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1.  Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model 
BMC Neurology  2013;13:106.
Background
Neuroprotective strategies in ischemic stroke are an important challenge in clinical and experimental research as an adjunct to reperfusion therapy that may reduce neurologic injury and improve outcome. The neuroprotective properties of levosimendan in traumatic brain injury in vitro, transient global brain ischemia and focal spinal cord ischemia suggest the potential for similar effects in transient brain ischemia.
Methods
Transient brain ischemia was induced for 60 min by intraluminal occlusion of the middle cerebral artery in 40 male Wistar rats under general anesthesia with s-ketamine and xylazine and with continuous monitoring of their blood pressure and cerebral perfusion. Five minutes before inducing reperfusion, a levosimendan bolus (24 μg kg -1) was administered over a 20 minute period. Infarct size, brain swelling, neurological function and the expression of inflammatory markers were quantified 24 hours after reperfusion.
Results
Although levosimendan limited the infarct size and brain swelling by 40% and 53%, respectively, no effect on neurological outcome or mortality could be demonstrated. Upregulation of tumor necrosis factor α and intercellular adhesion molecule 1 was significantly impeded. Cerebral blood flow during reperfusion was significantly reduced as a consequence of sustained autoregulation.
Conclusions
Levosimendan demonstrated significant neuroprotective properties in a rat model of transient brain ischemia by reducing reperfusion injury.
doi:10.1186/1471-2377-13-106
PMCID: PMC3750823  PMID: 23937651
Experimental stroke; Postconditioning; Levosimendan; Cerebral reperfusion injury
2.  Intracoronary Levosimendan during Ischemia Prevents Myocardial Apoptosis 
Background: Levosimendan is a calcium sensitizer that has been shown to prevent myocardial contractile depression in patients post cardiac surgery. This drug exhibits an anti-apoptotic property; however, the underlying mechanism remains elusive. In this report, we characterized the myocardial protective of levosimendan in preventing cardiomyocyte apoptosis and post-operative stunning in an experimental ischemia–reperfusion model. Methods: Three groups of pigs (n = 8 per group) were subjected to 40 min of global, cardioplegic ischemia followed by 240 min of reperfusion. Levosimendan (65 μg/kg body weight) was given to pigs by intravenous infusion (L-IV) before ischemia or intracoronary administration during ischemia (L-IC). The Control group did not receive any levosimendan. Echocardiography was used to monitor cardiac function in all groups. Apoptosis levels were assessed from the left ventricle using the terminal transferase mediated dUTP nick end labeling (TUNEL) assay and immunocytochemical detection of Caspase-3. Results: Pigs after ischemia–reperfusion had a much higher TUNEL%, suggesting that our treatment protocol was effective. Levels of apoptosis were significantly increased in Control pigs that did not receive any levosimendan (0.062 ± 0.044%) relative to those received levosimendan either before (0.02 ± 0.017%, p = 0.03) or during (0.02 ± 0.017%, p = 0.03) the ischemia phase. Longitudinal left ventricular contraction in pigs that received levosimendan before ischemia (0.75 ± 0.12 mm) was significantly higher than those received levosimendan during ischemia (0.53 ± 0.11 mm, p = 0.003) or Control pigs (0.54 ± 0.11 mm, p = 0.01). Conclusion: Our results suggested that pigs received levosimendan displayed a markedly improved cell survival post I–R. The effect on cardiac contractility was only significant in our perfusion heart model when levosimendan was delivered intravenously before ischemia.
doi:10.3389/fphys.2012.00017
PMCID: PMC3278776  PMID: 22347864
myocardial protection; apoptosis; ischemia/reperfusion injury; animal model
3.  Preoperative usages of levosimendan in patients undergoing coronary artery bypass grafting 
Objectives: Levosimendan (LS) is a new inotropic drug which belongs to the group of drugs known as calcium sensitizers. It is different from other inotropic agents by its inotropic and vasodilatory actions without an increase in myocardial oxygen consumption and considered as a good choice in high-risk patients undergoing cardiac surgery. We aimed to investigate the proper time of the administration and the effect of prophylactic usage of LS in patients with low left ventricular ejection fraction (LVEF) undergoing coronary artery bypass grafting (CABG). Methods: Forty patients who underwent isolated CABG with LVEF) less than 30% were evaluated retrospectively. Patients were divided into 3 groups according to the induction time of LS during different phases of the operation and compared to a non-LS control group. LS infusion (0.2 μg/kg/min) was applied 12 hours before the operation in Group 1 (G1) (n=10), after the induction of anaesthesia in Group 2 (G2) (n=10) and during the pump removal period in Group 3 (G3) (n=10) and non-LS control group 4 (G4) (n=10). Demographic data, operative characteristics, hemodynamic parameters and serum lactate, troponin, creatinine levels were compared between groups before and after LS treatment during pre and postoperative period. Data were evaluated by Fisher exact, Kruskal-Wallis, Mann-Whitney U, Chi-square and Wilcoxon rank tests. Results: We found that the duration of tracheal intubation, the intensive care unit stay and the hospital stay were significantly decreased in G1 and G2 when compared to the patients in G3 and G4. During postoperative period, in G1 and G2 one (10%) patient from each required intraaortic balloon pump (IABP), while in G3 two (20%) patients and in G4 five (50%) patients required IABP. Cardiac index (CI) was significantly increased in all groups from baseline to intensive care unit (ICU)1h and ICU24h. When groups compared each other significant increase was found in G1-G4 (p=0.001) and G2-G4 (p=0.007) at ICU1h. There was a significant increase in % EF especially in G1-G4 (p=0.011) and G2-G4 (p=0.007) at ICU1h. Systemic vascular resistance index significantly decreased in G1 and G2 in comparison to G3 and G4. However there was no significant decrease in pulmonary capillary wedge pressure of all 4 groups before and after LS. There was a significant decrease in mean pulmonary arterial pressure in G1 and G2 according to G4. Compared with the other groups preoperatively LS-treated patients (G1 and G2) had lower postoperative troponin I, serum lactate and creatinine concentrations. Conclusions: Our study shows that the elective preoperative initiation of LS especially 12 hours before the operation onset is associated with better improvement on cardiac functions as well as with lower mortality and complication rates, lower use of additional inotropic and vasopressor drugs, less need for intra-aortic balloon pump support and shorter length of stay in the ICU in patients with high perioperative risk or compromised left ventricular function. As a result, patients who received an infusion of LS 12 hours before surgery showed an evidence of less myocardial damage which suggested the preconditioning effect of the drug.
PMCID: PMC3902261  PMID: 24482709
Levosimendan; cardiac surgery; low cardiac output; preoperative usage
4.  Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model 
Heart  2001;86(1):81-87.
OBJECTIVE—To determine whether levosimendan, a calcium sensitiser that facilitates the activation of the contractile apparatus by calcium, improves myocardial contractile function during severe ischaemia and reperfusion without exacerbating the incidence of arrhythmias.
DESIGN—Pigs were pretreated orally twice daily for 10 days with 0.08 mg/kg levosimendan or placebo. On day 11 the left main coronary artery was ligated for 30 minutes, followed by 30 minutes of reperfusion. A bolus dose of levosimendan, 11.2 µg/kg intravenously, or placebo was given 30 minutes before coronary ligation, followed by a continuous infusion of 0.2 µg/kg/min levosimendan or placebo for the remainder of the experiment.
RESULTS—During the ischaemic period, cardiac output was higher in the levosimendan group than in the placebo group (mean (SD): 2.6 (0.5) v 2.0 (0.2) l/min, p < 0.05) and systemic vascular resistance was lower (2024 (188) v 2669 (424) dyne.s−1.cm−5, p < 0.005). During reperfusion, cardiac output and contractility (LVmaxdP/dt (pos), 956 (118) v 784 (130) mm Hg/s, p < 0.05) were increased by levosimendan. The incidence of ischaemic ventricular fibrillation and tachycardia was similar in the two groups but there were more arrhythmic events (ventricular tachycardia and ventricular fibrillation) in the levosimendan treated group (8/12 levosimendan v 1/9 control p = 0.05).
CONCLUSIONS—Levosimendan improved cardiac output and myocardial contractility during coronary artery ligation and reperfusion. However, it increased the number of arrhythmic events during ischaemia in this model of in vivo regional ischaemia.


Keywords: calcium sensitisers; myocardial ischaemia; arrhythmias
doi:10.1136/heart.86.1.81
PMCID: PMC1729816  PMID: 11410569
5.  The effects of levosimendan and glibenclamide on circulatory and metabolic variables in a canine model of acute hypoxia 
Intensive Care Medicine  2011;37(4):701-710.
Purpose
To study the effects of pretreatment with levosimendan (LEVO, a Ca2+-sensitizer and KATP+ channel opener) and/or the KATP+ channel antagonist glibenclamide (GLIB) on systemic hemodynamics, metabolism, and regional gastromucosal oxygenation during hypoxic hypoxemia.
Methods
Chronically instrumented, healthy dogs (24–32 kg, n = 6 per group, randomized cross-over design) were repeatedly sedated, mechanically ventilated (FiO2 ~0.3) and subjected to the following interventions: no pretreatment, LEVO pretreatment, GLIB pretreatment, or combined LEVO + GLIB pretreatment, each followed by hypoxic hypoxemia (FiO2 ~0.1). We measured cardiac output (CO, ultrasonic flow probes), oxygen consumption (VO2, indirect calorimetry), and gastromucosal microvascular hemoglobin oxygenation (μHbO2, spectrophotometry). Statistics: data are presented as mean ± SEM and compared by one-way ANOVA (direct drug effects within group) and two-way ANOVA (between all hypoxic conditions) both with Bonferroni corrections; p < 0.05.
Results
In LEVO-pretreated hypoxemia, CO was significantly higher compared to unpretreated hypoxemia. The increased CO was neither associated with an increased VO2 nor with markers of aggravated anaerobiosis (pH, BE, lactate). In addition, LEVO pretreatment did not further compromise gastromucosal μHbO2 in hypoxemia. After combined LEVO + GLIB pretreatment, systemic effects of GLIB were apparent, however, CO was significantly higher than during unpretreated and GLIB-pretreated hypoxemia, but equal to LEVO-pretreated hypoxemia, indicating that GLIB did not prevent the increased CO in LEVO-pretreated hypoxia.
Conclusions
LEVO pretreatment resulted in improved systemic circulation (CO) during hypoxemia without fueling systemic VO2, without aggravating systemic anaerobiosis markers, and without further compromising microvascular gastromucosal oxygenation. Thus, LEVO pretreatment may be an option to support the systemic circulation during hypoxia.
doi:10.1007/s00134-011-2144-1
PMCID: PMC3058361  PMID: 21380525
Levosimendan; Hypoxia; Glibenclamide; Microcirculation; Oxygen; Metabolism
6.  Is levosimendan effective in paediatric heart failure and post-cardiac surgeries? 
A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was ‘do children with heart failure post-cardiac surgery undergoing treatment with levosimendan have an acceptable haemodynamic improvement?’ The use of levosimendan as a vasoactive drug is an accepted intervention for patients with altered haemodynamics post-cardiac surgeries. However, the role of levosimendan and its efficacy have been debated. Eleven relevant papers were identified, which represented the best evidence to answer the question. The author, journal, date, country of publication and relevant outcomes are tabulated. The 11 studies comprised 3 randomized trials, 2 of which compared levosimendan and milrinone. A single-centre randomized study that included 40 infants showed that cardiac output (CO) and cardiac index (CI) increased overtime in the levosimendan group compared with the milrinone group. The significant interaction for CO (P = 0.005) and CI (P = 0.007) indicated different time courses in the two groups. A similar, European randomized study undertaken on neonates (n = 63) showed better lactate levels [P = 0.015 (intensive care admission); P = 0.048 (after 6 h) with low inotropic scores in the levosimendan group. Although the length of mechanical ventilation and mortality were less, this was statistically insignificant. A retrospective cohort analysis (n = 13) in children reported a reduced use of dobutamine and improvement in the ejection fraction from 29.8 to 40.5% (P = 0.015) with the use of levosimendan. In a questionnaire-based study from Finland, 61.1% of respondents felt that it had saved the lives of some children when the other treatments had failed. No study reported any adverse effect attributable to use of levosimendan. In conclusion, the above studies were in favour of levosimendan as a safe and feasible drug providing potential clinical benefit in low cardiac output syndrome (LCOS) and post-cardiac surgeries when other vasoactive drugs were insufficient to maintain stable haemodynamics. A small sample size was indeed a limitation in all the above studies. Furthermore, it is best used as a rescue drug on a named-patient basis. A small sample size was indeed a limitation in all the above studies. Larger, well-designed trials are required to further evaluate the efficacy and feasibility of levosimendan in paediatric heart failure and post-cardiac surgeries.
doi:10.1093/icvts/ivt297
PMCID: PMC3781809  PMID: 23832921
Review; Levosimendan; Paediatric heart failure; Paediatric cardiac surgeries
7.  Levosimendan: A Cardiovascular Drug to Prevent Liver Ischemia-Reperfusion Injury? 
PLoS ONE  2013;8(9):e73758.
Introduction
Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR) injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury.
Material and Methods
Levosimendan was administered to male Wistar rats 1 hour (early pretreatment) or 24 hours (late pretreatment) before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR) as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured.
Results
In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (pearly = 0.02; plate = 0.005), AST (pearly = 0.02; plate = 0.004) and less DNA damage by TUNEL test (pearly = 0.05; plate = 0.034) and PAR positivity (pearly = 0.02; plate = 0.04). Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment.
Conclusion
Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection.
doi:10.1371/journal.pone.0073758
PMCID: PMC3770697  PMID: 24040056
8.  Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure 
Heart  2006;92(12):1768-1772.
Background
Levosimendan is a novel inodilator that improves central haemodynamics and symptoms of patients with decompensated chronic heart failure. The role, however, of repeated levosimendan infusions in the management of these patients has not yet been properly assessed.
Purpose
This randomised placebo‐controlled trial investigated the effects of serial levosimendan infusions on cardiac geometry and function, and on biomarkers of myocardial injury and neurohormonal and immune activation (troponin T, N‐terminal B‐type natriuretic pro‐peptide (NT‐proBNP), C reactive protein (CRP) and interleukin (IL) 6) in patients with advanced heart failure.
Methods
25 patients with decompensated chronic heart failure were randomised (2:1) to receive five serial 24‐h infusions (every 3 weeks) of either levosimendan (n = 17) or placebo (n = 8), and were evaluated echocardiographically and biochemically before and after each drug infusion and 30 days after the final infusion.
Results
Following treatment, cardiac end‐systolic and end‐diastolic dimension and volume indices were significantly reduced only in the levosimendan‐treated patients (p<0.01). A significant decrease in NT‐proBNP (p<0.01), high‐sensitivity CRP (p<0.01) and plasma IL6 (p = 0.05) was also observed in the levosimendan group, whereas these markers remained unchanged in the placebo group; similar changes were observed after each drug infusion. Although the number of patients with a positive troponin T (⩾0.01 ng/ml) was not different between the two groups at baseline, it was significantly higher in the placebo‐treated group during the final evaluation (p<0.05).
Conclusion
Serial levosimendan treatments improved left ventricular performance and modulated neurohormonal and immune activation beneficially in patients with advanced heart failure, without increasing myocardial injury.
doi:10.1136/hrt.2006.079707
PMCID: PMC1861282  PMID: 17105880
9.  Effects of levosimendan/furosemide infusion on Plasma Brain Natriuretic Peptide, echocardiographic parameters and cardiac output in end-stage heart failure patients 
Summary
Background
Acute decompensation heart failure (ADHF) remains a cause of hospitalization in patients with end-stage congestive HF. The administration of levosimendan in comparison with a standard therapy in CHF patients admitted for ADHF was analysed.
Material/Methods
Consecutive patients admitted for ADHF (NYHA class III–IV) were treated with levosimendan infusion 0.1 μg/kg/min or with furosemide infusion 100–160 mg per day for 48 hours (control group). All subjects underwent determination of brain natriuretic peptide (BNP), non-invasive cardiac output (CO), and echocardiogram at baseline, at the end of therapy and 1 week after therapy.
Results
Seven patients admitted for 20 treatments in 16 months (age 66 years; mean admission/year 5.4) were treated with levosimendan and compared with 7 patients admitted for 15 treatments (age 69.1 years; mean admission/year 6.1). At the end of levosimendan therapy, BNP decreased (from 679.7±512.1 pg/ml to 554.2±407.6 pg/ml p=0.03), and 6MWT and LVEF improved (from 217.6±97.7 m to 372.2±90.4 m p=0.0001; from 22.8±9.1% to 25.4±9.8% p=0.05). Deceleration time, E/A, E/E’, TAPSE, pulmonary pressure and CO did not change significantly after levosimendan therapy and after 1 week. At follow-up, only 6-min WT and NYHA class showed a significant improvement (p=0.0001, p=0.001 respectively). The furosemide infusion reduced NYHA class and body weight (from 3.4±0.6 to 2.3±0.5 p=0.001; from 77.5±8.6 kg to 76±6.6 kg p=0.04), but impaired renal function (clearances from 56.3±21.9 ml/min to 41.2±10.1 ml/min p=0.04).
Conclusions
Treating end-stage CHF patients with levosimendan improved BNP and LVEF, but this effect disappeared after 1 week. The amelioration of 6MWT and NYHA class lasted longer after levosimendan infusion.
doi:10.12659/MSM.881433
PMCID: PMC3524718  PMID: 21358614
brain natriuretic peptide; end-stage heart failure; levosimendan
10.  Comparison of single-dose and repeated levosimendan infusion in patients with acute exacerbation of advanced heart failure 
Background
Levosimendan (LS) is a novel inodilator that improves cardiac performance, central hemodynamics, and symptoms of patients with decompensated chronic heart failure. The aim of this study was to compare the effects of single and repeated LS infusion on left ventricular performance, biomarkers, and neurohormonal activation in patients with acute heart failure.
Material/Methods
Twenty-nine consecutive patients with acute exacerbation of advanced heart failure were included in this study. LS was initiated as a bolus of 6 μg/kg followed by a continuous infusion of 0.1 μg/kg/min for 24 hours in both groups who received intravenous single and repeated (baseline and at 1 and 3 months) treatment. Physical examination, echocardiography, and biochemical tests (brain natriuretic peptide, tumour necrosis factor-α, interleukin-1β, 2, and 6) were performed before treatment and on 3 day of the treatment. The last evaluation was performed at 6 month after the baseline treatment.
Results
Twenty male and 9 female patients with mean age of 60.2±7.4 years were included in this study. A significant improvement in New York Heart Association functional status and myocardial performance index was detected only in the repeated LS treated patients at 6 month compared to the pretreatment status (p=0.03 and p<0.001; respectively). In addition, a significant decrease in brain natriuretic peptide (p<0.01) and plasma interleukin-6 (p=0.05) levels were also achieved only in patients who were given repeated LS.
Conclusions
Our study showed that repeated LS treatment is more effective compared to the single dose LS treatment in improving clinical status, hemodynamic and laboratory parameters in patients with acute exacerbation of advanced heart failure.
doi:10.12659/MSM.889767
PMCID: PMC3937020  PMID: 24549281
Levosimendan; Interleukin-6; Heart Failure
11.  Hyperglycemia raises the threshold of levosimendan- but not milrinone-induced postconditioning in rat hearts 
Background
The authors examined whether milrinone and levosimendan could exert cardiac postconditioning effects in rats under normoglycemia and hyperglycemia, and whether the effects could be mediated by mitochondrial permeability transition pore (mPTP).
Methods
Wistar rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received milrinone or levosimendan just before reperfusion under normoglycemic or hyperglycemic conditions with or without atractyloside, an mPTP opener.
Results
Under normoglycemia, both 30 μg/kg milrinone (29 ± 12%) and 10 μg/kg levosimendan (33 ± 13%) reduced infarct size compared with that in the control (58 ± 7%). Under hyperglycemia, milrinone (34 ± 13%) reduced infarct size at the same dose as under normoglycemia. In contrast, neither 10 nor 30 μg/kg levosimendan protected hyperglycemic hearts, and only 100 μg/kg levosimendan (32 ± 9%) reduced infarct size compared with that in the hyperglycemic control (58 ± 13%). All of these cardioprotective effects under normoglycemia and hyperglycemia are abolished by atractyloside.
Conclusion
Milrinone and levosimendan exert postconditioning effects via inhibition of mPTP opening. Hyperglycemia raises the threshold of levosimendan-induced postconditioning, while milrinone-induced postconditioning is not influenced by hyperglycemia.
doi:10.1186/1475-2840-11-4
PMCID: PMC3269349  PMID: 22239823
Hyperglycemia; Postconditioning; Myocardial Infarction; Milrinone; Levosimendan; Mitochondrial permeability transition pore
12.  Levosimendan attenuates multiple organ injury and improves survival in peritonitis-induced septic shock: studies in a rat model 
Critical Care  2014;18(6):652.
Introduction
The aim of this study was to investigate the effects of levosimendan on rodent septic shock induced by cecal ligation and puncture (CLP).
Methods
Three hours after peritonitis-induced sepsis, male Wistar rats were randomly assigned to receive an intravenous infusion of levosimendan (1.2 μg/kg/min for 10 min and then 0.3 μg/kg/min for 6 h) or an equivalent volume of saline and vehicle (5% dextrose) solution.
Results
The levosimendan-treated CLP animals had significantly higher arterial pressure and lower biochemical indices of liver and kidney dysfunction compared to the CLP animals (P < 0.05). Plasma interleukin-1β, nitric oxide and organ superoxide levels in the levosimendan-treated CLP group were less than those in CLP rats treated with vehicle (P < 0.05). In addition, the inducible nitric oxide synthase (iNOS) in lung and caspase-3 expressions in spleen were significantly lower in the levosimendan-treated CLP group (P < 0.05). The administration of CLP rats with levosimendan was associated with significantly higher survival (61.9% vs. 40% at 18 h after CLP, P < 0.05). At postmortem examination, the histological changes and neutrophil filtration index in liver and lung were significantly attenuated in the levosimendan-treated CLP group (vs. CLP group, P < 0.05).
Conclusions
In this clinically relevant model of septic shock induced by fecal peritonitis, the administration of levosimendan had beneficial effects on haemodynamic variables, liver and kidney dysfunction, and metabolic acidosis. (1) Lower levels of interleukin-1β, nitric oxide and superoxide, (2) attenuation of iNOS and caspase-3 expressions, and (3) decreases of neutrophil infiltration by levosimendan in peritonitis-induced sepsis animals suggest that anti-inflammation and anti-apoptosis effects of levosimendan contribute to prolonged survival.
doi:10.1186/s13054-014-0652-4
PMCID: PMC4274679  PMID: 25432865
13.  Effectiveness of prophylactic levosimendan in high-risk valve surgery patients 
Cardiovascular Journal of Africa  2013;24(7):260-264.
Background
Levosimendan has anti-ischaemic effects, improves myocardial contractility and increases systemic, pulmonary and coronary vasodilatation. These properties suggest potential advantages in high-risk cardiac valve surgery patients where cardioprotection would be valuable. The present study investigated the peri-operative haemodynamic effects of prophylactic levosimendan infusion in cardiac valve surgery patients with low ejection fraction and/or severe pulmonary arterial hypertension.
Methods
Between May 2006 and July 2007, 20 consecutive patients with severe pulmonary arterial hypertension (systolic pulmonary artery pressure ≥ 60 mmHg) and/or low ejection fraction (< 50%) who underwent valve surgery in our clinic were included in the study and randomised into two groups. Levosimendan was administered to 10 patients in group I and not to the 10 patients in the control group. Cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (MPAP) were recorded for each patient preoperatively and for 24 hours following the operation.
Results
CO and CI values were higher in the levosimendan group during the study period (p < 0.05). MPAP and PVR values were significantly lower in the levosimendan group for the 24-hour period (p < 0.05) and SVR values were significantly lower after 24 hours in both groups. When clinical results were considered, no difference in favour of levosimendan was detected regarding the mortality and morbidity rates between the groups.
Conclusion
Levosimendan improved the haemodynamics in cardiac valve surgery patients with low ejection fraction and/or severe pulmonary arterial hypertension, and facilitated weaning from cardiopulmonary bypass in such high-risk patients when started as a prophylactic agent.
doi:10.5830/CVJA-2013-047
PMCID: PMC3807672  PMID: 24217302
cardiac valve; cardiac surgery; pulmonary hypertension; levosimendan; left ventricular dysfunction
14.  Inhibition of Reverse-Mode Sodium-Calcium Exchanger Activity and Apoptosis by Levosimendan in Human Cardiomyocyte Progenitor Cell-Derived Cardiomyocytes after Anoxia and Reoxygenation 
PLoS ONE  2014;9(2):e85909.
Levosimendan, a known calcium sensitizer with positive inotropic and vasodilating properties, might also be cardioprotective during ischemia-reperfusion (I/R) insult. Its effects on calcium homeostasis and apoptosis in I/R injury remain unclear. Na+/Ca2+ exchanger (NCX) is a critical mediator of calcium homeostasis in cardiomyocytes, with reverse-mode NCX activity responsible for intracellular calcium overload and apoptosis of cardiomyocytes during I/R. We probed effects and underlying mechanisms of levosimendan on apoptosis and NCX activity in cultured human cardiomyocyte progenitor cells (CPC)-derived cardiomyocytes undergoing anoxia-reoxygenation (A/R), simulating I/R in vivo. Administration of levosimendan decreased apoptosis of CPC-derived cardiomyocytes induced by A/R. The increase in reverse-mode NCX activity after A/R was curtailed by levosimendan, and NCX1 was translocated away from the cell membrane. Concomitantly, endoplasmic reticulum (ER) stress response induced by A/R was attenuated in CPC-derived cardiomycytes treated with NCX-targeted siRNA or levosimendan, with no synergistic effect between treatments. Results indicated levosimendan inhibited reverse-mode NCX activity to protect CPC-derived cardiomyocytes from A/R-induced ER stress and cell death.
doi:10.1371/journal.pone.0085909
PMCID: PMC3911900  PMID: 24498266
15.  Rationale and Design of a Randomized, Double-Blind, Placebo Controlled Multicenter Trial to Study Efficacy, Security, and Long Term Effects of Intermittent Repeated Levosimendan Administration in Patients with Advanced Heart Failure: LAICA study 
Cardiovascular Drugs and Therapy  2013;27(6):573-579.
Background
Advanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation.
Methods
The LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 μg/kg/min dose, without a loading dose, every 30 days, or placebo.
Results
The main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events.
Conclusions
The LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.
doi:10.1007/s10557-013-6476-7
PMCID: PMC3830203  PMID: 23887741
Advanced heart failure; Levosimendan; Efficacy; Safety; Repeated administration; Outpatients
16.  Effect of levosimendan in experimental verapamil- induced myocardial depression 
Background
Calcium antagonist overdose can cause severe deterioration of hemodynamics unresponsible to treatment with beta adrenergic inotropes. The aim of the study was to evaluate in an experimental model the effects of levosimendan during severe calcium antagonist intoxication.
Methods
Twelve landrace-pigs were intoxicated with intravenous verapamil at escalating infusion rates. The infusion containing 2.5 mg/ml verapamil was used aiming to a reduction of cardiac output by 40% from the baseline value. Intoxicated pigs were randomized into two groups: control (saline) and levosimendan (intravenous bolus). Inotropic effect was measured as a change in a maximum of the positive slope of the left ventricular pressure (LV dP/dt). The survival and hemodynamics of the animals were followed for 120 min after the targeted reduction of cardiac output.
Results
In the control group, five out of six pigs died during the experiment. In the levosimendan group, one pig died before completion of the experiment (p = 0.04). In the levosimendan group a change in LV dP/dt was positive in four out of six pigs compared to one out of six pigs in the control group (p = ns).
Conclusions
In this experimental model, the use of levosimendan was associated with improved survival.
doi:10.1186/1757-7241-18-12
PMCID: PMC2847962  PMID: 20222974
17.  Early administration of levosimendan is associated with improved kidney function after cardiac surgery – a retrospective analysis 
Background
Several animal studies suggest beneficial effects on kidney function upon administration of levosimendan. As recent data from clinical studies are heterogeneous, we sought to investigate whether levosimendan is associated with improved postoperative kidney function in cardiac surgery patients with respect to timing of its administration.
Methods
Retrospective, single centre, observational analysis at a university hospital in Berlin, Germany. All adult patients without preoperative renal dysfunction that underwent coronary artery bypass grafting and/or valve reconstruction/replacement between 01/01/2007 and 31/12/2011 were considered for analyses.
Results
Out of 1.095 included patients, 46 patients were treated with levosimendan due to a severely reduced left ventricular systolic function preoperatively (LVEF < 35%) and/or clinical signs of a low cardiac output syndrome. Sixty-one percent received the drug whilst in the OR, 39% after postoperative intensive care unit admission. When levosimendan was given immediately after anaesthesia induction, creatinine plasma levels (p = 0.009 for nonparametric analysis of longitudinal data in a two-factorial design) and incidence of postoperative renal dysfunction (67.9% vs. 94.4%; p = 0.033) were significantly reduced in contrast to a later start of treatment. In addition, duration of renal replacement therapy was significantly shorter (79 [35;332] vs. 272 [132;703] minutes; p = 0.046) in that group.
Conclusions
Postoperative kidney dysfunction is a common condition in patients under going cardiac surgery. Patients with severely reduced left ventricular function and/or clinical signs of a low cardiac output syndrome who preoperatively presented with a normal kidney function may benefit from an early start of levosimendan administration, i.e. immediately after anaesthesia.
Trial registration
Clinicaltrials.gov-ID: NCT01918618.
doi:10.1186/s13019-014-0167-8
PMCID: PMC4240807  PMID: 25399779
Levosimendan; Kidney function; Renal effects; Cardiac surgery; Left ventricular ejection fraction
18.  Study of levosimendan during off-pump coronary artery bypass grafting in patients with LV dysfunction: A double-blind randomized study 
Indian Journal of Pharmacology  2014;46(1):29-34.
Objectives:
Levosimendan is a calcium sensitizer drug which has been used in cardiac surgery for the prevention of postoperative low cardiac output syndrome (LCOS) and in difficult weaning from cardiopulmonary bypass (CPB). This study aims to evaluate perioperative hemodynamic effects of levosimendan pretreatment in patients for off-pump coronary artery bypass graft (OPCABG) surgery with low left ventricular ejection fractions (LVEF < 30%).
Materials and Methods:
Fifty patients undergoing OPCABG surgery with low LVEF (<30%) were enrolled in the study. Patients were randomly divided in two groups: Levosimendan pretreatment (Group L) and placebo pretreatment (Group C) of 25 each. Group L, patients received levosimendan infusion 200 μg/kg over 24 h and in Group C Patients received placebo. The clinical parameters measured before and after the drug administration up to 48 h were heart rate (HR; for the hour after drug infusion), cardiac index (CI), and pulmonary capillary wedge pressure (PCWP). The requirement of inotropes, intraaortic balloon pump (IABP), CPB, intensive care unit (ICU) stay, and hospital stay were also measured.
Results:
The patients in group L exhibited higher CI and PCWP during operative in early postoperative period as compared to control group C. Group L also had a less requirement for inotropes, CPB support and IABP with shorter ICU stay as well as hospital stay.
Conclusion:
Levosimendan pretreatment (24 h infusion) in patient for OPCABG with poor LVEF shows better outcomes and hemodynamics in terms of inotropes, CPB and IABP requirements. It also reduces ICU stay.
doi:10.4103/0253-7613.125161
PMCID: PMC3912803  PMID: 24550581
Cardiac index; CPB; hemodynamic optimization; inotropic agents; LCOS; levosimendan; off-pump coronary artery bypass graft; OPCABG surgery; pulmonary capillary wedge pressure
19.  Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta-blockers 
European Journal of Heart Failure  2010;12(4):404-410.
Aims
The aim of this study is to compare the effects of a 24 h intravenous infusion of levosimendan and a 48 h infusion of dobutamine on invasive haemodynamics in patients with acutely decompensated chronic NYHA class III–IV heart failure. All patients were receiving optimal oral therapy including a β-blocker.
Methods and results
This was a multinational, randomized, double-blind, phase IV study in 60 patients; follow-up was 1 month. There was a significant increase in cardiac index and a significant decrease in pulmonary capillary wedge pressure (PCWP) at 24 and 48 h for both dobutamine and levosimendan. The improvement in cardiac index with levosimendan was not significantly different from dobutamine at 24 h (P = 0.07), but became significant at 48 h (0.44 ± 0.56 vs. 0.66 ± 0.63 L/min/m2; P = 0.04). At 24 h, the reduction in the mean change in PCWP from baseline was similar for levosimendan and dobutamine, however, at 48 h the difference was more marked for levosimendan (−3.6 ± 7.6 vs. −8.3 ± 6.7 mmHg; P = 0.02). No difference was observed between the groups for change in NYHA class, β-blocker use, hospitalizations, treatment discontinuations or rescue medication use. Reduction in B-type natriuretic peptide (BNP) was significantly greater with levosimendan at 48 h (P = 0.03). According to physician's assessment, the improvement in fatigue (P = 0.01) and dyspnoea (P = 0.04) was in favour of dobutamine treatment, and hypotension was significantly more frequent with levosimendan (P = 0.007). No increase in atrial fibrillation or ventricular tachycardia was seen in either group.
Conclusion
A 24 h levosimendan infusion achieved haemodynamic and neurohormonal improvement that was at least comparable at 24 h and superior at 48 h to a 48 h dobutamine infusion.
doi:10.1093/eurjhf/hfq032
PMCID: PMC2844760  PMID: 20335355
Levosimendan; Dobutamine; Decompensated heart failure; Invasive monitoring
20.  Neuroprotective properties of levosimendan in an in vitro model of traumatic brain injury 
BMC Neurology  2010;10:97.
Background
We investigated the neuroprotective properties of levosimendan, a novel inodilator, in an in vitro model of traumatic brain injury.
Methods
Organotypic hippocampal brain slices from mouse pups were subjected to a focal mechanical trauma. Slices were treated after the injury with three different concentrations of levosimendan (0.001, 0.01 and 0.1 μM) and compared to vehicle-treated slices. After 72 hrs, the trauma was quantified using propidium iodide to mark the injured cells.
Results
A significant dose-dependent reduction of both total and secondary tissue injury was observed in cells treated with either 0.01 or 0.1 μM levosimendan compared to vehicle-treated slices.
Conclusion
Levosimendan represents a promising new pharmacological tool for neuroprotection after brain injury and warrants further investigation in an in vivo model.
doi:10.1186/1471-2377-10-97
PMCID: PMC2978146  PMID: 20964834
21.  Levosimendan does not improve survival time in a rat model of verapamil toxicity 
Objective
Calcium channel blocker (CCB) toxicity, in particular that induced by verapamil and diltiazem, presents clinical challenges with no true antidote. Levosimendan, a calcium sensitizer, improves cardiac contractility in patients with heart failure. We tested the hypothesis that calcium channel sensitization will prolong survival in a rat model of severe verapamil poisoning.
Methods
This was a blinded, randomized, controlled animal study. Wistar rats (mean weight, 371 ± 50 g) were used. Verapamil (2.5 mg/ml) was infused at a rate of 37.5 mg/kg per hour. Bolus doses of levosimendan (5 μg/mL) were given at 0 min (12 μg/kg) and 5 min (18 μg/kg); saline control was of equal volume. The rats were intubated and maintained under general anesthesia with isoflurane. Electrocardiographic activity and core temperature were monitored during the poisoning and treatment phases. Each rat underwent femoral vein cannulation and was then randomized, in blinded fashion, to receive either levosimendan or an equal volume of saline at 0 and 5 minutes. Death, defined as 1 minute of asystole, was used as the primary endpoint.
Results
Rats treated with levosimendan died before the control group (7.37 ± 0.7 min [n = 7] vs. 16.4 ± 4.2 [n = 7] [p=.053]). All animals experienced bradycardia prior to asystole.
Discussion
Although levosimendan has the ability to sensitize and enhance binding of troponin C to Ca2+, this study did not show an improvement in survival time in the setting of verapamil toxicity. This may be attributed to levosimendan’s inhibition of phosphodiesterase, which possibly exacerbated the CCB-induced hypotension.
Conclusion
In this rat model, levosimendan as a solitary antidotal treatment for verapamil toxicity was not beneficial.
doi:10.1007/BF03160973
PMCID: PMC3550339  PMID: 19191208
verapamil; toxicity; levosimendan
22.  Prophylactic application of levosimendan in cardiac surgical patients with severe left ventricle dysfunction 
BACKGROUND:
Levosimendan improves myocardial contractility, and increases systemic, pulmonary and coronary vasodilation. The present study investigates the perioperative hemodynamic effects of a prophylactic infusion of levosimendan in high-risk cardiac surgery patients with severe left ventricle dysfunction, and compares short-term clinical outcomes with a historical control group in which dobutamine and milrinone were used.
PATIENTS AND METHODS:
A retrospective, observational study was performed in 10 adult patients with EuroSCOREs greater than six and severe left ventricle dysfunction. In the study group, prophylactic levosimendan infusion was started after the induction of general anesthesia (bolus 24 μg/kg over 10 min; continuous infusion 0.1 μg/kg/min over the next 24 h). The historical control group (12 patients) was treated with dobutamine and milrinone. The hemodynamic measurements were performed at eight predetermined time points. Short-term clinical outcomes recorded in both groups were the length of intensive care unit stay, the need for dialysis, the length of hospital stay, predicted mortality (logistic EuroSCORE) and 30-day mortality.
RESULTS:
Hemodynamic measurements performed in the study group revealed an increase in cardiac index 30 min after levosimendan infusion was started. Cardiac performance was sufficient throughout the entire perioperative period. The length of intensive care unit stay was not different between the groups, but the length of hospital stay (10.4±5.0 versus 26.6±17.6 days; P=0.01) and 30-day mortality (0% versus 41.7%; P=0.04) were significantly lower in levosimendan-treated patients.
CONCLUSIONS:
Levosimendan seemed to be an effective choice for preventing left ventricle failure in high-risk cardiac surgical patients with severe left ventricle dysfunction compared with patients receiving dobutamine and milrinone.
PMCID: PMC2722457  PMID: 19675817
EuroSCORE; High-risk cardiac surgery; Inotropic drugs; Left ventricle dysfunction; Levosimendan
23.  Comparative Hemodynamic Effects of Levosimendan Alone and in Conjunction with 4-Aminopyridine or Calcium Chloride in a Rodent Model of Severe Verapamil Poisoning 
Journal of Medical Toxicology  2010;6(2):85-93.
Levosimendan (Levo) increases sensitivity of troponin-C to calcium, thus increasing myocardial contractility. It is also a vascular K+-ATP channel agonist producing peripheral vasodilation. Previous research with levosimendan revealed an increase in cardiac output (CO) but not blood pressure (BP) in experimental verapamil poisoning. Levosimendan’s K+-channel agonist properties may augment verapamil’s vasodilatory effects. 4-Aminopyridine (4-AP) is a K+-channel antagonist. It has successfully reversed hypotension in experimental verapamil poisoning. We hypothesized that coadministration of these agents may improve BP and CO in verapamil poisoning. Anesthetized, ventilated, and canulated male Wistar rats were poisoned with verapamil. Animals received one of six treatments, which are as follows: (1) n-saline infusion (control), (2) Levo 6.25 μg/kg loading dose and 36 μg/kg/h infusion, (3) 4-AP 2 mg/kg loading dose and infusion (4-AP), (4) Levo+4-AP, (5) CaCl2 loading dose and infusion, and (6) Levo+CaCl2. Hemodynamic parameters were recorded for 60 min. Outcome measures were changes in CO, BP, and heart rate (HR) compared to control. All groups had similar pretoxicity and peak toxicity CO (50% of pretoxicity value), BP (50% or pretoxicity value), and HR. Control group CO, BP, and HR progressively dropped during the verapamil infusion. Levosimendan produced a statistically significant improvement in CO (75% of pretoxicity level) but not BP in comparison to control. 4-AP produced a significant improvement in CO (110% of pretoxicity) and BP (78% of pretoxicity). Levo+4-AP and Levo+CaCl2 groups improved CO (100% of pretoxicity) and BP (77% and 50% of pretoxicity, respectively), but there was no additive increase in CO or BP in animals compared to 4-AP or CaCl2 alone. Levosimendan moderately improved CO but not BP in verapamil poisoning. The hypotensive effects of levosimendan were not overcome by coadministration of either 4-AP or CaCl2. Levosimendan may not be an appropriate agent to use in the treatment of verapamil poisoning.
doi:10.1007/s13181-010-0073-y
PMCID: PMC3550276  PMID: 20473651
Poisoning; Overdose; Calcium channel blockers; Verapamil; Levosimendan; Aminopyridine; Rodent
24.  Efficiency and Safety of Prolonged Levosimendan Infusion in Patients with Acute Heart Failure 
Background. Levosimendan is an inotropic drug with unique pharmacological advantages in patients with acute heart failure. Scope of this study is to determine whether longer infusion patterns without the hypotension-inducing loading dose could justify an effective and safe alternative approach. Methods. 70 patients admitted to the emergencies with decompensated chronic heart failure received intravenously levosimendan without a loading dose up to 72 hours. Clinical parameters, BNP (Brain Natriuretic Peptide) and signal-averaged-ECG data (SAECG) were recorded up to 72 hours. Results. The 48-hour group demonstrated a statistically significant BNP decrease (P < .001) after 48 hours, which also maintained after 72 hours. The 72-hour group demonstrated a bordeline decrease of BNP after 48 hours (P = .039), necessitating an additional 24-hour infusion to achieve significant reduction after 72 hours (P < .004). SAECG data demonstrated a statistically significant decrease after 72 hours (P < .04). Apart from two deaths due to advanced heart failure, no major complications were observed. Conclusion. Prolonged infusion of levosimendan without a loading dose is associated with an acceptable clinical and neurohumoral response.
doi:10.4061/2011/342302
PMCID: PMC3087940  PMID: 21559263
25.  Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass 
BACKGROUND:
The calcium sensitizer levosimendan has been used in cardiac surgery for the treatment of postoperative low cardiac output syndrome (LCOS) and difficult weaning from cardiopulmonary bypass (CPB).
OBJECTIVES:
To evaluate the effects of preoperative treatment with levosimendan on 30-day mortality, the risk of developing LCOS and the requirement for inotropes, vasopressors and intra-aortic balloon pumps in patients with severe left ventricular dysfunction.
METHODS:
Patient with severe left ventricular dysfunction and an ejection fraction <25% undergoing coronary artery bypass grafting with CPB were admitted 24 h before surgery and were randomly assigned to receive levosimendan (loading dose 10 μg/kg followed by a 23 h continuous infusion of 0.1μg/kg/min) or a placebo.
RESULTS:
From December 1, 2002 to June 1, 2008, a total of 252 patients were enrolled (127 in the levosimendan group and 125 in the control group). Individuals treated with levosimendan exhibited a lower incidence of complicated weaning from CPB (2.4% versus 9.6%; P<0.05), decreased mortality (3.9% versus 12.8%; P<0.05) and a lower incidence of LCOS (7.1% versus 20.8%; P<0.05) compared with the control group. The levosimendan group also had a lower requirement for inotropes (7.9% versus 58.4%; P<0.05), vasopressors (14.2% versus 45.6%; P<0.05) and intra-aortic balloon pumps (6.3% versus 30.4%; P<0.05).
CONCLUSION:
Patients with severe left ventricle dysfunction (ejection fraction <25%) undergoing coronary artery bypass grafting with CPB who were pretreated with levosimendan exhibited lower mortality, a decreased risk for developing LCOS and a reduced requirement for inotropes, vasopressors and intra-aortic balloon pumps. Studies with a larger number of patients are required to confirm whether these findings represent a new strategy to reduce the operative risk in this high-risk patient population.
PMCID: PMC3628425  PMID: 23620700
Cardiac surgery; Hemodynamic optimization; Inotropic agents; Levosimendan; Postoperative low cardiac output

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