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Levosimendan, a new Ca2+-sensitizing inotropic agentYoung Lan Kwak, MD
Ca2+ sensitizers represent a new class of inotropic agents, which overcome the disadvantages associated with currently available inotropic agents in the following respects: (a) they are not associated with an increased risk of arrhythmias, cell injury and death due to Ca2+ overload in myocardial cells; (b) they do not increase the activation energy; and (c) they have the potential to reverse contractile dysfunction under pathophysiologic conditions, such as acidosis or myocardial stunning.SMALL>1 Levosimendan is a unique calcium sensitizer. Levosimendan appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This stabilizes the calcium-induced conformational change of troponin C, thereby (a) changing actin-myosin cross-bridge kinetics apparently without increasing the cycling rate of the cross-bridges or myocardial ATP consumption, (b) increasing the effects of calcium on cardiac myofilaments during systole and (c) improving contraction at low energy cost. Calcium concentration and, therefore, sensitization decline during diastole, allowing normal or improved diastolic relaxation. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels.2 By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic effect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca2+ sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent in experimental animals and humans.3 Levosimendan has been used as an injectable preparation for acute heart failure, but the effectiveness in chronic heart failure patients as an oral preparation has not yet been examined in clinical trials. Despite high oral bioavailability, its short half-life would be a disadvantage for an oral preparation and has delayed the development of an oral preparation. Levosimendan has predictable first-order pharmacokinetics.2 Elimination half-life of levosimendan is approximately 1 hour and it is completely metabolized. However, animal models have shown that it also has an acetylated metabolite, called OR-1896, that has a long half-life and is a potent calcium concentration-dependent calcium sensitizer, which may be responsible for most of the longer-term effects of levosimendan.4 There were two relatively large trials for the use of intravenous levosimendan. In the LIDO (Levosimendan Infusion versus Dobutamine in severe low output heart failure) trial, patients (n=203) with severe, low-output decompensated heart failure (HF) were randomized to levosimendan (an initial loading dose of 24 mg /kg followed by a 24-hour infusion of 0.1 to 0.2 mg/kg/min) or dobutamine (continuous infusion of 5 to 10 mg/kg/min for 24 hours). Patients treated with levosimendan were significantly more likely to achieve a 3 30 % increase in cardiac index and a 3 25 % decrease in PCWP (28 % of patients on levosimendan vs. 15 % of those on dobutamine, P = 0.022). At 30- and 180-day follow-up, the relative risk of worsening HF or death was significantly lower with levosimendan than with dobutamine (6-month mortality of 26 % in the levosimendan group vs. 38 % in the dobutamine group, P = 0.029).5 The RUSSLAN study (Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure After an Acute Myocardial Infarct) was performed in 504 patients with decompensated HF after acute myocardial infarction who received 1 of 4 different doses of levosimendan (0.1-0.4 mg/kg/min) or a placebo for 6 hours, respectively. During the first 24 hours and at 14 days, overall mortality was lower in patients treated with levosimendan than in placebo recipients and reduction of mortality was maintained at 180-day retrospective follow-up. However, a high frequency of ischaemia and hypotension (19%) was associated with the highest levosimendan infusion rate and lower levosimendan doses of 0.1-0.2 mg/kg/min were recommended in this study.6 Hemodynamic effects of levosimendan have been sustained as long as 7 days of continuous infusion without development of tolerance, but data are limited to a handful of subject beyond 48 hours.7 Generally, levosimendan was well tolerated, with most adverse events being secondary to its vasodilating properties and adverse events were dose related. Experiences with levosimendan for patients with ventricular dysfunction after cardiac surgery are limited. Levosimendan 8 or 24 µg/kg improved cardiac performance without increasing myocardial oxygen consumption or changing myocardial substrate utilization in 23 patients undergoing elective coronary artery bypass graft surgery.8 Although levosimendan has been reported to produce antiischemic, antistunning effects, recent animal studies using models of regional myocardial ischemia reported that levosimendan improved global hemodymanic parameters of myocardial function but also exerted disadvantageous effects such as induction of ventricular arrhythmias or local contractile impairment.9,10 Beneficial hemodynamic effects of levosimendan observed in patients with HF may not be generalized to regional contractile dysfunction related to acutely or chronically reduced myocardial blood flow.11 Further studies of levosimendan in the perioperative period are needed. References
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