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European Journal of Heart Failure 2006 8(8):804-809; doi:10.1016/j.ejheart.2006.03.003
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© 2006 European Society of Cardiology

Long-term effects of levosimendan infusion on inflammatory processes and sFas in patients with severe heart failure

Athanasios Trikas*, Charalambos Antoniades, Giorgos Latsios, Karmen Vasiliadou, Ioannis Karamitros, Dimitris Tousoulis, Costantinos Tentolouris and Christodoulos Stefanadis

Athens University Medical School, A' Cardiology Department Athens, Greece

* Corresponding author. 52, Bizaniou Street, Panorama Voulas - 16673, Athens, Greece. Tel.: +30 210 7782446; fax: +30 210 7485039. E-mail address: atrikas{at}otenet.gr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The calcium sensitizer levosimendan improves myocardial contractility in patients with heart failure, although its effects on inflammation and apoptosis are unknown.

Aim: To examine the effects of levosimendan on markers of inflammation and apoptosis, over a period of 30 d following a 24 h infusion, in patients with heart failure.

Methods: Thirty four patients with severe heart failure were randomised to receive a 24 h infusion of levosimendan or placebo, in a double-blind trial. Haemodynamic evaluation and blood sampling were performed at baseline, 24 h, 30 h, 48 h, 7 d and 30 d after the end of the infusion.

Results: Seven patients (1 levosimendan, 6 placebo), were excluded during follow-up. In the remaining 27 patients, levosimendan decreased serum IL-6 and sFAS, 24 h after the infusion (p<0.01 and p<0.05 vs baseline), an effect sustained for 7–30 d. Serum TNF-{alpha} and sTNF-R1 were decreased between 48 h (p<0.01 vs baseline for both) and 7 d (p<0.05 vs baseline for sTNF-R1) after infusion. Serum sTNF-R2 was decreased at 24 h (p<0.05 vs baseline) and remained lower than baseline for at least 7 d (p<0.05).

Conclusions: These findings indicate that levosimendan decreases the expression of proinflammatory cytokines, TNF-{alpha} receptors and sFAS, immediately after infusion, an effect which persists for 7–30 d.

Key Words: Levosimendan • Inflammatory process • Apoptosis • Heart failure

Received August 25, 2005; Revised February 2, 2006; Accepted March 8, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The calcium sensitizer levosimendan, improves myocardial contractility by stabilizing troponin C and enhancing calcium sensitivity of cardiac myofilaments [1,2], however, it has no effect on myocardial oxygen demand [3] and does not induce arrhythmias [4]. Previous studies have demonstrated that levosimendan improves haemodynamic performance more effectively than dobutamine in patients with severe heart failure, and it has been associated with improved long-term survival [5]. Although levosimendan has a short half-life, the improvement in cardiac output after a 24 h intravenous infusion, has been shown to last for more than 7 d [6]. It was recently shown that levosimendan may decrease serum levels of proinflammatory cytokines and depress apoptotic process 48 h after infusion [7], but its long-term effects on inflammatory processes and apoptosis are unknown.

In this double-blind, placebo controlled study, we examined the effect of levosimendan on serum levels of the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-P), serum levels of soluble tumor necrosis factor receptors 1 (sTNF-R1) and 2 (sTNF-R2), and on serum levels of the apoptotic marker soluble FAS (sFAS), at several time-points over a period of 30 d after completion of the infusion, in a population of patients with severe heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Population
The study population initially consisted of 34 patients with decompensated heart failure (NYHA class III-IV or IV, 26 ischaemic and 8 dilated), who had not been hospitalised for at least 4 weeks before recruitment (Table 1). All patients were recruited from the out-patient clinic of Hippokration Hospital in Athens, and had a left ventricular ejection fraction ≤35% at baseline. Patients with acute or chronic infectious, inflammatory diseases, recent myocardial infarction (<3 months), hepatic or renal impairment (creatinine>2.5 mg/dl), serious arrhythmias or supine systolic blood pressure <85 mmHg were excluded. During the study period, 7 patients (1 levosimendan, 6 placebo) were excluded from the study, since they were hospitalised and needed to have their medication modified.


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  		Table 1 Demographic characteristics of the participants

 
2.2. Protocol
The study was approved by Institutional Ethics Committee, and written consent was given by each patient. Patients were randomised to receive double-blind treatment with either intravenous levosimendan (n=17) or placebo (n=17) (Table 1). Levosimendan (Simdax, Abbott Laboratories) was given as a 10-min intravenous bolus (6 µg/kg) followed by a continuous infusion, initially at a rate of 0.1 µg/kg/min. Uptitration was performed until a maximum rate of 0.4 µg/kg/min was achieved or a dose-limiting event occurred, as previously described [8]. Placebo was administered at the same rate and for the same period of time as levosimendan. Blood samples were obtained at baseline, and then at 24 h, 30 h, 48 h, 7 d and 30 d after the end of infusion. Physical examination including ECG and echocardiographic evaluation of left ventricular ejection fraction was performed at each visit. All visits took place in the morning at a controlled temperature of 22-25 °C.

2.3. Biochemical measurements
Blood samples were centrifuged at 3500 rpm for 10 min and serum was stored at –80 °C until assay. Serum lipid levels were determined using standard laboratory methods, while serum levels of IL-6, TNF-P, sTNF-R1, sTNF-R2 and sFAS were determined by enzyme linked immunosorbent assay (kits by R&D systems, Germany for TNF-P, IL-6, kits by Bender for sTNF-R1 and sTNF-R2, and diaclone kit by Amersham for soluble Fas Ligand). For TNF-P measurement, we used the high sensitivity Quantikine test kit to measure bioactive trimeric TNF-P. The sensitivity of the test kits was 0.06 pg/ml for TNF-P, 0.0094 pg/ml for IL-6, 1 pg/ml for sTNF-R1, 3 pg/ml for sTNF-R2 and 0.5 ng/ml for sFas.

2.4. Statistical analysis
Statistical analyses were performed using the SPSS 12.0 statistical package for Windows (SPSS, Inc. Chicago, Illinois). Normally distributed data (tested by Kolmogorov-Smirnov test) are presented as means±SEMs, and non-normally distributed data are presented as medians(25th-75th percentiles). Comparisons between the two groups at baseline were performed using unpaired t-test for normally distributed and Mann Whitney-U test for non-normally distributed variables. Comparisons of time-course variations in the examined parameters throughout the study period were performed by 2-way analysis of variance for repeated measures on 1 factor, followed by Bonferroni's correction for multiple-paired comparisons. Correlations were assessed by Spearman's rank correlation method. A two-tailed p value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Levosimendan infusion, had no effect on renal function as evaluated by serum creatinine (data not shown), but it significantly decreased body mass index (BMI) from 25.36±1.22 kg/m2 at baseline to 23.5±1.04 kg/m2 at 24 h, 22.9±1.31 kg/m2 at 36 h, 22.6±1.25 kg/m2 at 48 h and 23.9±1.6 kg/m2 at 7 d. BMI returned to baseline 30 d after infusion (25.0±1.42 kg/m2). BMI was unchanged in the placebo group (27.72±1.86 kg/m2 at baseline to 27.21±1.54 kg/m2 at 24 h, 27.87±1.88 kg/m2 at 36 h, 27.77±1.34 kg/m2 at 48 h, 27.0±0.99 kg/m2 at 7 d, and 28.2±1.18 kg/m2 at 30 d after infusion. IL-6 was decreased 30 h after infusion of levosimendan (p<0.01 vs baseline), remained lower than baseline at 48 h (p<0.01) and 7 d (p<0.01), and returned to baseline levels 30 d after the infusion (Fig. 1a). There was no change in IL-6 levels in the placebo group (p=NS for all vs baseline). IL-6 was significantly lower in the levosimendan vs the placebo groups at 30 h, 48 h, 7 d and 30 d (Fig. 1a).


Figure 1
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  		Fig. 1 Effects of levosimendan on interleukin 6 (IL-6, panel a) and tumor necrosis factor alpha (TNF-P, panel b) serum levels. Values expressed as means±SEM; *p<0.05 and **p<0.01 for placebo (n=11, {square}) vs levosimendan (n=16, {diamondsuit}).

 
TNF-P was decreased in the levosimendan group 48 h after infusion (p<0.01 vs baseline) and returned to baseline at 30 d, levels were unchanged in the placebo group. TNF-P was lower in the levosimendan compared to the placebo group at 48 h (p<0.01), but this difference had disappeared 7 d after the infusion (Fig. 1b). The change in TNF-P from baseline to 48 h was correlated with the respective change in IL-6 levels (r=0.454, p<0.05).

sTNF-R1 was decreased 48 h after levosimendan infusion (p<0.05 vs baseline) but remained unchanged in the placebo group (p=NS for all vs baseline). sTNF-R1 was significantly lower in the levosimendan compared to the placebo group at 48 h (Fig. 2a) and returned to baseline 30 d after the infusion (Fig. 2a). The change in sTNF-R1 from baseline to its levels 48 h after infusion, was correlated with the respective changes in IL-6 (r=0.652, p<0.0001) and TNF-P (r=0.651, p<0.0001).


Figure 2
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  		Fig. 2 Effects of levosimendan on circulating levels of tumor necrosis factor receptors type-1 (TNF-R1, panel a) and type 2 (TNF-R2, panel b). Values expressed as means±SEM; *p<0.05 and **p<0.01 for placebo (n=11, {square}) vs levosimendan (n=16, {diamondsuit}).

 
sTNF-R2 was decreased 48 h after infusion in levosimendan group (p<0.05 vs baseline) and returned to baseline levels 30 d after the infusion. However, sTNF-R2 was significantly increased 30 h after the infusion in the placebo group (p<0.01 vs baseline) and remained higher than baseline values at 48 h, 7 d and 30 d (p<0.01 for all vs baseline). sTNF-R2 was lower in the levosimendan compared to the placebo group at 7 d and 30 d after infusion (Fig. 2b). At baseline, sTNF-R2 was correlated with ejection fraction (r=–0.386, p<0.05) and both TNF-P (r=0.381, p<0.05) and sTNF-R1 (r=0.463, p<0.05). The change in sTNF-R2 from baseline to 48 h after infusion was correlated with the respective changes in ejection fraction (r=–0.621, p<0.01), IL-6 (r=0.486, p<0.01), TNF-P (r=0.557, p<0.01) and sTNF-R1 (r=0.463, p<0.05).

sFAS was decreased in the levosimendan-treated group at 24 h (p<0.05 vs baseline) and returned to baseline levels 30 d after the infusion. sFAS was significantly increased in the placebo group 30 h after the infusion (p<0.05 vs baseline) and remained higher than baseline throughout the rest of the study period (p<0.01 for all vs baseline). sFAS was significantly lower in the levosimendan compared to the placebo group 30 h after infusion and remained significantly lower throughout the rest of the study period (Fig. 3a). Baseline sFAS was correlated with ejection fraction (r=–0.383, p<0.05), while the change of sFAS from baseline to its levels 48 h after infusion was correlated with the respective changes in IL-6 (r=0.591, p<0.001), TNF-P (r=0.801, p<0.0001), sTNF-R1 (r=0.682, p<0.0001) and sTNF-R2 (r=0.744, p<0.0001).


Figure 3
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  		Fig. 3 Effects of levosimendan on circulating levels of FAS (sFAS, panel a) and ejection fraction of the left ventricle (panel b). Values expressed as means±SEM; *p<0.05 and **p<0.01 for placebo (n=11, {square}) vs levosimendan (n=16, {diamondsuit}).

 
Ejection fraction was increased 24 h after levosimendan infusion and remained higher than baseline for at least 7 d (p<0.01 vs baseline for all time-points), while it returned to baseline at 30 d. No change in ejection fraction was observed in the placebo group. Ejection fraction was greater in the levosimendan compared to the placebo group, 48 h after the infusion (Fig. 3b).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In the present study, we examined the acute and long-term effects of levosimendan infusion on the inflammatory process and the apoptotic marker sFAS, in patients with severe heart failure. Levosimendan decreased IL-6 and sFAS 24 h after infusion, while this effect persisted for 7-30 d. However, TNF-P and sTNF-R1 were decreased for a short period of time between 48 h and 3 d after infusion. sTNF-R2 was decreased 24 h after infusion and remained lower than baseline for at least 7 d. These findings indicate that levosimendan depresses the expression of proinflammatory cytokines, soluble TNF receptors as well as sFAS circulating levels immediately after infusion, an effect which persists for 7-30 d.

4.1. Levosimendan and myocardial function
The calcium sensitizer levosimendan, improves myocardial contractility without adversely affecting lusitropy [1,2,4]. Levosimendan improves haemodynamic performance more effectively than dobutamine in severe heart failure, and it improves long-term prognosis in these patients [5-7]. The half-life of levosimendan in the human body is 1 h [9] while the half-life of its active metabolite (OR-1896), is about 80 h [9,10]. OR-1896 is mainly responsible for the prolonged haemodynamic effects of levosimendan (up to 10 d after infusion), which gradually disappear after 10-20 d [4,10]. In the present study, levosimendan improved ejection fraction 24 h after infusion, an effect which persisted for 7-30 d. Furthermore, levosimendan also decreased BMI, probably as a result of the improved haemodynamics observed in these patients.

4.2. Levosimendan and inflammation
The failing myocardium is a major source of proinflammatory cytokines [11,12], which contribute to the pathophysiology of heart failure [11-13]. Furthermore, peripheral hypoxia is an additional stimulus for increased TNF-P production in heart failure patients [12], while bowel wall oedema which occurs in decompensated congestive heart failure, is responsible for bacterial translocation, with subsequent endotoxin release and immune activation, as proposed by Anker et al. [13] and confirmed by recent studies [14-16].

Cytokines promote the transition from asymptomatic to symptomatic heart failure [17] since they depress myocardial contractility [18], they also promote cardiomyocyte apoptosis and contribute to cardiac remodelling [19].

Soluble TNF receptors TNF-R1 and TNF-R2, expressed in many cell types including cardiac myocytes [20], are more stable than TNF-P, and may better reflect longer-term average circulating levels of TNF-P, but data on their clinical role in heart failure are scarce [21]. Most biological activities of TNF-P, are signalled through TNF-R1 [20]. On the other hand, TNF-R2-dependent mechanisms may elicit cardioprotective effects that counter heart failure progression [22]. It is generally believed that elevation of soluble TNF-R1 and, to a greater extent, TNF-R2 observed in heart failure, may serve as endogenous antagonists to modulate the effects of elevated TNF-P, by binding to the TNF-P molecule or preventing its binding to cell receptors [23,24]. sTNF-R1 and sTNF-R2 are positively correlated with both TNF-P and the severity of heart failure, while they seem to be predictors of poor prognosis in these patients [25].

In the present study, levosimendan decreased IL-6 decreased 24 h after infusion, an effect persisting for at least 30 d. However, its effect on TNF-P levels appeared later (at 48 h) and it was of a limited duration (<7 d). Furthermore, levosimendan decreased the expression of both sTNF-R1 and sTNF-R2 48 h after infusion, and especially for sTNF-R2, this effect persisted for at least 7 d. The improved haemodynamics may partly explain the decreased expression of IL-6 and TNF-P from the failing myocardium, while levosimendan also seems to inhibit the stimuli for myocardial cytokine production and spill-over into the circulation [2]. Additionally, levosimendan-induced improvement of systolic function and peripheral vasorelaxation may also attenuate peripheral tissue hypo-perfusion leading to down-regulation of cytokine extra-cardiac production by transcriptional factors such us NF-kB [8,11]. The improvement of haemodynamics could also decrease lipopolysaccharide (LPS) release from congestive intestine, affecting NF-kB activation in peripheral blood leukocytes, as was recently proposed [26]. However, the long duration (up to 30 d after infusion) of the anti-inflammatory effects of levosimendan, cannot easily be explained by the presence of the drug itself or its metabolite OR-1896 or the improved haemodynamics which almost disappeared after 20 d, indicating that other indirect mechanisms may also be involved.

4.3. Levosimendan and sFAS
The progression of heart failure is partly due to ongoing loss of cardiomyocytes, as a result of apoptotic cell death [27]. Fas/APO-1 is a membrane protein which belongs to the TNF receptor super-family and mediates apoptosis [11]. The soluble form of Fas (sFAS) inhibits the action of the inducer of apoptotic cell death, Fas ligand [11,28], it is elevated in heart failure [29], and it has a prognostic role [30,31]. However, measurement of circulating sFAS is not specific for apoptosis, and it is also influenced by the inflammatory process.

In the present study, levosimendan decreased sFAS in patients with heart failure, an effect which was sustained for at least 7 d after infusion. The duration of this effect exceeds the half-life of levosimendans' active metabolite, implying that mechanisms not requiring the continuous presence of the drug may mediate this phenomenon.

The main limitations of the study are the lack of any data about the effect of levosimendan on hemoglobulin as well as other non-specific markers of inflammation such as acute phase proteins or leukocyte count. Furthermore, measurement of LPS or soluble CD14 levels (indicative of endotoxin-cell interaction) [13,31], would strengthen the results of the study.

4.4. Conclusions
We have shown that levosimendan decreases IL-6 and sFas levels 24 h after infusion, and that this effect persists for 7-30 d. However, TNF-P and sTNF-R1 levels were decreased for a shorter period of time (48 h-3 d), while the decrease in sTNF-R2 levels was observed earlier (at 24 h) and remained lower than baseline for at least 7 d. These findings indicate that levosimendan may have anti-inflammatory and possibly anti-apoptotic effects in patients with severe heart failure, which are observed for longer than the half-life period of the drug itself or its active metabolite.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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