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Piero Pollesello - One of the best experts on this subject based on the ideXlab platform.

  • use of Levosimendan in acute heart failure
    European Heart Journal, 2018
    Co-Authors: Velipekka Harjola, Piero Pollesello, George Giannakoulas, Dirk Von Lewinski, Simon Matskeplishvili, Alexandre Mebazaa, Zoltan Papp, Robert H G Schwinger, John Parissis
    Abstract:

    As a calcium sensitizer and inodilator that augments cardiac contractility without increasing myocardial oxygen demand or exacerbating ischaemia, Levosimendan may be well configured to deliver inotropic support in cases of acute heart failure (AHF). Other factors favouring Levosimendan in this setting include its extended duration of action due to the formation of an active metabolite and the lack of any attenuation of effect in patients treated with beta-blockers. Effects of Levosimendan on systemic haemodynamics include its significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in right and left ventricular filling and total peripheral resistance. Rapid and sustained reduction in levels of natriuretic peptides is a consistent effect of Levosimendan use and potentially favourable effects on other neurohormonal indicators of cardiac distress are also observed. Levosimendan has repeatedly been shown to be effective in relief of symptoms of AHF, notably dyspnoea and fatigue, while mortality data from clinical trials and registries suggest that Levosimendan is markedly less likely than catecholaminergic inotropes to worsen prognosis. The vasodilator pharmacology of Levosimendan is also pertinent to the drug’s use in AHF, in which setting organ under-perfusion is often a key pathology. These considerations suggest that Levosimendan may have a more favourable impact on the circumstances of the majority of AHF patients than adrenergic agents that act only or primarily as cardiac stimulants. They also suggest that Levosimendan may advantageously be integrated into a comprehensive strategy of early intervention designed and intended to prevent cardiac destabilization worsening to the point where hospitalization is necessary. Levosimendan should be used with caution and with tightened haemodynamic monitoring in patients who have low baseline blood pressure (systolic blood pressure <100 mmHg; diastolic blood pressure <60 mmHg), or who are at risk of a hypotensive episode.

  • Levosimendan meta analyses is there a pattern in the effect on mortality
    International Journal of Cardiology, 2016
    Co-Authors: Piero Pollesello, Matti Kivikko, John Parissis, Velipekka Harjola
    Abstract:

    Background Levosimendan is an inodilator developed for treatment of acute heart failure and other cardiac conditions where the use of an inodilator is considered appropriate. Levosimendan has been studied in different therapeutic settings including acutely decompensated chronic heart failure, advanced heart failure, right ventricular failure, cardiogenic shock, septic shock, and cardiac and non-cardiac surgery. This variety of data has been re-analysed in 25 meta-analyses from 15 different international research groups, based on different rationales to select the studies included. Methods We here review all previously published meta-analyses on Levosimendan to determine any common denominators for its effects on patient mortality. In addition, we also perform a comparative meta-analysis of the six phase II and III randomized double-blind trials which were taken into consideration by the regulatory authorities for the purpose of introducing Levosimendan into the market. Results Irrespective of clinical setting or comparator, all meta-analyses consistently show benefits for Levosimendan, with lower relative risk (or odds ratio) for patient mortality. In 3/25 of the meta-analyses these beneficial trends did not reach statistical significance, while in 22/25 significance was reached. The relative risk is consistent overall, and very similar to that obtained in our own meta-analysis that considered only the 'regulatory' studies. Conclusion The existing meta-analyses, now based on a population of over 6000 patients, provide the general message of significant benefits for Levosimendan in terms of patient mortality. The weight of evidence is now clearly in favour of usefulness/efficacy of Levosimendan, with data from multiple randomized trials and meta-analyses.

  • Levosimendan current data clinical use and future development
    Heart lung and vessels, 2013
    Co-Authors: Markku S Nieminen, Matti Kivikko, Sonja Fruhwald, Leo M A Heunks, P K Suominen, Anthony C Gordon, Piero Pollesello
    Abstract:

    Levosimendan is an inodilator indicated for the short-term treatment of acutely decompensated severe chronic heart failure, and in situations where conventional therapy is not considered adequate. The principal pharmacological effects of Levosimendan are (a) increased cardiac contractility by calcium sensitisation of troponin C, (b) vasodilation, and (c) cardioprotection. These last two effects are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that Levosimendan improves haemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers. Levosimendan also has favourable effects on neurohormone levels in heart failure patients. Levosimendan is generally well tolerated in acute heart failure patients: the most common adverse events encountered in this setting are hypotension, headache, atrial fibrillation, hypokalaemia and tachycardia. Levosimendan has also been studied in other therapeutic applications, particularly cardiac surgery - in which it has shown a range of beneficial haemodynamic and cardioprotective effects, and a favourable influence on clinical outcomes - and has been evaluated in repetitive dosing protocols in patients with advanced chronic heart failure. Levosimendan has shown preliminary positive effects in a range of conditions requiring inotropic support, including right ventricular failure, cardiogenic shock, septic shock, and Takotsubo cardiomyopathy.

  • a role for the risk pathway and katp channels in pre and post conditioning induced by Levosimendan in the isolated guinea pig heart
    British Journal of Pharmacology, 2008
    Co-Authors: E F Du Toit, Piero Pollesello, A Genis, L H Opie, A Lochner
    Abstract:

    Background and purpose: Myocardial reperfusion injury prevents optimal salvage of the ischaemic myocardium, and adjunct therapy that would significantly reduce reperfusion injury is still lacking. We investigated whether (1) the heart could be pre- and/or post-conditioned using Levosimendan (Levosimendan pre-conditioning (LPC) and Levosimendan post-conditioning (LPostC)) and (2) the prosurvival kinases and/or the sarcolemmal or mitochondrial KATP channels are involved. Experimental approach: Isolated guinea pig hearts were treated with two 5 min cycles of Levosimendan (0.1 μM) interspersed with vehicle perfusion, or two 5 min cycles of ischaemia/reperfusion, before coronary artery ligation (CAL) for 40 min at 36.5 °C. Hearts were treated with mitochondrial or sarcolemmal KATP channel blockers before LPC or LPostC. For post-conditioning, hearts received three 30 s cycles of ischaemia/reperfusion or Levosimendan/vehicle. Hearts were pretreated with Levosimendan immediately before CAL (without washout). Cardiac function, infarct size and reperfusion injury salvage kinase activity was assessed. Key results: LPC and LPostC halved the infarct size compared with controls (P<0.05). Treatment with KATP channel blockers before LPC or LPostC reversed this decrease. Pretreating hearts with Levosimendan increased activity of extracellular signal-regulated kinase (ERK) 42/44 on reperfusion and had the most marked infarct-lowering effect (P<0.05). Conclusions and implications: (1) Hearts could be pharmacologically pre- and post-conditioned with Levosimendan; (2) Levosimendan pretreatment is the most effective way to reduce infarct size, possibly by increasing ERK 42/44 activity; (3) benefits of LPC and LPostC were abolished by both KATP channel blockers and (4) LPC may be useful before elective cardiac surgery, whereas LPostC may be used after acute coronary artery events.

  • Levosimendan increases diastolic coronary flow in isolated guinea pig heart by opening atp sensitive potassium channels
    Journal of Cardiovascular Pharmacology, 2001
    Co-Authors: Petri Kaheinen, Jouko Levijoki, Piero Pollesello, Heimo Haikala
    Abstract:

    Levosimendan, a novel calcium sensitizer developed for the treatment of acute heart failure, is an inodilator that increases coronary flow. Because it was recently shown that Levosimendan stimulates potassium current through K(ATP) channels in isolated rat arterial cells, our aim was to assess whether the Levosimendan-induced increase in coronary flow is due to the opening of the K(ATP) channels in coronary smooth muscle. The effect of Levosimendan on the diastolic coronary flow velocity (DCFV) was measured in the Langendorff perfused spontaneously beating guinea-pig heart in the absence and presence of glibenclamide. Pinacidil was used as a reference compound, and the protein kinase C inhibitor bisindolylmaleimide was used to study the dilatory effect of Levosimendan when the K(ATP) channels in smooth muscle are not inhibited by PKC-dependent phosphorylation. Levosimendan (0.01-1 microM) increased DCFV concentration-dependently and was noncompetitively antagonized by 0.1 microM glibenclamide, whereas pinacidil was inhibited competitively by glibenclamide. In the presence of glibenclamide the positive inotropic and chronotropic effects of Levosimendan were unaltered. The effect of bisindolylmaleimide and Levosimendan on DCFV was additive. The results indicate that Levosimendan induced coronary vasodilation through the opening of the K(ATP) channels. Levosimendan and pinacidil probably have different binding sites on the K(ATP) channels. The additive effect of bisindolylmaleimide and Levosimendan on the increase of DCFV suggests that the latter binds to the unphosphorylated form of the channel.

Andrea Morelli - One of the best experts on this subject based on the ideXlab platform.

  • Levosimendan for patients with severely reduced left ventricular systolic function and or low cardiac output syndrome undergoing cardiac surgery a systematic review and meta analysis
    Critical Care, 2017
    Co-Authors: Filippo Sanfilippo, Luigi Tritapepe, Andrea Morelli, Joshua Knight, Sabino Scolletta, Cristina Santonocito, Federico Pastore, Ferdinando L Lorini, Antonio Arcadipane
    Abstract:

    Previous studies have shown beneficial effects of Levosimendan in high-risk patients undergoing cardiac surgery. Two large randomized controlled trials (RCTs), however, showed no advantages of Levosimendan. We performed a systematic review and meta-analysis (MEDLINE and Embase from inception until March 30, 2017), investigating whether Levosimendan offers advantages compared with placebo in high-risk cardiac surgery patients, as defined by preoperative left ventricular ejection fraction (LVEF) ≤ 35% and/or low cardiac output syndrome (LCOS). The primary outcomes were mortality at longest follow-up and need for postoperative renal replacement therapy (RRT). Secondary postoperative outcomes investigated included myocardial injury, supraventricular arrhythmias, development of LCOS, acute kidney injury (AKI), duration of mechanical ventilation, intensive care unit and hospital lengths of stay, and incidence of hypotension during drug infusion. Six RCTs were included in the meta-analysis, five of which investigated only patients with LVEF ≤ 35% and one of which included predominantly patients with LCOS. Mortality was similar overall (OR 0.64 [0.37, 1.11], p = 0.11) but lower in the subgroup with LVEF < 35% (OR 0.51 [0.32, 0.82], p = 0.005). Need for RRT was reduced by Levosimendan both overall (OR 0.63 [0.42, 0.94], p = 0.02) and in patients with LVEF < 35% (OR 0.55 [0.31, 0.97], p = 0.04). Among secondary outcomes, we found lower postoperative LCOS in patients with LVEF < 35% receiving Levosimendan (OR 0.49 [0.27, 0.89], p = 0.02), lower overall AKI (OR 0.62 [0.42, 0.92], p = 0.02), and a trend toward lower mechanical support, both overall (p = 0.07) and in patients with LVEF < 35% (p = 0.05). Levosimendan reduces mortality in patients with preoperative severely reduced LVEF but does not affect overall mortality. Levosimendan reduces the need for RRT after high-risk cardiac surgery.

  • effects of Levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome a pilot study
    Critical Care Medicine, 2006
    Co-Authors: Andrea Morelli, Alessandra Orecchioni, Jeanlouis Teboul, Monica Rocco, Giorgio Conti, Salvatore Maurizio Maggiore, Antoine Vieillardbaron, Andrea De Gaetano, Umberto Picchini, Iacopo Carbone
    Abstract:

    OBJECTIVE: Acute respiratory distress syndrome (ARDS) is frequently associated with increased pulmonary vascular resistance and thus with systolic load of the right ventricle. We hypothesized that Levosimendan, a new calcium sensitizer with potential pulmonary vasodilator properties, improves hemodynamics by unloading the right ventricle in patients with ARDS. DESIGN: Prospective, randomized, placebo-controlled, pilot study. SETTING: Twenty-two-bed multidisciplinary intensive care unit of a university hospital. PATIENTS: Thirty-five patients with ARDS in association with septic shock. INTERVENTIONS: Patients were randomly allocated to receive a 24-hr infusion of either Levosimendan 0.2 microg/kg/min (n = 18) or placebo (n = 17). Data from right heart catheterization, cardiac magnetic resonance, arterial and mixed venous oxygen tensions and saturations, and carbon dioxide tensions were obtained before and 24 hrs after drug infusion. MEASUREMENTS AND MAIN RESULTS: At a mean arterial pressure between 70 and 80 mm Hg (sustained with norepinephrine infusion), Levosimendan increased cardiac index (from 3.8 +/- 1.1 to 4.2 +/- 1.0 L/min/m) and decreased mean pulmonary artery pressure (from 29 +/- 3 to 25 +/- 3 mm Hg) and pulmonary vascular resistance index (from 290 +/- 77 to 213 +/- 50 dynes/s/cm(5)/m(2); each p < .05). Levosimendan also decreased right ventricular end-systolic volume and increased right ventricular ejection fraction (p < .05). In addition, Levosimendan increased mixed venous oxygen saturation (from 63 +/- 8 to 70 +/- 8%; p < .01). CONCLUSIONS: This study provides evidence that Levosimendan improves right ventricular performance through pulmonary vasodilator effects in septic patients with ARDS. A large multiple-center trial is needed to investigate whether Levosimendan is able to improve the overall prognosis of patients with sepsis and ARDS. (Less)

  • preconditioning effects of Levosimendan in coronary artery bypass grafting a pilot study
    BJA: British Journal of Anaesthesia, 2006
    Co-Authors: Luigi Tritapepe, V De Santis, Domenico Vitale, Mervyn Singer, M Santulli, Andrea Morelli, Italo Nofroni, Paolo Emilio Puddu, Paolo Pietropaoli
    Abstract:

    Background The calcium sensitizer Levosimendan protects against myocardial ischaemia and reperfusion injury in animal models. Methods The present pilot study investigated whether a short infusion before coronary artery bypass grafting (CABG) would protect the myocardium and improve postoperative haemodynamics. Twenty-four patients with stable angina undergoing elective CABG surgery were randomized to receive either placebo or Levosimendan (24 µg kg−1) infused i.v. over a 10 min period just before placing the patient on cardiopulmonary bypass. Results Perioperative haemodynamic variables, concentrations of cardiac troponin I over the 48 h postoperative period, and clinical outcomes were assessed. There were no adverse effects related to Levosimendan. Compared with control patients, Levosimendan-treated patients had lower postoperative troponin I concentrations (P Conclusion Patients receiving a short infusion of Levosimendan before CABG showed evidence of less myocardial damage, suggestive of a preconditioning effect. Larger outcome studies are thus indicated to confirm benefit.

  • effects of Levosimendan on systemic and regional hemodynamics in septic myocardial depression
    Intensive Care Medicine, 2006
    Co-Authors: Andrea Morelli, Alessandra Orecchioni, Mervyn Singer, Stefano De Castro, Jeanlouis Teboul, Monica Rocco, Giorgio Conti, Leonardo De Luca, Emanuele Di Angelantonio, Natesa G Pandian
    Abstract:

    Calcium desensitization plays an important part in the pathophysiology of septic myocardial depression. We postulated that Levosimendan, a new calcium sensitizer, would be beneficial in sepsis-induced cardiac dysfunction. Prospective, randomized, controlled study in two university hospital intensive care units Twenty-eight patients with persisting left ventricular dysfunction related to septic shock after 48 h of conventional treatment including dobutamine (5 µg/kg per minute). After 48 h of conventional treatment patients were randomized to receive a 24-h infusion of either Levosimendan (0.2 µg/kg per minute, n=15) or dobutamine (5 µg/kg per minute, n=13). Data from right heart catheterization, echocardiography, gastric tonometry, laser-Doppler flowmetry, and lactate concentrations and creatinine clearance were obtained before and after the 24-h drug infusion. Dobutamine did not change systemic or regional hemodynamic variables. By contrast, at the same mean arterial pressure Levosimendan decreased pulmonary artery occlusion pressure and increased cardiac index. Levosimendan decreased left ventricular end-diastolic volume and increased left ventricular ejection fraction. Levosimendan increased gastric mucosal flow, creatinine clearance, and urinary output while it decreased lactate concentrations. These findings show that Levosimendan improves systemic hemodynamics and regional perfusion in patients with septic cardiac dysfunction under conditions where administration of 5 µg/kg dobutamine per minute is no longer efficacious. Accordingly, our results suggest that Levosimendan can be an alternative to the strategy of increasing the dose of dobutamine under such conditions.

Mervyn Singer - One of the best experts on this subject based on the ideXlab platform.

  • Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction a subgroup analysis of the leopards randomised trial
    Intensive Care Medicine, 2019
    Co-Authors: David Antcliffe, Mervyn Singer, Shalini Santhakumaran, Robert M L Orme, Josie K Ward, Farah Albeidh, Kieran P Odea, Gavin D Perkins, Daniel F Mcauley, Alexina J Mason
    Abstract:

    Myocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, Levosimendan was suggested as a possible therapy; however, the Levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of Levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects. Two cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values. Levosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving Levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43–2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers. Adding Levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.

  • Levosimendan pre treatment improves outcomes in patients undergoing coronary artery bypass graft surgery
    BJA: British Journal of Anaesthesia, 2009
    Co-Authors: Luigi Tritapepe, Paolo Pietropaoli, Fabio Guarracino, V De Santis, Domenico Vitale, Fabio Pellegrini, Mervyn Singer
    Abstract:

    Background The calcium sensitizer Levosimendan has anti-ischaemic effects mediated via the opening of sarcolemmal and mitochondrial ATP-sensitive potassium channels. These properties suggest potential application in clinical situations where cardioprotection would be beneficial, such as cardiac surgery. We thus decided to investigate whether pharmacological pre-treatment with Levosimendan reduces intensive care unit (ICU) length of stay in patients undergoing elective myocardial revascularization under cardiopulmonary bypass. Methods One hundred and six patients undergoing elective coronary artery bypass grafting were randomly assigned in a double-blind manner to receive Levosimendan or placebo. Levosimendan (24 μg kg −1 ) or placebo was administered as a slow i.v. bolus over a 10 min period before the initiation of bypass. Results Tracheal intubation time and the length of ICU stay were significantly reduced in the Levosimendan group ( P 12 h was significantly higher in the control group (18.0% vs 3.8%; P =0.021). Compared with control patients, Levosimendan-treated patients had lower postoperative troponin I concentrations ( P P Conclusions Pre-treatment with Levosimendan in patients undergoing surgical myocardial revascularization resulted in less myocardial injury, a reduction in tracheal intubation time, less requirement for inotropic support, and a shorter length of ICU stay.

  • preconditioning effects of Levosimendan in coronary artery bypass grafting a pilot study
    BJA: British Journal of Anaesthesia, 2006
    Co-Authors: Luigi Tritapepe, V De Santis, Domenico Vitale, Mervyn Singer, M Santulli, Andrea Morelli, Italo Nofroni, Paolo Emilio Puddu, Paolo Pietropaoli
    Abstract:

    Background The calcium sensitizer Levosimendan protects against myocardial ischaemia and reperfusion injury in animal models. Methods The present pilot study investigated whether a short infusion before coronary artery bypass grafting (CABG) would protect the myocardium and improve postoperative haemodynamics. Twenty-four patients with stable angina undergoing elective CABG surgery were randomized to receive either placebo or Levosimendan (24 µg kg−1) infused i.v. over a 10 min period just before placing the patient on cardiopulmonary bypass. Results Perioperative haemodynamic variables, concentrations of cardiac troponin I over the 48 h postoperative period, and clinical outcomes were assessed. There were no adverse effects related to Levosimendan. Compared with control patients, Levosimendan-treated patients had lower postoperative troponin I concentrations (P Conclusion Patients receiving a short infusion of Levosimendan before CABG showed evidence of less myocardial damage, suggestive of a preconditioning effect. Larger outcome studies are thus indicated to confirm benefit.

  • effects of Levosimendan on systemic and regional hemodynamics in septic myocardial depression
    Intensive Care Medicine, 2006
    Co-Authors: Andrea Morelli, Alessandra Orecchioni, Mervyn Singer, Stefano De Castro, Jeanlouis Teboul, Monica Rocco, Giorgio Conti, Leonardo De Luca, Emanuele Di Angelantonio, Natesa G Pandian
    Abstract:

    Calcium desensitization plays an important part in the pathophysiology of septic myocardial depression. We postulated that Levosimendan, a new calcium sensitizer, would be beneficial in sepsis-induced cardiac dysfunction. Prospective, randomized, controlled study in two university hospital intensive care units Twenty-eight patients with persisting left ventricular dysfunction related to septic shock after 48 h of conventional treatment including dobutamine (5 µg/kg per minute). After 48 h of conventional treatment patients were randomized to receive a 24-h infusion of either Levosimendan (0.2 µg/kg per minute, n=15) or dobutamine (5 µg/kg per minute, n=13). Data from right heart catheterization, echocardiography, gastric tonometry, laser-Doppler flowmetry, and lactate concentrations and creatinine clearance were obtained before and after the 24-h drug infusion. Dobutamine did not change systemic or regional hemodynamic variables. By contrast, at the same mean arterial pressure Levosimendan decreased pulmonary artery occlusion pressure and increased cardiac index. Levosimendan decreased left ventricular end-diastolic volume and increased left ventricular ejection fraction. Levosimendan increased gastric mucosal flow, creatinine clearance, and urinary output while it decreased lactate concentrations. These findings show that Levosimendan improves systemic hemodynamics and regional perfusion in patients with septic cardiac dysfunction under conditions where administration of 5 µg/kg dobutamine per minute is no longer efficacious. Accordingly, our results suggest that Levosimendan can be an alternative to the strategy of increasing the dose of dobutamine under such conditions.

Matti Kivikko - One of the best experts on this subject based on the ideXlab platform.

  • Levosimendan meta analyses is there a pattern in the effect on mortality
    International Journal of Cardiology, 2016
    Co-Authors: Piero Pollesello, Matti Kivikko, John Parissis, Velipekka Harjola
    Abstract:

    Background Levosimendan is an inodilator developed for treatment of acute heart failure and other cardiac conditions where the use of an inodilator is considered appropriate. Levosimendan has been studied in different therapeutic settings including acutely decompensated chronic heart failure, advanced heart failure, right ventricular failure, cardiogenic shock, septic shock, and cardiac and non-cardiac surgery. This variety of data has been re-analysed in 25 meta-analyses from 15 different international research groups, based on different rationales to select the studies included. Methods We here review all previously published meta-analyses on Levosimendan to determine any common denominators for its effects on patient mortality. In addition, we also perform a comparative meta-analysis of the six phase II and III randomized double-blind trials which were taken into consideration by the regulatory authorities for the purpose of introducing Levosimendan into the market. Results Irrespective of clinical setting or comparator, all meta-analyses consistently show benefits for Levosimendan, with lower relative risk (or odds ratio) for patient mortality. In 3/25 of the meta-analyses these beneficial trends did not reach statistical significance, while in 22/25 significance was reached. The relative risk is consistent overall, and very similar to that obtained in our own meta-analysis that considered only the 'regulatory' studies. Conclusion The existing meta-analyses, now based on a population of over 6000 patients, provide the general message of significant benefits for Levosimendan in terms of patient mortality. The weight of evidence is now clearly in favour of usefulness/efficacy of Levosimendan, with data from multiple randomized trials and meta-analyses.

  • Levosimendan current data clinical use and future development
    Heart lung and vessels, 2013
    Co-Authors: Markku S Nieminen, Matti Kivikko, Sonja Fruhwald, Leo M A Heunks, P K Suominen, Anthony C Gordon, Piero Pollesello
    Abstract:

    Levosimendan is an inodilator indicated for the short-term treatment of acutely decompensated severe chronic heart failure, and in situations where conventional therapy is not considered adequate. The principal pharmacological effects of Levosimendan are (a) increased cardiac contractility by calcium sensitisation of troponin C, (b) vasodilation, and (c) cardioprotection. These last two effects are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that Levosimendan improves haemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers. Levosimendan also has favourable effects on neurohormone levels in heart failure patients. Levosimendan is generally well tolerated in acute heart failure patients: the most common adverse events encountered in this setting are hypotension, headache, atrial fibrillation, hypokalaemia and tachycardia. Levosimendan has also been studied in other therapeutic applications, particularly cardiac surgery - in which it has shown a range of beneficial haemodynamic and cardioprotective effects, and a favourable influence on clinical outcomes - and has been evaluated in repetitive dosing protocols in patients with advanced chronic heart failure. Levosimendan has shown preliminary positive effects in a range of conditions requiring inotropic support, including right ventricular failure, cardiogenic shock, septic shock, and Takotsubo cardiomyopathy.

  • intravenous Levosimendan vs dobutamine in acute decompensated heart failure patients on beta blockers
    European Journal of Heart Failure, 2010
    Co-Authors: Claeshakan Bergh, Matti Kivikko, Bert Andersson, Ulf Dahlstrom, Kolbjorn Forfang, Toni Sarapohja, Bengt Ullman, Gerhard Wikström
    Abstract:

    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.

  • Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function
    The Annals of Thoracic Surgery, 2009
    Co-Authors: Heidi Eriksson, Matti Kivikko, J Jalonen, Leo O Heikkinen, Mika Laine, Kari Leino, Anne Kuitunen, Kari Kuttila, Tarja Perakyla, Toni Sarapohja
    Abstract:

    Background Levosimendan is a compound with vasodilatory and inotropic properties. Experimental data suggest effective reversal of stunning and cardioprotective properties. Methods This prospective, randomized, placebo-controlled, double-blind study included 60 patients with 3-vessel coronary disease and left ventricular ejection fraction (LVEF) of less than 0.50. Levosimendan administration (12 μg/kg bolus, followed by an infusion of 0.2 μg/kg/min) was started immediately after induction anesthesia. Predefined strict hemodynamic criteria were used to assess the success of weaning. If weaning was not successful, CPB was reinstituted and an epinephrine infusion was started. If the second weaning attempt failed, intraaortic balloon pumping (IABP) was instituted. Results The groups had comparable demographics. The mean (standard deviation) preoperative LVEF was 0.36 (0.8) in both groups. The baseline cardiac index was 1.8 (0.3) L/min/m 2 in the Levosimendan group and 1.9 (0.4) L/min/m 2 in the placebo group. The mean duration of CPB to primary weaning attempt was 104 (25) minutes in the Levosimendan and 109 (22) minutes in the placebo group. Primary weaning was successful in 22 patients (73%) in the Levosimendan group and in 10 (33%) in the placebo group ( p = 0.002). The odds ratio for failure in primary weaning was 0.182 (95% confidence interval, 0.060 to 0.552). Four patients in the placebo group failed the second weaning and underwent IABP compared with none in the Levosimendan group ( p = 0.112). Conclusions Levosimendan significantly enhanced primary weaning from CPB compared with placebo in patients undergoing 3-vessel on-pump coronary artery bypass grafting. The need for additional inotropic or mechanical therapy was decreased.

  • Levosimendan vs dobutamine for patients with acute decompensated heart failure the survive randomized trial
    JAMA, 2007
    Co-Authors: Alexandre Mebazaa, Markku S Nieminen, Milton Packer, Robert J Padley, Roopal Thakkar, Alain Cohensolal, Franz X Kleber, Stuart J Pocock, Pentti Poder, Matti Kivikko
    Abstract:

    ContextBecause acute decompensated heart failure causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival.ObjectiveTo assess the effect of a short-term intravenous infusion of Levosimendan or dobutamine on long-term survival.Design, Setting, and PatientsThe Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, double-blind trial comparing the efficacy and safety of intravenous Levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients were randomized between March 2003 and December 2004.InterventionsIntravenous Levosimendan (n = 664) or intravenous dobutamine (n = 663).Main Outcome MeasureAll-cause mortality at 180 days.ResultsAll-cause mortality at 180 days occurred in 173 (26%) patients in the Levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74-1.13; P = .40). The Levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P<.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the Levosimendan group.ConclusionDespite an initial reduction in plasma B-type natriuretic peptide level in patients in the Levosimendan group compared with patients in the dobutamine group, Levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes.Trial Registrationclinicaltrials.gov Identifier: NCT00348504

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  • Levosimendan increases diastolic coronary flow in isolated guinea pig heart by opening atp sensitive potassium channels
    Journal of Cardiovascular Pharmacology, 2001
    Co-Authors: Petri Kaheinen, Jouko Levijoki, Piero Pollesello, Heimo Haikala
    Abstract:

    Levosimendan, a novel calcium sensitizer developed for the treatment of acute heart failure, is an inodilator that increases coronary flow. Because it was recently shown that Levosimendan stimulates potassium current through K(ATP) channels in isolated rat arterial cells, our aim was to assess whether the Levosimendan-induced increase in coronary flow is due to the opening of the K(ATP) channels in coronary smooth muscle. The effect of Levosimendan on the diastolic coronary flow velocity (DCFV) was measured in the Langendorff perfused spontaneously beating guinea-pig heart in the absence and presence of glibenclamide. Pinacidil was used as a reference compound, and the protein kinase C inhibitor bisindolylmaleimide was used to study the dilatory effect of Levosimendan when the K(ATP) channels in smooth muscle are not inhibited by PKC-dependent phosphorylation. Levosimendan (0.01-1 microM) increased DCFV concentration-dependently and was noncompetitively antagonized by 0.1 microM glibenclamide, whereas pinacidil was inhibited competitively by glibenclamide. In the presence of glibenclamide the positive inotropic and chronotropic effects of Levosimendan were unaltered. The effect of bisindolylmaleimide and Levosimendan on DCFV was additive. The results indicate that Levosimendan induced coronary vasodilation through the opening of the K(ATP) channels. Levosimendan and pinacidil probably have different binding sites on the K(ATP) channels. The additive effect of bisindolylmaleimide and Levosimendan on the increase of DCFV suggests that the latter binds to the unphosphorylated form of the channel.

  • Further Evidence for the Cardiac Troponin C Mediated Calcium Sensitization by Levosimendan: Structure-response and Binding Analysis with Analogs of Levosimendan
    Journal of molecular and cellular cardiology, 2000
    Co-Authors: Jouko Levijoki, Piero Pollesello, Tia Sorsa, Carola Tilgmann, Arto Annila, Juha Kaivola, Ilkka Kilpeläinen, Heimo Haikala
    Abstract:

    Levosimendan, an inodilatory drug discovered using troponin C as a target protein, has a cardiac effect deriving from the calcium sensitization of contractile proteins. The aim of this study was to give further evidence that Levosimendan binds to cardiac troponin C and that the binding involves amino acid residues on helixepsilon of the N-terminal domain of this calcium-binding protein. Nine organic molecules, obtained by chemical modification of Levosimendan, were tested both for their calcium-dependent binding to troponin C and troponin complex affinity HPLC columns, and for their ability to increase the calcium sensitivity of myofilaments in cardiac skinned fibers. A good correlation between the calcium sensitization and the calcium-dependent binding to troponin complex (r=0.90) and to cardiac troponin C (r=0.91) for the analogs of Levosimendan was shown. In addition, the effect of Levosimendan on the calcium-induced conformational changes in native and point-mutated cTnC was studied. Cys84-->Ser, Asp87-->Lys and Asp88-->Ala point-mutated cTnC were shown to maintain a high affinity to calcium, but their Ca(2+)titration curves were not influenced by Levosimendan as for the native protein. Finally, it was demonstrated that the NMR chemical shifts of the terminal methyl groups of Met47, Met81, and Met85 on calcium-saturated cTnC were changed after addition of Levosimendan in water solution at pH 7.4. This effect was not seen when adding an analog of Levosimendan, which did not bind to the troponin C affinity HPLC column and did not increase the calcium-induced tension in cardiac skinned fibers.

  • Levosimendan a calcium sensitizer in cardiac muscle induces relaxation in coronary smooth muscle through calcium desensitization
    Journal of Pharmacology and Experimental Therapeutics, 1999
    Co-Authors: Peggy Sue Bowman, Heimo Haikala, Richard J Paul
    Abstract:

    Levosimendan is a pyridazinone-dinitrile derivative belonging to a new class of cardiac inotropic drugs, Ca++ sensitizers. Levosimendan is also a vasodilator both in vitro and in vivo, but its mechanism is not well understood. The cardiac target protein of Levosimendan, troponin C, is a Ca++-binding EF-hand protein. This raises the possibility that Levosimendan may also interact with smooth muscle EF-hand proteins, such as, calmodulin, the regulatory myosin light chains, or S100 proteins. We investigated the effects of Levosimendan on [Ca++]i, and force in porcine coronary arteries, with receptor-mediated (U46619) or KCl stimulation. At high levels of stimulation, Levosimendan decreased force without changing or increasing [Ca++]i, measured with the Ca++-sensitive fluorescent probe fura-2 in the intact artery. With lower levels of U46619, Levosimendan (1 μM) lowered force by 70% and reduced [Ca++]i by 38%. The relationship between force and [Ca++]i for KCl stimulation are significantly rightward shifted, indicating Ca++desensitization by Levosimendan. In contrast, the phosphodiesterase III inhibitor, milrinone, does not shift the force-Ca++relations but elicits relaxation via lowering [Ca++]i. There was little change in pHi, indicating that the Ca++ desensitization by Levosimendan was not attributable to decreasing pHi. Levosimendan relaxes coronary arteries and lowers [Ca++]i by mechanisms different than milrinone. Our results indicate a lowering of [Ca++]i by Levosimendan consistent with opening of potassium channels and a relaxation that is independent of [Ca++]i. Our evidence points to a novel mechanism that might involve the direct effect of Levosimendan on the smooth muscle contractile or regulatory proteins themselves.

  • The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, Levosimendan.
    Cardiovascular research, 1997
    Co-Authors: Heimo Haikala, Petri Kaheinen, Jouko Levijoki, Inge-britt Linden
    Abstract:

    Objective: The role of phosphodiesterase III inhibition and calcium sensitization in the cardiac actions of Levosimendan, ( R )-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propane dinitrile, was studied. Methods: Various heart preparations were used to investigate positive inotropy, chronotropy, coronary flow and calcium sensitivity of contractile proteins. The cAMP- and cGMP-dependent protein kinases (PKA and PKG) were inhibited by KT5720 and KT5823, respectively. Furthermore, the synthesis of cAMP was stimulated by forskolin and increased phosphorylation of troponin I was induced by isoprenaline. Results: In Langendorff guinea-pig heart, Levosimendan (0.01–1 μM) and milrinone (0.1–10 μM) increased the left ventricular systolic peak pressure almost to the same extent. In the presence of KT5720 (1 μM) milrinone was devoid of positive inotropic activity. In contrast, KT5720 did not antagonize the inotropic effect of Levosimendan at ≤0.03 μM (= up to the EC50 of Levosimendan). The effects of Levosimendan and milrinone on heart rate and coronary flow were not affected by KT5720. The PKG inhibitor, KT5823 (1 μM), on the other hand, potentiated the Levosimendan-induced increase in coronary flow while it had no effect on the increase induced by milrinone. The mechanical parameters were not affected by KT5823. In the papillary muscle, the positive inotropic effect of milrinone but not that of Levosimendan was potentiated by forskolin (0.1 μM). In contrast to milrinone, the positive inotropy by Levosimendan was decreased by isoprenaline pretreatment (0.1 μM; 3 min). In line with this, the calcium-sensitizing effect of Levosimendan was decreased in skinned fibers prepared from isoprenaline-treated hearts. Conclusions: Our results indicate that the cardiac effects of Levosimendan at its therapeutically relevant concentrations were not mediated through PKA or PKG and its positive inotropy is therefore most probably due to the previously reported troponin-C-mediated calcium sensitization of contractile proteins.

  • Troponin C-mediated calcium sensitization induced by Levosimendan does not impair relaxation.
    Journal of cardiovascular pharmacology, 1995
    Co-Authors: Heimo Haikala, Jouko Levijoki, Erkki Nissinen, Ehsan Etemadzadeh, Inge-britt Linden
    Abstract:

    Levosimendan is a novel positive inotropic drug targeted to increase contraction force of the heart through its calcium-dependent binding to troponin C (cTnC). We investigated the calcium-sensitizing effect of Levosimendan on contractile proteins as well as its positive inotropic and lusitropic effects in paced guinea pig papillary muscle. We also studied the effect on energy consumption of myosin-actin crossbridges in a myosin ATPase assay. The calcium sensitization induced by Levosimendan in fibers skinned with saponin was dependent on the perforation velocity of cell membranes. Levosimendan was almost ineffective in slowly perforated fibers, but was the most potent calcium sensitizer in fibers with rapidly perforated cells. The perforation-dependent calcium sensitization was probably due to changes in phosphorylation state of contractile proteins during the slow dissection of fibers. It is noteworthy that the calcium-sensitizing effect of Levosimendan was not affected by acidic pH. Levosimendan at therapeutically relevant (0.3-10 microM) concentrations markedly increased calcium sensitivity both at pH 6.7 and 7.0, being more potent than EMD 53998, pimobendan, and MCI-154. The lack of effect of Levosimendan on maximum tension supports the hypothesis that Levosimendan increases calcium sensitivity through its action on cTnC. Unlike EMD 53998, Levosimendan did not increase myosin ATPase activity, indicating that it did not increase the cycling rate of myosinactin crossbridges. In paced papillary muscles, Levosimendan induced positive inotropic effect without changing relaxation time. Thus, Levosimendan was devoid of the main negative factors described for calcium sensitizers.