Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, přehledy
PubMed
32639325
PubMed Central
PMC7340234
DOI
10.1097/fjc.0000000000000859
PII: 00005344-202007000-00002
Knihovny.cz E-zdroje
- MeSH
- bezpečnost pacientů MeSH
- kardiotonika škodlivé účinky terapeutické užití MeSH
- kontrakce myokardu účinky léků MeSH
- lidé MeSH
- simendan škodlivé účinky terapeutické užití MeSH
- srdeční selhání diagnóza farmakoterapie mortalita patofyziologie MeSH
- vazodilatace účinky léků MeSH
- vazodilatancia škodlivé účinky terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- kardiotonika MeSH
- simendan MeSH
- vazodilatancia MeSH
Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.
Anaesthesia and Intensive Care Division San Camillo Forlanini Hospital Rome Italy
Complexo Hospitalario Universitario A Coruña La Coruña Spain
Critical Care Proprietary Products Orion Pharma Espoo Finland
Department of Anaesthesiology and Intensive Care Medicine Medical University of Graz Graz Austria
Department of Anaesthesiology and Intensive Care Medicine University of Lübeck Lübeck Germany
Department of Anaesthesiology and Intensive Care Sahlgrenska University Hospital Gothenburg Sweden
Department of Anaesthesiology University Hospital Ghent Belgium
Department of Cardiology and Internal Medicine Nicolaus Copernicus University Torun Poland
Department of Cardiology Campus Virchow Klinikum Charité University Medicine Berlin Berlin Germany
Department of Cardiology Faculty of Medicine University of Debrecen Debrecen Hungary
Department of Cardiology Medical School University of Cyprus Nicosia Cyprus
Department of Cardiology Niguarda Ca'Granda Hospital Milan Italy
Department of Cardiology North Estonia Medical Centre Tallinn Estonia
Department of Cardiology Oslo University Hospital Ullevaal Oslo Norway
Department of Clinical Sciences and Community Health Centro Cardiologico Monzino IRCCS Milan Italy
Department of Intensive Care Hôpital Erasme Brussels Belgium
Department of Intensive Care Medicine Amsterdam UMC Amsterdam the Netherlands
Department of Medicine Spittal Limmattal Schlieren Switzerland
Departments of Cardiology and Transplantation Sahlgrenska University Hospital Gothenburg Sweden
Dipartimento di Anestesia e Terapie Intensive Azienda Ospedaliero Universitaria Pisana Pisa Italy
Emergency Medicine Meilahti Central University Hospital University of Helsinki Helsinki Finland
Global Medical Affairs R and D Orion Pharma Espoo Finland
Heart Diseases Institute Hospital Universitari de Bellvitge Barcelona Spain
Heart Failure Clinic São Francisco Xavier Hospital CHLO Lisbon Portugal
Institute of Anaesthesiology University Hospital of Zurich Zurich Switzerland
Institute of Medical Sciences Uppsala University Uppsala Sweden
Intensive Care Department Consorci Sanitari Integral University of Barcelona Barcelona Spain
Intensive Care Unit National Health Service Leeds United Kingdom
Klinik für Innere Medizin 3 Kardiologie Universitätsklinikum Schleswig Holstein Kiel Germany
Lomonosov Moscow State University Medical Centre Moscow Russia
Medizinische Klinik 2 Klinikum Weiden Teaching Hospital of University of Regensburg Weiden Germany
Statistical Services R and D Orion Pharma Espoo Finland
Struttura Complessa di Anestesia 1 Policlinico di Modena Modena Italy
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Beregovich J, Bianchi C, D'Angelo R, et al. Haemodynamic effects of a new inotropic agent (dobutamine) in chronic cardiac failure. Br Heart J. 1975;37:629–634. PubMed PMC
Fabiato A, Fabiato F. Calcium and cardiac excitation-contraction coupling. Ann Rev Physiol. 1979;41:473–484. PubMed
Wohlfart B, Noble MI. The cardiac excitation-contraction cycle. Pharmacol Ther. 1982;16:1–43. PubMed
Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. 1. N Engl J Med. 1986;314:290–299. PubMed
Maskin CS, Sinoway L, Chadwick B, et al. Sustained hemodynamic and clinical effects of a new cardiotonic agent, WIN 47203, in patients with severe congestive heart failure. Circulation. 1983;67:1065–1070. PubMed
Dage RC, Roebel LE, Hsieh CP, et al. Cardiovascular properties of a new cardiotonic agent: MDL 17,043 (1.3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazole-2-one). J Cardiovasc Pharmacol. 1982;4:500–508. PubMed
Nagy L, Pollesello P, Papp Z. Inotropes and inodilators for acute heart failure: sarcomere active drugs in focus. J Cardiovasc Pharmacol. 2014;64:199–208. PubMed PMC
Herzig JW, Feile K, Rüegg JC. Activating effects of AR-L 115 BS on the Ca2+ sensitive force, stiffness and unloaded shortening velocity (Vmax) in isolated contractile structures from mammalian heart muscle. Arzneimittelforschung. 1981;31:188–191. PubMed
Solaro RJ, Rüegg JC. Stimulation of Ca++ binding and ATPase activity of dog cardiac myofibrils by AR-L 115BS, a novel cardiotonic agent. Circ Res. 1982;51:290–294. PubMed
Rüegg JC, Pfitzer G, Eubler D, et al. Effect on contractility of skinned fibres from mammalian heart and smooth muscle by a new benzimidazole derivative, 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone. Arzneimittelforschung. 1984;34:1736–1738. PubMed
Raasmaja A, Talo A, Haikala H, et al. Biochemical properties of OR-1259: a positive inotropic and vasodilatory compound with an antiarrhythmic effect. Adv Exp Med Biol. 1992;311:423. PubMed
Haikala H, Kaivola J, Nissinen E, et al. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol. 1995;27:1859–1866. PubMed
Pollesello P, Ovaska M, Kaivola J, et al. Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C. A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study. J Biol Chem. 1994;269:28584–28590. PubMed
Pääkkönen K, Annila A, Sorsa T, et al. Solution structure and main chain dynamics of the regulatory domain (residues 1-91) of human cardiac troponin C. J Biol Chem. 1998;273:15633–15638. PubMed
Haikala H, Linden IB. Mechanisms of action of calcium-sensitizing drugs. J Cardiovasc Pharmacol. 1995;26(suppl 1):S10–S19. PubMed
Sorsa T, Pollesello P, Solaro RJ. The contractile apparatus as a target for drugs against heart failure: interaction of levosimendan, a calcium sensitiser, with cardiac troponin C. Mol Cell Biochem. 2004;266:87–107. PubMed
Haikala H, Pollesello P. Calcium sensitivity enhancers. iDrugs. 2000;3:1199–1205. PubMed
Sorsa T, Heikkinen S, Abbott MB, et al. Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem. 2001;276:9337–9343. PubMed
Levijoki J, Pollesello P, Kaivola J, et al. Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analysis with analogs of levosimendan. J Mol Cell Cardiol. 2000;32:479–491. PubMed
Pineda-Sanabria SE, Robertson IM, Sun YB, et al. Probing the mechanism of cardiovascular drugs using a covalent levosimendan analog. J Mol Cell Cardiol. 2016;92:174–184. PubMed PMC
Lindert S, Li MX, Sykes BD, et al. Computer-aided drug discovery approach finds calcium sensitizer of cardiac troponin. Chem Biol Drug Des. 2015;85:99–106. PubMed PMC
Robertson IM, Sun YB, Li MX, et al. A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex. J Mol Cell Cardiol. 2010;49:1031–1041. PubMed PMC
Yokoshiki H, Katsube Y, Sunagawa M, et al. Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol. 1997;333:249–259. PubMed
Pagel PS, Hettrick DA, Warltier DC. Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br J Pharmacol. 1996;119:609–615. PubMed PMC
Kopustinskiene DM, Pollesello P, Saris NE. Potassium-specific effects of levosimendan on heart mitochondria. Biochem Pharmacol. 2004;68:807–812. PubMed
Kopustinskiene DM, Pollesello P, Saris NE. Levosimendan is a mitochondrial K(ATP) channel opener. Eur J Pharmacol. 2001;428:311–314. PubMed
Maytin M, Colucci WS. Cardioprotection: a new paradigm in the management of acute heart failure syndromes. Am J Cardiol. 2005;96:26G–31G. PubMed
Nieminen MS, Pollesello P, Vajda G, et al. Effects of levosimendan on the energy balance: preclinical and clinical evidence. J Cardiovasc Pharmacol. 2009;53:302–310. PubMed
Metzsch C, Linnér R, Steen S, et al. Levosimendan cardioprotection in acutely beta-1 adrenergic receptor blocked open chest pigs. Acta Anaesthesiol Scand. 2010;54:103–110. PubMed
Papp JG, Pollesello P, Varró AF, et al. Effect of levosimendan and milrinone on regional myocardial ischemia/reperfusion-induced arrhythmias in dogs. J Cardiovasc Pharmacol Ther. 2006;11:129–135. PubMed
du Toit EF, Genis A, Opie LH, et al. A role for the RISK pathway and K(ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated Guinea pig heart. Br J Pharmacol. 2008;154:41–50. PubMed PMC
Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth. 2009;102:198–204. PubMed
Takahashi R, Talukder MA, Endoh M. Inotropic effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium. Eur J Pharmacol. 2000;400:103–112. PubMed
Takahashi R, Talukder MA, Endoh M. Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium. J Cardiovasc Pharmacol. 2000;36:118–125. PubMed
Erdei N, Papp Z, Pollesello P, et al. The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br J Pharmacol. 2006;148:696–702. PubMed PMC
Kivikko M, Antila S, Eha J, et al. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharm Ther. 2002;40:465–471. PubMed
Farmakis D, Alvarez J, Gal TB, et al. Levosimendan beyond inotropy and acute heart failure: evidence of pleiotropic effects on the heart and other organs: an expert panel position paper. Int J Cardiol. 2016;222:303–312. PubMed
Szilágyi S, Pollesello P, Levijoki J, et al. The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig. Eur J Pharmacol. 2004;486:67–74. PubMed
de Cheffoy de Courcelles D, de Loore K, Freyne E, et al. Inhibition of human cardiac cyclic AMP-phosphodiesterases by R 80122, a new selective cyclic AMP-phosphodiesterase III inhibitor: a comparison with other cardiotonic compounds. J Pharmacol Exp Ther. 1992;263:6–14. PubMed
Szilagyi S, Pollesello P, Levijoki J, et al. Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone. J Cardiovasc Pharmacol. 2005;46:369–376. PubMed
Hasenfuss G, Pieske B, Castell M, et al. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation. 1998;98:2141–2147. PubMed
Kaheinen P, Pollesello P, Levijoki J, et al. Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart. J Cardiovasc Pharmacol. 2004;43:555–561. PubMed
Maack C, Eschenhagen T, Hamdani N, et al. Treatments targeting inotropy: a position paper of the Committees on Translational Research and Acute Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur Heart J. 2019;40:3626–3644. PubMed PMC
Xanthos T, Bassiakou E, Koudouna E, et al. Combination pharmacotherapy in the treatment of experimental cardiac arrest. Am J Emerg Med. 2009;27:651–659. PubMed
Lochner A, Colesky F, Genade S. Effect of a calcium-sensitizing agent, levosimendan, on the postcardioplegic inotropic response of the myocardium. Cardiovasc Drugs Ther. 2000;14:271–281. PubMed
Antila S, Eha J, Heinpalu M, et al. Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril. Eur J Clin Pharmacol. 1996;49:451–458. PubMed
Sundberg S, Lilleberg J, Nieminen MS, et al. Hemodynamic and neurohumoral effects of levosimendan, a new calcium sensitizer, at rest and during exercise in healthy men. Am J Cardiol. 1995;75:1061–1066. PubMed
Lilleberg J, Sundberg S, Nieminen MS. Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction. J Cardiovasc Pharmacol. 1995;26(suppl 1):S63–S69. PubMed
Ukkonen H, Saraste M, Akkila J, et al. Myocardial efficiency during levosimendan infusion in congestive heart failure. Clin Pharmacol Ther. 2000;68:522–531. PubMed
Lilleberg J, Nieminen MS, Akkila J, et al. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J. 1998;19:660–668. PubMed
Ukkonen H, Saraste M, Akkila J, et al. Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Ther. 1997;61:596–607. PubMed
Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol. 2000;36:1903–1912. PubMed
Jörgensen K, Bech-Hanssen O, Houltz E, et al. Effects of levosimendan on left ventricular relaxation and early filling at maintained preload and afterload conditions after aortic valve replacement for aortic stenosis. Circulation. 2008;117:1075–1081. PubMed
Fredholm M, Jörgensen K, Houltz E, et al. Inotropic and lusitropic effects of levosimendan and milrinone assessed by strain echocardiography: a randomised trial. Acta Anaesthesiol Scand. 2018;62:1246–1254. PubMed
Parissis JT, Paraskevaidis I, Bistola V, et al. Effects of levosimendan on right ventricular function in patients with advanced heart failure. Am J Cardiol. 2006;98:1489–1492. PubMed
Yilmaz MB, Yontar C, Erdem A, et al. Comparative effects of levosimendan and dobutamine on right ventricular function in patients with biventricular heart failure. Heart Vessels. 2009;24:16–21. PubMed
Russ MA, Prondzinsky R, Carter JM, et al. Right ventricular function in myocardial infarction complicated by cardiogenic shock: improvement with levosimendan. Crit Care Med. 2009;37:3017–3023. PubMed
Lilleberg J, Laine M, Palkama T, et al. Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. Eur J Heart Fail. 2007;9:75–82. PubMed
Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003;107:81–86. PubMed
Antila S, Kivikko M, Lehtonen L, et al. Pharmacokinetics of levosimendan and its circulating metabolites in patients with heart failure after an extended continuous infusion of levosimendan. Br J Clin Pharmacol. 2004;57:412–415. PubMed PMC
Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA. 2007;297:1883–1891. PubMed
Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail. 2013;1:103–111. PubMed
Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan, a novel calcium sensitiser, in severe low output heart failure: results of a randomised, double-blind comparison with dobutamine (LIDO Study). Lancet. 2002;360:196–202. PubMed
Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation. 2000;102:2222–2227. PubMed
Moiseyev VS, Põder P, Andrejevs N, et al. Safety and efficacy of a novel calcium sensitiser, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction: a randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J. 2002;23:1422–1432. PubMed
Mebazaa A, Nieminen MS, Filippatos GS, et al. Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE. Eur J Heart Fail. 2009;11:304–311. PubMed PMC
Landoni G, Biondi-Zoccai G, Greco M, et al. Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit Care Med. 2012;40:634–646. PubMed
Sikora J, Pstragowski K, Skibinska N, et al. Impact of levosimendan on platelet function. Thromb Res. 2017;159:76–81. PubMed
Yan SB, Wang XY, Shang GK, et al. Impact of perioperative levosimendan administration on risk of bleeding after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Cardiovasc Drugs. 2020;20:149–160. PubMed
Mehta RH, Leimberger JD, van Diepen S, et al. LEVO-CTS Investigators. Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. N Engl J Med. 2017;376:2032–2042. PubMed
Gong B, Li Z, Yat Wong PC. Levosimendan treatment for heart failure: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth. 2015;29:1415–1425. PubMed
SIMDAX. Summary of Product Characteristics. Available at: https://www.simdax.com/siteassets/simdax-spc.pdf. Accessed April 23, 2020.
Nieminen MS, Buerke M, Cohen-Solál A, et al. The role of levosimendan in acute heart failure complicating acute coronary syndrome: a review and expert consensus opinion. Int J Cardiol. 2016;218:150–157. PubMed
Harjola VP, Giannakoulas G, von Lewinski D, et al. Use of levosimendan in acute heart failure. Eur Heart J Suppl. 2018;20(suppl I):I2–I10. PubMed PMC
Pollesello P, Ben Gal T, Bettex D, et al. Short-term therapies for treatment of acute and advanced heart failure: why so few drugs available in clinical use, why even fewer in the pipeline? J Clin Med. 2019;8:e1834. PubMed PMC
Gheorghiade M, Adams KF, Cleland JG, et al. Phase III clinical trial end points in acute heart failure syndromes: a virtual roundtable with the Acute Heart Failure Syndromes International Working Group. Am Heart J. 2009;157:957–970. PubMed
Zannad F, Garcia AA, Anker SD, et al. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J Heart Fail. 2013;15:1082–1094. PubMed
Tacon CL, McCaffrey J, Delaney A. Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials. Intensive Care Med. 2012;38:359–367. PubMed
Nony P, Boissel JP, Lievre M, et al. Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients. A meta-analysis. Eur J Clin Pharmacol. 1994;46:191–196. PubMed
Pollesello P, Parissis J, Kivikko M, et al. Levosimendan meta-analyses: is there a pattern in the effect on mortality? Int J Cardiol. 2016;209:77–83. PubMed
Mebazaa A, Parissis J, Porcher R, et al. Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med. 2011;37:290–301. PubMed
Nieminen MS, Böhm M, Cowie MR, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J. 2005;26:384–416. PubMed
Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Eur Heart J. 2008;29:2388–2442. PubMed
McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J. 2012;33:1787–1847. PubMed
Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200. PubMed
Farmakis D, Agostoni P, Baholli L, et al. A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure: an expert panel consensus. Int J Cardiol. 2019;297:83–90. PubMed
Agostoni P, Farmakis DT, Garcia-Pinilla JM, et al. Hemodynamic balance in acute and advanced heart failure: an expert perspective on the role of levosimendan. Card Fail Rev. 2019;5:155–161. PubMed PMC
Bouchez S, Fedele F, Giannakoulas G, et al. Levosimendan in acute and advanced heart failure: an expert perspective on posology and therapeutic application. Cardiovasc Drugs Ther. 2018;32:617–624. PubMed PMC
Oliva F, Comin-Colet J, Fedele F, et al. Repetitive levosimendan treatment in the management of advanced heart failure. Eur Heart J Suppl. 2018;20(suppl I):I11–I20. PubMed PMC
Delgado JF, Oliva F, Reinecke A. The inodilator levosimendan in repetitive doses in the treatment of advanced heart failure. Eur Heart J Suppl. 2017;19(suppl C):C8–C14. PubMed PMC
Pölzl G, Altenberger J, Baholli L, et al. Repetitive use of levosimendan in advanced heart failure: need for stronger evidence in a field in dire need of a useful therapy. Int J Cardiol. 2017;243:389–439. PubMed
Nieminen MS, Altenberger J, Ben-Gal T, et al. Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus. Int J Cardiol. 2014;174:360–367. PubMed
Toller W, Algotsson L, Guarracino F, et al. Perioperative use of levosimendan: best practice in operative settings. J Cardiothorac Vasc Anesth. 2013;27:361–366. PubMed
Toller W, Heringlake M, Guarracino F, et al. Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion. Int J Cardiol. 2015;184:323–336. PubMed
Shi WY, Li S, Collins N, et al. Peri-operative levosimendan in patients undergoing cardiac surgery: an overview of the evidence. Heart Lung Circ. 2015;24:667–672. PubMed
Herpain A, Bouchez S, Girardis M, et al. Use of levosimendan in intensive care unit settings: an opinion paper. J Cardiovasc Pharmacol. 2019;73:3–14. PubMed PMC
Yilmaz MB, Grossini E, Silva Cardoso JC, et al. Renal effects of levosimendan: a consensus report. Cardiovasc Drugs Ther. 2013;27:581–590. PubMed PMC
Nieminen MS, Dickstein K, Fonseca C, et al. The patient perspective: quality of life in advanced heart failure with frequent hospitalisations. Int J Cardiol. 2015;191:256–264. PubMed
Nieminen MS, Fonseca C, Brito D, et al. The potential of the inodilator levosimendan in maintaining quality of life in advanced heart failure. Eur Heart J Suppl. 2017;19(suppl C):C15–C21. PubMed PMC
Mushtaq S, Andreini D, Farina S, et al. Levosimendan improves exercise performance in patients with advanced chronic heart failure. ESC Heart Fail. 2015;2:133–141. PubMed PMC
Campodonico J, Mapelli M, Spadafora E, et al. Surfactant proteins changes after acute hemodynamic improvement in patients with advanced chronic heart failure treated with Levosimendan. Respir Physiol Neurobiol. 2018;252–253:47–51. PubMed
Nieminen MS, Buerke M, Parissis J, et al. Pharmaco-economics of levosimendan in cardiology: a European perspective. Int J Cardiol. 2015;199:337–341. PubMed
Papp Z, Édes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012;159:82–87. PubMed
Pollesello P, Papp Z, Papp JG. Calcium sensitizers: what have we learned over the last 25 years? Int J Cardiol. 2016;203:543–548. PubMed
Bistola V, Arfaras-Melainis A, Polyzogopoulou E, et al. Inotropes in acute heart failure: from guidelines to practical use: therapeutic options and clinical practice. Card Fail Rev. 2019;5:133–139. PubMed PMC
Fuhrmann JT, Schmeisser A, Schulze MR, et al. Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit Care Med. 2008;36:2257–2266. PubMed
García-Gonzáles MJ, Domínguez-Rodríguez A, Ferrer-Hita JJ, et al. Cardiogenic shock after primary percutaneous coronary intervention: effects of levosimendan compared with dobutamine on haemodynamics. Eur J Heart Fail. 2006;8:723–728. PubMed
Dominguez-Rodriguez A, Samimi-Fard S, Garcia-Gonzalez MJ, et al. Effects of levosimendan versus dobutamine on left ventricular diastolic function in patients with cardiogenic shock after primary angioplasty. Int J Cardiol. 2008;128:214–217. PubMed
Samimi-Fard S, García-González MJ, Domínguez-Rodríguez A, et al. Effects of levosimendan versus dobutamine on long-term survival of patients with cardiogenic shock after primary coronary angioplasty. Int J Cardiol. 2008;127:284–287. PubMed
Christoph A, Prondzinsky R, Russ M, et al. Early and sustained haemodynamic improvement with levosimendan compared to intraaortic balloon counterpulsation (IABP) in cardiogenic shock complicating acute myocardial infarction. Acute Card Care. 2008;10:49–57. PubMed
Omerovic E, Råmunddal T, Albertsson P, et al. Levosimendan neither improves nor worsens mortality in patients with cardiogenic shock due to ST-elevation myocardial infarction. Vasc Health Risk Manag. 2010;6:657–663. PubMed PMC
Guarracino F, Cariello C, Danella A, et al. Effect of levosimendan on ventriculo-arterial coupling in patients with ischemic cardiomyopathy. Acta Anaesthesiol Scand. 2007;51:1217–1224. PubMed
Guarracino F, Baldassarri R, Pinsky MR. Ventriculo-arterial decoupling in acutely altered hemodynamic states. Crit Care. 2013;17:213. PubMed PMC
Hering D, Jaguszewski M. Levosimendan: new hope therapy for takotsubo syndrome. Cardiol J. 2016;23:616–617. PubMed
De Santis V, Vitale D, Tritapepe L, et al. Use of levosimendan for cardiogenic shock in a patient with the apical ballooning syndrome. Ann Intern Med. 2008;149:365–367. PubMed
Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a F0622-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012;126:697–706. PubMed PMC
Lyon AR, Bossone E, Schneider B, et al. Current state of knowledge on takotsubo syndrome: a position statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2016;18:8–27. PubMed
Harrison RW, Hasselblad V, Mehta RH, et al. Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth. 2013;27:1224–1232. PubMed
Cholley B, Caruba T, Grosjean S, et al. Effect of levosimendan on low cardiac output syndrome in patients with low ejection fraction undergoing coronary artery bypass grafting with cardiopulmonary bypass: the LICORN Randomized Clinical Trial. JAMA. 2017;318:548–556. PubMed PMC
Landoni G, Lomivorotov VV, Alvaro G, et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. 2017;376:2021–2031. PubMed
Lee CT, Lin YC, Yeh YC, et al. Effects of levosimendan for perioperative cardiovascular dysfunction in patients receiving cardiac surgery: a meta-analysis with trial sequential analysis. Intensive Care Med. 2017;43:1929–1930. PubMed
Guarracino F, Heringlake M, Cholley B, et al. Use of levosimendan in cardiac surgery: an update after the LEVO-CTS, CHEETAH, and LICORN trials in the light of clinical practice. J Cardiovasc Pharmacol. 2018;71:1–9. PubMed PMC
Wang W, Zhou X, Liao X, et al. The efficacy and safety of prophylactic use of levosimendan on patients undergoing coronary artery bypass graft: a systematic review and meta-analysis. J Anesth. 2019;33:543–550. PubMed
van Diepen S, Mehta RH, Leimberger JD, et al. Levosimendan in patients with reduced left ventricular function undergoing isolated coronary or valve surgery. J Thorac Cardiovasc Surg. 2020;159:2302–2309.e6. PubMed
Weber C, Esser M, Eghbalzadeh K, et al. Levosimendan reduces mortality and low cardiac output syndrome in cardiac surgery. Thorac Cardiovasc Surg. 2019. 10.1055/s-0039-3400496; PMID: 31770777. epub ahead of press. PubMed DOI
Qiu J, Jia L, Hao Y, et al. Efficacy and safety of levosimendan in patients with acute right heart failure: a meta-analysis. Life Sci. 2017;184:30–36. PubMed
Fedele F, Severino P, Calcagno S, et al. Heart failure: TNM-like classification. J Am Coll Cardiol. 2014;63:1959–1960. PubMed
Zager RA, Johnson AC, Lund S, et al. Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Ren Physiol. 2006;290:F1453–F1462. PubMed
Rehberg S, Ertmer C, Vincent JL, et al. Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock. Crit Care Med. 2010;38:2016–2023. PubMed
Grossini E, Molinari C, Pollesello P, et al. Levosimendan protection against kidney ischemia/reperfusion injuries in anesthetized pigs. J Pharmacol Exp Ther. 2012;342:376–388. PubMed
Fedele F, Bruno N, Brasolin B, et al. Levosimendan improves renal function in acute decompensated heart failure: possible underlying mechanisms. Eur J Heart Fail. 2014;16:281–288. PubMed
Lannemyr L, Ricksten S-E, Rundqvist B, et al. Differential effects of levosimendan and dobutamine on glomerular filtration rate in patients with heart failure and renal impairment: a randomized double-blind controlled trial. J Am Heart Assoc. 2018;7:e008455. PubMed PMC
Bragadottir G, Redfors B, Ricksten SE. Effects of levosimendan on glomerular filtration rate, renal blood flow, and renal oxygenation after cardiac surgery with cardiopulmonary bypass: a randomized placebo-controlled study. Crit Care Med. 2013;41:2328–2335. PubMed
Lannemyr L, Bragadottir G, Redfors B, et al. Effects of milrinone on renal perfusion, filtration and oxygenation in patients with acute heart failure and low cardiac output early after cardiac surgery. J Crit Care. 2020;57:225–230. PubMed
Sanfilippo F, Knight JB, Scolletta S, et al. 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. Crit Care. 2017;21:252. PubMed PMC
Putzu A, Clivio S, Belletti A, et al. Perioperative levosimendan in cardiac surgery: a systematic review with meta-analysis and trial sequential analysis. Int J Cardiol. 2018;251:22–31. PubMed
Niu ZZ, Wu SM, Sun WY, et al. Perioperative levosimendan therapy is associated with a lower incidence of acute kidney injury after cardiac surgery: a meta-analysis. J Cardiovasc Pharmacol. 2014;63:107–112. PubMed
Bove T, Matteazzi A, Belletti A, et al. Beneficial impact of levosimendan in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Heart Lung Vessel. 2015;7:35–46. PubMed PMC
Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116:1482–1487. PubMed
Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict mortality in the community population with heart failure. Am Heart J. 2007;154:260–266. PubMed
Altenberger J, Parissis JT, Costard-Jaeckle A, et al. Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial. Eur J Heart Fail. 2014;16:898–906. PubMed
Comín-Colet J, Manito N, Segovia-Cubero J, et al. Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION-HEART multicentre randomised trial. Eur J Heart Fail. 2018;20:1128–1136. PubMed
LAICA Study Investigators. Efficacy and security of intermittent repeated levosimendan administration in patients with advanced heart failure: a randomized, double-blind, placebo controlled multicenter trial: LAICA study. Presented at the European Society of Cardiology–Heart Failure Association Congress; 21 May 2016; Florence, Italy.
Silvetti S, Nieminen MS. Repeated or intermittent levosimendan treatment in advanced heart failure: an updated meta-analysis. Int J Cardiol. 2016;202:138–143. PubMed
Silvetti S, Greco T, Di Prima AL, et al. Intermittent levosimendan improves mid-term survival in chronic heart failure patients: meta-analysis of randomised trials. Clin Res Cardiol. 2014;103:505–513. PubMed
Pölzl G, Allipour Birgani S, Comín-Colet J, et al. Repetitive levosimendan infusions for patients with advanced chronic heart failure in the vulnerable post-discharge period. ESC Heart Fail. 2019;6:174–181. PubMed PMC
Kocabeyoglu SS, Kervan U, Sert DE, et al. Optimization with levosimendan improves outcomes after left ventricular assist device implantation. Eur J Cardiothorac Surg. 2020;57:176–182. PubMed
Sim I. Mobile devices and health. N Engl J Med. 2019;381:956–968. PubMed
Andrès E, Talha S, Zulfiqar AA, et al. Current research and new perspectives of telemedicine in chronic heart failure: narrative review and points of interest for the clinician. J Clin Med. 2018;7:544. PubMed PMC
Wells R, Stockdill ML, Dionne-Odom JN, et al. Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers (ENABLE CHF-PC): study protocol for a randomized controlled trial. Trials. 2018;19:422. PubMed PMC
Schumann J, Henrich EC, Strobl H, et al. Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome. Cochrane Database Syst Rev. 2018;1:CD009669. PubMed PMC
Morelli A, De Castro S, Teboul JL, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2005;31:638–644. PubMed
Zangrillo A, Putzu A, Monaco F, et al. Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials. J Crit Care. 2015;30:908–913. PubMed
Ouanes-Besbes L, Ouanes I, Dachraoui F, et al. Weaning difficult-to-wean chronic obstructive pulmonary disease patients: a pilot study comparing initial hemodynamic effects of levosimendan and dobutamine. J Crit Care. 2011;26:15–21. PubMed
Aso S, Matsui H, Fushimi K, et al. In-hospital mortality and successful weaning from venoarterial extracorporeal membrane oxygenation: analysis of 5,263 patients using a national inpatient database in Japan. Crit Care. 2016;20:80. PubMed PMC
Affronti A, di Bella I, Carino D, et al. Levosimendan may improve weaning outcomes in venoarterial ECMO patients. ASAIO J. 2013;59:554–557. PubMed
Distelmaier K, Roth C, Schrutka L, et al. Beneficial effects of levosimendan on survival in patients undergoing extracorporeal membrane oxygenation after cardiovascular surgery. Br J Anaesth. 2016;117:52–58. PubMed PMC
Sangalli F, Avalli L, Laratta M, et al. Effects of levosimendan on endothelial function and hemodynamics during weaning from veno-arterial extracorporeal life support. J Cardiothorac Vasc Anesth. 2016;30:1449–1453. PubMed
Jacky A, Rudiger A, Krüger B, et al. Comparison of levosimendan and milrinone for ECLS weaning in patients after cardiac surgery—a retrospective before and after study. J Cardiothorac Vasc Anesth. 2018;32:2112–2119. PubMed
Yilmaz MB, Yalta K, Yontar C, et al. Levosimendan improves renal function in patients with acute decompensated heart failure: comparison with dobutamine. Cardiovasc Drugs Ther. 2007;21:431–435. PubMed
Hou ZQ, Sun ZX, Su CY, et al. Effect of levosimendan on estimated glomerular filtration rate in hospitalized patients with decompensated heart failure and renal dysfunction. Cardiovasc Ther. 2013;31:108–114. PubMed
Zemljic G, Bunc M, Yazdanbakhsh AP, et al. Levosimendan improves renal function in patients with advanced chronic heart failure awaiting cardiac transplantation. J Card Fail. 2007;13:417–421. PubMed
Silva-Cardoso J, Ferreira J, Oliveira-Soares A, et al. Effectiveness and safety of levosimendan in clinical practice. Rev Port Cardiol. 2009;28:143–153. PubMed
Zangrillo A, Alvaro G, Belletti A, et al. Effect of levosimendan on renal outcome in cardiac surgery patients with chronic kidney disease and perioperative cardiovascular dysfunction: a substudy of a multicenter randomized trial. J Cardiothorac Vasc Anesth. 2018;32:2152–2159. PubMed
Damman K, Voors AA. Levosimendan improves renal function in acute decompensated heart failure: cause and clinical application. Cardiovasc Drugs Ther. 2007;21:403–404. PubMed
Singh P, Ricksten SE, Bragadottir G, et al. Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. Clin Exp Pharmacol Physiol. 2013;40:138–147. PubMed PMC
Santoro F, Ieva R, Ferraretti A, et al. Safety and feasibility of levosimendan administration in takotsubo cardiomyopathy: a case series. Cardiovasc Ther. 2013;31:e133–7. PubMed
Schulz R, Rose J, Martin C, et al. Development of short-term myocardial hibernation. Its limitation by the severity of ischemia and inotropic stimulation. Circulation. 1993;88:684–695. PubMed
Beohar N, Erdogan AK, Lee DC, et al. Acute heart failure syndromes and coronary perfusion. J Am Coll Cardiol. 2008;52:13–16. PubMed
Duncker DJ, Koller A, Merkus D, et al. Regulation of coronary blood flow in health and ischemic heart disease. Prog Cardiovasc Dis. 2015;57:409–422. PubMed PMC
Pelliccia F, Kaski JC, Crea F, et al. Pathophysiology of takotsubo syndrome. Circulation. 2017;135:2426–2441. PubMed
Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med. 2007;35:1599–1608. PubMed
Suzuki T, Suzuki Y, Okuda J, et al. Sepsis-induced cardiac dysfunction and F062-adrenergic blockade therapy for sepsis. J Intensive Care. 2007;5:22. PubMed PMC
Belletti A, Benedetto U, Biondi-Zoccai G, et al. The effect of vasoactive drugs on mortality in patients with severe sepsis and septic shock. A network meta-analysis of randomized trials. J Crit Care. 2017;37:91–98. PubMed
Wang Q, Yokoo H, Takashina M, et al. Anti-inflammatory profile of levosimendan in cecal ligation-induced septic mice and in lipopolysaccharide-stimulated macrophages. Crit Care Med. 2015;43:e508–20. PubMed
Tsao CM, Li KY, Chen SJ, et al. Levosimendan attenuates multiple organ injury and improves survival in peritonitis-induced septic shock: studies in a rat model. Crit Care. 2014;18:1683–1712. PubMed PMC
Morelli A, Donati A, Ertmer C, et al. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Care. 2010;14:R232. PubMed PMC
Torraco A, Carrozzo R, Piemonte F, et al. Effects of levosimendan on mitochondrial function in patients with septic shock: a randomized trial. Biochimie. 2014;102:166–173. PubMed
Hajjej Z, Meddeb B, Sellami W, et al. Effects of levosimendan on cellular metabolic alterations in patients with septic shock: a randomized controlled pilot study. Shock. 2017;48:307–312. PubMed PMC
Singer M. Catecholamine treatment for shock: equally good or bad? Lancet. 2007;370:636–637. PubMed
Andreis DT, Singer M. Catecholamines for inflammatory shock: a Jekyll-and-Hyde conundrum. Intensive Care Med. 2016;42:1387–1397. PubMed
Coquerel D, Sainsily X, Dumont L, et al. The apelinergic system as an alternative to catecholamines in low-output septic shock. Crit Care. 2018;22:10. PubMed PMC
He X, Su F, Taccone FS, et al. A selective V(1A) receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock. Crit Care Med. 2016;44:23–31. PubMed PMC
Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377:419–430. PubMed
Creteur J, Bouckaert Y, Mélot C, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2006;32:790. author reply 791–2. PubMed
Gordon AC, Perkins GD, Singer M, et al. Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med. 2016;375:1638–1648. PubMed
Angus DC, Mira JP, Vincent JL. Improving clinical trials in the critically ill. Crit Care Med. 2010;38:527–532. PubMed
Hodgson C, Cuthbertson BH. Improving outcomes after critical illness: harder than we thought! Intensive Care Med. 2016;42:1772–1774. PubMed
Marshall JC. Global collaboration in acute care clinical research: opportunities, challenges, and needs. Crit Care Med. 2017;45:311–320. PubMed
Iwashyna TJ, Deane AM. Individualizing endpoints in randomized clinical trials to better inform individual patient care: the TARGET proposal. Crit Care. 2016;20:218. PubMed PMC
Mebazaa A, Laterre PF, Russell JA, et al. Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure. J Intensive Care. 2016;4:24. PubMed PMC
Girbes ARJ, de Grooth H-J. Time to stop randomized and large pragmatic trials for intensive care medicine syndromes: the case of sepsis and acute respiratory distress syndrome. J Thorac Dis. 2020;12(suppl 1):S101–S109. PubMed PMC
Zhang YH, Zhang J, Qing EM, et al. Comparison on efficacy and safety between domestic levosimendan versus dobutamine for patients with acute decompensated heart failure [in Chinese]. Zhonghua Xin Xue Guan Bing Za Zhi. 2012;40:153–156. PMID: 22490717. PubMed
Zhang YH, Qing EM, Zhang J, et al. Hemodynamic and efficacies of domestic levosimendan versus dobutamine in patients with acute decompensated heart failure [in Chinese]. Zhonghua Yi Xue Za Zhi. 2012;92:555–558. PMID: 22490161. PubMed
Wang L, Cui L, Wei JP, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in decompensated heart failure [in Chinese]. Zhonghua Xin Xue Guan Bing Za Zhi. 2010;38:527–530. PMID: 21033135. PubMed
Suominen PK. Single-center experience with levosimendan in children undergoing cardiac surgery and in children with decompensated heart failure. BMC Anesthesiol. 2011;11:18. PubMed PMC
Lechner E, Moosbauer W, Pinter M, et al. Use of levosimendan, a new inodilator, for postoperative myocardial stunning in a premature neonate. Pediatr Crit Care Med. 2007;8:61–63. PubMed
Momeni M, Rubay J, Matta A, et al. Levosimendan in congenital cardiac surgery: a randomized, double-blind clinical trial. J Cardiothorac Vasc Anesth. 2011;25:419–424. PubMed
Pellicer A, Riera J, Lopez-Ortego P, et al. Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery. Pediatr Res. 2013;73:95–103. PubMed
Ebade AA, Khalil MA, Mohamed AK. Levosimendan is superior to dobutamine as an inodilator in the treatment of pulmonary hypertension for children undergoing cardiac surgery. J Anesth. 2013;27:334–339. PubMed
Ottenheijm CA, Heunks LM, Hafmans T, et al. Titin and diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173:527–534. PubMed PMC
Dres M, Dubé BP, Mayaux J, et al. Coexistence and Impact of limb muscle and diaphragm weakness at time of liberation from mechanical ventilation in medical intensive care unit patients. Am J Respir Crit Care Med. 2017;195:57–66. PubMed
Van Hees HW, Dekhuijzen PN, Heunks LM. Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179:41–47. PubMed
Hooijman PE, Beishuizen A, de Waard MC, et al. Diaphragm fiber strength is reduced in critically ill patients and restored by a troponin activator. Am J Respir Crit Care Med. 2014;189:863–865. PubMed PMC
Doorduin J, Sinderby CA, Beck J, et al. The calcium sensitizer levosimendan improves human diaphragm function. Am J Respir Crit Care Med. 2012;185:90–95. PubMed
Roesthuis L, van der Hoeven H, Sinderby C, et al. Effects of levosimendan on respiratory muscle function in patients weaning from mechanical ventilation. Intensive Care Med. 2019;45:1372–1381. PubMed PMC
Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377:162–172. PubMed
Kurian KM, Forbes RB, Colville S, et al. Cause of death and clinical grading criteria in a cohort of amyotrophic lateral sclerosis cases undergoing autopsy from the Scottish Motor Neurone Disease Register. J Neurol Neurosurg Psychiatry. 2009;80:84–87. PubMed
Paulukonis ST, Roberts EM, Valle JP, et al. Survival and cause of death among a cohort of confirmed amyotrophic lateral sclerosis cases. PLoS One. 2015;10:e0131965. PubMed PMC
Gowland A, Opie-Martin S, Scott KM, et al. Predicting the future of ALS: the impact of demographic change and potential new treatments on the prevalence of ALS in the United Kingdom, 2020-2116. Amyotroph Lateral Scler Frontotemporal Degener. 2019;20:264–274. PubMed PMC
Andrews JA, Cudkowicz ME, Hardiman O, et al. VITALITY-ALS, a phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19:259–266. PubMed
de Jongh AD, van Eijk RPA, van den Berg LH. Evidence for a multimodal effect of riluzole in patients with ALS? J Neurol Neurosurg Psychiatry. 2019;90:1183–1184. PubMed
Khairoalsindi OA, Abuzinadah AR. Maximizing the survival of amyotrophic lateral sclerosis patients: current perspectives. Neurol Res Int. 2018;2018:6534150. PubMed PMC
Writing Group of the Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16:505–512. PubMed
Christensen TH, Kedes L. The myogenic regulatory circuit that controls cardiac/slow twitch troponin C gene transcription in skeletal muscle involves E-box, MEF-2, and MEF-3 motifs. Gene Expr. 1999;8:247–261. PubMed PMC
Al-Chalabi A, Heunks LMA, Papp Z, et al. Potential of the cardiovascular drug levosimendan in the management of amyotrophic lateral sclerosis: an overview of a working hypothesis. J Cardiovasc Pharmacol. 2019;74:389–399. PubMed
Al-Chalabi A, Shaw P, Leigh PN, et al. Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry. 2019;90:1165–1170. PubMed PMC
Rababa'h AM, Alzoubi KH, Baydoun S, et al. Levosimendan prevents memory impairment induced by diabetes in rats: role of oxidative stress. Curr Alzheimer Res. 2019;16:1300–1308. PubMed
Rababa'h AM, Alzoubi KH, Atmeh A. Levosimendan enhances memory through antioxidant effect in rat model: behavioral and molecular study. Behav Pharmacol. 2018;29:344–350. PubMed
Grossini E, Pollesello P, Bellofatto K, et al. Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats. J Liver Transpl. 2014;20:361–375. PubMed
Lim H, He D, Qiu Y, et al. Rational discovery of dual-indication multi-target PDE/Kinase inhibitor for precision anti-cancer therapy using structural systems pharmacology. PLoS Comput Biol. 2019;15:e1006619. PubMed PMC
Nieminen MS, Fruhwald S, Heunks LM, et al. Levosimendan: current data, clinical use and future development. Heart Lung Vessel. 2013;5:227–245. PubMed PMC
Kivikko M, Pollesello P, Tarvasmäki T, et al. Effect of baseline characteristics on mortality in the SURVIVE trial on the effect of levosimendan vs dobutamine in acute heart failure: sub-analysis of the Finnish patients. Int J Cardiol. 2016;215:26–31. PubMed
Sandner P, Ziegelbauer K. Product-related research: how research can contribute to successful life-cycle management. Drug Discov Today. 2008;13:457–463. PubMed