Short-term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure

BACKGROUND: Both levosimendan and prostaglandin E1 (PGE1) have beneficial effects on hemodynamic parameters and outcome compared to dobutamine in decompensated chronic heart failure (CHF). AIMS: We compared short-term effects of levosimendan versus PGE1 on hemodynamic parameters and B-type natriuretic peptide levels (BNP) in patients with decompensated CHF. METHODS AND RESULTS: 73 patients (cardiac index < 2.5 L/min/m2, pulmonary capillary wedge pressure (PCP) >15 mmHg) with decompensated CHF were randomised to treatment with either a 24 h-infusion of levosimendan (n=38) or a chronic infusion of PGE1 (n = 35). Hemodynamic parameters and BNP were measured at baseline, 24 and 48 h, BNP levels were also measured after 1 week. Baseline characteristics including concomitant medication were similar in both groups. Levosimendan and PGE1 increased cardiac output (CO) after 24 and 48 h. Levosimendan increased CO twice as much as PGE1 (24 h: Levosimendan +1.1 +/- 0.1 L/min, PGE1 +0.6 +/- 0.1 L/min, p < 0.001). Both drugs produced a comparable reduction in PCP and pulmonary artery pressure after 24 and 48 h. Levosimendan decreased BNP by 28% after 24 h and 22% after 48 h, but effects disappeared after 1 week. In contrast, PGE1 decreased BNP by 15% after 48 h (no change at 24 h), but a decrease of 20% was sustained at 1 week. CONCLUSIONS: The differential beneficial effects of levosimendan (greater increase in CO) and PGE1 (sustained decrease in BNP) may have a potential impact on clinical outcome.     

Levosimendan and prostaglandin E1 for uptitration of beta-blockade in patients with refractory, advanced chronic heart failure

BACKGROUND: In advanced chronic heart failure (CHF) 20% of patients do not tolerate beta-blockers and 50% do not reach target doses. AIM: To test whether levosimendan or prostaglandin E1 (PGE1) can facilitate uptitration of beta-blockers in advanced CHF. METHODS AND RESULTS: Seventy-five advanced CHF patients (LVEF<35%, NYHA class IIIb or IV) intolerant to beta-blocker uptitration to target doses (10 mg bisoprolol/day) were randomised to a monthly 24 h infusion with levosimendan (n=39) or a chronic infusion with PGE1 (n=36) for 3 months. Bisoprolol was uptitrated following predefined criteria. At 12 weeks, bisoprolol dose increased from 4 mg to 10 mg in both groups. Heart failure worsening occurred in 29 levosimendan patients (74%) versus 16 PGE1 patients (44%, p=0.008). Uptitration was impossible in 9 levosimendan patients (23%) versus 2 PGE1 patients (6%, p=0.03). The combined endpoint of death or urgent heart transplantation or implantation of a ventricular assist device was reached by 12 levosimendan patients (31%) versus 4 PGE1 patients (11%, p=0.04). After 1 year, LVEF increased from 23+/-7% to 28+/-11% (p=0.0004), and BNP decreased from 994+/-806 to 659+/-564 pg/ml (p=0.03). CONCLUSION: Levosimendan and PGE1 facilitate uptitration of beta-blockers in previously intolerant CHF patients. PGE1 treatment allowed uptitration in more patients and resulted in a better clinical outcome compared to levosimendan. This approach increased LVEF and decreased BNP after 1 year.     

The Ca2+-sensitizer levosimendan improves oxidative damage, BNP and pro-inflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine

AIM: To investigate the effect of a new inotropic drug, levosimendan compared with dobutamine on levels of brain natriuretic peptide (BNP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and malondialdehyde (MDA) in patients with severe decompensated heart failure. METHODS AND RESULTS: Twenty-nine consecutive patients (22 males and 7 females), mean age 70.5+/-9.9 years, with decompensated heart failure on standard medical therapy, were randomised to receive either a 24 h infusion of levosimendan (n=15) or dobutamine (n=14). Blood samples were drawn at baseline, 48 h and 5 days post infusion. Levosimendan produced a significant reduction in BNP compared to baseline, at both 48 h (744.1+/-100 vs 1136.3+/-93.7 pg/ml, p=0.04) and 5 days (446+/-119.3 vs 1136.3+/-93.7 pg/ml, p=0.03), while IL-6 values decreased after 5 days (4.8+/-1.3 vs 8.6+/-1.5 pg/ml, p=0.01). MDA levels were significantly lower 5 days after levosimendan compared to baseline (2.3+/-0.2 vs 3+/-0.3 microM, p=0.01). TNF-alpha levels did not differ between the groups. The comparison of percentage alteration compared to baseline showed that BNP (-44.5+/-7.6% vs 4.8+/-18.7%, p=0.025), MDA (-21.8+/-5.1% vs 14.9+/-8.5%, p=0.001) and IL-6 (-38.8+/-12.5% vs 70.2+/-24%, p=0.001) levels were significantly lower in the levosimendan group 5 days after treatment compared to the dobutamine group. CONCLUSIONS: Treatment with levosimendan in advanced decompensated heart failure exerts a beneficial hemodynamic, anti-inflammatory and antioxidant effect. These findings may give an insight into the favourable impact on mortality that levosimendan appears to have in published multicenter trials.     

Short-term effect of levosimendan on free light chain kappa and lambda levels in patients with decompensated chronic heart failure

To investigate the effects of levosimendan, a positive inotropic agent, on the new heart failure markers immunoglobulin free light chains kappa and lambda (FLC-κ and FLC-λ) in decompensated chronic heart failure (HF), 59 patients with New York Heart Association (NYHA) class III–IV HF were enrolled. Patients were randomized into levosimendan (n = 31) and standard HF treatment (n = 29) groups. Serum FLC-κ and FLC-λ, brain natriuretic peptide (BNP), and ejection fraction (EF) were measured before treatment and on the 5th day of treatment initiation. Forty-two percent of subjects were females (n = 25) and overall mean age was 64.1 ± 10.7 years. FLC-κ (P < 0.05) and FLC-λ (P < 0.05) were significantly decreased in the levosimendan group compared to baseline, but no difference in either marker in the standard treatment group was observed. Pre- and post-treatment FLC-κ/FLC-λ ratios in both groups were similar, whereas FLC-κ and FLC-λ levels and the FLC-κ/FLC-λ ratio showed no significant correlation with NYHA class, brain natriuretic peptide (BNP) and ejection fraction (EF) levels; and BNP and EF changes after the treatment. Symptomatic improvement in the levosimendan group according to the NYHA class was significantly better than in the standard treatment group (P = 0.044). While 55.2% of patients in the levosimendan group showed a 1-degree shift to lower NYHA classes, 10.3% showed a 2-degree decrease. In conclusion, levosimendan caused short-term hemodynamic and symptomatic improvements, with a more pronounced decrease in FLC levels in patients with advanced decompensated HF.     

Effects of levosimendan on coronary artery flow and cardiac performance in patients with advanced heart failure

BACKGROUND: Levosimendan has inotropic and vasodilatory effects. We investigated the effects of levosimendan on coronary flow and associated changes in neurohormonal activation and cardiac performance in patients with advanced heart failure. METHODS: Forty-two patients with NYHA III-IV and a left ventricular ejection fraction (EF) 25+/-6%, were randomised to levosimendan 0.1 microg/kg/min (n=21) or placebo for 24 h. Before and 24 h after each treatment, we assessed: the maximal velocity (Vmax), time integral (VTI) and deceleration time (DT) of the diastolic coronary flow wave (CF) in LAD using transthoracic Doppler echocardiography, pulmonary artery systolic pressure by Doppler echocardiography, E/E' ratio using Doppler imaging of mitral inflow velocity, tissue Doppler imaging of the mitral annulus and B-type natriuretic peptide (BNP) levels. RESULTS: By ANOVA, there was a greater increase in CF-Vmax (43+/-23 vs.25+/-8 cm/s), CF-DT (904+/-250 vs. 667+/-151 ms), and EF and a greater decrease in BNP, pulmonary artery systolic pressure and E/E? after levosimendan than after placebo (p<0.05). Compared to baseline, the percent changes in CF-VTI were related to the concomitant changes in EF, E/E?, and BNP after treatment with levosimendan (r=0.69, r=?0.51 and r=?0.80, p<0.05 respectively). CONCLUSION: Treatment with levosimendan improves coronary flow and microcirculation in parallel with an improvement in cardiac performance and neurohormonal activation in patients with advanced heart failure.     

Levosimendan: A calcium-sensitizing agent for the treatment of patients with decompensated heart failure

Levosimendan is a new inodilator. Its mechanism of action includes calcium sensitization of contractile proteins and the opening of adenosine triphosphate-dependent K channels. The combination of positive inotropy with antiischemic effects of K-channel opening offers potential benefits in comparison with currently available intravenous inotropes, which are contraindicated in patients with ongoing myocardial ischemia. Levosimendan has been extensively studied in various animal models of heart failure, in which the drug has increased contractility without adverse effects on diastolic function. These results have been repeated in patients with heart failure, in whom levosimendan dosedependently increases cardiac output and reduces pulmonary capillary wedge pressure. The active metabolite of levosimendan (OR-1896) significantly prolongs the duration of the hemodynamic effects of the therapeutic 24-hour levosimendan infusion. Levosimendan has been studied in two major trials with decompensated patients (LIDO and RUSSLAN), in which it showed outcome benefits in comparison with dobutamine and placebo, respectively. A third comparative study (CASINO) recently suggested mortality benefits with levosimendan over placebo and dobutamine. Currently, two large prospective trials (SURVIVE and REVIVE) in patients who are hospitalized because of worsening heart failure are underway. These trials will conclusively prove whether levosimendan should be added to the standard treatment in patients who are hospitalized because of cardiac decompensation.     

Levosimendan produces an additional clinical and hemodynamic benefit in patients with decompensated heart failure successfully submitted to a fluid removal treatment

A pivotal role in treating decompensated heart failure (HF) is played by inotropes and calcium sensitizers such as levosimendan. In this study, the authors evaluated whether levosimendan could determine further clinical and hemodynamic benefits in 31 HF patients (New York Heart Association [NYHA] class III or IV), after successful treatment with diuretics (n=15) or ultrafiltration (n=16). Systolic, diastolic, dicrotic, and mean arterial pressures; systemic vascular resistance (SVR); some classic hemodynamic variables (cardiac output [CO], stroke volume [SV], dP/dt(max) ); and indices of cardiovascular system performance (cardiac cycle efficiency [CCE], cardiac power output) have been assessed by the pressure recording analytical method (PRAM), a minimally invasive monitoring system, before levosimendan infusion, at the end of treatment (EoT), and 36?hours after EoT (post-36). A significant increase in CCE, CO, SV, and dP/dt(max) and a significant decrease in diastolic and dicrotic arterial pressures and in SVR have been observed at EoT and at post-36. After the addition of levosimendan, a further reduction in signs and symptoms of HF and NYHA class was observed. Five patients showed an opposite trend of several hemodynamic parameters without any significant clinical improvement (nonresponders). In conclusion, most HF patients treated with diuretics or ultrafiltration receive additional clinical and hemodynamic benefits from levosimendan. The characterization of nonresponders could help in optimizing its use.     

Levosimendan: from basic science to clinical practice

Levosimendan is a new cardiac enhancer that exerts positive inotropic effects on the failing heart mediated by calcium sensitization of contractile proteins as well as peripheral vasodilatory effects mediated by opening of ATP-sensitive potassium channels in vascular smooth-muscle cells. Levosimendan is the most well-studied calcium sensitizer in the real clinical practice, producing greater hemodynamic and symptomatic improvement in patients with acute heart failure syndromes (AHFS) than those with traditional inotropes. Immunomodulatory and anti-apoptotic properties of levosimendan may be an additional biologic mechanism that prevents further cytotoxic and hemodynamic consequences of abnormal immune and neurohormonal responses in AHFS. Recent mortality trials showed that levosimendan does not improve short- and long-term prognosis in AHFS in comparison to dobutamine or placebo. However, in patients with a previous history of CHF and on beta-blocker on admission, levosimendan seems to have a beneficial effect on short-term mortality. According to the recent guidelines of the European Society of Cardiology, levosimendan is indicated in patients with symptomatic low cardiac output HF secondary to cardiac systolic dysfunction without severe hypotension (Class IIa, Level of Evidence B).     

急性失代偿充血性心力衰竭患者氨基端脑钠肽前体水平与血流动力学参数间的相关性分析

目的 通过对血氨基端B-型尿钠肽前体（ NT-proBNP）水平、左室射血分数（LVEF）和左室舒张期末内径（ LVEDd）与急性失代偿性心力衰竭患者的有创血流动力学指标进行相关性分析,评估NT-proBNP在急性失代偿性心力衰竭治疗监测中的意义.方法 连续入选我院重症监护病房急性失代偿性充血性心力衰竭（NYHAⅢ～Ⅳ）、LVEF＜40％、Swan Ganz导管检查肺毛细血管楔压（PCWP）≥13mmHg患者共32例.在植入Swan Ganz导管前8小时内,进行血NT-proBNP水平检测及超声心动图检查;冰盐水热稀释法连续测量平均肺动脉压（MPAP）、PCWP、系统血管阻力指数（ SVRI）和心脏指数（CI）三次,并记录平均值.对NT-proBNP水平与LVEF、LVEDd及有创血流动力学指标进行线性相关性分析.结果LVEF、LVEDd与CI及PCWP之间无显著相关性;NT-proBNP与CI具有显著相关性（r=-0.356,P＜ 0.05）,与PCWP无显著相关性;有创血流动力学指标中,MPAP,PCWP,SVRI与CI具有显著相关性（r=-0.358,r=-0.309,r=-0.576,P＜0.05）,MPAP与PCWP具有显著相关性（r=-0.822,P＜0.05）;其它有创血流动力学参数间无显著相关性.结论 急性失代偿充血性心力衰竭患者的常用血流动力学指标中,仅NT-proBNP与CI具有显著相关性,NT-proBNP水平对监测血流动力学状态有重要意义.     

Anti-inflammatory and anti-apoptotic effects of levosimendan in decompensated heart failure: a novel mechanism of drug-induced improvement in contractile performance of the failing heart

Recent experimental and clinical observations indicate that over-expression of pro-inflammatory cytokines is actively implicated to chronic heart failure progression through their cytotoxic and negative inotropic effects. Calcium-sensitizing agents, such as levosimendan, promotes inotropy by stabilizing troponin C in a configuration that enhances the calcium sensitivity of cardiac myofilaments, preserving also diastolic relaxation. Levosimendan also opens ATP-dependent potassium channels in peripheral vessels, leading to vasodilatation. Large scale randomized clinical trials have shown that levosimendan administration in patients with severe heart failure due to left ventricular systolic dysfunction results in favorable hemodynamic changes, symptomatic benefit, and a reduction in short-term morbidity and mortality. This review describes current knowledge about novel cellular mechanisms associated with beneficial effects of levosimendan on cardiac contractile performance, focusing mainly on its immunomodulatory and anti-apoptotic properties. Levosimendan-induced improvement in contractile reserve and clinical status of severe heart failure patients, seems to be related with the reduction of major pro-inflammatory cytokines (TNF-alpha, IL-6) and soluble apoptosis signaling molecules Fas/Fas Ligand. Modulation of pro-inflammatory and pro-apoptotic pathways into the failing heart by levosimendan may be an additional pathophysiologic mechanism that prevents further clinical and hemodynamic consequences of abnormal immune responses in decompensated heart failure and beneficially affects the progression of the syndrome.     

Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure

A single levosimendan administration has recently been shown to result in clinical and hemodynamic improvement in patients with decompensated heart failure (HF), but without survival benefits. In this study, the effects of levosimendan and dobutamine on plasma levels of proinflammatory and proapoptotic mediators in decompensated HF were compared and correlated with the concomitant effects on cardiac function and prognosis. Sixty-nine patients were randomized to received 24-hour intravenous infusions of levosimendan (n = 23), dobutamine (n = 23), or placebo (n = 23). Echocardiographic, hemodynamic, and biochemical assessments were performed at baseline, immediately after treatment, and 48 hours later. Patients were subsequently followed for 4 months for disease progression. End-systolic wall stress, the left ventricular ejection fraction, pulmonary capillary wedge pressure, and cardiac index were significantly improved in the levosimendan group but remained practically unaffected in the other groups. Plasma N-terminal-pro-B-type natriuretic peptide, tumor necrosis factor-alpha, and soluble Fas ligand levels were significantly decreased only in the levosimendan group (from 1,900 +/- 223 to 1,378 +/- 170 pg/ml, 13.4 +/- 1.0 to 12.3 +/- 1.2 pg/ml, and 68.2 +/- 3.7 to 59.8 +/- 3.6 pg/ml, respectively; p <0.05 for all); interleukin-6 was also borderline reduced (p = 0.051). Levosimendan-induced reduction in end-systolic wall stress was significantly correlated with respective decreases in N-terminal-pro-B-type natriuretic peptide (r = 0.671, p <0.01), tumor necrosis factor-alpha (r = 0.586, p <0.01), soluble Fas (r = 0.441, p <0.05), and soluble Fas ligand (r = 0.614, p <0.01). Event-free survival was significantly longer in the levosimendan group (p <0.05). In conclusion, the superiority of levosimendan over dobutamine in improving central hemodynamics and left ventricular performance in decompensated HF seems to be related to its anti-inflammatory and antiapoptotic effects.     

Effects of Levosimendan on Quality of Life and Emotional Stress in Advanced Heart Failure Patients

AIM: Levosimendan improves central hemodynamics and symptoms in acutely decompensated chronic heart failure (CHF) patients. However, its effects on quality of life, emotional stress and functional capacity of patients with advanced CHF have not been properly investigated. METHODS AND RESULTS: Sixty-three advanced CHF patients (NYHA III-IV, LVEF<30%) were randomized (2:1) to receive either a 24-h levosimendan infusion of 0.1 mug/kg/min or placebo. Questionnaires addressing quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall, Duke's Activity Status Index (DASI)] and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)], as well as plasma BNP and 6-min walking distance (6MWT as a marker of exercise capacity) were assessed before treatment and at hospital discharge. A significant improvement in NYHA class (2.1 +/- 0.7 from 3.3 +/- 0.7, p < 0.01), 6 MWT (305 +/- 152 from 215 +/- 142 m, p < 0.01) and plasma BNP (598 +/- 398 from 1,078 +/- 756 pg/ml, p < 0.01) was observed post-treatment only in levosimendan-treated group. KCCQ functional (45 +/- 19 from 35 +/- 17%, p < 0.05) and overall (34 +/- 13 from 28 +/- 11%, p < 0.05), DASI (26 +/- 13 from 22 +/- 12, p < 0.05), Zung SDS (38 +/- 12 from 42 +/- 13, p < 0.01) and BDI (11 +/- 6 from 14 +/- 8, p < 0.05) scores also improved in levosimendan-treated patients, while remained unchanged in the placebo group. The hospital length stay was shorter in levosimendan group compared to placebo (3.2 +/- 1.7 versus 5.8 +/- 2.1 days, p < 0.01). Levosimendan-induced BNP reduction was significantly correlated with concomitant increase in 6MWT (r = 0.643, p < 0.001) as well as with the decrease of BDI (r = 0.30, p < 0.05) and Zung SDS (r = 0.25, p = 0.05). CONCLUSION: Levosimendan seems to have a beneficial effect on quality of life, physical activity and emotional stress in advanced CHF patients, reducing concurrently hospitalization length.     

Levosimendan versus dobutamine in heart failure patients treated chronically with carvedilol

Introduction : Although beta‐blockers are highly effective in the treatment of heart failure (HF), many patients with HF receiving a beta‐blocker continue to become decompensated and require hospitalization for worsening HF. Levosimendan and dobutamine are used to manage decompensated HF, but their comparative effects on left ventricular (LV) function in patients prescribed beta‐blockers are unknown. Aims : The aim of this study was to compare the effects of dobutamine and levosimendan on LV systolic and diastolic functions in chronic HF patients treated chronically with carvedilol. Forty patients with chronic HF who had NYHA class III to IV symptoms, a LV ejection fraction (LVEF) <40%, and ongoing treatment with carvedilol were enrolled in this randomized (1:1), dobutamine controlled, open‐label study. Before and 24 h after treatment, LVEF, mitral inflow peak E and A wave velocity, E/A ratio, the deceleration time of the E wave (DT), isovolumic relaxation time (IVRT), peak systolic (Sm) and early diastolic (Em) mitral annular velocity, and systolic pulmonary artery pressure (SPAP) were measured by echocardiography. Results : Levosimendan produced a statistically significant increase in LVEF (28 ± 5% vs. 33 ± 3%), Sm (6.5 ± 1.2 cm/s vs. 7.4 ± 0.9 cm/s), DT (120 ± 10 ms vs. 140 ± 15 ms), and Em (7.5 ± 0.4 cm/s vs. 8.1 ± 0.5 cm/s) and significant decrease in E/A ratio (2.1 ± 0.3 vs. 1.7 ± 0.4) and SPAP (55 ± 5 mmHg vs. 40 ± 7 mmHg). No significant change occurred in LV systolic and diastolic function parameters, or SPAP with dobutamine treatment. Levosimendan did not significantly alter the heart rate (72 ± 4 bpm vs. 70 ± 3 bpm), systolic (105 ± 5 mmHg vs. 102 ± 4 mmHg), or diastolic blood pressure (85 ± 5 mmHg vs. 83 ± 5 mmHg) whereas with dobutamine treatment, all these parameters significantly increased. Conclusions : Dobutamine and levosimendan have different effects on LV functions in patients treated chronically with carvedilol. These differences should be considered when selecting inotropic therapy for decompensated HF receiving long‐term carvedilol.     

Effect of levosimendan on ventricular arrhythmias and prognostic autonomic indexes in patients with decompensated advanced heart failure secondary to ischemic or dilated cardiomyopathy

Positive inotropes used for the treatment of heart failure have been arrhythmogenic. Levosimendan is a novel calcium sensitizer with vasodilating properties and a complex mechanism of action. Its effect on ventricular arrhythmias and 24-hour Holter electrocardiographically derived prognostic autonomic nervous system-related markers, because it occurs in parallel with changes in cardiac function and neurohormonal response, has not been systematically assessed. Forty-five patients (mean age 65 +/- 1.3 years) with heart failure refractory to conventional therapy and a mean ejection fraction of 23 +/- 1.2%, randomized to levosimendan or placebo, were studied. After Holter electrocardiographic recording, 1 drug was infused for 24 hours (levosimendan at a dose of 0.1 mug/kg/min). During this period, another Holter recording was performed to assess changes in ventricular arrhythmogenesis, 24-hour heart rate variability indexes, QTc, QT variability, and QT/RR slope. Clinical evaluation, echocardiography, and B-type natriuretic peptide measurements were performed at baseline and after treatment. After levosimendan, clinical and echocardiographic improvement was observed, associated with beneficial neurohormonal modulation (mean B-type natriuretic peptide level after levosimendan 668 +/- 108 vs 1,009 +/- 122 pg/ml at baseline, p <0.05). Episodes of nonsustained ventricular tachycardia increased with levosimendan (21.9 +/- 9.6 vs 3.0 +/- 1.2, p <0.05). Levosimendan and placebo exerted a neutral effect on all autonomic markers assessed. In conclusion, levosimendan at low doses increases nonsustained ventricular arrhythmias, without affecting Holter-derived, prognostically significant autonomic markers. At the same time, it is associated with improvements in cardiac function and neurohormonal response. These findings may have important clinical and prognostic implications.     

Effects of levosimendan on right ventricular function in patients with advanced heart failure

Right ventricular (RV) dysfunction frequently complicates advanced left ventricular heart failure and contributes to an unfavorable prognosis. Levosimendan is a novel inodilator that beneficially affects hemodynamics and left ventricular systolic and diastolic function in patients with advanced heart failure. However, its effects on RV function have not yet been properly assessed in these patients. In this randomized trial, the impact of levosimendan or placebo on various echocardiographic parameters of RV systolic and diastolic function was investigated in 54 patients with advanced heart failure due to left ventricular systolic dysfunction. Tissue Doppler imaging maximal systolic tricuspid annular velocity (S wave) increased significantly only in the levosimendan group (8.2 +/- 3.2 vs 9.0 +/- 3.0 cm/s, p <0.03). Tissue Doppler imaging RV early diastolic velocity (E wave) and the ratio of early to late diastolic velocities (E/A) also increased significantly after levosimendan administration (p <0.01 and p <0.05, respectively). Systolic pulmonary arterial pressure decreased significantly (54 +/- 11 vs 43 +/- 11 mm Hg, p <0.01) in the levosimendan-treated patients. Levosimendan beneficially modulated neurohormonal and inflammatory status by decreasing B-type natriuretic peptide levels (p <0.05) and by altering the ratio of interleukin-6 to interleukin-10 in favor of the latter (p <0.05). In conclusion, levosimendan could offer further therapeutic advantages in patients with advanced heart failure by improving systolic and diastolic RV function.     

Levosimendan reduces plasma B-type natriuretic peptide and interleukin 6, and improves central hemodynamics in severe heart failure patients

BACKGROUND: Plasma B-type natriuretic peptide (BNP) and interleukin 6 (IL-6) levels have recently been demonstrated as significant neurohormonal markers associated with the progression of chronic heart failure (CHF). Additionally, clinical studies have shown that the calcium sensitizer, levosimendan, beneficially affects the central hemodynamics of CHF patients and improves their long-term prognosis. This study investigates whether levosimendan-induced hemodynamic improvement of CHF patients is related to the respective changes of NT-proBNP and IL-6 levels. METHODS: Circulating levels of NT-pro BNP and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA) in 12 patients with decompensated advanced CHF at baseline, immediately after the end of a 24-h levosimendan infusion and 72 h after the initiation of treatment. Hemodynamic parameters of patients (pulmonary wedge and pulmonary artery pressure (PAP), systemic and pulmonary vascular resistance (PVR), stroke volume, and cardiac output and index) were also monitored during the same period. RESULTS: NT-proBNP and IL-6 levels were significantly reduced in severe CHF patients within 72 h after the initiation of levosimendan treatment (p<0.01 and p<0.05, respectively). A significant reduction of pulmonary wedge (p<0.01) and artery pressure values (p<0.05) was also found during the same period. A good correlation between the levosimendan-induced changes in NT-proBNP levels and the respective reduction of pulmonary wedge pressure (r(s)=0.65, p<0.05) was observed. CONCLUSIONS: Our results indicate that changes of NT-pro BNP and IL-6 levels may be useful biochemical markers related with the levosimendan-induced improvement in central hemodynamics and the clinical status of decompensated advanced CHF patients.     

Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure

OBJECTIVES: We sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin. BACKGROUND: Levosimendan is a calcium sensitizer for treatment of acute decompensated heart failure. METHODS: A double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 microg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 microg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 microg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a > or =15% increase in stroke volume (SV) at 23 h to 24 h; 2) a > or =25% decrease in pulmonary capillary wedge pressure (PCWP) (and > or =4 mm Hg) at 23 h to 24 h; 3) a > or =40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a > or =50% decrease in PCWP during two consecutive measurements. RESULTS: The response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p< or =0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages. CONCLUSIONS: Dosing of levosimendan with a 10-min bolus of 6 to 24 microg/kg followed by an infusion of 0.05 to 0.2 microg/kg/min is well tolerated and leads to favorable hemodynamic effects.     

Both levosimendan and dobutamine treatments result in significant reduction of NT-proBNP levels, but levosimendan has better and prolonged neurohormonal effects than dobutamine

Levosimendan and dobutamine are comparable inotropic drugs as regards their hemodynamic effects and clinical outcomes in decompensated heart failure (HF). The aim of this study was to compare the effects of levosimendan and dobutamine treatment on NT-proBNP levels in patients with decompensated HF. Forty-four patients with decompensated HF and ejection fraction <35% received either a 24-h infusion of levosimendan (n=26) or dobutamine (n=18). NT-proBNP was measured at baseline and 12 h, 24 h and 48 h after the initiation of drug infusion. NT-proBNP levels at baseline, 12 h, 24 h and 48 h were 16,879+/-2437, 16,004+/-2635, 12,881+/-2305 and 11,078+/-2092 pg/ml, respectively, in the levosimendan group and 16,031+/-3463, 15,908+/-3806, 12,271+/-3299 and 14,840+/-4009 pg/ml, respectively, in the dobutamine group. NT-proBNP decreased significantly at 24 h in response to both levosimendan and dobutamine treatment (p<0.01 and p<0.05, respectively) with no significant difference among the treatment groups. In the dobutamine group, NT-proBNP increased at 48 h (p=n.s. vs. baseline), in contrast, NT-proBNP reduction continued for up to 48 h in the levosimendan group (p<0.001 vs. baseline). Although not statistically different, a greater percentage of NT-proBNP reduction was observed with levosimendan treatment at both 24 h (-25+/-7% vs. -20+/-10%) and 48 h (-32+/-7% vs. -20+/-11%) compared to dobutamine. Both levosimendan and dobutamine treatments result in significant reduction of NT-proBNP levels at the end of the 24-h infusion. However, compared to dobutamine, levosimendan has better and prolonged effects on NT-proBNP levels in decompensated HF.     

Pharmacodynamic Interactions of Levosimendan and Felodipine in Patients with Coronary Heart Disease

OBJECTIVE: The aim was to study the pharmacodynamic interactions and safety of the co-administration of the calcium sensitizer levosimendan and the calcium antagonist felodipine in patients with coronary heart disease (CHD) and with normal ejection fraction (EF). METHODS: The study was a randomized, double blind, placebo-controlled, crossover study in 24 male patients with Canadian Cardiovascular Society (CCS) class II CHD, consisting of four treatment periods, each period lasting for 7-10 days. In the first period the patients received either oral levosimendan (LS) (0.5 mg) or placebo (PL) four times daily and were then crossed over to the other therapy for the second and third period. After the third period the patients were changed back to the therapy administered in the first period. Open label felodipine (FD), 5 mg once daily, was co-administered on the third and fourth treatment period. Differences between the four treatments (LS, PL, FD and LS + FD) in systolic time intervals, exercise capacity, heart rate, blood pressure and 24-hour continuous electrocardiography (Holter) were assessed. RESULTS: The differences between treatments regarding heart rate corrected electromechanical systole (QS2i), pre-ejection period (PEP) and heart rate corrected left ventricular ejection time (LVETi) were significant (p < 0.001, p < 0.001 and p = 0.004, respectively). Levosimendan shortened QS2i by 10 ms (95% CI [-15, -4]), PEP by 6 ms (95% CI [-10, -3]) and LVETi by 7 ms (95% CI [-13, -2]) compared with placebo, indicating a moderate positive inotropic effect. The results were similar, when levosimendan was administered concomitantly with felodipine. Levosimendan did not significantly change systolic blood pressure and no potentiation of response was seen with concomitant administration with felodipine. The increase in heart rate after levosimendan and its combination with felodipine was equal (6-7 bpm). There was no difference in mean cumulative exercise time between the treatments. The combination of levosimendan and felodipine was well tolerated. CONCLUSION: No clinically significant pharmacodynamic interactions between levosimendan and felodipine were seen. Levosimendan did not aggravate myocardial ischemia. Levosimendan can safely be administered to patients with CHD together with a dihydropyridine calcium antagonist.     

The pathogenesis of heart failure in infants with congenital heart disease.

BACKGROUND: The clinical symptoms of heart failure in infants with left-to-right shunts are thought to be explained by well-known hemodynamic disturbances such as pulmonary hypertension and overcirculation, but previous studies have not, thus far, found the expected correlations with hemodynamic and clinical parameters. Based on the neurohormonal model of heart failure, we hypothesised that the clinical symptoms of infants with left-to-right shunts are also related to neurohormonal disorders. METHODS: We compared various neurohormonal and hemodynamic parameters measured invasively in 70 infants with left-to-right shunts to the respiratory rate and gain in weight over a corresponding period of time. Heart rate correlated significantly with respiratory rate (r = 0.62***, p < 0.001) and gain in weight (r = -0.31*, p = 0.015), but more conventional measures of severity, such as the ratio of pulmonary to systemic flows, failed to show comparable correlations with clinical symptoms. Respiratory rate was related to levels of norepinephrine (r = 0.47***, p < 0.001) and plasma renin activity (r = 0.65***, p < 0.001). The important impact of autonomic imbalance on respiratory rate was underlined by an analysis of variability of heart rate in 26 infants that showed significantly reduced values for the domains of time and frequency. We were not able to find a conclusive multiple regression model with which to explain the symptom "failure to thrive". CONCLUSIONS: A increased heart rate, reduced variability in heart rate, and elevated levels of norepinephrine and renin are significant predictors of clinical symptoms such as tachypnea in infants with congenital cardiac malformations. The neurohormonal hypothesis, in which heart failure is interpreted not only as a hemodynamic derangement but also as a neurohormonal disorder, may be valid for infants with congenital cardiac malformations.