Numerous adverse effects and an increased mortality are the reasons why many clinicians are often unsuccessful with the inotropic agents presently in use. New therapeutic agents have been developed in the last few years to assist the clinician in the stabilization, support and treatment of cardiovascular disease.One of the newest groups of inotropic agents is a group of agents, which increase the affinity of myofibrils for calcium and are called calcium sensitizers. Calcium sensitizers are the newest heterogeneous group of inotropic agents. The best known representatives of this group are levosimendan and pimobendan. Positive inotropic effects of levosimendan are achieved by its binding to troponin C and calcium, thereby stabilizing the tropomyosin molecule and prolonging the duration of actinmyosin overlap without a change in the net concentration of intracellular calcium. The vasodilatory effect of levosimendan is reached through activation of ATP-dependent potassium channels. This leads to a decrease in both afterload and preload, increased coronary blood flow and a resultant anti-ischemic effect. Levosimendan is therefore categorized as an antiischemic inotropic agent. Furthermore, experiments have confirmed that levosimendan as an opener of KATP - channels in the mitochondria and the sarcolemma of myocites may have an effect on the myocardium preconditioning

INO HUSEDZINOVIC

RUDI MILANOVIC

SANJA HUSEDZINOVIC

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 13www.signavitae.comLevosimendan in acute heart failureABSTRACTNumerous adverse effects and an increased mortality are the reasons why many clinicians are often unsuccessful with the inotropic agents presently in use.  New therapeutic agents have been developed in the last few years to assist the clinician in the stabilization, support and treatment of cardiovascular disease.One of the newest groups of inotropic agents is a group of agents, which increase the affinity of myofibrils for calcium and are called calcium sensitizers. Calcium sensitizers are the newest heterogeneous group of inotropic agents. The best known representatives of this group are levosimendan and pimobendan. Positive inotropic effects of levosimendan are achieved by its binding to troponin C and calcium, thereby stabilizing the tropomyosin molecule and prolonging the duration of actin-myosin overlap without a change in the net concentration of intracellular calcium. The vasodilatory effect of levosimendan is reached through activation of ATP-dependent potassium channels. This leads to a decrease in both afterload and preload, increased coronary blood flow and a resultant anti-ischemic effect. Levosimendan is therefore categorized as an anti-ischemic inotropic agent. Furthermore, experiments have confirmed that levosimendan as an opener of KATP – channels in the mitochondria and the sarcolemma of myocites may have an effect on the myocardium preconditioning.INO HUSEDZINOVIC  (  )•SANJA HUSEDZINOVICDepartment for anesthesiology, resuscitation  and intensive care medicineUniversity Hospital Dubrava ZagrebGojko Susak Avenue No 610000 Zagreb, CroatiaPhone: 01 290 2433Fax: 01 290 3440E-mail: inoh@kbd.hrRUDI MILANOVICDepartment of Surgery, University Hospital Dubrava ZagrebINO HUSEDZINOVIC • RUDI MILANOVIC • SANJA HUSEDZINOVICREVIEW   SIGNA VITAE 2009; 3 Suppl 1: S 13 - 16Key words: levosimendan, inotropic state, preconditioning, low cardiac output syndromeIn 1908, Sir James McKenzie first described “low cardiac output syn-drome”. Clinically, this syndrome results in global hypoperfusion, whose treatment requires inotropic support by vasoactive medications, or mechanical intervention to support and improve cardiac work. In the early 1900s′ the mainstay of cardiac treatment was digi-talis with the addition of a salt reduced diet. Accumulated fluids within pleural and peritoneal spaces were eliminated by mechanical means or by drainage. The use of diuretics was instituted dur-ing the 1920’s. The treatment of con-gestive heart failure entered a second phase in the 1950’s, when vasodilators were introduced into the physicians’ therapeutic armamentarium. With the introduction of the inotropic agents in 1980s’, a third great period in the thera-py of heart failure had begun.The catecholamine inotropic agents were among the earliest vasoactive agents and remain important and useful today although there can be some neg-ative consequences of their use (table 1). A major side effect is an increase in myocardial oxygen consumption. (1)A lack of tachyphylaxis and tachycardia, and being independent of β-adrenergic receptors conditions, gives a clinical advantage to phosphodiesterase III ADVERSE EFFECTS OF CATECHOLAMINES ADMINISTRATION• increase of oxygen consumption • arrhythmogenic effect• tachyphylaxis• increased risk of sudden cardiac death• difficulty during β-blockers administration• dependency about functional condition of β-adrenergic receptorsTable 1. Adverse effects of catecholamines administration.14 www.signavitae.cominhibitors, when comparing them with the catecholamines.Despite having a different mechanism of action, phosphodiesterase III inhibi-tors, just like catecholamine inotropic agents, increase the intracellular level of calcium, thereby possibly damaging the myofibrils and causing significant rhythm disorders.Numerous adverse effects and an increased mortality are the reasons why many clinicians are often unsuccess-ful with the inotropic agents presently in use.  New therapeutic agents have been developed in the last few years to assist the clinician in the stabilization, support and treatment of cardiovascu-lar disease.One of the newest groups of inotropic agents is a group of agents, which increase the affinity of myofibrils for calcium and are called calcium sensi-tizers. Calcium sensitizers are the new-est heterogeneous group of inotropic agents. The best known representa-tives of this group are levosimendan and pimobendan. Levosimendan is manufactured by the Finnish phar-maceutical company Orion and was first registered in 2000 in Sweden. The European Association of Cardiologists incorporated it into the 2005 guidelines for the treatment of acute heart failure. (2) Calcium sensitizers are divided into three groups (table 2) depending on their mode of interaction with the mus-cle fiber.Positive inotropic effects of levosi-mendan are achieved by its binding to troponin C and calcium, thereby sta-bilizing the tropomyosin molecule and prolonging the duration of actin-myosin overlap without a change in the net concentration of intracellular calcium. The vasodilatory effect of levosimendan is reached through activation of ATP-dependent potassium channels. This leads to a decrease in both afterload and preload, increased coronary blood flow and a resultant anti-ischemic effect. Levosimendan is therefore cat-egorized as an anti-ischemic inotropic agent. (3) Additionally, the incidence CALCIUM SENSITIZERSName   Chemical structure  Classification  DescriptionEMD57033       tiadiazinone                         group III        used in veterinary                                                                                                            medicineORG 30029        carboximidamide              group III?        laboratory                                                                                                              InvestigationCGP 48506         benzodiazocine          direct contact          lab. investigation                                                                             with actin (group II)                                                                      or myosine??MCI-154          piridazinone                      group I                    clinical investigation                                                                                                            in JapanPimobendan    piridazinone                       group I                    clinical useLevosimendan      piridazinone                      group II                    clinical useTable 2. Calcium sensitizers.Figure 1. Mechanisms of action of calcium sensitizers.CALCIUM SENSITIZERSGroup III Group IGroup II 15www.signavitae.comof arrhythmias is extremely low, there is no development of tolerance to its pharmacological effects, and the simul-taneous administration of β-blockers and calcium channels blockers do not produce serious adverse effects. Clinical studies conducted on patients with acute and chronic heart failure treated with β-adrenergic agonists and phosphodiesterase III inhibitors have given evidence to the limits of their use. This is why numerous randomized clinical trials investigating the promising effects of levosimendan are being con-ducted. According to available data, of all the vasoactive medicaments the only vasoactive agent which improves the clinical recovery of patients with acute heart failure is levosimendan. (4)Apart from having an acute effect, levosimendan achieves a prolonged hemodynamic effect due to its two metabolites OR-1855 and OR-1896. These two metabolites reach an opti-mal plasma concentration two days after being administered and they can be effective for 7-9 days after being administered via a 24 hour infusion of levosimendan.The “Dose-ranging” study was the first double-blind and placebo controlled study analyzing the effects of different doses of levosimendan and comparing them with dobutamine and placebo. After being administered for 24 hours all doses of levosimendan statistical-ly had a significant decrease of the PCWP in comparison to dobutamine and placebo. The infusion of different doses of levosimendan 0.4 and 0.6 μg/kg/min caused a statistically sig-nificant increase of the cardiac minute volume. (5)The “Dose-escalation” study was con-ducted on 146 patients with acute heart failure and left ventricle systolic dys-function. Levosimendan was adminis-tered as a bolus dose of 6μg/kg and subsequently as a continuous infusion up to a maximum dose of 0.4 μg/kg/min. Levosimendan had increased the stroke volume output and decreased the PCWP in comparison to placebo. With a favorable hemodynamic effect after a 6 hour administration levosimendan of oxygen in the myocardium remained unchanged. (9)In a randomized placebo controlled and fourfold-blind study, the first one ever, conducted on patients who underwent OPCABG surgery, with normal left ven-tricle function, the authors have given evidence of new therapy options of levosimendan. Namely, the administra-tion of levosimendan at 12μg/kg/min through 10 minutes in comparison to 24μg/kg/min and placebo showed a more favorable effect on the systolic function of the heart. In conclusion the authors recommend levosimendan as a new therapy option for the investi-gated group of patients. (10)In another double-blind randomized and placebo controlled study the dose of levosimendan of 12μg/kg through 10 minutes in comparison with placebo administered to patients undergoing OPCABG surgery also had a favorable hemodynamic effect on the systolic function of the left heart. (11)Somewhat later it was also proven that there was a prolonged favorable hemodynamic effect of levosimendan using two independent methods – thermodilution and transesophageal ultrasound. (12).Most of our cells possess endogenous showed a good clinical effect signifi-cantly decreasing dyspnea and fatigue in acutely decompensate patients. (6)In two large randomized studies, RUS-SLAN and LIDO, it was documented that positive hemodynamic effects and a lower mortality was seen in patients who received levosimendan in com-parison to patients who received dob-utamine or placebo. (7,8) Also, there is much interest in levosimendan admin-istration in patients with open-heart sur-gery, especially in those with off-pump procedure. Levosimendan was investigated in numerous prospective clinical studies involving patients undergoing cardiac surgery. In the first randomized and double-blind study Lileberg et al. inves-tigated the coronary hemodynamics and oxygen consumption in the myo-cardium after the administration of lev-osimendan. Patients were divided into two groups with respect to the dose of levosimendan of 8μg/kg/min or 24μg/kg/min and placebo. After both doses of levosimendan, there was a significant rise in the cardiac minute output and a decrease in systemic and pulmonary vascular resistance. The flow through the coronary sinus increased from 28 to 42 ml meanwhile the consumption Figure 2. Preconditioning mechanisms - opening of KATP – channels in the sarcolemma and the mitochondria.16 www.signavitae.comprotective mechanisms which if acti-vated prior to ischemia protect the cell from the damage induced by ischemia. This protective mechanism is called preconditioning and the stimuli along with short-term ischemia can be some drugs. Murry et al. first described ischemic preconditioning in 1986. Warltier, two years later describes pre-conditioning via inhalational anesthet-ics. Preconditioning mechanisms are attained through the opening of KATP – channels in the sarcolemma or the mitochondria (figure 2). (13)Experiments have confirmed the role of levosimendan as an opener of KATP – channels in the mitochondria and the sarcolemma of myocites. Tritapepe et al. (14) administered an infusion of 24μg/kg of levosimendan through 10 minutes directly prior to the applica-tion of a cardiopulmonary bypass. By monitoring the perioperative hemody-namic parameters and the concen-tration of cardiac troponin I through a period of 48 hours they have proven a lower postoperative concentration of troponin I (P<0.05) and a higher car-diac index (P<0.05) in comparison to the control group. The group of patients that received a short infusion of levosi-mendan directly prior to CABG had shown signs of less damage to the myocardium which is indicative of the effects of preconditioning.This result is of great clinical significance because a short-term administration of levosimendan directly prior to ischemia could decrease the intraoperative dam-age of the myocardium.    CONCLUSIONHistorically, the catecholamines ino-tropic agents were first line medications used in the treatment of cardiovascular compromise, but their benefits were often overshadowed by major compli-cations, such as increased mortality. The introduction of many newer agents in newer classes, such as those which produce their effects do not change the intracellular calcium values represent safer, better choices for treatment. Fur-thermore, through the preconditioning mechanisms, levosimendan may have an effect on the process of periopera-tive protection of the myocardium.REFERENCES1. Priebe HJ. Vasoactive drugs (IARS Review Course Lectures). Anesth Analg 2004;64:79-83.2. Nieminen MS, Bohn M, Cowie MR, Drexler H, Filippatos GS, Jondeau G, et al, editors. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure. Eur Heart J 2005;26:284-416.3. Lehonen LA. Levosimendan: a parenteral calcium-sensitizing drug with additional vasodilatatory properties. Expert Opin Investing Drugs 2001;10:955-70.4. Mebaza A, Erhardt L. Levosimendan: a new dual – action drug in the treatment of acute heart failure. Int J Clin Pract 2003;57:410-6.5. Niemenn MS, Akkila J. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 2000;36:1903-12. 6. Slawsky MT, Colucci WS. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation 2000;102:2222-7.7. Moiseyev VS, Poder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik LB, et al, editors. 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 2002;23:1422-32.8. Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, et al, editors. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002;360:196-202.9. Lilleberg J, Nieminen MS. Effects of a new calcium sensitizer, levosimendan, on hemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 1998;19:660-8.10. Barisin S, Husedzinovic I, Sonicki Z, Bradic N, Barisin A, Tonkovic D. Levosimendan in Off–Pump Coronary Artery Bypass; A Four – times Masked Controlled Study. J Cardivasc Pharmaco 2004;44:703-8.11. Husedžinović I, Barišin S, Bradić N, Barišin A, Sonicki Z, Milanović R.  Levosimendan as a new strategy during off – pump coronary artery bypass grafting: Double – blind randomized placebo – controlled trial. Croat Med J 2005;46(6):950-6.12. Husedzinovic I, Bradic N, Barisin S. Levosimendan-hemodynamic support during off-pump coronary artery bypass graft surgery. Intensive Care Med 2005;31(suppl 1)S97.13. Murry CE, Jennings RB. Preconditioning with ischemia: a delay of lethal cell injury in ischaemic myocardium. Circulation 1986;74:1124-36.14. Tritapepe L, De Santis V. Preconditioning effects of levosimendan in coronary artery bypass grafting-a pilot study. BJA 2007;96:694-700.

Levosimendan in acute heart failure

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