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.     

Calcium sensitization with pimobendan: pharmacology, haemodynamic improvement, and sudden death in patients with chronic congestive heart failure

Calcium sensitization increases myocardial contractility byimproving energy utlization of the myocardium, without an increasein intracellular concentrations of cyclic adenosine monophosphate.The calcium sensitizer most extensively studied up to now ispimobendan (UD-CG 115 BS). Vasodilatation results primarilyfrom phosphodiesterase III inhibition Orally administered pimobendan appears rapidly in plasma. Apeak concentration is reached 1.5 h after drug intake; eliminationfrom the plasma compartment has a half-life of 1.5 h. First-passhepatic O-desmethylation of pimobendan produces the active metaboliteUD-CG 212; plasma concentration curves of UD-CG 212 are similarto those of pimobendan, with apeak concentration 1–2 hlater than the peak concentration of the parent compound. In patients with chronic congestive heart failure, pimobendanproduces a dose-dependent and prolonged decrease in pulmonarycapillary wedge pressure and an increase in cardiac output.Maintenance doses ofpimobendan are well tolerated and may leadto lasting symptomatic improvement in patients with heart failure;open and blinded trials show that exercise tolerance increases.No attenuation of these effects is seen during long-term therapywith pimobendan. Patients in chronic congestive heart failure frequently diesuddenly; many inotropic agents increase the incidence of suddendeath in these patients. Although proarrhythmia has never beenobserved with pimobendan, arrhythmia suppression with amiodaroneseems prudent in heart failure patients receiving maintenancedoses of pimobendan.     

Improved systolic and diastolic myocardial function with intracoronary pyruvate in patients with congestive heart failure

BACKGROUND: Pyruvate increases myocardial performance in isolated myocardium and improves hemodynamics in patients with congestive heart failure. AIMS: To investigate the influence of pyruvate on detailed parameters of systolic and diastolic left ventricular (LV) function. METHODS AND RESULTS: In patients with heart failure due to dilated cardiomyopathy (LVEF 30+/-4%, n=9) pyruvate was infused intracoronarily. LV function was analysed before, during and after application of different pyruvate concentrations using a LV-micromanometer catheter. LV volumes were determined using cine ventriculography. Pyruvate increased maximum rate of LV isovolumic pressure rise (Peak +dP/dt) from 802+/-106 to 1125+/-103 mmHg/s (P<0.05). Left ventricular end-diastolic pressure declined in parallel from 17+/-2 to 12+/-2 mmHg (P<0.05) and heart rate decreased from 79+/-4 to 72+/-5 min(-1) (P<0.05). Stroke volume index increased from 34+/-4 to 43+/-6 ml/m(2) (P<0.05), end-diastolic LV volume remained unchanged, thus left ventricular ejection fraction increased with pyruvate from 30+/-4 to 39+/-4% (P<0.05). Maximum rate of LV isovolumic pressure decline (Peak -dP/dt) was significantly increased with pyruvate (from 794+/-94 to 980+/-108 mmHg/s; P<0.05) and mean arterial pressure increased from 80+/-5 to 88+/-4 mmHg (P<0.05). Discontinuation of pyruvate resulted in immediate reversibility of its effects. CONCLUSION: Intracoronary pyruvate improves systolic and diastolic myocardial function and increases ejection fraction without increasing heart rate. Pyruvate thus exhibits the profile of a favourable inotropic agent, however, further investigation for the treatment of patients with acute heart failure is mandatory.     

Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure

AIMS: To determine the duration of haemodynamic and neurohormonal action of a 24-h infusion of levosimendan in heart failure. METHODS AND RESULTS: This was a double-blind, parallel group study in patients with New York Heart Association class II to IV heart failure. Twenty-two patients, with left ventricular ejection fraction <35% and pulmonary capillary wedge pressure (PCWP) above 12 mmHg, were randomised to receive either levosimendan (12 microg/kg followed by a continuous infusion of 0.1-0.2 microg/min) or placebo. Invasively measured cardiac output (CO) increased from 4.3 l/min to 5.4 l/min in the levosimendan group at 6 h. PCWP decreased from 20 mmHg to 15 mmHg in response to levosimendan. Echocardiographically measured maximal effect on PCWP occurred after 6 h, whereas CO reached its highest value at 24 h. The estimated duration of the decrease in PCWP was 7-9 days, and in CO was 12-13 days. Plasma NT-proANP and NT-proBNP levels reached their lowest values at days 3 and 2, and the treatment effect was estimated to last 16 and 12 days, respectively. The long-acting haemodynamic responses reflect levels of the active metabolites OR-1896 and OR-1855, maximal metabolite levels occurred at day 3. CONCLUSIONS: Levosimendan infusion achieved a rapid improvement in haemodynamic parameters in patients with congestive heart failure with maximal effects occurring 1-3 days after starting the infusion, effects were sustained for up to at least a week.     

Hemodynamic effects of lisinopril after long-term administration in congestive heart failure

To determine whether acute effects of the angiotensin converting enzyme inhibitor lisinopril are maintained during long-term therapy, 19 patients were studied using right-sided heart catheterization before an initial randomized dose of lisinopril and again after 12 weeks of maintenance lisinopril therapy. During initial evaluation, lisinopril produced significant decreases in mean systemic arterial pressure, pulmonary artery wedge pressure, systemic vascular resistance, mean pulmonary arterial pressure, mean right atrial pressure and pulmonary vascular resistance, and concomitant increases in cardiac index and stroke volume index. After 12 weeks of therapy with lisinopril, the dosage of which was titrated to produce optimal relief of symptoms of congestive heart failure (CHF), repeat hemodynamic studies revealed persistent significant reductions in baseline systemic arterial pressure, pulmonary artery wedge pressure, mean pulmonary arterial pressure and systemic vascular resistance. However, the increases in cardiac index and stroke volume index were not statistically significant. To determine if further acute hemodynamic changes occur during long-term therapy, the patients were readministered a dose of lisinopril. This caused further decreases in systemic arterial pressure, mean pulmonary arterial pressure, pulmonary artery wedge pressure, systemic vascular resistance and mean right atrial pressure, and an increase in cardiac index. Lisinopril did not change stroke work index at either initial or rechallenge study. This study indicates that in patients with CHF treated with lisinopril, acute hemodynamic effects persist after 12 weeks of therapy, and acute hemodynamic response continues to occur upon drug readministration.     

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.     

Cardiovascular effects of berberine in patients with severe congestive heart failure

Berberine, an alkaloid of the protoberberine family, has been shown to have strong positive inotropic and peripheral resistance-lowering effects in dogs with and without heart failure. To determine the acute cardiovascular effects of berberine in humans, 12 patients with refractory congestive heart failure were studied before and during berberine intravenous infusion at rates of 0.02 and 0.2 mg/kg per min for 30 minutes. The lower infusion dose produced no significant circulatory changes, apart from a reduction in heart rate (14%). The 0.2 mg/kg per min dose elicited several significant changes: (a) Decreases in systemic (48%, p less than 0.01) and pulmonary vascular resistance (41%, p less than 0.01), and in right atrium (28%, p less than 0.05) and left ventricular end-diastolic pressures (32%, p less than 0.01). (b) Increases in cardiac index (45%, p less than 0.01), stroke index (45%, p less than 0.01), and LV ejection fraction measured by contrast angiography (56%, p less than 0.01). (c) Increases in hemodynamic and echocardiographic indices of LV performance: peak measured velocity of shortening (45%, p less than 0.01), peak shortening velocity at zero load (41%, p less than 0.01), rate of development of pressure at developed isovolumic pressure of 40 mmHg (20%, p less than 0.01), percent fractional shortening (50%, p less than 0.01), and the mean velocity of circumferential fiber shortening (54%, p less than 0.01). (d) Decrease of arteriovenous oxygen difference (28%, p less than 0.05) with no changes in total body oxygen uptake, arterial oxygen tension, or hemoglobin dissociation properties.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amiloride improves hemodynamics in patients with chronic congestive heart failure treated with chronic digoxin and diuretics

Potassium-sparing diuretics have been reported to decrease the positive inotropic effect of digoxin. We studied the hemodynamic effects of amiloride in patients taking digoxin for chronic heart failure. Eleven men with a history of congestive heart failure were studied in a double blind, cross-over, placebo controlled trial with the patients on digoxin alternating placebo with amiloride. After 7 days on the trial drug, a Swan-Ganz catheter was placed in the pulmonary artery and measurements made at rest and with increasing degrees of supine bicycle exercise. Right-sided and pulmonary artery wedge pressures and systemic arterial pressures, as well as cardiac outputs, were measured. After a 7 day washout period, placebo (P) and Amiloride (A) were switched and after 7 days on the therapy, a second hemodynamic study at rest and varying degrees of supine bicycle exercise was repeated. At rest there were no significant differences in the right-sided, pulmonary arterial wedge pressure or cardiac outputs between the patients on Amiloride (A) versus placebo (P). During exercise there were significant differences between (P) and (A) at the 50 watt-second stage of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of supplemental oxygen administration in congestive heart failure

Objectives. This study sought to determine the hemodynamic effects of oxygen therapy in heart failure.Background. High dose oxygen has detrimental hemodynamic effects in normal subjects, yet oxygen is a common therapy for heart failure. Whether oxygen alters hemodynamic variables in heart failure is unknown.Methods. We studied 10 patients with New York Heart Association functional class III and IV congestive heart failure who inhaled room air and 100% oxygen for 20 min. Variables measured included cardiac output, stroke volume, pulmonary capillary wedge pressure, systemic and pulmonary vascular resistance, mean arterial pressure and heart rate. Graded oxygen concentrations were also studied (room air, 24%, 40% and 100% oxygen, respectively; n = 7). In five separate patients, muscle sympathetic nerve activity and ventilation were measured during 100% oxygen.Results. The 100% oxygen reduced cardiac output (from 3.7 ± 0.3 to 3.1 ± 0.4 liters/min [mean ± SE], p < 0.01) and stroke volume (from 46 ± 4 to 38 ± 5 ml/beat per min, p < 0.01) and increased pulmonary capillary wedge pressure (from 25 ± 2 to 29 ± 3 mm Hg, p < 0.05) and systemic vascular resistance (from 1,628 ± 154 to 2,203 ± 199 dynes's/cm⁵, p < 0.01). Graded oxygen led to a progressive decline in cardiac output (one-way analysis of variance, p < 0.0001) and stroke volume (p < 0.017) and an increase in systemic vascular resistance (p < 0.005). The 100% oxygen did not alter sympathetic activity or ventilation.Conclusions. In heart failure, oxygen has a detrimental effect on cardiac output, stroke volume, pulmonary capillary wedge pressure and systemic vascular resistance. These changes are independent of sympathetic activity and ventilation.     

己酮可可碱治疗慢性充血性心力衰竭患者的远期疗效

目的观察己酮可可碱（PTX）治疗慢性充血性心力衰竭（CHF）患者远期疗效。方法81例CHF患者在常规抗心衰治疗基础上被随机分成PTX组（PTX200mg,每日3次,n=41）和安慰剂组（n=40）,共治疗12个月。观察治疗前后血浆细胞因子水平、NYHA心功能分级、心脏结构和功能、生活质量、运动耐量的变化以及PTX治疗对再住院率和病死率的影响。结果74例CHF患者完成随访。与安慰组比较,PTX可显著降低血浆中高敏C反应蛋白、肿瘤坏死因子-α和单核细胞趋化蛋白-1的水平（均P<0.05）。此外,PTX在降低左室舒张末内径[（56±9）mmvs（61±7）mm,P<0.05]、增加左室射血分数[（48±11）%vs（41±12）%,P<0.05]和降低再住院率（34%vs61%,P<0.05）等方面较安慰剂组更显著,但两组间病死率无显著差异。结论在常规抗心衰治疗基础上加用PTX可进一步改善CHF患者的临床状态,降低再住院率。     

Electrophysiologic effects of milrinone in patients with congestive heart failure

The electrophysiologic effects of milrinone, a new inotropic agent, have not been characterized in humans. Accordingly, 10 patients with class III or IV congestive heart failure underwent hemodynamic and electrophysiologic testing before and during an infusion of milrinone (0.5 micrograms/kg/min). Cardiac index increased from a mean of 1.65 +/- 0.51 to 2.19 +/- 0.68 liters/min/m2 (p less than 0.03) and pulmonary artery capillary pressure decreased from 30 +/- 9 to 22 +/- 9 mm Hg (p less than 0.01), without a significant change in systemic arterial pressure. Holter monitoring was performed for 48 hours at baseline and during infusion of milrinone. Frequency of ventricular premature complexes and ventricular couplets did not change significantly. Frequency of ventricular tachycardia (VT) increased significantly, although no patients would be classified as having a proarrhythmic effect based on a clinical model. PR, QRS, QTc, heart rate, AH, HV, atrial, atrioventricular and ventricular effective and functional refractory periods were not affected. Milrinone decreased 1:1 atrioventricular maximal conduction from 399 +/- 133 to 374 +/- 111 ms (p less than 0.01); ventriculoatrial conduction was not significantly affected. During programmed right ventricular stimulation, 5 patients had inducible VT at baseline (3 sustained, 2 non-sustained), whereas after drug administration, none had it (p less than 0.05). Thus, intravenous milrinone is an effective inotropic drug that also enhances atrioventricular conduction and may decrease the incidence of inducible VT in patients with congestive heart failure.     

常规药物与联合曲美他嗪治疗充血性心力衰竭的临床观察

目的观察曲美他嗪对充血性心力衰竭(CHF)患者心功能影响。方法 80例病情稳定的CHF患者(NYHAⅡ～Ⅳ级),随机分为两组:对照组(40例,采用心力衰竭常规药物治疗)和治疗组(40例,常规药物治疗+曲美他嗪20mg,3次/d),治疗6个月。治疗前后观察心力衰竭症状和体征,测定左心室射血分数(LVEF)、左心室质量指数(LVMI)和左心室舒张末期内径(LVEDD),记录NYHA分级和心功能等指标的变化。结果入选前两组基线资料有可比性,治疗后曲美他嗪组的心功能改善的总有效率为95.0%,对照组为52.5%;曲美他嗪组LVMI[(106.7±13.6)g/m~2]低于对照组[(136.7±14.8)g/m~2],曲美他嗪组LVEF(51.4%±6.9%)高于对照组(43.6%±7.7%)(均为P0.05)。末见明显不良反应。结论在常规心力衰竭治疗基础上加用曲美他嗪,能改善CHF患者的心脏收缩功能,安全性好。     

美托洛尔治疗心力衰竭的临床观察

目的 观察美托洛尔治疗充血性心力衰竭的临床疗效。方法 将40例充血性心力衰竭患者随机分为美托洛尔治疗组和对照组各20例,治疗组给予美托洛尔加常规抗心力衰竭治疗,对照组仅常规抗心力衰竭治疗,分别观察3周和2年的治疗效果。结果治疗3周后两组的心功能改善和猝死无显著差别,治疗2年后治疗组心功能改善明显优于对照组,而猝死的发生明显低于对照组。结论 美托洛尔对充血性心力衰竭有显著疗效,能够改善心功能和降低猝死率。     

Renal effects of xamoterol in patients with moderate heart failure

Summary The acute renal effects of xamoterol, a partial beta₁-agonist, were studied in 12 patients with congestive heart failure (NYHA II–III) in stable condition on diuretic therapy for at least 6 weeks. Each patient was given a single intravenous infusion of xamoterol (0.2 mg/kg) or placebo in random order 2 weeks apart. Using constant infusion and lithium clearance techniques, clearance and excretion measurements were made in the supine position at 30- to 60-min intervals before, during, and up to 6 hours after infusion. Blood pressure, heart rate, renal plasma flow, glomerular filtration rate, and urinary flow rate remained unchanged, but xamoterol lowered sodium excretion by 30% (p<0.05). The decrease started 120 minutes after infusion. Proximal reabsorption of sodium increased after xamoterol infusion, whereas plasma values of aldosterone and angiotensin II were unaffected. It is concluded that the acute renal effects of xamoterol imply an impaired sodium excretion determined by the tubular actions of the drug. The present results suggest that xamoterol may aggravate one of the important abnormalities intrinsic to the pathology of congestive heart failure. These findings are in contrast to the beneficial effects of xamoterol demonstrated in many clinical trials where xamoterol was given orally for a longer period.     

Comparative effects of long-term therapy with captopril and ibopamine in chronic congestive heart failure in old patients

Little is known concerning the long-term drug management of chronic heart failure (CHF) in old patients (greater than or equal to 75 years). Accordingly, this double-blind, placebo-controlled trial compared the long-term (over 6 months) effect of captopril (37.5-75 mg/day) and of ibopamine (150-300 mg/day) on exercise testing, symptoms and subjective feeling of well-being, in 150 CHF elderly patients (mean age 75 years) under treatment with digitalis and/or diuretics. During an additional open follow-up of approximately 1.5 years, morbid events and deaths were also recorded. Captopril and ibopamine performed better (p less than 0.01) than placebo, improving the 6-min walking distance (captopril from 300 to 404 m, ibopamine from 282 to 385 m; placebo from 283 to 299 m). NYHA status, symptom score and patients' global assessment. The difference between the active study drugs was not statistically significant (p greater than 0.05). Complicating events, including diuretic use, frequency of hospitalization, worsening of CHF and deaths, were grouped by patient-years. These events were significantly (p less than 0.01) lower (captopril: 28/75 patient-years; ibopamine 33/74 patient-years) in the active treatment groups with respect to placebo (58/96 patient-years). Captopril and ibopamine showed a different safety profile. Creatinine increase (2 patients), symptomatic hypotension (4 patients), hyperkalemia (2 patients) and upper respiratory symptoms were mostly associated with captopril treatment. Gastrointestinal adverse events were observed in 11 patients under ibopamine treatment. The study provides evidence of the clinical usefulness of both captopril or ibopamine in the long-term treatment of CHF in old patients. The safety profile of each drug will suggest the preferred therapeutic application.     

带有心力衰竭预警功能的CRT-D InSync Sentry的临床应用

目的联合有心脏再同步治疗（CRT）和植入型心律转复除颤器（ICD）功能的CRT-D已开始应用于临床治疗充血性心力衰竭，尤其是带有心力衰竭预警功能的InSync Sentry可以预警心功能的恶化，提示医生及早干预，减少心力衰竭的发生。本文旨在初步总结InSync Sentry的临床应用。方法6例药物治疗无效的充血性心力衰竭患者接受了CRT-D InSync Sentry治疗。其中3例患者既往有恶性室性心律失常发作史。基础病因为扩张性心肌病5例，缺血性心肌病1例。结果6例患者均成功植入InSync Sentry，平均左心室导线起搏阈值1．24V，除颤能量≤20J，无并发症发生。随访2-13个月，1例患者发生2次室性心动过速导致的电击事件；1例患者由于心功能恶化出现2次报警事件，药物治疗后好转。结论CRT-D植入相对安全，能有效预防心脏性猝死，成功预警心功能恶化，改善预后。     

Peripheral hemodynamic effects of captopril in patients with congestive heart failure

In 14 patients with severe congestive heart failure, the effects of captopril on the forearm circulation were evaluated with strain gauge plethysmography. Changes in plasma renin activity, angiotensin II, norepinephrine, epinephrine, bradykinin, prostaglandin E2, and 6-keto-prostaglandin F1 alpha concentrations were also measured. To determine whether the prostaglandins contribute to the peripheral hemodynamic response to captopril, the hemodynamic and hormonal measurements were repeated after pretreatment with indomethacin, an inhibitor of prostaglandin synthesis. Ninety minutes after administering a single dose of captopril (25 mg), mean blood pressure and venous pressure decreased (p less than 0.01 and p less than 0.05, respectively), forearm blood flow and maximum venous volume increased (p less than 0.05 for both), and forearm vascular resistance and forearm venous tone decreased (p less than 0.05 for both). Captopril also improved forearm venous distensibility (p less than 0.05). Pretreatment with oral indomethacin (50 mg) significantly blunted all of these captopril-induced hemodynamic changes. The blockage of the renin-angiotensin system by captopril was unaltered by indomethacin pretreatment. Captopril significantly increased plasma bradykinin, prostaglandin E2, and 6-keto-prostaglandin F1 alpha (p less than 0.05 for each). Indomethacin pretreatment did not affect the captopril-induced increase in bradykinin, but it did completely eliminate the increase in the prostaglandins. Plasma catecholamines did not change with captopril. These data suggest that the vasodilator prostaglandins play a significant role in captopril's peripheral vasodilative effects in congestive heart failure.