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European Journal of Heart Failure 2005 7(5):882-887; doi:10.1016/j.ejheart.2005.02.002
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© 2005 European Society of Cardiology

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

Catherine Avgeropouloua, Ioanna Andreadoub,*, Sophia Markantonis-Kyroudisb, Maritina Demopouloub, Platon Missovoulosa, Aris Androulakisa and Ioannis Kallikazarosa

a State Cardiology Department Hippokration Hospital, 114 Vassilissis Sophias, Athens, Greece
b Laboratory of Biopharmaceutics and Pharmacokinetics School of Pharmacy, University of Athens, Panepistimiopolis 15771, Athens, Greece

* Corresponding author. Tel.: +30 210 7274827; fax: +30 210 7274747.


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
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 µM, 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.

Key Words: Levosimendan • Heart failure • Dobutamine • Oxidative damage • BNP • Pro-inflammatory cytokines

Received July 6, 2004; Revised December 22, 2004; Accepted February 8, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Chronic heart failure is a complex clinical condition mainly manifested by progressive left ventricular dysfunction [1]. Plasma brain natriuretic peptide (BNP), a molecule located and released predominantly from the left ventricle in response to increased filling pressure [2,3], possesses diuretic and natriuretic properties [4,5], and has been reported to be a significant prognostic index of morbidity and mortality [6,7] in patients with heart failure.

Recent studies have indicated that pro-inflammatory cytokines such as IL-6 and TNF-{alpha} can modulate cardiac, muscular and vascular functions, by a variety of mechanisms including production of oxygen free radicals and apoptosis [8,9]. Elevated levels of TNF-{alpha} and IL-6, have been associated with increased morbidity and mortality in patients with advanced heart failure [10–14].

The implication of oxidative stress in the pathophysiology of heart failure is established. Circulating malondialdehyde (MDA), a marker of lipid peroxidation, has been positively correlated not only with the presence of heart failure, but also with NYHA functional class [15].

Levosimendan is a novel inotropic and vasodilator agent used in decompensated heart failure. Its effect is mediated by stereoselective sensitisation of calcium binding to cardiac troponin C, [16,17] thus improving the hearts contractile function without increasing intracellular calcium concentration. The LIDO study (Levosimendan Infusion versus Dobutamine), demonstrated that in patients with severe heart failure levosimendan is superior to dobutamine in terms of hemodynamic performance. In addition, the levosimendan group showed lower mortality rates in comparison to the dobutamine group for a period of up to 6 months [18].

In the light of the above findings we chose to investigate the possible short-term effect of levosimendan versus dobutamine on the pro-inflammatory cytokines, TNF-{alpha} and IL-6, on MDA and on BNP, in an effort to provide an explanation for its established long-term benefits.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study population
The study population consisted of 29 patients (22 males and 7 females) aged 52–88 years (mean 70.5±9.9 years) with established heart failure (HF) defined as functional class IV according to NYHA criteria. The diagnosis of HF was based on clinical and echocardiographic criteria. The aetiology was ischemic cardiomyopathy in the majority of patients (22 out of 29). All patients were receiving ACE-inhibitors and diuretic treatment.

Exclusion criteria included low systolic blood pressure (<85–90 mm Hg), significant mitral or aortic valvular stenosis, restrictive or hypertrophic cardiomyopathy, sustained ventricular tachycardia or ventricular fibrillation, atrioventricular block of second or third degree, severe renal failure (creatinine clearance<30 ml/min) and hepatic failure.

Study patients gave informed consent before entering the study, and the local scientific committee approved the study protocol. All patients were hospitalised in the Hippokration State Hospital between November 13, 2002 and December 2, 2003.

2.2. Study protocol
The patients were randomised to receive a 24-h infusion of either levosimendan (Simdax®, Abbott Laboratories) or dobutamine (Inotrex®, Farmaserv Lilly). The levosimendan group comprised 15 patients, whereas the dobutamine group 14 patients. The loading dose for levosimendan was a 10-min intravenous bolus of 12 µg/kg, followed by a 0.1 µg/kg/min intravenous infusion over 24 h. Dobutamine was administered as a constant intravenous infusion in a dose ranging from 5 to 10 µg/kg/min depending on the clinical response. The dosage regimen of other drugs given to the patients as part of their standard medical treatment was not altered during the study period, except for the adjustment of intravenous diuretics according to the clinical response. Dosage modifications during the infusion of levosimendan were made in the case of arterial pressure <80 mmHg or heart rate increase >25 beats/min compared to baseline rhythm. All patients were under continuous ECG monitoring, with frequent blood pressure recordings during the 24 h drug infusion and 24 h urinary output measurement for the whole study period. Blood samples were collected by venipuncture at baseline, 48 h and 5 days post infusion. Blood was immediately centrifuged and plasma or serum aliquots were stored frozen at –80 °C until analysis. All samples were analyzed within 1 month.

The following additional tests were carried out at baseline and post infusion: full hematologic and biochemical profile, 12-lead ECG, and full clinical assessment.

2.3. Measurement of MDA
MDA concentration was determined spectrophotometrically at 586 nm and expressed as micromoles as previously described [19,20].

2.4. Measurement of BNP
BNP levels were determined in whole blood specimens with EDTA as anticoagulant, using the bedside device Triage® BNP Test (Biosite, San Diego, California), according to the manufacturer's specifications. The Triage® BNP Test is a single use fluorescence immunoassay device designed for this purpose.

2.5. Measurement of pro-inflammatory cytokines
TNF-{alpha}, and IL-6 were measured in the serum samples, collected as described above, using commercially available enzyme-linked immunosorbent assay kits according to the manufacturer's specifications (Instant ELISA, Bender MedSystems Diagnostics, Vienna, Austria). The sensitivity for each test was 2.5 and 1.4 pg/ml for TNF-{alpha} and IL-6, respectively.

2.6. Statistical analysis
All results are expressed as means±standard error (SEM).

The paired samples T-Test and Wilcoxon signed-rank test were used to determine differences between two time periods concerning the variables MDA,TNF-{alpha}, BNP and IL-6.

Repeated Measures Analysis of Variance and Friedman test were used to determine the effect of factor "time" on the behaviour of the variables MDA, TNF-{alpha}, BNP and IL-6.

To indicate the trend from baseline to 5 days of treatments the mean percentage change of each variable at each time point are given together with the standard error of their mean. The mean percentage changes from baseline were calculated using the following equation:


Formula

where n=number of patients; ti=measurement at time ti; ai=measurement at baseline.

Statistical analysis was performed via SPSS 10.0 (Statistical Package for Social Sciences) software. All tests were considered to be significant at a p<0.05 level of significance.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
Baseline characteristics of the levosimendan and dobutamine groups are shown in Table 1.


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  		Table 1 Cardiovascular history, risk factors of the study population and medical treatment on admission and during hospitalization

 
The mean fractional shortening at baseline was 14.4±1.6% for the dobutamine group and 13.1±1.5% for the levosimendan group (Table 1). The fractional shortening was only used at baseline as an index of cardiac dysfunction severity.

Levosimendan was tolerated by all patients with maintenance or even mild improvement of blood pressure, no significant increase of heart rate, no pro-arrhythmic effect and an overall improvement of clinical status and symptoms of dyspnea. Urinary output increased significantly the day post infusion to the point that less diuretic therapy was needed.

BNP, MDA, IL-6 and TNF-{alpha} levels expressed as mean±SEM measured at baseline, 48 h and 5 days following levosimendan and dobutamine administration are shown in Table 2. BNP levels were significantly lower in the levosimendan group at 48 h (p=0.04) and at 5 days post infusion (p=0.03) compared to the baseline. In contrast, BNP levels in the dobutamine group did not decrease 48 h and 5 days post-infusion. In all patients, levels of BNP were markedly elevated at baseline, a finding in accordance with the advanced stage of the disease and with those of published studies [21,22]. Circulating MDA concentration was significantly lower after 5 days of treatment with levosimendan (p=0.01), while it remained unchanged in dobutamine treated patients (Table 2). Circulating levels of the pro-inflammatory cytokine IL-6 were lower in levosimendan treated patients after 5 days compared to baseline values (p=0.01). Dobutamine did not decrease IL-6 levels 48 h or 5 days post-infusion (Table 2).


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  		Table 2 Effects of levosimendan and dobutamine therapy on circulating cytokines, MDA and hemodynamic response and on percentage variation of the above variables compared to baseline values

 
The mean percentage change in BNP from the baseline value in the different study groups is illustrated in Fig. 1. After 5 days, BNP levels were significantly lower in the levosimendan group compared to the dobutamine group (p=0.025).


Figure 1
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  		Fig. 1 Effect of levosimendan and dobutamine treatments on percentage variation of BNP compared to baseline values. Note the significant reduction in BNP levels 5 days after the levosimendan infusion in comparison to dobutamine *p<0.05 vs dobutamine.

 
The effect of levosimendan and dobutamine treatments on the mean percentage changes in MDA, IL-6 and TNF-{alpha} from the baseline value is shown in Table 2. Treatment with levosimendan produced an obvious difference in the levels of MDA (p=0.001) between the two groups on day 5, and of IL-6 levels after 5 days (p=0.001). In contrast, TNF-{alpha} levels remained unaffected by both treatments after 48 h and 5 days.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The present study indicates that a 24-h constant infusion of the new calcium sensitizer levosimendan is superior to the commonly used beta-agonist dobutamine in terms of decreasing BNP levels and pro-inflammatory cytokine levels as well as oxidative stress in patients with decompensated advanced chronic heart failure 5 days after treatment. The study period was limited to a 5-day in hospital period, so that variables such as diet, drugs, and physical activity could be stabilized. Moreover, the basic aim of our study was to evaluate the acute effect of levosimendan.

It is widely accepted that high BNP levels represent a powerful and sensitive predictor of mortality and morbidity for patients with heart failure [23] and drug regimens, which lead to a reduction in BNP, have a favorable impact on prognosis [24–26]. In our study, all patients had extremely high levels of BNP, which reflected their advanced disease stage. However, only the group that received levosimendan showed a prompt and sustained decrease in BNP levels. Levosimendan promotes contractility without increasing calcium influx into the cell and decreases peripheral resistance by opening adenosine triphosphate-dependent potassium channels leading to vasodilatation [27]. The resulting increase in cardiac output and renal perfusion improves diuresis, thus explaining the drop in BNP levels observed at 48 h in our study. From a clinical standpoint, levosimendan improved the patients' symptoms and diuresis during and following drug administration.

Pro-inflammatory cytokine levels increase with progression of heart failure and, at high concentrations exert a negative inotropic effect and induce apoptosis [8]. IL-6 especially when elevated is considered to be an independent prognostic factor for mortality in such patients [6,28].

Administration of levosimendan significantly decreased the levels of IL-6 by day 5 in our study. TNF-{alpha} levels on the other hand did not show a similar change. The latter can be explained by the fact that circulating soluble receptors for TNF-{alpha} may stabilize TNF-{alpha} molecules thus leading to an enhanced plasma half-life [29,30]. IL-6 gene and protein expression is one of the consequences of TNF-{alpha} binding with the TNFR1 receptor, and therefore we can assume that IL-6 is a downstream product of TNF-{alpha}. Thus, we can hypothesize that treatment with levosimendan had a more prompt impact on the end product of TNF-{alpha} activity, IL-6.

A very recent study showed that levosimendan treatment caused a significant reduction in IL-6 and a slight decrease in TNF-{alpha} in patients with decompensated advanced heart failure, NYHA class III and IV, after 48 h compared to placebo [31]. The disparity of the results may be due to the advanced stage of the disease in our patients, since our study population consisted only of patients with NYHA class IV symptoms of heart failure.

Oxidative stress, defined as increased formation of reactive oxygen species, is prominent in advanced heart failure [32]. Oxidative stress impairs cardiac functions through damage to the cellular proteins and membranes by initiation of lipid peroxidation, thereby inducing cellular death and apoptosis. Moreover, it seems to exert direct negative inotropic effects through the reduction of cytosolic intracellular free calcium [33]. Thus, there is strong circumstantial evidence that oxidative stress is a prognostic factor in CHF. Keith et al., 1998 showed that MDA levels were significantly different between control subjects and patients with CHF [34]. In our study levosimendan in contrast to dobutamine decreased oxidative stress —as measured by MDA levels, an end product of lipid peroxidation—by day 5 indicating a possible antioxidant role for levosimendan.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
We demonstrated that the new inotropic agent levosimendan exerted a beneficial effect on the neurohormonal, immune and oxidative stress profile of our advanced heart failure patients. This was observed both within 48 h and up to five days post infusion, which may be explained by the presence of the active metabolites of the drug, OR-1896 and OR-1855, which have long elimination half-lives (70–80 h) [35,36]. These findings may give some insight into the favourable impact of the drug on the 6-month mortality rate as shown by the LIDO trial as well as by the recently announced CASINO study [37].

This study may serve as a springboard for the design of a larger multicenter trial, which will provide additional insight into the optimisation of chronic heart failure treatment.

5.1. Study Limitations
The treatment was not guided by invasive monitoring and dobutamine served more as a positive control as it was given at low doses. Our aim was to mimic the every day clinical situation where hemodynamic monitoring in this group of patients is not widely applied. Moreover, higher doses of dobutamine are generally avoided in ischemic patients.


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

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