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

[1] Effects of Levosimendan versus Dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure [J].

Adamopoulos, Stamatis ;

Parissis, John T. ;

Iliodromitis, Efstathios K. ;

Paraskevaidis, Ioannis ;

Tsiapras, Dimitrios ;

Farmakis, Dimitrios ;

Karatzas, Dimitrios ;

Gheorghiade, Mihai ;

Filippatos, Gerasimos S. ;

Kremastinos, Dimitrios T. .

AMERICAN JOURNAL OF CARDIOLOGY, 2006, 98 (01) :102-106

[2] Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O2 consumption in dogs [J].

Banfor, Patricia N. ;

Preusser, Lee C. ;

Campbell, Thomas J. ;

Marsh, Kennan C. ;

Polakowski, James S. ;

Reinhart, Glenn A. ;

Cox, Bryan F. ;

Fryer, Ryan M. .

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2008, 294 (01) :H238-H248

[3]

Boknik P, 1997, J PHARMACOL EXP THER, V280, P277

[4] Beneficial effects of the Ca2+ sensitizer levosimendan in human myocardium [J].

Brixius, K ;

Reicke, S ;

Schwinger, RHG .

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2002, 282 (01) :H131-H137

[5] Intracoronary levosimendan prevents myocardial ischemic damages and activates survival signaling through ATP-sensitive potassium channel and nitric oxide [J].

Caimmi, Philippe Primo ;

Molinari, Claudio ;

Uberti, Francesca ;

Micalizzi, Ezio ;

Valente, Guido ;

Mary, David A. S. G. ;

Vacca, Giovanni ;

Grossini, Elena .

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY, 2011, 39 (04) :E59-E67

[6] Levosimendan improves cardiopulmonary resuscitation and survival by KATP channel activation [J].

Carnmarata, GAAM ;

Weil, MH ;

Sun, SJ ;

Huang, L ;

Fang, XS ;

Tang, WC .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2006, 47 (05) :1083-1085

[7] Cardiotonic drugs differentially alter cytosolic [Ca2+] to left ventricular relationships before and after ischemia in isolated guinea pig hearts [J].

Chen, Q ;

Camara, AKS ;

Rhodes, SS ;

Riess, ML ;

Novalija, E ;

Stowe, DF .

CARDIOVASCULAR RESEARCH, 2003, 59 (04) :912-925

[8] Calcium sensitisation impairs diastolic relaxation in post-ischaemic myocardium: implications for the use of Ca2+ sensitising inotropes after cardiac surgery [J].

Choi, Yeong-Hoon ;

Cowan, Douglas B. ;

Wahlers, Thorsten C. W. ;

Hetzer, Roland ;

del Nido, Pedro J. ;

Stamm, Christof .

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY, 2010, 37 (02) :376-383

[9] Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE [J].

Cleland, JGF ;

Freemantle, N ;

Coletta, AP ;

Clark, AL .

EUROPEAN JOURNAL OF HEART FAILURE, 2006, 8 (01) :105-110

[10] 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].

Cohen-Solal, Alain ;

Logeart, Damien ;

Huang, Bidan ;

Cai, Danlin ;

Nieminen, Markku S. ;

Mebazaa, Alexandre .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2009, 53 (25) :2343-2348

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