A multicenter, randomized, double-blind, placebo-controlled trial of pimobendan, a new cardiotonic and vasodilator agent, in patients with severe congestive heart failure.

Pimobendan, a new oral cardiotonic and vasodilator agent, increases myocardial contractile force through specific inhibition of phosphodiesterase type III and increased calcium sensitivity of the myocardial contractile elements. The effects of pimobendan on left ventricular performance and maximal exercise capacity were studied in a multicenter, randomized, double-blind, placebo-controlled trial involving 52 patients with severe congestive heart failure despite diuretics, digoxin, and angiotensin-converting enzyme inhibitors. The acute hemodynamic evaluation included three single doses of 2.5, 5.0, and 10.0 mg of oral pimobendan, which was subsequently administered at a daily dose of 5 or 10 mg for 4 weeks. Acute administration of pimobendan significantly increased the resting cardiac index and lowered pulmonary capillary wedge pressure in a dose-dependent manner, whereas heart rate and systemic arterial pressure were not substantially altered. Patients receiving pimobendan, 5 and 10 mg daily, had a significantly greater increase in maximal exercise duration than those receiving placebo, that is, 144 +/- 30 and 124 +/- 33 seconds versus 58 +/- 25 seconds (p = 0.05). Peak oxygen uptake increased by 1.7 +/- 0.8 and 2.2 +/- 1.3 ml/kg/min in patients receiving pimobendan at a daily dose of 5 and 10 mg, respectively, whereas it decreased by 0.1 +/- 0.6 ml/kg/min in patients receiving placebo (p = 0.06). Thus pimobendan acutely improves resting left ventricular performance and chronically increases exercise duration and peak oxygen uptake in patients with severe congestive heart failure concomitantly treated with digoxin, diuretics, and angiotensin-converting enzyme inhibitors.     

Hemodynamic effects of pimobendan given orally in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Pimobendan (UD-CG 115 BS) was administered orally to 23 patients with congestive heart failure (functional class IV) caused by coronary artery disease (11 patients) or idiopathic dilated cardiomyopathy (12). All patients received maintenance doses of digoxin, furosemide and warfarin. Baseline data, collected during 15 hours, stayed within a 10% range. A 10-mg oral dose of pimobendan increased the heart rate from 95 +/- 20 to 109 +/- 24 beats/min (p less than 0.003). The pulmonary artery wedge pressure decreased from 23.0 +/- 5.9 to 10.1 +/- 5.2 mm Hg (p less than 0.0001), the cardiac index increased from 1.9 +/- 0.4 to 3.3 +/- 0.7 liters/min/m2 (p less than 0.0001) and the left ventricular stroke work index increased from 2,005 +/- 927 to 3,065 +/- 1,161 ml/mm Hg/m2 (p less than 0.0001). Statistically significant improvements in hemodynamic variables were still present 10 hours after the administration of pimobendan. Most patients felt better and reported no angina or other side effect, the incidence of ventricular arrhythmias was unchanged and no electrocardiographic changes suggesting ischemia were observed. Patients with severe congestive heart failure experienced a prolonged improvement of their cardiovascular condition after a single dose of pimobendan.     

Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan in the failing human myocardium.

Previous studies have shown reduced effects of cAMP-dependent positive inotropic agents in the failing human myocardium; thus other cAMP-independent mechanisms of action may be useful to increase force of contraction in this condition. The purpose of this investigation was to determine whether a positive inotropic effect of the cAMP-phosphodiesterase (PDE) inhibitor pimobendan is observed in the failing human myocardium and to study whether other factors, such as an increase in the Ca2+ sensitivity of myofilaments, play a functional role in the increase in force of contraction. Pimobendan produced a positive inotropic effect in isolated preparations from nonfailing donor hearts; however, in moderately (New York Heart Association class II-III, NYHA II-III) and severely (NYHA IV) failing myocardium, this effect was reduced. In addition, in NYHA IV specimens pimobendan inhibited the crude cAMP-PDE (crude PDE) and the isoenzymes I-III (PDE I-III) in a concentration-dependent way. As judged from the IC50 values found in this tissue for the inhibition of PDE III and of crude PDE, the potency of the compound was 18.1 times greater on PDE III. Consistent with a cAMP-PDE-dependent mechanism of action, the positive inotropic effect was potentiated by isoproterenol and inhibited by adenosine in failing myocardium. In failing myocardium, pimobendan also increased the sensitivity of skinned cardiac fibers to Ca2+ and shifted the Ca(2+)-tension relation to the left. This sensitizing effect began at 0.01 mumol/l in NYHA II-III and NYHA IV and rose to about 200% at 300 mumol/l in both groups. In contrast, the demethylated metabolite UD-CG 212 Cl failed to produce positive inotropic effects in failing myocardium alone, but in the presence of isoproterenol, it exerted an increase in force of contraction. The potency of UD-CG 212 Cl for PDE III inhibition in NYHA IV was greater than that of pimobendan. The metabolite pronouncedly decreased the sensitivity of skinned cardiac fibers to Ca2+ at 30-300 mumol/l in NYHA II-III and NYHA IV. It is concluded that in the failing human heart pimobendan inhibited PDE III and sensitized contractile proteins for Ca2+. Both effects appear to be involved in the positive inotropic effect of the compound, because its metabolite, UD-CG 212 Cl, had no effect on force of contraction and on the Ca2+ sensitivity of skinned cardiac fibers but inhibited PDE III even more potently than pimobendan.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of long-term treatment with pimobendan on neurohumoral factors in patients with non-ischemic chronic moderate heart failure.

To evaluate the effects of the addition of pimobendan to an optimal basic regimen on plasma levels of neurohumoral factors in patients with non-ischemic, moderate heart failure during 2-year follow-up. This prospective, observational study involved 16 patients with non-ischemic, moderate heart failure [New York Heart Association (NYHA) functional class IIM-III] receiving an optimal basic regimen of digitalis, diuretics and angiotensin-converting enzyme inhibitor. Eight patients (Group P) were also administered pimobendan at a dose of 2.5 or 5 mg daily, while the other 8 served as controls (Group C). After 3 months of pimobendan administration, the plasma levels of norepinephrine and atrial natriuretic peptide and brain natriuretic peptide decreased and left ventricular ejection fraction improved. After 1 year, the cardiac symptoms, assessed using the Specific Activity Scale as well as the NYHA functional class, improved and the left ventricular end-diastolic diameter decreased. These improvements in Group P were maintained for 2 years. However, in Group C, the cardiac symptoms and the neurohumoral factor levels remained unchanged or deteriorated during this study, and one patient died of heart failure. Long-term combination therapy with the optimal basic regimen and pimobendan has potentially beneficial effects on neurohumoral factor levels and cardiac symptoms in patients with non-ischemic, chronic moderate heart failure.     

Angiotensin II levels, hemodynamics, and sympathoadrenal function after low-dose captopril in heart failure

The angiotensin converting enzyme inhibitor captopril improves the altered hemodynamics in many patients with chronic heart failure, but the first dose may precipitate hypotension. Ten patients with chronic heart failure were studied, nine with high plasma concentrations of renin and one with a low concentration. Frequent measurements of plasma concentrations of angiotensin II, renin, and catecholamines were made over 60 minutes after a small dose (6.25 mg) of captopril and related to concurrently measured hemodynamic variables. Captopril caused a decrease in systemic and pulmonary artery pressure and an increase in cardiac index, and these changes coincided with reductions in the plasma concentrations of angiotensin II and increases in plasma concentrations of renin. The hemodynamic changes were accompanied by reductions in the plasma concentrations of norepinephrine but transient increases in plasma concentrations of epinephrine in patients in whom vasomotor syncope developed. The patient with a low plasma renin concentration showed little hemodynamic response to the drug. It is concluded that vasomotor syncope occurs quite frequently in patients with severe chronic heart failure after captopril in a small dose and is associated with a selective increase in epinephrine secretion from the adrenal medulla.     

Plasma urotensin II level in patients with chronic congestive heart failure

Urotensin II (UTII) is recently discovered neurohumoral factor influencing function and structure of the myocardium and remodeling of the vessels, and it may contribute to pathogenesis of chronic congestive heart failure. The aim of the study was estimation of plasma concentration of UTII in patients with chronic congestive heart failure. The investigations were performed on 79 patients (37 women and 42 men) aged 43-87 yr. (mean 69.2 +/- 9.8 yr.) and 15 healthy individuals. In all patients, echocardiographic examination of the left ventricle structure and function was performed and serum concentration of electrolytes and creatinine were measured. Plasma levels of UTII were determined before treatment and after 1 week, 2 and 4 weeks of treatment using RIA Peninsula Lab. Inc. Plasma level of UTII in patients suffering from chronic congestive heart failure was significantly lower than in healthy individuals before the treatment and after achieving compensation of the circulatory system using standard treatment, independently from sex, kind of heart failure (systolic-diastolic or diastolic) or coexistence arterial hypertension or pulmonary hypertension, ischemic heart disease or diabetes and impaired glucose tolerance. Treatment of chronic congestive heart failure resulted in a transient increase in UTII concentration except for patients with diastolic heart failure or diabetes. Only patients without ischemic heart disease have a permanent increase in UTII concentration at the time of the treatment. After achieving compensation of the circulatory system in the patients suffering from systolic-diastolic heart failure, UTII concentration was significantly lower than in the patients suffering from diastolic heart failure, in the patients suffering from ischemic heart disease significantly lower than in patients without ischemic heart disease, in the patients with arterial hypertension significantly higher than in those with normal arterial tension, in group of the patients with pulmonary hypertension lower than in group of the patients without pulmonary hypertension and significantly higher in group of the patients suffering from diabetes or impaired glucose tolerance than in group of the patients without this metabolic disorders.     

Pharmacotherapy in congestive heart failure: ACE inhibitors and anemia in congestive heart failure

The use of angiotensin-converting enzyme inhibitors can be accompanied by a number of adverse events, including cough, angioedema, and hyperkalemia, as well as a peculiar form of functional renal insufficiency. Other, less obvious side effects accompany ACE inhibitor use, such as a reduction in red blood cell production. This feature of ACE inhibitor use may be employed to good effect, as in the management of post-transplant erythrocytosis. Alternatively, the suppressive effect of ACE inhibitors on red blood cell production may intensify the anemia of chronic renal failure and/or congestive heart failure. The untreated congestive heart failure patient typically has an increased red blood cell mass as a consequence of increased erythropoietin levels, with the latter governed by congestive heart failure-related renal hypoxia. This is not expressed as an increase in hemoglobin concentration because of the increase in plasma volume that marks advanced congestive heart failure. ACE inhibitor therapy can be expected to both reduce plasma volume and decrease red blood cell production. As a result, the hemoglobin concentration changes very little in the ACE inhibitor-treated congestive heart failure patient and usually falls in the low normal range. Recently, erythropoietin has been employed to good effect in congestive heart failure patients with borderline anemia. (c)2000 by CHF, Inc.     

Hormonal, global, and regional haemodynamic responses to a vascular antagonist of vasopressin in patients with congestive heart failure with and without hyponatraemia

The pathophysiological role of an increase in circulating vasopressin in sustaining global and regional vasoconstriction in patients with congestive heart failure has not been established, particularly in patients with hyponatraemia. To assess this further, 20 patients with congestive heart failure refractory to digoxin and diuretics were studied before and 60 minutes after the intravenous injection (5 micrograms/kg) of the vascular antagonist of vasopressin [1(beta-mercapto-beta,beta-cyclopentamethylene-propionic acid), 2-(0-methyl) tyrosine] arginine vasopressin. Ten patients were hyponatraemic (plasma sodium less than 135 mmol/l) and 10 were normonatraemic. In both groups of patients the vascular vasopressin antagonist did not alter systemic or pulmonary artery pressures, right atrial pressure, pulmonary capillary wedge pressure, cardiac index, or vascular resistances. Furthermore, there was no change in skin and hepatic blood flow in either group after the injection of the vascular antagonist. Only one patient in the hyponatraemic group showed considerable haemodynamic improvement. He had severe congestive heart failure and a high concentration of plasma vasopressin (51 pmol/l). Plasma renin activity, vasopressin, or catecholamine concentrations were not significantly changed in response to the administration of the vasopressin antagonist in either the hyponatraemic or the normonatraemic groups. Patients with hyponatraemia, however, had higher baseline plasma catecholamine concentrations, heart rate, pulmonary pressure and resistance, and lower hepatic blood flow than patients without hyponatraemia. Plasma vasopressin and plasma renin activity were slightly, though not significantly, higher in the hyponatraemic group. Thus the role of vasopressin in sustaining regional or global vasoconstriction seems limited in patients with congestive heart failure whether or not concomitant hyponatraemia is present. Vasopressin significantly increases the vascular tone only in rare patients with severe congestive heart failure and considerably increased vasopressin concentrations. Patients with hyponatraemia do, however, have raised baseline catecholamine concentrations, heart rate, pulmonary arterial pressure and resistance, and decreased hepatic blood flow.     

Hormonal, global, and regional haemodynamic responses to a vascular antagonist of vasopressin in patients with congestive heart failure with and without hyponatraemia.

The pathophysiological role of an increase in circulating vasopressin in sustaining global and regional vasoconstriction in patients with congestive heart failure has not been established, particularly in patients with hyponatraemia. To assess this further, 20 patients with congestive heart failure refractory to digoxin and diuretics were studied before and 60 minutes after the intravenous injection (5 micrograms/kg) of the vascular antagonist of vasopressin [1(beta-mercapto-beta,beta-cyclopentamethylene-propionic acid), 2-(0-methyl) tyrosine] arginine vasopressin. Ten patients were hyponatraemic (plasma sodium less than 135 mmol/l) and 10 were normonatraemic. In both groups of patients the vascular vasopressin antagonist did not alter systemic or pulmonary artery pressures, right atrial pressure, pulmonary capillary wedge pressure, cardiac index, or vascular resistances. Furthermore, there was no change in skin and hepatic blood flow in either group after the injection of the vascular antagonist. Only one patient in the hyponatraemic group showed considerable haemodynamic improvement. He had severe congestive heart failure and a high concentration of plasma vasopressin (51 pmol/l). Plasma renin activity, vasopressin, or catecholamine concentrations were not significantly changed in response to the administration of the vasopressin antagonist in either the hyponatraemic or the normonatraemic groups. Patients with hyponatraemia, however, had higher baseline plasma catecholamine concentrations, heart rate, pulmonary pressure and resistance, and lower hepatic blood flow than patients without hyponatraemia. Plasma vasopressin and plasma renin activity were slightly, though not significantly, higher in the hyponatraemic group. Thus the role of vasopressin in sustaining regional or global vasoconstriction seems limited in patients with congestive heart failure whether or not concomitant hyponatraemia is present. Vasopressin significantly increases the vascular tone only in rare patients with severe congestive heart failure and considerably increased vasopressin concentrations. Patients with hyponatraemia do, however, have raised baseline catecholamine concentrations, heart rate, pulmonary arterial pressure and resistance, and decreased hepatic blood flow.     

Relation between endothelin-1 spillover in the lungs and pulmonary vascular resistance in patients with chronic heart failure

Objectives. The aim of this study was to clarify the origin of plasma endothelin-1 and to determine the relation between pulmonary vascular resistance and endothelin-1 secretion in the pulmonary circulation in patients with chronic congestive heart failure.Background. Plasma levels of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, are increased in congestive heart failure, but the source has not been clarified. Recent studies have indicated a relation between endothelin-1 and pulmonary hypertension. We therefore evaluated the contribution of endothelin-1 secretion in the pulmonary circulation to the regulation of pulmonary vascular resistance in patients with chronic heart failure.Methods. A comparison was made of the plasma levels of endothelin-1 between the main pulmonary artery and the pulmonary capillary wedge region, as well as between the femoral artery and the femoral vein in 62 patients with chronic heart failure. Stepwise multivariate regression analysis was used to detect independent predictors of pulmonary vascular resistance among the various vasoconstrictor hormones in these patients.Results. There was no significant difference in plasma endothelin-1 levels between the femoral artery and vein. In contrast, plasma endothelin-1 increased significantly from the main pulmonary artery to the pulmonary capillary wedge region ([mean ± SEM] 3.1 ± 0.23 vs. 4.6 ± 0.36 pg/ml, p < 0.01), and the increase was related to the severity of heart failure. Among the various vasoconstrictor factors, such as plasma active renin concentration, plasma angiotensin II, plasma norepinephrine, femoral venous plasma endothelin-1 and pulmonary endothelin-1 spillover, only endothelin-1 spillover in the lungs showed an independent and significant correlation with pulmonary vascular resistance (r = 0.82, p < 0.001).Conclusions. The main source of circulating endothelin-1 is not the peripheral vascular bed but the pulmonary vascular bed in patients with chronic heart failure. In addition, endothelin-1 secretion in the lungs may regulate the pulmonary vascular resistance in patients with chronic heart failure. These findings are consistent with a significant role for endogenous endothelin-1 in the pathophysiology of heart failure, espscially in the pulmonary circulation.     

Pimobendan (UDCG 115 BS) in long-term therapy of chronic heart failure]

Pimobendan is a positive inotropic agent with additional calcium-sensitizing effects of the phosphodiesterase III-inhibitor group. In short-term studies, beneficial hemodynamic effects have been demonstrated in patients with congestive heart failure. The aim of this prospective study was to examine the long-term effect of pimobendan (during at least 6 months) on subjective state, hemodynamic parameters, and arrhythmias in patients with congestive heart failure NYHA classes II and III. After double-blind randomization, 24 patients received pimobendan 5 mg bid or placebo orally in addition to a basic therapy (diuretics, digitalis). After 3 months, pimobendan-treated patients showed a significant clinical improvement (p < 0.03). In the placebo group, one patient underwent acute cardiac transplantation due to rapid clinical deterioration; another patient died suddenly after 5 months. No cardiac events occurred in the pimobendan group. In comparison to placebo, no proarrhythmogenic effect of pimobendan was detected. Clinical stabilization of patients in the pimobendan group was not paralleled by improvement of the hemodynamic parameters of left-ventricular performance.     

Alpha 2-receptor-mediated vasoconstriction in patients with congestive heart failure

alpha 2-Adrenoceptors exist postsynaptically to subserve vasoconstriction and presynaptically to modulate norepinephrine release into the synaptic cleft. Because adrenoceptors may down-regulate in response to chronic stimulation, we investigated the activity of alpha 2-receptor-mediated vasoconstriction in patients with congestive heart failure, who had increased levels of plasma norepinephrine. We used the isolated forearm model and intra-arterial infusions of subsystemic doses of yohimbine, a specific alpha 2-blocker, in 11 patients with heart failure and in 15 normal subjects. Yohimbine produced a dose-related increase in forearm blood flow and decrease in forearm vascular resistance. These findings were consistent with a direct vasodilator effect mediated by blockade of the postsynaptic alpha 2-vascular receptor. Furthermore, the vasodilator responses in patients with heart failure were similar to the normal subjects in terms of the percent increase in forearm blood flow, the dose-response relation, and the fractional response to hyperemia and phentolamine; thus, alpha 2-receptor-mediated vasoconstriction is neither enhanced nor down-regulated in heart failure. In addition, in patients with heart failure and in normal subjects, yohimbine produced an increase in the forearm venous norepinephrine concentration, consistent with an inhibition of the presynaptic alpha 2-receptor resulting in an augmented release of norepinephrine into the synaptic cleft. Thus, these data suggest that the postsynaptic alpha 2-receptor is an important mediator of vasoconstriction in patients with heart failure. Despite chronic elevations in plasma norepinephrine in patients with heart failure, alpha 2-receptor mechanisms subserving vasoconstriction and inhibition of norepinephrine release into the synaptic cleft are still functional in heart failure.     

Clinical effects of long-term administration of pimobendan in patients with moderate congestive heart failure

Summary The long-term efficacy of the positive inotropic and vasodilator drug, pimobendan, was assessed in 21 patients suffering from symptomatic heart failure. Patients were randomized to 16 weeks of double-blind therapy with either 2.5 or 5.0mg/day of pimobendan (n = 10), or a matching placebo (n = 11). Patients were blinded on the study drug if their clinical status had not substantially worsened during the study. Of the placebo-treated patients, 5 patients were withdrawn from the study because of a deterioration of their heart failure, while none of the active treated group was withdrawn because of increased symptoms. Quality of life, assessed by the specific activity scale derived from the metabolic costs of individual physical activity, was 3.45 ± 0.90 (SD) mets in the baseline state and increased significantly after week 16, averaging 5.07 ± 1.40 and 4.67 ± 1.47 mets at weeks 16 and 24, respectively. In the placebo-treated group, the specific activity scale was 3.27 ± 1.21 mets at the baseline and remained unchanged throughout the study period. Patients treated with pimobendan were able to significantly increase their exercise duration. The accompanying increase in peak oxygen uptake was statistically insignificant, due to the limited number of patients enrolled in the study. These results suggest that in contrast to the recent pessimistic view of the long-term efficacy of cardiotonic drugs, pimobendan is beneficial in treating patients with congestive heart failure and may favorably modify their prognosis. Further largescale evaluation of this agent is warranted.     

Acute and Chronic Effects of Propionyl-L-Carnitine on the Hemodynamics, Exercise Capacity, and Hormones in Patients with Congestive Heart Failure

Carnitine is an important cofactor in the intermediary metabolism of the heart, and carnitine deficiency is associated with congestive heart failure. We therefore studied the effects of acute (IV bolus, 30 mg/kg body weight) and chronic administration (1.5 mg/d for 1 month) of propionyl-L-carnitine on hemodynamics, hormone levels, ventricular function, exercise capacity, and peak oxygen consumption in 30 patients with chronic congestive heart failure (NYHA II–III, mean EF 29.5 ± 7%) in a phase II, parallel, single-blind, randomized, and placebo-controlled study. Acute administration of propionyl-L-carnitine caused a significant reduction in pulmonary artery and pulmonary wedge pressures at both day 1 (P < 0.001) and day 30 (P < 0.05) of the study but no other hemodynamics changes. Hormone levels did not change following acute administration of the drug. Chronic administration of propionyl-L-carnitine increased peak oxygen consumption by 45% (from 16.0 ± 3 to 23.5 ± 2 mL/kg/min, P ± 0.001), exercise time by 21% (from 8.1 ± 0.5 to 9.8 ± 0.4 minutes, P < 0.01), and peak exercise heart rate by 12% (P < 0.01). These changes were concomitant with a reduction of pulmonary artery pressure. In the treated group, there was a slight, but significant (P < 0.01), reduction in left ventricular dimensions. Hemodynamics and hormones measured after 1 month of oral therapy remained unchanged, except for a fall in pulmonary artery pressures, with a nonsignificant trend towards a fall in filling pressures and plasma norepinephrine. The chronic changes in the propionyl-L-carnitine group were seen at 15 days of treatment, and no further changes in these parameters were seen at 1 month. We conclude that propionyl-L-carnitine increases exercise capacity and reduces ventricular size in patients with congestive heart failure. The drug has no significant effects on hemodynamics or neurohormone levels. The use of a single-blind design reduces the impact of the positive finding on exercise capacity.     

Intractable heart failure despite angiotensin-converting enzyme inhibitors, digoxin, and diuretics: long-term effectiveness of add-on therapy with pimobendan

In 25 patients whose chronic congestive heart failure (CHF) had recently worsened to New York Heart Association class IV, pimobendan (5 to 20 mg/day) was added to maximum conventional therapy consisting of digoxin, diuretics, angiotensin-converting enzyme inhibitors, coumadin derivatives to prevent thromboembolic complications, and amiodarone to suppress serious ventricular rhythm disturbances. CHF was fatal in less than 1 month in five patients (two had shown some initial improvement). The other 20 had sustained improvement by at least one functional class, interrupted by episodes of CHF that usually responded to intravenous therapy. Median survival was 12 months (range 10 days to greater than 3 years); five patients died suddenly, 12 died of intractable CHF, and two died of other causes. Six patients were alive 3 years after the onset of treatment with pimobendan. Add-on therapy with pimobendan produced a sustained improvement in many patients with severe CHF that was no longer responding to a combination of digoxin, diuretics, and angiotensin-converting enzyme inhibitors.     

慢性阻塞性肺部疾病合并充血性心力衰竭患者B型脑钠肽的变化及临床意义

目的探讨慢性阻塞性肺部疾病（COPD）合并充血性心力衰竭（CHF）患者血浆B型脑钠肽（BNP）水平的变化及临床意义。方法选择120例COPD患者作为研究对象,其中COPD合并CHF组54例,COPD急性发作（AECOPD）组66例,选择健康体检正常者36例作为对照组,采用免疫荧光法快速测定BNP水平。比较三组间血浆BNP水平的差异。COPD合并CHF患者治疗好转后复查血浆BNP水平,比较治疗前、后血浆BNP水平的变化。结果COPD合并CHF组和AECOPD组血浆BNP水平分别为（798．41±231．64）pg／ml和（148．73±87．39）pg／ml;对照组血浆BNP水平为（46．83±15．54）pg／ml。COPD合并CHF患者与对照组及AECOPD患者比较,血浆BNP水平差异均有统计学意义（P〈0．01）;治疗后血浆BNP水平[（136．73±64．82）pg／ml]与治疗前比较明显下降（P〈0．01）。结论血浆BNP水平测定对COPD合并CHF患者有重要的鉴别诊断价值,可作为COPD合并CHF患者治疗效果的评价指标。     

Increase in plasma norepinephrine during prazosin therapy for chronic congestive heart failure

To investigate the mechanism of pharmacodynamic tolerance reported to occur during prazosin therapy of chronic congestive heart failure, we measured plasma norepinephrine, plasma epinephrine, plasma renin activity (PRA) and plasma aldosterone, as well as hemodynamics in eight patients with chronic congestive heart failure, functional class III and IV (NYHA), before and during 10 weeks of prazosin therapy.Initially, prazosin therapy produced significant hemodynamic improvement, but no significant changes were noted in norepinephrine, epinephrine, plasma renin activity or aldosterone. During ambulatory therapy, fluid retention developed in four patients, and three of them had symptoms or clinical evidence of congestive heart failure for which they required an increase in diuretic or prazosin therapy. Plasma norepinephrine levels for the whole group were signficantly higher after four weeks of therapy (p < 0.01). Repeat inpatient studies after 10 weeks showed a persistent hemodynamic response to prazosin in seven patients. One patient demonstrated complete hemodynamic tolerance whereas three others showed partial tolerance. In these four patients the cardiac output increased only to 3.78 ± 1.17 liters/min compared to 5.04 ± 2.11 liters/min during initial prazosin therapy. Plasma norepinephrine increased further and levels were significantly higher for the whole group than before prazosin therapy (p < 0.05). No significant changes in epinephrine, plasma renin activity or aldosterone were demonstrated.This increase in plasma norepinephrine suggests that the sympathetic nervous system could be involved in the pharmacodynamic tolerance to prazosin therapy in congestive heart failure. Further studies are necessary to extend these results.     

Effect of pimobendan in patients with chronic heart failure

OBJECTIVE:

To assess the effects of a calcium sensitizer, pimobendan, in patients with mild to moderate chronic heart failure.

PATIENTS AND METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.     

Acute and long-term effects of pimobendan (UD-CG 115) in NYHA II and III heart failure. Results of a randomized multicenter double-blind study]

The effects of pimobendan (UD-CG 115) on hemodynamics and exercise capacity after acute (single dose) and chronic (6 month) oral treatment, as well as acute treatment after 6 months were investigated in 67 patients with chronic heart failure of NYHA classes II or III, which had persisted in spite of treatment with diuretics and digitalis. They were treated with pimobendan (2.5 mg bid or 5 mg) or placebo in a randomized, double-blind multicenter trial. With a single administration before and after 6 months' treatment there was-compared to placebo-a significant fall in pulmonary capillary pressure (PCP) at rest (R) and during exercise (E) of 7% to 24%. Right atrial pressure (R) and pulmonary arterial pressure (PAP) (R, E) decreased after pimobendan on day 1; cardiac index (E) increased significantly. All other parameters were not influenced. After chronic therapy, PCP (E), PAP (E), LV stroke work index (E), and pulmonary resistance (R and E) values were significantly lowered by pimobendan when compared to day 1. Exercise duration was prolonged after 6 months by 83 s and 47 s after 5 and 10 mg/day, resp., compared to the placebo group (group difference not significant). Subjective wellbeing was improved in all three groups (no group difference). Clinical symptoms were not altered; six patients (two in each group) died suddenly. Another nine patients discontinued the trial prematurely because of poor efficacy or adverse events (no group difference). Overall, pimobendan was well-tolerated and had favorable effects on both acute and chronic hemodynamics and on exercise capacity. There was no evidence of any tolerance development.     

Increase in bicycloprostaglandin E2 metabolite in congestive heart failure in response to captopril

Vasodilating prostaglandins may be increased in patients with chronic congestive heart failure (CHF) to balance out the effects of vasoconstricting forces. Significant increases in plasma levels of bicycloprostaglandin E2 metabolite (PGEm), a chemically stable degradation product of the vasodilating prostaglandin E2, were found in response to captopril (39.4 +/- 7.8 vs. 46.2 +/- 8.2 pg/ml; p less than 0.01). With chronic captopril treatment bicyclo-PGEm remained elevated for 12 h after the last dose after 1 and 2 months (75.5 +/- 5.5; p less than 0.05 and 72.1 +/- 6.3 pg/ml; p less than 0.05, respectively). Upon readministration of captopril during chronic captopril treatment the significant increase of bicyclo-PGEm in response to captopril was sustained, as were changes in plasma renin activity, angiotensin II, and blood pressure. Plasma catecholamines were unchanged with captopril or decreased slightly, vasopressin remained moderately increased throughout. Taken together, the results suggest that vasodilating prostaglandin E2 production might play a part in captopril's beneficial action in chronic congestive heart failure.