Levosimendan: Beyond its simple inotropic effect in heart failure

Athens University Medical School, 1st Cardiology Department, Hippokration Hospital, Vasilissis Sofias 114, 115 28, Athens, Greece.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 06/2007; 114(2):184-97. DOI: 10.1016/j.pharmthera.2007.01.008
Source: PubMed


Classic inotropic agents provide short-term haemodynamic improvement in patients with heart failure, but their use has been associated with poor prognosis. A new category of inotropic agents, the Ca(2+) sensitizers, may provide an alternative longer lasting solution. Levosimendan is a relatively new Ca(2+) sensitizer which offers haemodynamic and symptomatic improvement by combining a positive inotropic action via Ca(2+) sensitization and a vasodilatory effect via adenosine triphosphate(ATP)-sensitive K(+) (K(ATP)), Ca(2+)-activated K(+) (K(Ca)(2+)) and voltage-dependent K(+) (K(V)) channels activation. Levosimendan also seems to induce a prolonged haemodynamic improvement in patients with heart failure as a result of the long half-life of its active metabolite, OR-1896. Furthermore, there is also evidence that levosimendan may have additional antiinflammatory and antiapoptotic properties, affecting important pathways in the pathophysiology of heart failure. Despite the initial reports for a clear benefit of levosimendan on short- and long-term mortality in patients with severe heart failure, the results from the recent clinical trials are rather disappointing, and it is still unclear whether it is superior to dobutamine in affecting survival of patients with severe heart failure. In conclusion, levosimendan is a promising agent for the treatment of decompensated heart failure. As further to its positive inotropic effect, it affects multiple pathways with key roles in the pathophysiology of heart failure. The results of the ongoing trials examining the effect of levosimendan on mortality in patients with heart failure will hopefully resolve the controversy as to whether levosimendan is superior to classic inotropic agents for the treatment of severe heart failure.

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Available from: Charalambos Antoniades, May 19, 2014
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    • "In this connection, the pharmacological/toxic action of drugs may not be due to the drug itself, but to its active metabolite(s) in the body. For instance, the half-life of intravenously administered levosimendan, an inotropic drug, is very short (∼1.5 h), but it can cause a prolonged hemodynamic improvement in patients with heart failure because of its long half-life active metabolite, OR-1896 [88] [89]. In addition, genotoxic metabolites of estradiol can bind onto DNA and cause depurination, thereby developing breast cancer in women [90]. "
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    • "Therefore, a possible correlation should be clarified in future larger studies. Third, owing to the lack of investigation of specific variables, we cannot conclude whether anti-ischemic and anti-inflammatory effects, as well as effects at the cellular level [13], have contributed to the improved microcirculatory blood flow with levosimendan. In addition, we investigated the changes in microvascular perfusion of the sublingual mucosa which might not be representative of alterations in other tissues [1]. "
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    ABSTRACT: The purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of ≥ 20% in the microvascular flow index of small vessels (MFIs) among groups. The study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 μg·kg(-1)·min(-1) (n = 20) or an active comparator (dobutamine 5 μg·kg(-1)·min(-1); control; n = 20) for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test. Microcirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group (24 hrs: MFIm 3.0 (3.0; 3.0) vs. 2.9 (2.8; 3.0); P = .02; MFIs 2.9 (2.9; 3.0) vs. 2.7 (2.3; 2.8); P < .001). The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group (dMFIm 10 (3; 23)% vs. 0 (-1; 9)%; P = .007; dMFIs 47 (26; 83)% vs. 10 (-3; 27); P < .001). In addition, the heterogeneity index decreased only in the levosimendan group (dHI -93 (-100; -84)% vs. 0 (-78; 57)%; P < .001). There was no statistically significant correlation between systemic and microcirculatory flow variables within each group (each P > .05). Compared to a standard dose of 5 μg·kg(-1)·min(-1) of dobutamine, levosimendan at 0.2 μg·kg(-1)·min(-1) improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels. NCT00800306.
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    • "However , their clinical value is limited by the narrow therapeutic index of these agents, associated toxicity including arrhythmias , and only modest efficacy in chronic therapy (Lehmann et al., 2003). In contrast, levosimendan and other calciumsensitizing agents are able to enhance the contractile status of the heart (mechanism recently reviewed in Antoniades et al., 2007) without concomitant elevations in calcium, and thus, they represent a potentially valuable alternative to ABBREVIATIONS: PDE3, phosphodiesterase 3; K ATP , ATP-sensitive potassium channel; BK Ca , large conductance Ca 2ϩ -activated K ϩ channels; 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-dihydropy- ridazin-3(2H)-one; MAP, mean arterial pressure; HR, heart rate; PCO, peripheral cardiac output; ANOVA, analysis of variance. "
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    ABSTRACT: Levosimendan enhances cardiac contractility primarily via Ca(2+) sensitization, and it induces vasodilation through the activation of ATP-sensitive potassium channels and large conductance Ca(2+)-activated K(+) channels. However, the concentration-dependent hemodynamic effects of levosimendan and its metabolites (R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide (OR-1896) and (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (OR-1855) have not been well defined. Thus, levosimendan (0.03, 0.10, 0.30, and 1.0 mumol/kg/30 min; n = 6) was infused as four escalating 30-min i.v. doses targeting therapeutic to supratherapeutic concentrations of levosimendan (C(max), approximately 62.6 ng/ml); metabolites were infused at one-half log-unit lower doses and responses compared to dobutamine (beta(1)-agonist) and milrinone (phosphodiesterase 3 inhibitor). Peak concentrations of levosimendan, OR-1896, and OR-1855 at the end of the high dose were 323 +/- 14, 83 +/- 2, and 6 +/- 2 ng/ml, respectively (OR-1855 rapidly metabolized to OR-1896; peak = 82 +/- 3 ng/ml). Levosimendan and OR-1896 produced dose-dependent reductions in blood pressure and peripheral resistance with a rank potency, based on ED(15) values, of OR-1896 (0.03 mumol/kg) > OR-1855 > levosimendan > milrinone (0.24 mumol/kg); an ED(15) for dobutamine could not be defined. Only dobutamine produced increases in pulse pressure (30 +/- 5%) and rate-pressure product (34 +/- 4%). All of the compounds, with the exception of OR-1855, elicited dose-dependent increases in dP/dt with a rank potency, based on ED(50) values, of dobutamine (0.03 mumol/kg) > levosimendan > OR-1896 > milrinone (0.09 mumol/kg), although only levosimendan produced sustained increases in cardiac output (9 +/- 4%). Thus, levosimendan and OR-1896 are hemodynamically active at sub- to supratherapeutic concentrations (whereas the effects of OR-1855 in the rat are thought to be predominantly mediated by conversion to OR-1896) and produce direct inotropic effects and also direct relaxation of the peripheral vasculature, which clearly differentiates them from dobutamine, which does not elicit K(+) channel activation, suggesting a more balanced effect on the cardiac-contractile state and K(+) channel-mediated changes in vascular resistance.
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