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PubMed2007

[Role of Levosimendan in intensive care treatment of myocardial insufficiency].

Levosimendan is a calcium sensitizer that is currently in the focus of intensive care medicine because it may be superior to standard inotropic agents in the treatment of acute myocardial insufficiency. The effects of levosimendan mainly depend on three predominant mechanisms: 1) positive inotropic effect by increasing the sensitivity of cardiac myofilaments to calcium ions, 2) vasodilatory effect by stimulation of adenosine triphosphate-sensitive potassium channels and 3) inhibition of phosphodiesterase-III. In a large number of experimental and clinical studies further possible indications for levosimendan have been described, e.g. cardioprotection during ischemia, cardiogenic shock, septic myocardial insufficiency and pulmonary hypertension. This review article critically summarizes the current scientific and clinical knowledge about levosimendan, its pharmacologic characteristics, mechanisms of action as well as indications and potential risks.

Calcium↗
PubMed2003

The calcium sensitizer levosimendan attenuates endotoxin-evoked myocardial dysfunction in isolated guinea pig hearts.

OBJECTIVE: Sepsis-evoked myocardial dysfunction is possibly due to decreased myofilament calcium sensitivity, and a calcium sensitizer may thus specifically improve contractility in sepsis by enhancing myofilament calcium sensitivity. We examined whether the calcium sensitizer levosimendan mitigates myocardial dysfunction and improves contractility in hearts isolated from endotoxin-treated guinea pigs. DESIGN AND SETTING: Prospective, controlled, randomized animal study in a university research laboratory. SUBJECTS: Guinea pig hearts isolated 4 h (n=10) or 18 h (n=8) following E. coli LPS (4 mg/kg i.p.) and hearts from sham-treated controls (n=11 and n=6). INTERVENTIONS: Isolated hearts were perfused at constant aortic pressure [Krebs-Henseleit buffer, heart rate: 300/min, left ventricular (LV) diastolic pressure: 6-8 mmHg], and LV developed pressure (LVd P) and LVd P/d t were continuously assessed. Levosimendan was added to the perfusate in incremental concentrations (0.03, 0.1, 0.3 microM). MEASUREMENTS AND RESULTS: Endotoxin resulted in a significant decrease in LVd P by 20+/-6% and 43+/-8%, in +LVd P/d t by 16+/-5% and 44+/-7%, and in -LVd P/d t by 27+/-8% and 47+/-8% after 4 and 18 h, respectively. In septic hearts levosimendan increased LV function concentration-dependently by 32+/-4% (LVd P), 33+/-5% (+LVd P/d t), and 37+/-7% (-LVd P/d t) 4 h and by 31+/-6% (LVd P), 33+/-6% (+LVd P/d t), and 32+/-7% (-LVd P/d t) 18 h after LPS. However, levosimendan increased myocardial function similarly in control hearts. CONCLUSIONS: While the calcium sensitizer levosimendan markedly improved LV contractility in hearts from both endotoxic and sham animals, it failed to specifically abolish endotoxin-evoked myocardial dysfunction. Thus, decreased calcium sensitivity either does not play a major role in endotoxin-evoked cardiomyopathy or the location of its pathomechanism differs from levosimendan's site of action.

Animals↗
PubMed2005

Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression.

OBJECTIVE: Calcium desensitization plays an important part in the pathophysiology of septic myocardial depression. We postulated that levosimendan, a new calcium sensitizer, would be beneficial in sepsis-induced cardiac dysfunction. DESIGN AND SETTING: Prospective, randomized, controlled study in two university hospital intensive care units. PATIENTS AND PARTICIPANTS: Twenty-eight patients with persisting left ventricular dysfunction related to septic shock after 48 h of conventional treatment including dobutamine (5 microg/kg per minute). INTERVENTIONS: After 48 h of conventional treatment patients were randomized to receive a 24-h infusion of either levosimendan (0.2 microg/kg per minute, n=15) or dobutamine (5 microg/kg per minute, n=13). MEASUREMENTS AND RESULTS: Data from right heart catheterization, echocardiography, gastric tonometry, laser-Doppler flowmetry, and lactate concentrations and creatinine clearance were obtained before and after the 24-h drug infusion. Dobutamine did not change systemic or regional hemodynamic variables. By contrast, at the same mean arterial pressure levosimendan decreased pulmonary artery occlusion pressure and increased cardiac index. Levosimendan decreased left ventricular end-diastolic volume and increased left ventricular ejection fraction. Levosimendan increased gastric mucosal flow, creatinine clearance, and urinary output while it decreased lactate concentrations. CONCLUSIONS: These findings show that levosimendan improves systemic hemodynamics and regional perfusion in patients with septic cardiac dysfunction under conditions where administration of 5 microg/kg dobutamine per minute is no longer efficacious. Accordingly, our results suggest that levosimendan can be an alternative to the strategy of increasing the dose of dobutamine under such conditions.

Cardiac Output, Low↗
PubMed2002

Effects of OR-1896, a metabolite of levosimendan, on force of contraction and Ca2+ transients under acidotic condition in aequorin-loaded canine ventricular myocardium.

We performed experiments in canine ventricular trabeculae loaded with aequorin to elucidate the influence of acidosis on the positive inotropic effect (PIE) of OR-1896 (R)- N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-acetamide, an active metabolite of levosimendan. The concentration-response curve (CRC) for OR-1896 was biphasic in acidotic conditions (pH(o) 6.6) that was essentially the same as that in control conditions (pH(o) 7.4). The CRC for PIE of OR-1896 reached a plateau at 10(-6) M (first phase) and it became steeper again at 10(-3) M (second phase). Under acidotic conditions the efficacy of the first phase was 10% of the maximal response to isoproterenol (ISO(max)) and the PIE was associated with an increase in Ca(2+) transients of 2% of ISO(max) (P<0.05). The sensitivity of myofilaments to Ca(2+) ions was increased by OR-1896 in acidotic conditions, whereas the relationship of Ca(2+) transients and contractile force during an increase in elevation of the extracellular Ca(2+) concentration and during application of dihydroouabain was shifted prominently to the right in acidotic conditions. In conclusion, OR-1896 elicited a PIE due to an increase in the sensitivity of myofilaments to Ca(2+) ions even in acidotic conditions. The PIE of OR-1896 in acidotic conditions was much less than that in control conditions because the effect of the compound to induce an increase in intracellular Ca(2+) mobilization was markedly attenuated in acidotic conditions.

Acetamides↗
PubMed2002

The contractility enhancing effect of the calcium sensitiser levosimendan is not attenuated by carvedilol in healthy subjects.

OBJECTIVE: It was assessed whether the contractility enhancing effect of the calcium sensitiser levosimendan is altered by carvedilol. METHODS: Twelve healthy subjects received 2 mg levosimendan i.v. both alone and in addition to a 7-9-day treatment with 25 mg carvedilol orally, twice daily, in a cross-over, placebo-controlled, double-blind, randomised study. Systolic time intervals, heart rate, and blood pressure were measured at baseline and up to 2 h after drug administration. RESULTS: When levosimendan was administered in addition to carvedilol, the shortening of electromechanical systole QS2i (indicating increased contractility) was similar to that found with levosimendan alone ( P=0.475). Also, the maximum heart rate change was similar, although a statistically significant difference in heart rate was detected due to minor differences at two time points during the 2-h follow-up ( P=0.018). There were no differences in diastolic blood pressure response ( P=0.962), but the systolic blood pressure response was attenuated by about 4 mmHg with the combination ( P=0.013). CONCLUSIONS: The contractility enhancing effect of levosimendan was not altered in healthy subjects who had received carvedilol for at least 1 week. Heart rate and diastolic blood pressure responses were not altered either, while the systolic blood pressure response was blunted.

Administration, Oral↗
PubMed2000

Pharmacokinetic and pharmacodynamic interactions between the novel calcium sensitiser levosimendan and warfarin.

OBJECTIVE: To study the effects of possible interactions between levosimendan and warfarin on pharmacokinetics and pharmacodynamics. Furthermore, the effects of levosimendan on blood coagulation were investigated. METHODS: Open, randomised cross-over design with two treatment phases was used. During one phase, levosimendan (0.5 mg four times daily) was given orally to ten healthy subjects for 9 days. On the fourth treatment day with levosimendan, a single oral dose of warfarin (25 mg) was given. Pharmacokinetic parameters of levosimendan from the third and fourth treatment days were compared with each other. During the other treatment phase the subjects received only a single dose of warfarin. Pharmacokinetic parameters of warfarin alone were compared with those determined after concomitant administration of levosimendan. Changes in blood coagulation parameters were evaluated after levosimendan and warfarin alone and after concomitant administration. RESULTS: Warfarin did not change the pharmacokinetics of levosimendan. The distribution volume of warfarin was higher and elimination half-life shorter after concomitant levosimendan administration than after warfarin alone. However, concomitant levosimendan administration did not potentiate the effects of warfarin on blood coagulation assessed using activated partial thromboplastin time (APTT) and thromboplastin time (TT-SPA). Levosimendan alone for 3 days did not change APTT or TT-SPA values. There were no changes in the protein binding of levosimendan or warfarin upon concomitant administration. Continuous treatment with oral levosimendan caused headache, which was probably due to cerebral vasodilation. CONCLUSIONS: Concomitant levosimendan administration did not potentiate the effect of warfarin on blood coagulation after a single dose. Levosimendan itself had no effects on blood coagulation.

Adult↗
PubMedDate not supplied

Haemodynamic interactions between the novel calcium sensitiser levosimendan and isosorbide-5-mononitrate in healthy subjects.

OBJECTIVE: The new calcium sensitiser levosimendan also possesses vasodilatory effects due to potassium-channel opening. The aim of the present study was to assess the possible haemodynamic interactions between levosimendan and isosorbide-5-mononitrate in young healthy men. METHODS: The study was crossover, placebo controlled, double blind, randomised, and it comprised of four study days with one medication--levosimendan, isosorbide-5-mononitrate, levosimendan plus isosorbide-5-mononitrate or placebo--given on each. Levosimendan was administered i.v. as an initial bolus dose of 12 microg/kg over 10 min, followed by a continuous infusion of 0.2 microg/kg/min for a total time of 2 h. Isosorbide-5-mononitrate (20 mg) was given orally as a single dose. Leg blood flow and venous capacity (venous occlusion plethysmography), cardiac output (impedance cardiography), skin blood flow (laser-Doppler flowmetry), blood pressure and heart rate were recorded at baseline, and 20 min, 1 h, 2 h, 4 h and 6 h after the start of the infusion. An orthostatic test was performed at baseline and at 2 h 15 min. Twelve healthy, male subjects were included. Their mean age was 24 years (range 20-34 years). RESULTS: Levosimendan increased leg blood flow by 32%, and no additive effect of the combination of levosimendan and isosorbide-5-mononitrate was observed. The effects of levosimendan on heart rate and blood pressure were minimal and in close conformity with previous studies. In general, there were no additive effects of the combination compared with each drug alone at rest. The only additive effect was seen in the orthostatic response. Heart rate increased by 40 beats min(-1) with the combination (95% confidence interval compared with placebo 11-24 beats min(-1)), by 30 beats min(-1) with levosimendan (2-15 beats min(-1)), by 28 beats min(-1) with isosorbide-5-mononitrate (1-15 beats min(-1)), and by 22 beats min(-1) with placebo. Furthermore, three subjects were unable to stand upright for the stipulated time with the combination, and the orthostatic test had to be discontinued prematurely. There were no changes in the conduction intervals in the electrocardiogram on any of the treatments. The combination had no influence on the occurrence of headache compared with isosorbide-5-mononitrate alone. CONCLUSION: No major additive haemodynamic effects of the combination of levosimendan and isosorbide-5-mononitrate compared with each drug alone could be observed at rest. However, during an orthostatic test, the circulatory response was significantly potentiated with the combination, and three of the subjects were unable to stand upright for the stipulated time.

Adult↗
PubMed2004

[Levosimendan-long-term inodilation in an infant with myocardial infarction].

An infant with myocardial infarction due to congenital stenosis of the left coronary artery with consecutive left ventricular dysfunction and mitral regurgitation developed refractory pulmonary hypertension (PHT) and recurrent PHT crises. Catecholamines to support cardiac function, or pulmonary vasodilators like inhaled nitric oxide showed no effect. Treatment with Levosimendan (Simdax), a new inodilator, combining both inotropic and pulmonary vasodilating effects, improved left ventricular dysfunction, increased cardiac index, decreased pulmonary vascular resistance and reduced frequency and extent of the PHT crises. This case may suggest the use of Levosimendan as a long-term inotropic agent and pulmonary vasodilator in children with depressed cardiac function.

Cardiac Output, Low↗
PubMed1999

The effects of levosimendan on the left ventricular function and protein phosphorylation in post-ischemic guinea pig hearts.

The widely accepted theories for the decreased function in the stunned myocardium relate to Ca2+ desensitization and free radical-mediated tissue damage of the myofilaments. The aim of the present study was to examine whether the depressed contractile function and Ca2+ responsiveness of the stunned myocardium may be restored by a new Ca2+ sensitizer (levosimendan), which has been shown to improve the Ca2+ response of the myofilaments. The effects of levosimendan on the left ventricular function and the in vivo protein phosphorylation were examined in both the non-ischemic and the stunned myocardium. Myocardial stunning was induced in Langendorff-perfused guinea pig hearts by suspending the circulation for 8 min, followed by a 20-min reperfusion period. Perfusion of post-ischemic guinea pig hearts with levosimendan (0.03-0.48 microM, 6 min) was associated with dose- and time-dependent increases in both dP/dtmax (contractility) and dP/dtmin (speed of relaxation). When the effectiveness of levosimendan was compared in non-ischemic and post-ischemic hearts, no significant differences were noted in the relative stimulatory effects on contractility and relaxation, at any given time point (time-response curve) or concentration (dose-response curve). Perfusion of the guinea pig hearts with a high (0.3 microM) levosimendan concentration did not reveal any qualitative or quantitative difference in the phosphodiesterase inhibitory potential of the compound (elevation of tissue cyclic AMP levels and characteristics of protein phosphorylation) between the non-ischemic and the post-ischemic myocardium. However, when isoproterenol was administered to induce maximal in vivo phosphorylation of cardiac phosphoproteins, an attenuation of the 32P-incorporation into troponin I was noted in the post-ischemic hearts. The decrease in isoproterenol-induced 32P-incorporation into troponin I was associated with similar alterations in the tissue level of this protein. We conclude that the Ca2+ sensitizer levosimendan exerts dose- and time-dependent positive inotropic and lusitropic effects on the post-ischemic myocardium, lending support to the hypothesis tha Ca2+ desensitization of the myofibrils is involved in myocardial stunning.

Animals↗
PubMed2006

Successful administration of levosimendan in a patient with low-gradient low-output aortic stenosis.

Aortic valve replacement in patients suffering from low-gradient aortic stenosis and congestive heart failure is associated with high operative mortality, and the perioperative use of inotropes is common. Levosimendan is a calcium sensitizer with positive inotropic and vasodilatory effects and has been developed for treatment of decompensated heart failure. Although its use in patients with low-gradient aortic stenosis is not established, we hypothesized that it might have beneficial effects on outcome after aortic valve replacement. We report on a high-risk operation in a 73-year-old man with low-gradient aortic stenosis, congestive heart failure and coronary artery disease. Levosimendan was administered perioperatively (0.1 mg/kg/min 16 hours prior to the operation without a loading dose) and allowed rapid recovery of the patient, who required only brief treatment in the intensive care unit. No levosimendan-specific adverse events were observed, in particular no hypotension. The excellent postoperative result was maintained after the patient was discharged from hospital.

Aged↗
PubMed2005

The myofilament force-calcium relationship as a target for positive inotropic therapy in congestive heart failure.

To-date positive inotropic therapy in the treatment of congestive heart failure has resulted in adverse effects on long term survival. These agents increase calcium cycling through beta-adrenergic stimulation or phosphodiesterase inhibition. An alternative method of producing positive inotropy is to increase the myofilament sensitivity to calcium. This can occur at several levels within the myofilament, and has potential benefits with respect to avoiding increased calcium cycling and producing a more favourable energy efficient positive inotropy. A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction. We have learnt a considerable amount about the function of specific sites within the myofilament by the use of genetically engineered mouse models, which have shown diverse effects of various myofilament sites on global left ventricular function. Levosimendan is a novel inotropic agent that has several mechanisms of action including calcium sensitization, and is undergoing clinical trials at present. This review article will provide a comprehensive molecular, biophysical and physiological insight into the concepts underlying the myofilament force-calcium relationship and its potential as a target for positive inotropic therapy in heart failure.

Actin Cytoskeleton↗
PubMed2005

Levosimendan use reduces matrix metalloproteinase-2 in patients with decompensated heart failure.

BACKGROUND: Extracellular matrix metabolism (ECM) has an important role in left ventricular (LV) remodeling in chronic heart failure (CHF). Matrix metalloproteinases (MMPs) are involved in the regulation of extracellular matrix (ECM) metabolism. We investigated the effect of levosimendan, a novel calcium sensitizer, on serum levels of MMP-2. METHODS: Our study population consisted of 60 consecutive patients with advanced heart failure who were admitted to hospital with an acute decompensation of their CHF. Patients were randomized to levosimendan (n = 30; 18 men, aged 65 +/- 3 years) or placebo (n = 30; 15 men, aged 67 +/- 4 years). Serum MMP-2 levels were assessed before and after treatment with levosimendan or placebo, using a commercially available ELISA. RESULTS: Serum levels of MMP-2 were reduced from 427 ng/ml 95%CI 372-484 to 371 ng/ml 95%CI 329-413 in the levosimendan treated group and from 433 ng/ml 95%CI 422-444 to 425 ng/ml 95%CI 414-436 in the placebo group. Repeated measurements ANOVA showed that treatment with levosimendan significantly affected levels of MMP-2 (p = 0.019). CONCLUSIONS: The present study showed that levosimendan may beneficially affect ECM remodeling in patients with acutely decompensated CHF. Whether these effects translate into added clinical benefits, as suggested by an improved ejection fraction in the levosimendan group, deserves further investigation.

Aged↗
PubMed2005

Ca2+-sensitisers--a promising option to treat heart failure?

Because the number of transplants is still fewer than the number of patients waiting for a donor organ, new concepts of therapy are needed that allow patients to bridge the time gap until heart transplantation or even to improve symptoms while on treatment. Ca(2+)-sensitisers are agents that directly influence myofilaments and/or the cross-bridge-cycle. Depending on the molecular mechanisms underlying their action, Ca(2+)-sensitisers have been divided into three classes. While, a number of Ca(2+)-sensitising drugs have been described, currently only the Ca(2+)-sensitisers pimobendan and levosimendan are in clinical use. This review provides a survey on the molecular mechanisms and the therapeutic effectiveness of Ca(2+)-sensitisers for the treatment of human heart failure.

Calcium↗
PubMed2006

Effects of levosimendan on myocardial infarct size and hemodynamics in a closed-chest porcine ischemia-reperfusion model.

INTRODUCTION: Levosimendan is a positive inotropic drug with vasodilator action and proposed myocardioprotective properties. In a canine model, levosimendan increased coronary collateral flow and reduced myocardial infarct size (IS). We investigated the effect of levosimendan on IS and hemodynamics in the closed-chest porcine ischemia-reperfusion model, which is devoid of coronary collaterals. METHODS: Infusion with levosimendan (0.2 microg/kg/min following a bolus of 24 microg/kg) or saline was initiated 30 min prior to ischemia in anaesthetized pigs (n = 10 in both groups). Balloon occlusion of the left anterior descending coronary artery for 45 min was followed by 2 1/2 h of reperfusion. Hemodynamics were monitored with a Swan-Ganz catheter and a left ventricular pressure micromanometer. Left ventricular systolic and diastolic function was estimated by dP/dt(max) and tau, respectively. Myocardial area at risk (AAR) and IS were assessed in vivo by myocardial perfusion imaging (MPI) and ex vivo by histopathology (fluorescein staining for AAR, tetrazolium staining for IS). RESULTS: Prior to ischemia, levosimendan improved left ventricular systolic and diastolic function with coincident preload and afterload reduction. Cardiac output increased by 10 +/- 4% (p = 0.04), dP/dt(max) by 15 +/- 5% (p = 0.01). Pulmonary capillary wedge pressure decreased by 18 +/- 3% (p = 0.04), tau by 11 +/- 2% (p = 0.001), and mean arterial pressure by 11 +/- 2% (p < 0.001). A similar trend was observed during ischemia-reperfusion. The ratio of IS/AAR was not reduced by levosimendan compared to saline as evaluated by histopathology (76 +/- 4% vs. 64 +/- 7%, p = 0.12) and by MPI (94 +/- 2% vs. 87 +/- 5%, p = 0.14). CONCLUSION: Levosimendan improves hemodynamics but does not reduce IS in an ischemia-reperfusion model without coronary collaterals.

Animals↗
PubMed2006

The role of potassium channels in relaxant effect of levosimendan in rat small mesenteric arteries.

We investigated both the effect of levosimendan and the role of various potassium channels in KCl-precontracted rat small mesenteric arteries. Levosimendan (10(-6)-10(-3) M) or cromakalim (CRO, 10(-7)-10(-4) M) produced concentration-dependent relaxation responses in small mesenteric arteries precontracted by 30 mM KCl. The relaxant responses to levosimendan in KCl-precontracted arteries did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation of rat small mesenteric arterial segments with ATP-dependent potassium channel (KATP) blocker glibenclamide (GLI, 10(-6) M) for 30 min significantly inhibited the relaxant responses to both levosimendan and CRO. Neither the Ca(2+)-activated potassium channel (KCa) blocker iberiotoxin (10(-7) M) nor the voltage-dependent potassium channel (KV) blocker 4-aminopyridine (5 mM) incubation for 30 min caused significant alterations in relaxant responses to levosimendan in KCl-precontracted small mesenteric arteries. These findings suggested that levosimendan-induced relaxation responses in isolated rat small mesenteric arteries were neither depended on endothelium nor inhibited by the blockers of KV or KCa but, they rather seem to depend on the activation of KATP.

Animals↗
PubMed2000

Levosimendan: A promising agent for the treatment of hospitalized patients with decompensated heart failure.

Levosimendan is a new inodilator, whose mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-dependent potassium channels. The combination of positive inotropy with anti-ischemic effects of K-channel opening offers many potential benefits in comparison to currently available intravenous inotropes, that are more or less contraindicated in patients with ongoing myocardial ischemia. Levosimendan has been extensively studied in various animal models of heart failure, in which the drug has increased contractility without adverse effects on diastolic function. These results have been repeated in patients with heart failure, by whom levosimendan dose-dependently increases cardiac output and reduces pulmonary capillary wedge pressure. On higher doses, the drug can induce tachycardia and hypotension. In clinical trials, drug-induced ventricular arrhythmia have been rare. Recently, trials in patients with decompensated heart failure have suggested that short-term intravenous treatment with levosimendan might improve the survival of these critical patients. These results highlight the importance of adequate treatment of the acute heart failure patients for their long-term outcome.

Animals↗