heart failure, but it sometimes causes intoxication, and long term administration of cardiotonic agents that increase myocardial cAMP concentration does not improve the mortality of patients with chronic heart failure (20,21). Van der Giessen et al (22) reported that the positive inotropic properties were negligible in awake pigs with myocardial infarction. This is not incompatible with our finding that the effect was less in patients with OMI. It has been reported that pimobendan also has potent phosphodiesterase-inhibiting (23) and calcium-sensitizing properties (24). It is impossible to identify which effect was predominant in this study. Pimobendan appears to be a promising agent for the treatment of chronic heart failure.