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

被引：243

作者：

Papp, Zoltan ^{[1
]}

Edes, Istvan ^{[1
]}

Fruhwald, Sonja ^{[2
]}

De Hert, Stefan G. ^{[3
]}

Salmenpera, Markku ^{[4
]}

Leppikangas, Heli ^{[5
]}

Mebazaa, Alexandre ^{[6
]}

Landoni, Giovanni ^{[7
]}

Grossini, Elena ^{[8
]}

Caimmi, Philippe ^{[9
]}

Morelli, Andrea ^{[10
]}

Guarracino, Fabio ^{[11
]}

Schwinger, Robert H. G. ^{[12
]}

Meyer, Sven ^{[13
]}

Algotsson, Lars ^{[14
]}

Wikstrom, Bernt Gerhard ^{[15
]}

Jorgensen, Kirsten ^{[16
]}

Filippatos, Gerasimos ^{[17
,18
]}

Parissis, John T. ^{[18
]}

Garcia Gonzalez, Martin J. ^{[19
]}

Parkhomenko, Alexander ^{[20
]}

Yilmaz, Mehmet Birhan ^{[21
]}

Kivikko, Matti ^{[22
]}

Pollesello, Piero ^{[23
]}

Follath, Ferenc ^{[24
]}

机构：

[1] Univ Debrecen, Inst Cardiol, Med & Hlth Sci Ctr, H-4032 Debrecen, Hungary

[2] Dept Anesthesiol & Intens Care Med, Div Anesthesiol Cardiovasc Surg & Intens Care Med, A-8036 Graz, Austria

[3] Univ Ghent, Ghent Univ Hosp, Dept Anesthesiol, B-9000 Ghent, Belgium

[4] Helsinki Univ Hosp, Dept Anesthesiol & Intens Care Med, Helsinki, Finland

[5] Tampere Univ Hosp, Dept Anesthesiol, Tampere, Finland

[6] Univ Paris 07, INSERM, Lariboisiere Hosp, Dept Anaesthesia & Intens Care,UMR 942, Paris, France

[7] Univ Vita Salute San Raffaele, Dept Anesthesiol & Intens Care, Milan, Italy

[8] Univ E Piedmont Avogadro, Dept Clin & Expt Med, Novara, Italy

[9] Univ E Piedmont Avogadro, Sch Med, Osped Maggiore della Carita, Dept Cardiac Surg, Novara, Italy

[10] Univ Rome, Dept Anesthesiol & Intens Care, Rome, Italy

[11] Univ Hosp Pisa, Cardiothorac Dept, Cardiothorac Anaesthesia & Intens Care Unit, Pisa, Italy

[12] Teaching Hosp Univ Regensburg, Klinikum Weiden, Clin Internal Med 2, D-92637 Weiden, Germany

[13] Univ Med Ctr Hamburg Eppendorf, Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, D-20246 Hamburg, Germany

[14] Lund Univ, Fac Med, Dept Anesthesiol & Intens Care, Lund, Sweden

[15] Akad Hosp, Dept Med Sci, SE-75185 Uppsala, Sweden

[16] Sahlgrens Univ Hosp, Dept Cardiothorac Anesthesia & Intens Care, S-41345 Gothenburg, Sweden

[17] Attikon Univ Hosp, Dept Cardiol 2, Athens, Greece

[18] Attikon Univ Hosp, Heart Failure Unit, Athens, Greece

[19] Hosp Univ Canarias, Dept Cardiol, Coronary Care Unit, Tenerife, Spain

[20] Natl Sci Ctr, Strazhesko Inst Cardiol, Kiev, Ukraine

[21] Cumhuriyet Univ, Sch Med, Dept Cardiol, Sivas, Turkey

[22] Orion Pharma, Med Affairs, FIN-02101 Espoo, Finland

[23] Orion Pharma, Cardiol & Crit Care, FIN-02101 Espoo, Finland

[24] Univ Zurich Hosp, Off HAL 18 D2, CH-8091 Zurich, Switzerland

来源：

INTERNATIONAL JOURNAL OF CARDIOLOGY | 2012年 / 159卷 / 02期

关键词：

Levosimendan; Mechanism of action; Ca2+-sensitization; Positive inotropy; Vasodilation; Cardioprotection; ADVANCED HEART-FAILURE; CARDIAC TROPONIN-C; GUINEA-PIG HEART; PERCUTANEOUS CORONARY INTERVENTION; RANDOMIZED CONTROLLED-TRIALS; LEFT-VENTRICULAR DYSFUNCTION; ACUTE MYOCARDIAL-INFARCTION; FAILING HUMAN MYOCARDIUM; IMPROVES RENAL-FUNCTION; K-ATP CHANNELS;

D O I：

10.1016/j.ijcard.2011.07.022

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The molecular background of the Ca2+-sensitizing effect of levosimendan relates to its specific interaction with the Ca2+-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K+ channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K+ channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

引用

页码：82 / 87

页数：6

共 99 条

[21] Levosimendan Facilitates Weaning From Cardiopulmonary Bypass in Patients Undergoing Coronary Artery Bypass Grafting With Impaired Left Ventricular Function [J].

Eriksson, Heidi I. ;

Jalonen, Jouko R. ;

Heikkinen, Leo O. ;

Kivikko, Matti ;

Laine, Mika ;

Leino, Kari A. ;

Kuitunen, Anne H. ;

Kuttila, Kari T. ;

Perakyla, Tarja K. ;

Sarapohja, Toni ;

Suojaranta-Ylinen, Raili T. ;

Valtonen, Mika ;

Salmenpera, Markku T. .

ANNALS OF THORACIC SURGERY, 2009, 87 (02) :448-454

[22] Tissue protection mediated by mitochondrial K+ channels [J].

Facundo, HTF ;

Fornazari, M ;

Kowaltowski, AJ .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2006, 1762 (02) :202-212

[23] Compartmentation of cyclic nucleotide signaling in the heart - The role of cyclic nucleotide phosphodiesterases [J].

Fischmeister, Rodolphe ;

Castro, Liliana R. V. ;

Abi-Gerges, Aniella ;

Rochais, Francesca ;

Jurevicius, Jonas ;

Leroy, Jerome ;

Vandecasteele, Gregoire .

CIRCULATION RESEARCH, 2006, 99 (08) :816-828

[24] Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial [J].

Follath, F ;

Cleland, JGF ;

Just, H ;

Papp, JGY ;

Scholz, H ;

Peuhkurinen, K ;

Harjola, VP ;

Mitrovic, V ;

Abdalla, M ;

Sandell, EP ;

Lehtonen, L .

LANCET, 2002, 360 (9328) :196-202

[25] 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 [J].

Fruhwald, Friedrich M. ;

Fahrleitner-Pammer, Astrid ;

Berger, Rudolf ;

Leyva, Francisco ;

Freemantle, Nick ;

Erdmann, Erland ;

Gras, Daniel ;

Kappenberger, Lukas ;

Tavazzi, Luigi ;

Daubert, Jean-Claude ;

Cleland, John G. F. .

EUROPEAN HEART JOURNAL, 2007, 28 (13) :1592-1597

[26] Cardiogenic shock after primary percutaneous coronary intervention:: Effects of levosimendan compared with dobutamine on haemodynamics [J].

Garcia-Gonzalez, Martin J. ;

Dominguez-Rodriguez, Alberto ;

Ferrer-Hita, Julio J. ;

Abreu-Gonzalez, Pedro ;

Munoz, Miguel Bethencourt .

EUROPEAN JOURNAL OF HEART FAILURE, 2006, 8 (07) :723-728

[27] Clinical significance of acute neurohormonal response after levosimendan treatment [J].

Giannakoulas, George ;

Giannoglou, George ;

Vassilikos, Vasilis ;

Martiadou, Kostantina ;

Kalpidis, Panagiotis ;

Parharidis, George ;

Louridas, George .

AMERICAN JOURNAL OF CARDIOLOGY, 2006, 98 (08) :1123-1124

[28] Direct myocardial effects of levosimendan in humans with left ventricular dysfunction - Alteration of force-frequency and relaxation-frequency relationships [J].

Givertz, Michael M. ;

Andreou, Costa ;

Conrad, Chester H. ;

Colucci, Wilson S. .

CIRCULATION, 2007, 115 (10) :1218-1224

[29] Levosimendan induces NO production through p38 MAPK, ERK and Akt in porcine coronary endothelial cells: role for mitochondrial KATP channel [J].

Grossini, E. ;

Molinari, C. ;

Caimmi, P. P. ;

Uberti, F. ;

Vacca, G. .

BRITISH JOURNAL OF PHARMACOLOGY, 2009, 156 (02) :250-261

[30] Modulation of Programmed Forms of Cell Death by Intracoronary Levosimendan During Regional Myocardial Ischemia in Anesthetized Pigs [J].

Grossini, Elena ;

Caimmi, Philippe Primo ;

Platini, Francesca ;

Molinari, Claudio ;

Uberti, Francesca ;

Cattaneo, Marco ;

Valente, Guido ;

Mary, David A. S. G. ;

Vacca, Giovanni ;

Tessitore, Luciana .

CARDIOVASCULAR DRUGS AND THERAPY, 2010, 24 (01) :5-15

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