Heart Failure Reviews

, 14:265 | Cite as

Levosimendan: from basic science to clinical practice

  • John T. Parissis
  • Pinelopi Rafouli-Stergiou
  • Ioannis Paraskevaidis
  • Alexandre Mebazaa


Levosimendan is a new cardiac enhancer that exerts positive inotropic effects on the failing heart mediated by calcium sensitization of contractile proteins as well as peripheral vasodilatory effects mediated by opening of ATP-sensitive potassium channels in vascular smooth-muscle cells. Levosimendan is the most well-studied calcium sensitizer in the real clinical practice, producing greater hemodynamic and symptomatic improvement in patients with acute heart failure syndromes (AHFS) than those with traditional inotropes. Immunomodulatory and anti-apoptotic properties of levosimendan may be an additional biologic mechanism that prevents further cytotoxic and hemodynamic consequences of abnormal immune and neurohormonal responses in AHFS. Recent mortality trials showed that levosimendan does not improve short- and long-term prognosis in AHFS in comparison to dobutamine or placebo. However, in patients with a previous history of CHF and on beta-blocker on admission, levosimendan seems to have a beneficial effect on short-term mortality. According to the recent guidelines of the European Society of Cardiology, levosimendan is indicated in patients with symptomatic low cardiac output HF secondary to cardiac systolic dysfunction without severe hypotension (Class IIa, Level of Evidence B).


Inotropes Prognosis Pathophysiologic mechanisms Calcium sensitizing agents 


  1. 1.
    Gheorghiade M, Zannad F, Sopko G et al for International Working Group on Acute Heart Failure Syndromes (2005) Acute heart failure syndromes: current state and framework for future research. Circulation 112:3958–3968. doi: 10.1161/CIRCULATIONAHA.105.590091 Google Scholar
  2. 2.
    Dickstein K, Cohen-Solal A, Filippatos G et al (2008) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur J Heart Fail 10:933–989. doi: 10.1016/j.ejheart.2008.08.005 CrossRefPubMedGoogle Scholar
  3. 3.
    Parissis J, Farmakis D, Nieminen M (2007) Classical inotropes and new cardiac enhancers. Heart Fail Rev 12:149–156. doi: 10.1007/s10741-007-9014-5 CrossRefPubMedGoogle Scholar
  4. 4.
    Gheorghiade M, Abraham WT, Albert NM et al (2006) Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 296:2217–2226. doi: 10.1001/jama.296.18.2217 CrossRefPubMedGoogle Scholar
  5. 5.
    Petersen J, Felker M (2008) Inotropes in the management of acute heart failure. Crit Care Med 36(Suppl):106–111CrossRefGoogle Scholar
  6. 6.
    Munger MA (2006) Management of acute decompensated heart failure: treatment, controversy, and future directions. Pharmacotherapy 26:131S–138S. doi: 10.1592/phco.26.8part2.131S CrossRefPubMedGoogle Scholar
  7. 7.
    Zannad F, Adamopoulos C, Mebazaa A et al (2006) The challenge of acute decompensated heart failure. Heart Fail Rev 11:135–139. doi: 10.1007/s10741-006-9484-x CrossRefPubMedGoogle Scholar
  8. 8.
    Antoniades C, Tousoulis D, Koumallos N et al (2007) Levosimendan: beyond its simple inotropic effect in heart failure. Pharmacol Ther 114:184–197. doi: 10.1016/j.pharmthera.2007.01.008 CrossRefPubMedGoogle Scholar
  9. 9.
    Lehmann A, Boldt J, Kirchner J (2003) The role of Ca++-sensitizers for the treatment of heart failure. Curr Opin Crit Care 9:337–344. doi: 10.1097/00075198-200310000-00002 CrossRefPubMedGoogle Scholar
  10. 10.
    Tavares M, Rezlan E, Vostroknoutova I et al (2008) New pharmacologic therapies for acute heart failure. Crit Care Med 36(Suppl):112–120CrossRefGoogle Scholar
  11. 11.
    Pollesello P, Papp Z (2007) The Cardioprotective effects of levosimendan: preclinical and clinical evidence. J Cardiovasc Pharmacol 50:257–263CrossRefPubMedGoogle Scholar
  12. 12.
    Grover GJ, Garlid KD (2000) ATP-Sensitive potassium channels: a review of their cardioprotective pharmacology. J Mol Cell Cardiol 32:677–695. doi: 10.1006/jmcc.2000.1111 CrossRefPubMedGoogle Scholar
  13. 13.
    Kowaltowski AJ, Seetharaman S, Paucek P et al (2001) Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol 280:H649–H657PubMedGoogle Scholar
  14. 14.
    Papp Z, Csaps K, Pollesello P et al (2005) Pharmacological mechanisms contributing to the clinical efficacy of levosimendan. Cardiovasc Drug Rev 23:87–114Google Scholar
  15. 15.
    Tavares M, Andrade A, Mebazaa A (2008) Levosimendan use in several scenarios of acute heart failure. Arq Bras Cardiol 90:211–215. doi: 10.1590/S0066-782X2008000300012 CrossRefPubMedGoogle Scholar
  16. 16.
    Flevari P, Parissis JT, Leftheriotis D et al (2006) Effect of levosimendan on ventricular arrhythmias and prognostic autonomic indexes in patients with decompensated advanced heart failure secondary to ischemic or dilated cardiomyopathy. Am J Cardiol 98(12):1641–1645. doi: 10.1016/j.amjcard.2006.07.043 CrossRefPubMedGoogle Scholar
  17. 17.
    Cleland JG, Freemantle N, Coletta AP et al (2006) Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 8:105–110. doi: 10.1016/j.ejheart.2005.12.003 CrossRefPubMedGoogle Scholar
  18. 18.
    Mebazaa A, Nieminen MS, Packer M et al (2007) Levosimendan vs. dobutamine for patients with acute decompensated heart failure: SURVIVE Randomized Trial. JAMA 297:1883–1891. doi: 10.1001/jama.297.17.1883 CrossRefPubMedGoogle Scholar
  19. 19.
    Antila S, Pesonen U, Lehtonen L et al (2004) Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators. Eur J Pharm Sci 23:213–222. doi: 10.1016/j.ejps.2004.07.005 CrossRefPubMedGoogle Scholar
  20. 20.
    Follath F, Cleland JG, Just H et al (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomized double-blind trial. Lancet 360:196–202. doi: 10.1016/S0140-6736(02)09455-2 CrossRefPubMedGoogle Scholar
  21. 21.
    Moiseyev VS, Poder P, Andrejevs N et al (2002) Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infraction. A randomized, placebo-controlled, double-blind study RUSSLAN. Eur Heart J 23:1422–1432. doi: 10.1053/euhj.2001.3158 CrossRefPubMedGoogle Scholar
  22. 22.
    Nieminen MS, Akkila J, Hasenfuss G et al (2000) Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 36:1903–1912. doi: 10.1016/S0735-1097(00)00961-X CrossRefPubMedGoogle Scholar
  23. 23.
    Slawsky MT, Colucci WS, Gottlieb SS et al (2000) Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study investigators. Circulation 102:2222–2227PubMedGoogle Scholar
  24. 24.
    Kivikko M, Antila S, Eha J et al (2002) Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol 42:43–51. doi: 10.1177/0091270002042001005 CrossRefPubMedGoogle Scholar
  25. 25.
    Kivikko M, Antila S, Eha J et al (2002) Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther 40:465–471PubMedGoogle Scholar
  26. 26.
    Lilleberg J, Laine M, Palkama T et al (2007) Duration of the hemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. Eur J Heart Fail 9:75–82. doi: 10.1016/j.ejheart.2006.04.012 CrossRefPubMedGoogle Scholar
  27. 27.
    Parissis J, Karavidas A, Bistola V et al (2008) Effects of levosimendan on flow-mediated vasodilation and soluble adhesion molecules in patients with advanced chronic heart failure. Atherosclerosis 197:278–282. doi: 10.1016/j.atherosclerosis.2007.04.023 CrossRefPubMedGoogle Scholar
  28. 28.
    Nanas JN, Papazoglou P, Tsagalou EP et al (2005) Efficacy and safety of intermittent, long-term, concomitant dobutamine and levosimendan infusions in severe heart failure refractory to dobutamine alone. Am J Cardiol 95:768–771. doi: 10.1016/j.amjcard.2004.11.033 CrossRefPubMedGoogle Scholar
  29. 29.
    Parissis J, Adamopoulos S, Farmakis D et al (2006) Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure. Heart 92:1768–1772PubMedGoogle Scholar
  30. 30.
    Fonarow GC, Peacock WF, Horwich TB, ADHERE Scientific Advisory Committee Investigators et al (2008) Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE. Am J Cardiol 101(2):231–237. doi: 10.1016/j.amjcard.2007.07.066 CrossRefPubMedGoogle Scholar
  31. 31.
    Parissis J, Panou F, Farmakis D et al (2005) Effects of levosimendan on markers of left ventricular diastolic function and neurohormonal activation in patients with advanced heart failure. Am J Cardiol 96:423–426. doi: 10.1016/j.amjcard.2005.03.092 CrossRefPubMedGoogle Scholar
  32. 32.
    Maeda K, Tsutamoto T, Wada A et al (2000) High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol 36:1587–1593. doi: 10.1016/S0735-1097(00)00912-8 CrossRefPubMedGoogle Scholar
  33. 33.
    Farmakis D, Parissis J, Bistola V et al (2008) Plasma B-type natriuretic peptide reduction predicts long-term response to levosimendan therapy in acutely decompensated chronic heart failure. Int J Cardiol, (Oct), 28. Epub ahead of printGoogle Scholar
  34. 34.
    Hasenfuss G, Pieske B, Castell M et al (1998) Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 98:2141–2147PubMedGoogle Scholar
  35. 35.
    Adamopoulos S, Parissis J, Kremastinos D (2001) A glossary of circulating cytokines in chronic heart failure. Eur J Heart Fail 3:517–526. doi: 10.1016/S1388-9842(01)00156-8 CrossRefPubMedGoogle Scholar
  36. 36.
    Adamopoulos S, Parissis J, Iliodromitis E et al (2006) Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure. Am J Cardiol 98:102–106. doi: 10.1016/j.amjcard.2006.01.068 CrossRefPubMedGoogle Scholar
  37. 37.
    Parissis J, Adamopoulos S, Antoniades C et al (2004) Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. Am J Cardiol 93:1309–1312. doi: 10.1016/j.amjcard.2004.01.073 CrossRefPubMedGoogle Scholar
  38. 38.
    Keith M, Geranmayegan A, Sole MJ et al (1998) Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 31:1352–1356. doi: 10.1016/S0735-1097(98)00101-6 CrossRefPubMedGoogle Scholar
  39. 39.
    Parissis J, Andreadou I, Markantonis S et al (2007) Effects of levosimendan on circulating markers of oxidative and nitrosative stress in patients with advanced heart failure. Atherosclerosis 195:e210–e215. doi: 10.1016/j.atherosclerosis.2007.07.011 CrossRefPubMedGoogle Scholar
  40. 40.
    Pacher P, Schulz R, Liaudet L et al (2005) Nitrosative stress and pharmacological modulation of heart failure. Trends Pharmacol Sci 26:302–310. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  41. 41.
    Zemljic G, Bunc M, Yazdanbakhsh A et al (2007) Levosimendan improves renal function in patients with advanced chronic heart failure awaiting cardiac transplantation. J Card Fail 13:417–421. doi: 10.1016/j.cardfail.2007.03.005 CrossRefPubMedGoogle Scholar
  42. 42.
    Kurien S, Warfield KT, Wood CM et al (2006) Effects of standard heart failure therapy and concomitant treatment with intravenous furosemide or inotropes (dobutamine, dopamine, and/or milrinone) on renal function and mortality in patients treated with nesiritide. Am J Cardiol 98:1627–1630. doi: 10.1016/j.amjcard.2006.07.044 CrossRefPubMedGoogle Scholar
  43. 43.
    Yilmaz MB, Yalta K, Yontar C et al (2007) Levosimendan improves renal function in patients with acute decompensated heart failure: comparison with dobutamine. Cardiovasc Drugs Ther 21:431–435. doi: 10.1007/s10557-007-6066-7 CrossRefPubMedGoogle Scholar
  44. 44.
    Damman K, Voors A (2007) Levosimendan improves renal function in acute decompensated heart failure: cause and clinical application. Cardiovasc Drugs Ther 21:403–404. doi: 10.1007/s10557-007-6070-y EditorialCrossRefPubMedGoogle Scholar
  45. 45.
    Tachibana H, Cheng HJ, Ukai T et al (2005) Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure. Am J Physiol Heart Circ Physiol 288:H914–H922. doi: 10.1152/ajpheart.00465.2004 CrossRefPubMedGoogle Scholar
  46. 46.
    Givertz MM, Andreou C, Conrad CH et al (2007) Direct myocardial effects of levosimendan in humans with left ventricular dysfunction: alteration of force-frequency and relaxation-frequency relationships. Circulation 115:1218–1224PubMedGoogle Scholar
  47. 47.
    Haikala H, Nissinen E, Etemadzadeh E et al (1995) Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. J Cardiovasc Pharmacol 25:794–801. doi: 10.1097/00005344-199505000-00016 CrossRefPubMedGoogle Scholar
  48. 48.
    Lilleberg J, Nieminen MS, Akkila J et al (1998) 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 19:660–668. doi: 10.1053/euhj.1997.0806 CrossRefPubMedGoogle Scholar
  49. 49.
    Dernellis J, Panaretou M (2005) Effects of levosimendan on restrictive left ventricular filling in severe heart failure: a combined hemodynamic and Doppler echocardiographic study. Chest 128:2633–2639. doi: 10.1378/chest.128.4.2633 CrossRefPubMedGoogle Scholar
  50. 50.
    Jorgensen K, Bech-Hanssen O, Houltz E et al (2008) Effects of levosimendan on left ventricular relaxation and early filling at maintained preload and afterload conditions after aortic valve replacement for aortic stenosis. Circulation 117:1075–1081. doi: 10.1161/CIRCULATIONAHA.107.722868 CrossRefPubMedGoogle Scholar
  51. 51.
    Parissis J, Paraskevaidis I, Bistola V et al (2006) Effects of levosimendan on right ventricular function in patients with advanced heart failure. Am J Cardiol 98:1489–1492. doi: 10.1016/j.amjcard.2006.06.052 CrossRefPubMedGoogle Scholar
  52. 52.
    Kasikcioglu H, Uyarel H, Tartan Z et al (2007) Do calcium sensitizers affect right ventricular functions in patients with chronic heart failure? Int J Cardiol 118:246–248. doi: 10.1016/j.ijcard.2006.06.054 CrossRefPubMedGoogle Scholar
  53. 53.
    De Luca L, Proietti P, Celotto A et al (2005) Levosimendan improves hemodynamics and coronary flow reserve after percutaneous coronary intervention in patients with acute myocardial infraction and left ventricular dysfunction. Am Heart J 150:563–568. doi: 10.1016/j.ahj.2004.10.013 CrossRefPubMedGoogle Scholar
  54. 54.
    Kersten JR, Montgomery MW, Pagel PS et al (2000) Levosimendan, a new positive inotropic drug, decreases myocardial infraction size via activation of K(ATP) channels. Anesth Analg 90:5–11. doi: 10.1097/00000539-200001000-00003 CrossRefPubMedGoogle Scholar
  55. 55.
    De Luca L, Colucci WS, Nieminen MS, Massie BM, Gheorghiade M (2006) Evidence-based use of levosimendan in different clinical settings. Eur Heart J 27:1908–1920. doi: 10.1093/eurheartj/ehi875 CrossRefPubMedGoogle Scholar
  56. 56.
    Ikonomidis I, Parissis J, Paraskevaidis I et al (2007) Effects of levosimendan on coronary artery flow and cardiac performance in patients with advanced heart failure. Eur J Heart Fail 9:1172–1177. doi: 10.1016/j.ejheart.2007.10.002 CrossRefPubMedGoogle Scholar
  57. 57.
    Michaels AD, McKeown B, Kostal M et al (2005) Effects of intravenous levosimendan on human coronary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake. Circulation 111:1504–1509. doi: 10.1161/01.CIR.0000159252.82444.22 CrossRefPubMedGoogle Scholar
  58. 58.
    Cianfrocca C, Pelliccia F, Auriti A et al (2007) Levosimendan allows detection of contractile reserve in patients with chronic ischaemic left ventricular dysfunction and non-diagnostic dobutamine echocardiography. Eur J Heart Fail 9:897–900. doi: 10.1016/j.ejheart.2007.05.003 CrossRefPubMedGoogle Scholar
  59. 59.
    Parissis J, Papadopoulos C, Nikolaou M et al (2007) Effects of levosimendan on quality of life and emotional stress in advanced heart failure patients. Cardiovasc Drugs Ther 21:263–268. doi: 10.1007/s10557-007-6034-2 CrossRefPubMedGoogle Scholar
  60. 60.
    Jiang W, Alexander J, Christopher E et al (2001) Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure. Arch Intern Med 161:1849–1856. doi: 10.1001/archinte.161.15.1849 CrossRefPubMedGoogle Scholar
  61. 61.
    Joynt KE, Whellan DJ, O’Connor CM (2004) Why is depression bad for the failing heart? A review of the mechanistic relationship between depression and heart failure. J Cardiac Fail 10:258–270. doi: 10.1016/j.cardfail.2003.09.008 CrossRefGoogle Scholar
  62. 62.
    Cleland JG, Takala A, Apajasalo M, Zethraeus N, Kobelt G et al (2003) Intravenous levosimendan treatment is cost-effective compared with dobutamine in severe low-output heart failure: an analysis based on the international LIDO trial. Eur J Heart Fail 5(1):101–108. doi: 10.1016/S1388-9842(02)00246-5 CrossRefPubMedGoogle Scholar
  63. 63.
    Oliveira MT Jr, Follador W, Martins ML et al (2008) Cost analysis of the treatment of acute decompensated heart failure. Levosimendan versus dobutamine. Arquivos Brasileiros de Cardiologia 85(1):9–14Google Scholar
  64. 64.
    Parissis J, Farmakis D, Bistola V et al (2007) Levosimendan for the treatment of acute heart failure syndromes: Time to identify subpopulations of responding patients. Am J Cardiol 99:146–147. doi: 10.1016/j.amjcard.2006.10.007 CrossRefPubMedGoogle Scholar
  65. 65.
    Giannakoulas G, Giannoglou G, Vassilikos V et al (2006) Clinical significance of acute neurohormonal response after levosimendan treatment. Am J Cardiol 98:1123–1124. doi: 10.1016/j.amjcard.2006.07.007 CrossRefPubMedGoogle Scholar
  66. 66.
    Bettencourt P, Azevedo A, Pimenta J et al (2004) N-terminal-pro brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 110:2168–2174. doi: 10.1161/01.CIR.0000144310.04433.BE CrossRefPubMedGoogle Scholar
  67. 67.
    Bettencourt P, Januzzi J (2008) Amino-terminal pro-B-type natriuretic peptide testing for inpatient monitoring and treatment guidance of acute destabilized heart failure. Am J Cardiol 101(1):67A–71A. doi: 10.1016/j.amjcard.2007.11.026 CrossRefGoogle Scholar
  68. 68.
    Kremastinos D (2008) Acute heart failure: an old syndrome revisited. Hellenic J Cardiol; HJC = Hellenike Kardiologike Epitheorese 49:199–200Google Scholar
  69. 69.
    Parissis J, Filippatos G, Farmakis D, Adamopoulos S, Paraskevaidis I, Kremastinos D (2005) Levosimendan for the treatment of acute heart failure syndromes. Expert Opin Pharmacother 6(15):2741–2751. doi: 10.1517/14656566.6.15.2741 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • John T. Parissis
    • 1
  • Pinelopi Rafouli-Stergiou
    • 1
  • Ioannis Paraskevaidis
    • 1
  • Alexandre Mebazaa
    • 2
  1. 1.Heart Failure Clinic and Second Cardiology DepartmentAttikon University HospitalAthensGreece
  2. 2.Hospital Lariboisiere APHPUniversity ParisParisFrance

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