Levosimendan: Molecular mechanisms and clinical implications: Consensus of experts on the mechanisms of action of levosimendan

International Journal of Cardiology

Volumn 159, Issue 2, 2012, Pages 82-87

  Papp, Zoltán ^a   Édes, István ^a   Fruhwald, Sonja ^b   De Hert, Stefan G ^c   Salmenperä, Markku ^d   Leppikangas, Heli ^e   Mebazaa, Alexandre ^f   Landoni, Giovanni ^g   Grossini, Elena ^h   Caimmi, Philippe ⁱ   Morelli, Andrea ^j   Guarracino, Fabio ^k   Schwinger, Robert H G ^l   Meyer, Sven ^m   Algotsson, Lars ⁿ   Wikström, Bernt Gerhard ^o   Jörgensen, Kirsten ^p   Filippatos, Gerasimos ^q   Parissis, John T ^q   González, Martín J García ^r   Parkhomenko, Alexander ^s   Yilmaz, Mehmet Birhan ^t   Kivikko, Matti ^u   Pollesello, Piero ^v   Follath, Ferenc ^w   more..

^a UNIVERSITY OF DEBRECEN   (Hungary)

^b MEDICAL UNIVERSITY OF GRAZ   (Austria)

^c GHENT UNIVERSITY HOSPITAL   (Belgium)

^d HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

^e TAMPERE UNIVERSITY HOSPITAL   (Finland)

^f APHP   (France)

^g VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

^h UNIVERSITY OF EASTERN PIEDMONT   (Italy)

ⁱ MAGGIORE DELLA CARITÀ HOSPITAL   (Italy)

^j SAPIENZA UNIVERSITY OF ROME   (Italy)

^k UNIVERSITY HOSPITAL OF PISA   (Italy)

^l UNIVERSITY OF REGENSBURG   (Germany)

^m UNIVERSITY HEART CENTER HAMBURG   (Germany)

ⁿ LUND UNIVERSITY   (Sweden)

^o UPPSALA UNIVERSITY HOSPITAL   (Sweden)

^p SAHLGRENSKA UNIVERSITY HOSPITAL   (Sweden)

^q NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS   (Greece)

^r HOSPITAL UNIVERSITARIO DE CANARIAS   (Spain)

^s Ukranian Strazhesko Institute of Cardiology   (Ukraine)

^t CUMHURIYET UNIVERSITY SCHOOL OF MEDICINE   (Turkey)

^u Orionintie 1   (Finland)

^v Orionintie 1   (Finland)

^w UNIVERSITY HOSPITAL ZURICH   (Switzerland)

more..

Author keywords

Ca2+ sensitization; Cardioprotection; Levosimendan; Mechanism of action; Positive inotropy; Vasodilation

Indexed keywords

ADENOSINE TRIPHOSPHATE; ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; CALCIUM ION; CALCIUM SENSITIZER; DOBUTAMINE; DRUG METABOLITE; INOTROPIC AGENT; ISOENZYME; LEVOSIMENDAN; N [4 (1,4,5,6 TETRAHYDRO 4 METHYL 6 OXO 3 PYRIDAZINYL)PHENYL]ACETAMIDE; NEUROHORMONE; OR 1855; PHOSPHODIESTERASE; PLACEBO; TROPONIN C; UNCLASSIFIED DRUG;

CONSENSUS; DRUG EFFECT; DRUG HALF LIFE; DRUG MECHANISM; DRUG RECEPTOR BINDING; ENANTIOMER; ENERGY TRANSFER; ENZYME INHIBITION; HEADACHE; HEART ATRIUM FIBRILLATION; HEART FAILURE; HEART MUSCLE CELL; HEART PROTECTION; HUMAN; HYPOKALEMIA; HYPOTENSION; MITOCHONDRION; MYOFILAMENT; PLEIOTROPY; PRIORITY JOURNAL; REVIEW; SMOOTH MUSCLE FIBER; TACHYCARDIA; VASODILATATION;

ANIMALS; CARDIOTONIC AGENTS; CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; CONSENSUS; HUMANS; HYDRAZONES; PYRIDAZINES; VASODILATOR AGENTS;

EID: 84864990939     PISSN: 01675273     EISSN: 18741754     Source Type: Journal    
DOI: 10.1016/j.ijcard.2011.07.022     Document Type: Review

References (99)

1. R.J. Solaro CK-1827452, a sarcomere-directed cardiac myosin activator for acute and chronic heart disease IDrugs 12 2009 243 251
2. S. Sakata, D. Lebeche, and N. Sakata Targeted gene transfer increases contractility and decreases oxygen cost of contractility in normal rat hearts Am J Physiol Heart Circ Physiol 292 2007 H2356 H2363
3. F. Follath, J.G. Cleland, and H. Just Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial Lancet 360 2002 196 202 (Pubitemid 34804646)
4. V.S. Moiseyev, P. Poder, and N. Andrejevs Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN) Eur Heart J 23 2002 1422 1432 (Pubitemid 36285574)
5. A. Mebazaa, M.S. Nieminen, and M. Packer Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial Jama 297 2007 1883 1891 (Pubitemid 46707842)
6. A. Delaney, C. Bradford, J. McCaffrey, S.M. Bagshaw, and R. Lee Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials Int J Cardiol 138 2010 281 289
7. G. Landoni, A. Mizzi, and G. Biondi-Zoccai Levosimendan reduces mortality in critically ill patients. A meta-analysis of randomized controlled studies Minerva Anestesiol 76 2010 276 286
8. G. Landoni, A. Mizzi, and G. Biondi-Zoccai Reducing mortality in cardiac surgery with levosimendan: a meta-analysis of randomized controlled trials J Cardiothorac Vasc Anesth 24 2010 51 57
9. J.T. Parissis, I. Andreadou, V. Bistola, I. Paraskevaidis, G. Filippatos, and D.T. Kremastinos Novel biologic mechanisms of levosimendan and its effect on the failing heart Expert Opin Investig Drugs 17 2008 1143 1150
10. E.P. Sandell, M. Hayha, and S. Antila Pharmacokinetics of levosimendan in healthy volunteers and patients with congestive heart failure J Cardiovasc Pharmacol 26 Suppl 1 1995 S57 S62
11. M. Kivikko, S. Antila, J. Eha, L. Lehtonen, and P.J. Pentikainen 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 2002 465 471 (Pubitemid 35153452)
12. J. Puttonen, S. Kantele, and A. Ruck Pharmacokinetics of intravenous levosimendan and its metabolites in subjects with hepatic impairment J Clin Pharmacol 48 2008 445 454 (Pubitemid 351389111)
13. T. Sorsa, P. Pollesello, P.R. Rosevear, T. Drakenberg, and I. Kilpelainen Stereoselective binding of levosimendan to cardiac troponin C causes Ca2 +-sensitization Eur J Pharmacol 486 2004 1 8 (Pubitemid 38130154)
14. T. Sorsa, S. Heikkinen, and M.B. Abbott Binding of levosimendan, a calcium sensitizer, to cardiac troponin C J Biol Chem 276 2001 9337 9343
15. I.M. Robertson, Y.B. Sun, M.X. Li, and B.D. Sykes A structural and functional perspective into the mechanism of Ca(2+)-sensitizers that target the cardiac troponin complex J Mol Cell Cardiol 2010
16. I. Edes, E. Kiss, and Y. Kitada Effects of levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart Circ Res 77 1995 107 113
17. Z. Papp, J. Van Der Velden, A. Borbely, I. Edes, and G.J. Stienen Effects of Ca2+-sensitizers in permeabilized cardiac myocytes from donor and end-stage failing human hearts J Muscle Res Cell Motil 25 2004 219 224 (Pubitemid 44961624)
18. P.M. Janssen, N. Datz, O. Zeitz, and G. Hasenfuss Levosimendan improves diastolic and systolic function in failing human myocardium Eur J Pharmacol 404 2000 191 199
19. M.M. Givertz, C. Andreou, C.H. Conrad, and W.S. Colucci Direct myocardial effects of levosimendan in humans with left ventricular dysfunction: alteration of force-frequency and relaxation-frequency relationships Circulation 115 2007 1218 1224 (Pubitemid 46594765)
20. K. Jorgensen, O. Bech-Hanssen, E. Houltz, and S.E. Ricksten 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 2008 1075 1081
21. P. Pollesello, M. Ovaska, and J. Kaivola 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 269 1994 28584 28590
22. S. Szilagyi, P. Pollesello, and J. Levijoki The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig Eur J Pharmacol 486 2004 67 74 (Pubitemid 38130162)
23. P.N. Banfor, L.C. Preusser, and T.J. Campbell Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O2 consumption in dogs Am J Physiol Heart Circ Physiol 294 2008 H238 H248
24. J.A. Segreti, K.C. Marsh, J.S. Polakowski, and R.M. Fryer Evoked changes in cardiovascular function in rats by infusion of levosimendan, OR-1896 [(R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide], OR-1855 [(R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one], dobutamine, and milrinone: comparative effects on peripheral resistance, cardiac output, dP/dt, pulse rate, and blood pressure J Pharmacol Exp Ther 325 2008 331 340 (Pubitemid 351439154)
25. N. Gruhn, J.E. Nielsen-Kudsk, S. Theilgaard, L. Bang, S.P. Olesen, and J. Aldershvile Coronary vasorelaxant effect of levosimendan, a new inodilator with calcium-sensitizing properties J Cardiovasc Pharmacol 31 1998 741 749 (Pubitemid 28217595)
26. N. Erdei, Z. Papp, P. Pollesello, I. Edes, and Z. Bagi The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles Br J Pharmacol 148 2006 696 702 (Pubitemid 43993060)
27. J. Hohn, J. Pataricza, and A. Petri Levosimendan interacts with potassium channel blockers in human saphenous veins Basic Clin Pharmacol Toxicol 94 2004 271 273 (Pubitemid 38954893)
28. + channel in rat ventricular cells J Pharmacol Exp Ther 283 1997 375 383 (Pubitemid 27438984)
29. J. Pataricza, I. Krassoi, J. Hohn, A. Kun, and J.G. Papp Functional role of potassium channels in the vasodilating mechanism of levosimendan in porcine isolated coronary artery Cardiovasc Drugs Ther 17 2003 115 121 (Pubitemid 37174684)
30. B.J. De Witt, I.N. Ibrahim, and E. Bayer An analysis of responses to levosimendan in the pulmonary vascular bed of the cat Anesth Analg 94 2002 1427 1433 table of contents. (Pubitemid 34556617)
31. E. Grossini, C. Molinari, P.P. Caimmi, F. Uberti, and G. Vacca Levosimendan induces NO production through p38 MAPK, ERK and Akt in porcine coronary endothelial cells: role for mitochondrial K(ATP) channel Br J Pharmacol 156 2009 250 261
32. P. Kaheinen, P. Pollesello, J. Levijoki, and H. Haikala Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels J Cardiovasc Pharmacol 37 2001 367 374 (Pubitemid 32240418)
33. R. Takahashi, M.A. Talukder, and M. Endoh Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium J Cardiovasc Pharmacol 36 2000 118 125 (Pubitemid 30419131)
34. P. Boknik, J. Neumann, and G. Kaspareit Mechanisms of the contractile effects of levosimendan in the mammalian heart J Pharmacol Exp Ther 280 1997 277 283 (Pubitemid 27171413)
35. K. Brixius, S. Reicke, and R.H. Schwinger Beneficial effects of the Ca(2+) sensitizer levosimendan in human myocardium Am J Physiol Heart Circ Physiol 282 2002 H131 H137
36. Y.H. Choi, D.B. Cowan, T.C. Wahlers, R. Hetzer, P.J. Del Nido, and C. Stamm Calcium sensitisation impairs diastolic relaxation in post-ischaemic myocardium: implications for the use of Ca(2+) sensitising inotropes after cardiac surgery Eur J Cardiothorac Surg 37 2010 376 383
37. R. Fischmeister, L.R. Castro, and A. Abi-Gerges Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases Circ Res 99 2006 816 828 (Pubitemid 44556380)
38. M. Zaccolo cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies Br J Pharmacol 158 2009 50 60
39. M.K. Lancaster, and S.J. Cook The effects of levosimendan on [Ca2+]i in guinea-pig isolated ventricular myocytes Eur J Pharmacol 339 1997 97 100 (Pubitemid 28015436)
40. G. Hasenfuss, B. Pieske, M. Castell, B. Kretschmann, L.S. Maier, and H. Just Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium Circulation 98 1998 2141 2147 (Pubitemid 28527473)
41. H. Haikala, P. Kaheinen, J. Levijoki, and I.B. Linden The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan Cardiovasc Res 34 1997 536 546 (Pubitemid 27272673)
42. G. Hasenfuss, B. Pieske, B. Kretschmann, C. Holubarsch, N.R. Alpert, and H. Just Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics J Cardiovasc Pharmacol 26 Suppl 1 1995 S45 S51
43. E.J. Tsai, and D.A. Kass Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics Pharmacol Ther 122 2009 216 238
44. S.E. Lehnart, L.S. Maier, and G. Hasenfuss Abnormalities of calcium metabolism and myocardial contractility depression in the failing heart Heart Fail Rev 14 2009 213 224
45. R.J. Hajjar, F.U. Muller, W. Schmitz, P. Schnabel, and M. Bohm Molecular aspects of adrenergic signal transduction in cardiac failure J Mol Med 76 1998 747 755 (Pubitemid 28475169)
46. R. Latini, S. Masson, N. de Angelis, and I. Anand Role of brain natriuretic peptide in the diagnosis and management of heart failure: current concepts J Card Fail 8 2002 288 299 (Pubitemid 35253199)
47. A. Cohen-Solal, D. Logeart, B. Huang, D. Cai, M.S. Nieminen, and A. Mebazaa Lowered B-type natriuretic peptide in response to levosimendan or dobutamine treatment is associated with improved survival in patients with severe acutely decompensated heart failure J Am Coll Cardiol 53 2009 2343 2348
48. J.T. Parissis, I. Paraskevaidis, and V. Bistola Effects of levosimendan on right ventricular function in patients with advanced heart failure Am J Cardiol 98 2006 1489 1492 (Pubitemid 44779479)
49. J.T. Parissis, I. Andreadou, and S.L. Markantonis Effects of levosimendan on circulating markers of oxidative and nitrosative stress in patients with advanced heart failure Atherosclerosis 195 2007 e210 e215
50. S. Kyrzopoulos, S. Adamopoulos, and J.T. Parissis Levosimendan reduces plasma B-type natriuretic peptide and interleukin 6, and improves central hemodynamics in severe heart failure patients Int J Cardiol 99 2005 409 413 (Pubitemid 40363991)
51. J.T. Parissis, S. Adamopoulos, and C. Antoniades Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure Am J Cardiol 93 2004 1309 1312 (Pubitemid 38595693)
52. S. Adamopoulos, J.T. Parissis, and E.K. Iliodromitis Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure Am J Cardiol 98 2006 102 106 (Pubitemid 43902695)
53. G. Giannakoulas, G. Giannoglou, and V. Vassilikos Clinical significance of acute neurohormonal response after levosimendan treatment Am J Cardiol 98 2006 1123 1124 (Pubitemid 44486130)
54. J.T. Parissis, A. Karavidas, and V. Bistola Effects of levosimendan on flow-mediated vasodilation and soluble adhesion molecules in patients with advanced chronic heart failure Atherosclerosis 197 2008 278 282 (Pubitemid 351284474)
55. K. Kaptan, K. Erinc, and A. Ifran Levosimendan has an inhibitory effect on platelet function Am J Hematol 83 2008 46 49
56. I. Ikonomidis, J.T. Parissis, and I. Paraskevaidis Effects of levosimendan on coronary artery flow and cardiac performance in patients with advanced heart failure Eur J Heart Fail 9 2007 1172 1177 (Pubitemid 350138499)
57. M.S. Nieminen, P. Pollesello, G. Vajda, and Z. Papp Effects of levosimendan on the energy balance: preclinical and clinical evidence J Cardiovasc Pharmacol 53 2009 302 310
58. D.A. Kass, and R.J. Solaro Mechanisms and use of calcium-sensitizing agents in the failing heart Circulation 113 2006 305 315
59. H. Tachibana, H.J. Cheng, and T. Ukai Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure Am J Physiol Heart Circ Physiol 288 2005 H914 H922
60. A. Morelli, J.L. Teboul, and S.M. Maggiore Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study Crit Care Med 34 2006 2287 2293 (Pubitemid 44260011)
61. J. Lilleberg, M.S. Nieminen, and J. Akkila 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 1998 660 668 (Pubitemid 28224690)
62. H. Ukkonen, M. Saraste, and J. Akkila Myocardial efficiency during levosimendan infusion in congestive heart failure Clin Pharmacol Ther 68 2000 522 531
63. C.P. Harkin, P.S. Pagel, J.P. Tessmer, and D.C. Warltier Systemic and coronary hemodynamic actions and left ventricular functional effects of levosimendan in conscious dogs J Cardiovasc Pharmacol 26 1995 179 188
64. J.R. Kersten, M.W. Montgomery, P.S. Pagel, and D.C. Warltier Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels Anesth Analg 90 2000 5 11 (Pubitemid 30022959)
65. D.M. Kopustinskiene, P. Pollesello, and N.E. Saris Potassium-specific effects of levosimendan on heart mitochondria Biochem Pharmacol 68 2004 807 812 (Pubitemid 39044509)
66. + channels Biochim Biophys Acta 1762 2006 202 212 (Pubitemid 43006026)
67. H.I. Eriksson, J.R. Jalonen, and L.O. Heikkinen Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function Ann Thorac Surg 87 2009 448 454
68. S. Sonntag, S. Sundberg, L.A. Lehtonen, and F.X. Kleber The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia J Am Coll Cardiol 43 2004 2177 2182 (Pubitemid 38757582)
69. M.J. Garcia-Gonzalez, A. Dominguez-Rodriguez, J.J. Ferrer-Hita, P. Abreu-Gonzalez, and M.B. Munoz Cardiogenic shock after primary percutaneous coronary intervention: effects of levosimendan compared with dobutamine on haemodynamics Eur J Heart Fail 8 2006 723 728 (Pubitemid 44637270)
70. L. De Luca, P. Proietti, and A. Celotto Levosimendan improves hemodynamics and coronary flow reserve after percutaneous coronary intervention in patients with acute myocardial infarction and left ventricular dysfunction Am Heart J 150 2005 563 568 (Pubitemid 41317630)
71. L. Tritapepe, V. De Santis, and D. Vitale Preconditioning effects of levosimendan in coronary artery bypass grafting - a pilot study Br J Anaesth 96 2006 694 700 (Pubitemid 43786683)
72. D.L. Prior, B.D. Flaim, A.I. MacIsaac, and M.Y. Yii Pre-operative use of levosimendan in two patients with severe aortic stenosis and left ventricular dysfunction Heart Lung Circ 15 2006 56 58 (Pubitemid 43355910)
73. S.G. De Hert, S. Lorsomradee, H. vanden Eede, S. Cromheecke, and P.J. Van der Linden A randomized trial evaluating different modalities of levosimendan administration in cardiac surgery patients with myocardial dysfunction J Cardiothorac Vasc Anesth 22 2008 699 705
74. S.G. De Hert, S. Lorsomradee, S. Cromheecke, and P.J. Van der Linden The effects of levosimendan in cardiac surgery patients with poor left ventricular function Anesth Analg 104 2007 766 773 (Pubitemid 46548294)
75. E.F. du Toit, A. Genis, L.H. Opie, P. Pollesello, and A. Lochner 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 154 2008 41 50 (Pubitemid 351620393)
76. J.G. Papp, P. Pollesello, A.F. Varro, and A.S. Vegh Effect of levosimendan and milrinone on regional myocardial ischemia/reperfusion-induced arrhythmias in dogs J Cardiovasc Pharmacol Ther 11 2006 129 135 (Pubitemid 44449102)
77. G.A. Cammarata, M.H. Weil, S. Sun, L. Huang, X. Fang, and W. Tang Levosimendan improves cardiopulmonary resuscitation and survival by K(ATP) channel activation J Am Coll Cardiol 47 2006 1083 1085
78. A. Honisch, N. Theuring, B. Ebner, C. Wagner, R.H. Strasser, and C. Weinbrenner Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-III inhibition Basic Res Cardiol 105 2009 155 167
79. I.N. Jamali, J.R. Kersten, P.S. Pagel, D.A. Hettrick, and D.C. Warltier Intracoronary levosimendan enhances contractile function of stunned myocardium Anesth Analg 85 1997 23 29 (Pubitemid 27342270)
80. A. Lochner, F. Colesky, and S. Genade Effect of a calcium-sensitizing agent, levosimendan, on the postcardioplegic inotropic response of the myocardium Cardiovasc Drugs Ther 14 2000 271 281 (Pubitemid 30447229)
81. Q. Chen, A.K. Camara, S.S. Rhodes, M.L. Riess, E. Novalija, and D.F. Stowe Cardiotonic drugs differentially alter cytosolic [Ca2+] to left ventricular relationships before and after ischemia in isolated guinea pig hearts Cardiovasc Res 59 2003 912 925 (Pubitemid 38366247)
82. M. Maytin, and W.S. Colucci Cardioprotection: a new paradigm in the management of acute heart failure syndromes Am J Cardiol 96 2005 26G-31G.
83. M. Louhelainen, E. Vahtola, and P. Kaheinen Effects of levosimendan on cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats Br J Pharmacol 150 2007 851 861 (Pubitemid 46536624)
84. E. Grossini, P.P. Caimmi, and F. Platini Modulation of programmed forms of cell death by intracoronary levosimendan during regional myocardial ischemia in anesthetized pigs Cardiovasc Drugs Ther 24 2010 5 15
85. P.P. Caimmi, and C. Molinari Intracoronary levosimendan prevents myocardial ischemic damages and activates survival signaling through ATP-sensitive potassium channel and nitric oxide Eur J Cardiothorac Surg 39 2011 e59-e67.
86. J.T. Parissis, F. Panou, and D. Farmakis Effects of levosimendan on markers of left ventricular diastolic function and neurohormonal activation in patients with advanced heart failure Am J Cardiol 96 2005 423 426 (Pubitemid 41058875)
87. L.A. Schwarte, O. Picker, S.R. Bornstein, A. Fournell, and T.W. Scheeren Levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation in dogs Crit Care Med 33 2005 135 142 discussion 246-7. (Pubitemid 40116548)
88. P.S. Pagel, D.A. Hettrick, and D.C. Warltier Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs Br J Pharmacol 119 1996 609 615 (Pubitemid 26335328)
89. M.B. Yilmaz, K. Yalta, and C. Yontar Levosimendan improves renal function in patients with acute decompensated heart failure: comparison with dobutamine Cardiovasc Drugs Ther 21 2007 431 435 (Pubitemid 350231513)
90. G. Zemljic, M. Bunc, A.P. Yazdanbakhsh, and B. Vrtovec Levosimendan improves renal function in patients with advanced chronic heart failure awaiting cardiac transplantation J Card Fail 13 2007 417 421 (Pubitemid 47176926)
91. H. Leppikangas, J.J. Tenhunen, L. Lindgren, J.P. Salenius, and E. Ruokonen Effects of levosimendan on indocyanine green plasma disappearance rate and the gastric mucosal-arterial pCO2 gradient in abdominal aortic aneurysm surgery Acta Anaesthesiol Scand 52 2008 785 792 (Pubitemid 351829483)
92. K. Dickstein, A. Cohen-Solal, and G. Filippatos 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. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM) Eur Heart J 29 2008 2388 2442
93. A. Mebazaa, M.S. Nieminen, and G.S. Filippatos Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE Eur J Heart Fail 11 2009 304 311
94. A.P. Coletta, J.G. Cleland, N. Freemantle, and A.L. Clark Clinical trials update from the European Society of Cardiology Heart Failure meeting: SHAPE, BRING-UP 2 VAS, COLA II, FOSIDIAL, BETACAR, CASINO and meta-analysis of cardiac resynchronisation therapy Eur J Heart Fail 6 2004 673 676 (Pubitemid 39070524)
95. J.G. Cleland, N. Freemantle, A.P. Coletta, and A.L. Clark Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE Eur J Heart Fail 8 2006 105 110 (Pubitemid 43012109)
96. F.M. Fruhwald, A. Fahrleitner-Pammer, and R. Berger Early and sustained effects of cardiac resynchronization therapy on N-terminal pro-B-type natriuretic peptide in patients with moderate to severe heart failure and cardiac dyssynchrony Eur Heart J 28 2007 1592 1597 (Pubitemid 47227112)
97. M. Salmenpera, and H. Eriksson Levosimendan in perioperative and critical care patients Curr Opin Anaesthesiol 22 2009 496 501
98. R. Maharaj, and V. Metaxa Levosimendan and mortality after coronary revascularisation: a meta-analysis of randomised controlled trials Crit Care 15 2011 R140 [Epub ahead of print]
99. L.G. Shewan, and A.J. Coats Ethics in the authorship and publishing of scientific articles Int J Cardiol 144 2010 1 2