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Background: Pulmonary hypertension (PH) is a long-term disease that impacts approximately 1% of the world's population. Currently, levosimendan (Lev) is proposed for PH treatment. However, the mechanism of Lev in the treatment of PH is unknown., Methods: We used hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) to establish a PH cell model. A number of cell biology methods were performed to assay alterations in cell proliferation, migration and apoptosis after Lev treatment. qRT-PCR and WB were performed to test the levels of circUSP34 and miR-1298, and BMP/Smad protein respectively. In addition, the regulatory relationship between circUSP34 or BMPR2 with miR-1298 was verified through the use of double luciferase as well as RIP assay. In addition, we explored the regulatory effect of Lev on the circUSP34/miR-1298/BMP/Smad axis using a rat PH model., Results: Our results demonstrate that Lev inhibited PASMCs cell proliferation, migration and promoted apoptosis exposed to hypoxia. In hypoxia-treated PASMCs, circUSP34 expression got downregulated while miR-1298 upregulated, whereas the addition with Lev resulted in upregulation of circUSP34 expression and downregulation of miR-1298 expression, indicating that circUSP34 can target and regulate miR-1298. In addition, miR-1298 targets and regulates the expression of BMPR2. In a rat PH model induced by hypoxia combined with SU5416, Lev upregulated circUSP34 targeting miR-1298-mediated BMP/Smad axis to alleviate the PH phenotype., Conclusion: We have shown that Lev can be used as a therapeutic drug for PH patients, which works through the circUSP34/miR-1298/BMP/Smad axis to alleviate PH symptoms., (© 2024. The Author(s).)

In patients with severe septic cardiomyopathy, levosimendan has been found to improve myocardial contractility more effectively than dobutamine, although the underlying mechanisms remain unclear. This study aims to compare the effects of levosimendan and dobutamine on cardiac function and inflammatory markers in patients with septic cardiomyopathy, and to further investigate the advantages and disadvantages of both treatments. We included 40 patients with septic cardiomyopathy treated in the intensive care unit of our hospital from September 2020 to September 2023. The patients were randomly divided into a levosimendan group (n=20) and a dobutamine group (n=20). Plasma concentrations of interleukin-6 (IL-6), interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were measured by immunofluorescence at the start of treatment, 24 hours, and 48 hours. Cardiac troponin I (cTnI) concentrations were determined by chemiluminescence, and left ventricular ejection fraction (LVEF) was measured using the Simpson method. After 24 hours of treatment, there were no significant differences in IL-6, IL-1β, and TNFα levels between the two groups (P>0.05). However, at 48 hours, the IL-6 level in the levosimendan group was significantly lower than that in the dobutamine group (319.43±226.05 pg/ml vs. 504.57±315.20 pg/ml, P=0.039), while IL-1β and TNF-α levels showed no significant differences (P>0.05). Additionally, the cTnI level in the levosimendan group was significantly lower than that in the dobutamine group (1.01±0.54 ng/ml vs. 1.40±0.63 ng/ml, P=0.042), and LVEF was significantly higher in the levosimendan group (50.60±6.11% vs. 46.90±4.95%, P=0.042). These findings suggest that levosimendan may reduce plasma IL-6 levels, alleviate myocardial injury, and improve myocardial contractility in patients with septic cardiomyopathy compared to dobutamine.

Purpose: In recent decades, the occurrence of heart failure with preserved ejection fraction (HFpEF) has outweighed that of heart failure with reduced ejection fraction by degrees, but few drugs have been demonstrated to improve long-term clinical outcomes in patients with HFpEF. Levosimendan, a calcium-sensitizing cardiotonic agent, improves decompensated heart failure clinically. However, the anti-HFpEF activities of levosimendan and underlying molecular mechanisms are unclear., Methods: In this study, a double-hit HFpEF C57BL/6N mouse model was established, and levosimendan (3 mg/kg/week) was administered to HFpEF mice aged 13 to 17 weeks. Different biological experimental techniques were used to verify the protective effects of levosimendan against HFpEF., Results: After four weeks of drug treatment, left ventricular diastolic dysfunction, cardiac hypertrophy, pulmonary congestion, and exercise exhaustion were significantly alleviated. Junction proteins in the endothelial barrier and between cardiomyocytes were also improved by levosimendan. Among the gap junction channel proteins, connexin 43, which was especially highly expressed in cardiomyocytes, mediated mitochondrial protection. Furthermore, levosimendan reversed mitochondrial malfunction in HFpEF mice, as evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4, and cytochrome C levels. Interestingly, after levosimendan administration, myocardial tissue from HFpEF mice showed restricted ferroptosis, indicated by an increased GSH/GSSG ratio; upregulated GPX4, xCT, and FSP-1 expression; and reduced intracellular ferrous ion, MDA, and 4-HNE levels., Conclusion: Regular long-term levosimendan administration can benefit cardiac function in a mouse model of HFpEF with metabolic syndromes (namely, obesity and hypertension) by activating connexin 43-mediated mitochondrial protection and sequential ferroptosis inhibition in cardiomyocytes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Delayed cerebral ischemia associated with cerebral vasospasm (CVS) in aneurysmal subarachnoid hemorrhage significantly affects patient prognosis. Levosimendan has emerged as a potential treatment, but clinical data are lacking. The aim of this study is to decipher levosimendan's effect on cerebral hemodynamics by automated quantitative measurements of brain computed tomography perfusion (CTP)., Methods: We conducted a retrospective analysis of a database of a neurosurgical intensive care unit. All patients admitted from January 2018 to July 2022 for aneurysmal subarachnoid hemorrhage and treated with levosimendan for CVS who did not respond to other therapies were included. Quantitative measurements of time to maximum (Tmax), relative cerebral blood volume (rCBV), and relative cerebral blood flow (rCBF) were automatically compared with coregistered CTP before and after levosimendan administration in oligemic regions., Results: Of 21 patients included, CTP analysis could be performed in 16. Levosimendan improved Tmax from 14.4 s (interquartile range [IQR] 9.1-21) before treatment to 7.1 s (IQR 5.5-8.1) after treatment (p < 0.001). rCBV (94% [IQR 79-103] before treatment and 89% [IQR 72-103] after treatment, p = 0.63) and rCBF (85% [IQR 77-90] before treatment and 87% [IQR 73-98] after treatment, p = 0.98) remained stable. The subgroup of six patients who did not develop cerebral infarction attributed to delayed cerebral ischemia showed an approximately 10% increase (rCBV 85% [IQR 79-99] before treatment vs. 95% [IQR 88-112] after treatment, p = 0.21; rCBF 81% [IQR 76-87] before treatment vs. 89% [IQR 84-99] after treatment, p = 0.4)., Conclusions: In refractory CVS, levosimendan use was associated with a significant reduction in Tmax in oligemic regions. However, this value remained at an abnormal level, indicating the presence of a persistent CVS. Further analysis raised the hypothesis that levosimendan causes cerebral vasodilation, but other studies are needed because our design does not allow us to quantify the effect of levosimendan from that of the natural evolution of CVS., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Purpose: Pulmonary hypertension (PH) is a common cause of postoperative mortality in cardiac surgery that is commonly treated with conventional inhaled therapies, specifically nitric oxide and prostacyclin. Alternative therapies include inhaled milrinone and levosimendan, which are receiving more research interest and are increasing in clinical use as they may cut costs while allowing for easier administration. We sought to conduct a scoping review to appraise the evidence base for the use of these two novel inhaled vasodilators as an intervention for PH in cardiac surgery., Source: We searched Embase and MEDLINE for relevant articles from 1947 to 2022., Principal Findings: We identified 17 studies including 969 patients. The included studies show that inhaled milrinone and levosimendan are selective pulmonary vasodilators with potential benefits ranging from ease of weaning from cardiopulmonary bypass to reduction in ventricular dysfunction. Nevertheless, high-quality data are limited, and study design and comparators are extremely heterogeneous, limiting the potential validity and generalizability of findings., Conclusion: The findings of this scoping review suggest that milrinone and levosimendan may be effective alternatives to current inhaled therapies for cardiac dysfunction in the setting of PH. Nevertheless, randomized trials have focused on specific agents and consistent outcome measures are needed to better validate the early-stage promise of these agents., Study Registration: Open Science Framework ( https://osf.io/z3k6f/ ); first posted 21 July 2022., (© 2024. Canadian Anesthesiologists' Society.)

Background: Levosimendan (Levo) is a drug commonly used to treat heart failure. Recent studies have suggested that Levo may have neuroprotective effects, but it is still unknown how exactly it contributes to hypoxia-induced brain damage. Thus, the aim of this study was to investigate how Levo affects hypoxia-induced brain damage and to clarify any possible underlying mechanisms., Methods: One group of rats (Levo group) was pretreated with Levo via oral force-feeding for four weeks. Another group (Ferrostatin-1 (Fer-1) group) was pretreated with intraperitoneal injections of Fer-1 for four weeks. A rat model of chronic hypoxia was created by treating rats with 13% O 2 for 14 days in a closed hypoxia chamber. For each group (Control, Model, Levo, Fer-1), we evaluated learning and memory capacity and the morphology and structure of neurons in the rats' brain tissue. Other measurements included tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6); malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px); Fe 2+ ; apoptosis; cleaved caspase-3, caspase-3; phosphatase and tensin homolog (PTEN), protein kinase B (Akt), phosphorylated Akt (p-Akt); and ferroptosis-related proteins Nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11)., Results: The Model group rats had considerably fewer neurons than the Control group, with loosely arranged cells, and markedly impaired learning and memory abilities ( p < 0.05). Oxidative damage and inflammation in brain tissues of the Model group were significantly intensified, accompanied by a substantial increase in neuronal apoptosis ( p < 0.05). PTEN protein, Fe 2+ concentration, and cleaved caspase-3 expression were all significantly upregulated, whereas p-Akt, Nrf2, GPX4, and SLC7A11 proteins were dramatically downregulated ( p < 0.05). Both the Levo and Fer-1 groups demonstrated significantly more neurons and closely arranged cells than the Model group, along with a notable improvement in learning and memory abilities ( p < 0.05). Oxidative damage and inflammation in brain tissues of the Levo and Fer-1 groups were markedly alleviated, and neuronal apoptosis was suppressed ( p < 0.05). p-Akt, Nrf2, GPX4, and SLC7A11 proteins were dramatically upregulated, whereas the expression of cleaved caspase-3, PTEN protein, and Fe 2+ content was considerably downregulated ( p < 0.05)., Conclusions: Levo effectively mitigates brain injury in rats with chronic hypoxia, likely by regulating ferroptosis via the PTEN/Akt signaling pathway.

Levosimendan's calcium sensitizing effects in heart muscle cells are well established; yet, its potential impact on skeletal muscle cells has not been evidently determined. Despite controversial results, levosimendan is still expected to interact with skeletal muscle through off-target sites (further than troponin C). Adding to this debate, we investigated levosimendan's acute impact on fast-twitch skeletal muscle biomechanics in a length-dependent activation study by submersing single muscle fibres in a levosimendan-supplemented solution. We employed our MyoRobot technology to investigate the calcium sensitivity of skinned single muscle fibres alongside their stress-strain response in the presence or absence of levosimendan (100 µM). While control data are in agreement with the theory of length-dependent activation, levosimendan appears to shift the onset of the 'descending limb' of active force generation to longer sarcomere lengths without notably improving myofibrillar calcium sensitivity. Passive stretches in the presence of levosimendan yielded over twice the amount of enlarged restoration stress and Young's modulus in comparison to control single fibres. Both effects have not been described before and may point towards potential off-target sites of levosimendan.

Heart failure is the final stage of several cardiovascular diseases, and the key to effectively treating heart failure is to reverse or delay ventricular remodelling. Levosimendan is a novel inotropic and vasodilator agent used in heart failure, whereas the impact of levosimendan on ventricular remodelling is still unclear. This study aims to investigate the impact of levosimendan on ventricular remodelling in patients with left ventricular systolic dysfunction. Electronic databases were searched to identify eligible studies. A total of 66 randomized controlled trials involving 7968 patients were included. Meta-analysis results showed that levosimendan increased left ventricular ejection fraction [mean difference (MD) = 3.62, 95% confidence interval (CI) (2.88, 4.35), P < 0.00001] and stroke volume [MD = 6.59, 95% CI (3.22, 9.96), P = 0.0001] and significantly reduced left ventricular end-systolic volume [standard mean difference (SMD) = -0.52, 95% CI (-0.67, -0.37), P < 0.00001], left ventricular end-diastolic volume index [SMD = -1.24, 95% CI (-1.61, -0.86), P < 0.00001], and left ventricular end-systolic volume index [SMD = -1.06, 95% CI (-1.43, -0.70), P < 0.00001]. In terms of biomarkers, levosimendan significantly reduced the level of brain natriuretic peptide [SMD = -1.08, 95% CI (-1.60, -0.56), P < 0.0001], N-terminal pro-brain natriuretic peptide [SMD = -0.99, 95% CI (-1.41, -0.56), P < 0.00001], and interleukin-6 [SMD = -0.61, 95% CI (-0.86, -0.35), P < 0.00001]. Meanwhile, levosimendan may increase the incidence of hypotension [risk ratio (RR) = 1.24, 95% CI (1.12, 1.39), P < 0.0001], hypokalaemia [RR = 1.57, 95% CI (1.08, 2.28), P = 0.02], headache [RR = 1.89, 95% CI (1.50, 2.39), P < 0.00001], atrial fibrillation [RR = 1.31, 95% CI (1.12, 1.52), P = 0.0005], and premature ventricular complexes [RR = 1.86, 95% CI (1.27, 2.72), P = 0.001]. In addition, levosimendan reduced all-cause mortality [RR = 0.83, 95% CI (0.74, 0.94), P = 0.002]. In conclusion, our study found that levosimendan might reverse ventricular remodelling when applied in patients with left ventricular systolic dysfunction, especially in patients undergoing cardiac surgery, decompensated heart failure, and septic shock., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Abstract: Studies have examined the therapeutic effect of levosimendan on cardiovascular diseases such as heart failure, perioperative cardiac surgery, and septic shock, but the specific mechanism in mice remains largely unknown. This study aimed to investigate the relaxation mechanism of levosimendan in the thoracic aorta smooth muscle of mice. Levosimendan-induced relaxation of isolated thoracic aortic rings that were precontracted with norepinephrine or KCl was recorded in an endothelium-independent manner. Vasodilatation by levosimendan was not associated with the production of the endothelial relaxation factors nitric oxide and prostaglandins. The voltage-dependent K + channel (K V ) blocker (4-aminopyridine) and selective K Ca blocker (tetraethylammonium) had no effect on thoracic aortas treated with levosimendan, indicating that K V and K Ca channels may not be involved in the levosimendan-induced relaxation mechanism. Although the inwardly rectifying K + channel (K ir ) blocker (barium chloride) and the K ATP channel blocker (glibenclamide) significantly inhibited levosimendan-induced vasodilation in the isolated thoracic aorta, barium chloride had a much stronger inhibitory effect on levosimendan-induced vasodilation than glibenclamide, suggesting that levosimendan-induced vasodilation may be mediated by K ir channels. The vasodilation effect and expression of K ir 2.1 induced by levosimendan were further enhanced by the PKC inhibitor staurosporine. Extracellular calcium influx was inhibited by levosimendan without affecting intracellular Ca 2+ levels in the isolated thoracic aorta. These results suggest that K ir channels play a more important role than K ATP channels in regulating vascular tone in larger arteries and that the activity of the K ir channel is enhanced by the PKC pathway., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Interconnected mechanisms of ischemia and reperfusion (IR) has increased the interest in IR in vitro experiments using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We developed a whole-cell computational model of hiPSC-CMs including the electromechanics, a metabolite-sensitive sarcoplasmic reticulum Ca2+-ATPase (SERCA) and an oxygen dynamics formulation to investigate IR mechanisms. Moreover, we simulated the effect and action mechanism of levosimendan, which recently showed promising anti-arrhythmic effects in hiPSC-CMs in hypoxia. The model was validated using hiPSC-CM and in vitro animal data. The role of SERCA in causing relaxation dysfunction in IR was anticipated to be comparable to its function in sepsis-induced heart failure. Drug simulations showed that levosimendan counteracts the relaxation dysfunction by utilizing a particular Ca2+-sensitizing mechanism involving Ca2+-bound troponin C and Ca2+ flux to the myofilament, rather than inhibiting SERCA phosphorylation. The model demonstrates extensive characterization and promise for drug development, making it suitable for evaluating IR therapy strategies based on the changing levels of cardiac metabolites, oxygen and molecular pathways., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 μg/kg + 0.1 μg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O 2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca 2+ levels and enhanced Ca 2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Levosimendan is used for the short-term treatment of severe heart failure or other cardiac conditions. The area of existing clinical applications for levosimendan has increased significantly. This study aimed to assess whether levosimendan and its metabolites impact the mechanisms related to platelet activation. In this study, we included patients with coronary artery disease receiving antiplatelet therapy. We analyzed the pharmacodynamic profile using three independent methods to assess platelet activity. The results of the conducted studies indicate a mechanism of levosimendan that affects the function of platelets, causing higher inhibition of platelet receptors and, thus, their aggregation. It is essential to clarify whether levosimendan may affect platelets due to the need to maintain a balance between bleeding and thrombosis in patients treated with levosimendan. This is especially important in the case of perioperative bleeding. This study was conducted in vitro; the research should be continued and carried out in patients to check the complete pharmacokinetic and pharmacodynamic profile.

Introduction: The postoperative hemodynamic management after lung transplant (LUTX) is guided by limited evidence. We aimed to describe and evaluate risk factors and outcomes of postoperative vasoactive support of LUTX recipients., Methods: In a single-center retrospective analysis of consecutive adult LUTX, two cohorts were identified: (1) patients needing prolonged vasoactive support (>12 h from ICU admission) (VASO+); (2) or not (VASO-). Postoperative hemodynamic characteristics were thoroughly analyzed. Risk factors and outcomes of VASO+ versus VASO- cohorts were assessed by multivariate logistic regression and propensity score matching., Results: One hundred and thirty-eight patients were included (86 (62%) VASO+ versus 52 (38%) VASO-). Vasopressors (epinephrine, norepinephrine, dopamine) were used in the first postoperative days (vasoactive inotropic score at 12 h: 6 [4-12]), while inodilators (dobutamine, levosimendan) later. Length of vasoactive support was 3 [2-4] days. Independent predictors of vasoactive use were: LUTX indication different from cystic fibrosis (p = .003), higher Oto score (p = .020), longer cold ischemia time (p = .031), but not preoperative cardiac catheterization. VASO+ patients showed concomitant hemodynamic and graft impairment, with longer mechanical ventilation (p = .010), higher primary graft dysfunction (PGD) grade at 72 h (PGD grade > 0 65% vs. 31%, p = .004, OR 4.2 [1.54-11.2]), longer ICU (p < .001) and hospital stay (p = .013). Levosimendan as a second-line inodilator appeared safe., Conclusions: Vasoactive support is frequently necessary after LUTX, especially in recipients of grafts of lesser quality. Postoperative hemodynamic dysfunction requiring vasopressor support and graft dysfunction may represent a clinical continuum with immediate and long-term consequences. Further studies may elucidate if this represents a possible treatable condition., (© 2023 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: The hemodynamic status of newborns with intracranial arteriovenous shunts (AVSs) may be extremely complex. Mini-invasive hemodynamic monitoring through innovative techniques such as Near-Infrared Spectroscopy (NIRS) and Pressure Recording Analytical Method (PRAM) may help in understanding hemodynamics in newborns with AVSs. Levosimendan is a calcium sensitizer and inodilator, and it is known to improve ventricular function, but its use in newborns is limited. In our cases, we evaluated the effect of levosimendan on hemodynamics through NIRS and PRAM., Case Presentation: Herein, we report the cases of two neonates with intracranial arteriovenous shunts, in whom we used levosimendan to manage cardiac failure refractory to conventional treatment. Levosimendan was used at a dosage of 0.1 mcg/kg/min for 72 h. Combined use of NIRS and PRAM helped in real-time monitoring of hemodynamic effects; in particular, levosimendan determined significant improvement in myocardium contractility as well as a reduction of heart rate., Conclusion: In two neonatal cases of AVSs, levosimendan led to an overall hemodynamic stabilization, documented by the combination of NIRS and PRAM. Our results suggest introducing levosimendan as a second-line treatment in cases of severe cardiac dysfunction due to AVSs without improvement using standard treatment strategies. Future prospective and larger studies are highly warranted., (© 2023. Società Italiana di Pediatria.)

Levosimendan (up to 10 µM) given alone failed to increase force of contraction in isolated electrically stimulated (1 Hz) left atrial (LA) preparations from wild-type mice. Only in the additional presence of 0.1 µM rolipram, an inhibitor of the activity of phosphodiesterase IV, levosimendan increased force of contraction in LA and increased the phosphorylation state of phospholamban at amino acid serine 16. Levosimendan alone increased the beating rate in isolated spontaneously beating right atrial preparations from mice and this effect was potentiated by rolipram. The positive inotropic and the positive chronotropic effects of levosimendan in mouse atrial preparations were attenuated by 10 µM propranolol. Finally, we studied the contractile effects of levosimendan in isolated electrically stimulated (1 Hz) right atrial preparations from the human atrium (HAP), obtained during cardiac surgery. We detected concentration-dependent positive inotropic effects of levosimendan alone that reached plateau at 1 µM levosimendan in HAP (n = 11). Levosimendan shortened time of tension relaxation in HAP. Cilostamide (1 µM), an inhibitor of phosphodiesterase III, or propranolol (10 µM) blocked the positive inotropic effect of levosimendan in HAP. Levosimendan (1 µM) alone increased in HAP the phosphorylation state of phospholamban. In conclusion, we present evidence that levosimendan acts via phosphodiesterase III inhibition in the human atrium leading to phospholamban phosphorylation and thus explaining the positive inotropic effects of levosimendan in HAP., (© 2022. The Author(s).)

Aims: Heart failure with reduced ejection fraction (HFrEF) is a disease with high mortality and morbidity. Recent positive inotropic drug developments focused on cardiac myofilaments, that is, direct activators of the myosin molecule and Ca 2+ sensitizers for patients with advanced HFrEF. Omecamtiv mecarbil (OM) is the first direct myosin activator with promising results in clinical studies. Here, we aimed to elucidate the cellular mechanisms of the positive inotropic effect of OM in a comparative in vitro investigation where Ca 2+ -sensitizing positive inotropic agents with distinct mechanisms of action [EMD 53998 (EMD), which also docks on the myosin molecule, and levosimendan (Levo), which binds to troponin C] were included., Methods: Enzymatically isolated canine cardiomyocytes with intact cell membranes were loaded with Fura-2AM, a Ca 2+ -sensitive, ratiometric, fluorescent dye. Changes in sarcomere length (SL) and intracellular Ca 2+ concentration were recorded in parallel at room temperature, whereas cardiomyocyte contractions were evoked by field stimulation at 0.1 Hz in the presence of different OM, EMD, or Levo concentrations., Results: SL was reduced by about 23% or 9% in the presence of 1 μM OM or 1 μM EMD in the absence of electrical stimulation, whereas 1 μM Levo had no effect on resting SL. Fractional sarcomere shortening was increased by 1 μM EMD or 1 μM Levo to about 152%, but only to about 128% in the presence of 0.03 μM OM. At higher OM concentrations, no significant increase in fractional sarcomere shortening could be recorded. Contraction durations largely increased, whereas the kinetics of contractions and relaxations decreased with increasing OM concentrations. One-micromole EMD or 1 μM Levo had no effects on contraction durations. One-micromole Levo, but not 1 μM EMD, accelerated the kinetics of cardiomyocyte contractions and relaxations. Ca 2+ transient amplitudes were unaffected by all treatments., Conclusions: Our data revealed major distinctions between the cellular effects of myofilament targeted agents (OM, EMD, or Levo) depending on their target proteins and binding sites, although they were compatible with the involvement of Ca 2+ -sensitizing mechanisms for all three drugs. Significant part of the cardiotonic effect of OM relates to the prolongation of systolic contraction in combination with its Ca 2+ -sensitizing effect., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Patients with advanced heart failure (HF) have high morbidity and mortality, with only a small proportion being eligible for advanced therapies. Intermittent outpatient levosimendan infusion has been shown to provide symptomatic relief and reduce the rate of HF events. Our aim was to assess the safety and efficacy of outpatient levosimendan administration in an advanced HF population., Methods: This is a report of a single-center experience of consecutive advanced HF patients referred for intermittent intravenous outpatient administration of levosimendan, between January 2018 and March 2021. Baseline and follow-up evaluation included clinical assessment, laboratory tests, transthoracic echocardiography and cardiopulmonary exercise testing. Baseline and clinical follow-up data were compared using the Wilcoxon signed-rank test., Results: A total of 24 patients (60.8 years, 83% male, mean left ventricular ejection fraction [LVEF] 24%), with a median of 1.5 HF hospitalizations in the previous six months, were referred for outpatient levosimendan pulses, the majority as a bridge to transplantation or due to clinical deterioration. At six-month follow-up there was a significant reduction in HF hospitalizations to 0.4±0.7 (p<0.001). NYHA class IV (52.2% to 12.5%, p=0.025) and NT-proBNP (8812.5 to 3807.4 pg/ml, p=0.038) were also significantly reduced. Exercise capacity was significantly improved, including peak oxygen uptake (p=0.043) and VE/VCO 2 slope (p=0.040). LVEF improved from 24.0% to 29.7% (p=0.008). No serious adverse events were reported., Conclusion: Repeated levosimendan administration in advanced HF patients is a safe procedure and was associated with a reduction in HF hospitalizations, functional and LVEF improvement, and reduction in NT-proBNP levels during follow-up., (Copyright © 2023 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Inotropic agents are generally recommended to use in patients with acute decompensated heart failure (HF) with reduced ejection fraction (HFrEF) concurrent to end-organ dysfunction. However, due to certain pharmacological limitations like developing life threatening arrhythmia and tolerance, cannot be employed as much as needed. Meanwhile, Calcium ion (Ca 2+ ) sensitisers exhibits their inotropic action by increasing the sensitivity of the cardiomyocyte to intracellular Ca 2+ ion and have been reported as emerging therapeutic alternative in HF cases. Levosimendan (LEVO) is an inodilator and with its unique pharmacology justifying its use in a wide range of cardiac alterations in HF particularly in undergoing cardiac surgery. It is also reported to be better than classical inotropes in maintaining cardiac mechanical efficacy and reducing congestion in acute HF with hypotension. This review paper was designed to compile various evidence about basic pharmacology and potential clinical aspects of LEVO in cardiac surgery and other HF associated alterations. This will benefit directly to the researcher in initiating research and to fill the gaps in the area of thrust.

Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer's disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14 C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the Tau P301L -BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies., (© 2023. The Author(s).)

Objective: Traumatic brain injury (TBI) is an essential and common health problem worldwide. Levosimendan is an inotropic and vasodilator drug used to treat heart failure. Moreover, it exerts pleiotropic effects and, thus, protective effects on many organs. The present study aimed to investigate the effect of levosimendan on necrosis, apoptosis, and reactive oxygen species in rats with TBI., Methods: The study included 28 female Wistar-Albino rats weighing 200-250 g. The rats were divided into 4 groups with 7 rats each as follows: Group 1: No trauma group (Control), Group 2: Traumatized, untreated group (T), Group 3: Levosimendan was administered at a dose of 12 μg/kg intraperitoneally 1 hour after the trauma (L1), Group 4: Levosimendan was administered at a dose of 12 μg/kg intraperitoneally 2 hours after the concussion (L2). After the experiment, the rats were decapitated, and the brain tissue was removed. Necrosis was assessed with Cresyl violet staining, apoptosis was assessed with immunohistochemical analysis, superoxide dismutase and catalase levels were measured with the spectrophotometric method, and malondialdehyde (MDA) levels were assessed by High-Performance Liquid Chromatography., Results: The number of necrotic cells in the L1 and L2 groups was significantly lower than in the K and T groups (P = 0.015 and P = 0.03, respectively). Although the active caspase-3 level was signified considerably in the T, L1, and L2 groups compared to the K group, no significant difference was found among these 3 groups (P > 0.05). The results of superoxide dismutase levels were similar to those of active caspase-3. catalase level was significantly higher in the K group than in the T and L2 groups (P = 0.045). Malondialdehyde activity was considerably higher in the L1 and L2 groups compared to the K group (P = 0.023)., Conclusions: Our results indicated that levosimendan may exert a neuroprotective effect by reducing necrosis in TBI and that levosimendan does not affect apoptosis and antioxidant levels in TBI. Comprehensive studies are needed to elucidate the effect of levosimendan on TBI fully., (Copyright © 2022. Published by Elsevier Inc.)

Abstract: OR-1855 and OR-1896 are 2 hemodynamically active metabolites of the inodilator levosimendan, with calcium sensitizing activity, but their mechanism of action is still not fully understood. It has been previously reported that the positive inotropic effect of levosimendan is not potentiated by the adenylate cyclase activator forskolin, whereas forskolin does potentiate the effects of the phosphodiesterase (PDE) inhibitor milrinone. To ascertain whether the active metabolites follow the same pattern of levosimendan, the positive inotropic effects of OR- 1855 and OR-1896 were studied in guinea-pig-isolated papillary muscle in the presence and absence of forskolin. OR-1855 and OR-1896 were also tested as inhibitors of PDE-III and PDE-IV. Our results show that 0.1 µM forskolin did not potentiate the positive inotropic effect of OR-1855 or OR-1896, as in the case of the parent compound levosimendan. As in previous studies, the positive inotropic effect of milrinone was markedly potentiated in the presence of forskolin. From these data, we propose an explanation for the divergent behavior of the calcium sensitizing drugs and PDE inhibitors., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS)., Methods and Results: Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1-5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1-5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001)., Conclusion: Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Poor patient outcomes after aneurysmal subarachnoid hemorrhage (SAH) occur due to a multifactorial process, mainly involving cerebral inflammation (CI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia, followed by neurodegeneration. CI is mainly triggered by enhanced synthesis of serotonin (5-HT), prostaglandin F2alpha (PGF2a), and cytokines such as interleukins. Levosimendan (LV), a calcium-channel sensitizer, has already displayed anti-inflammatory effects in patients with severe heart failure. Therefore, we wanted to elucidate its potential anti-inflammatory role on the cerebral vasculature after SAH., Methods: Experimental SAH was induced by using an experimental double-hemorrhage model. Sprague Dawley rats were harvested on day 3 and day 5 after the ictus. The basilar artery was used for isometric investigations of the muscular media tone. Vessel segments were either preincubated with LV or without, with precontraction performed with 5-HT or PGF2a followed by application of acetylcholine (ACh) or LV., Results: After preincubation with LV 10 -4 M and 5-HT precontraction, ACh triggered a strong vasorelaxation in sham segments (LV 10 -4 M, E max 65%; LV 10 -5 M, E max 48%; no LV, E max 53%). Interestingly, SAH D3 (LV 10 -4 , E max 76%) and D5 (LV 10 -4 , E max 79%) segments showed greater vasorelaxation compared with sham. An LV series after PGF2a precontraction showed significantly enhanced relaxation in the sham (P=0.004) and SAH groups (P=0.0008) compared with solvent control vessels., Conclusions: LV application after SAH seems to beneficially influence DCVS by antagonizing 5-HT- and PGF2a-triggered vasoconstriction. Considering this spasmolytic effect, LV might have a role in the treatment of SAH, additionally in selected patients suffering takotsubo cardiomyopathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ischemic heart disease (IHD) is one of the leading causes of mortality worldwide. Preserving functionality and preventing arrhythmias of the heart are key principles in the management of patients with IHD. Levosimendan, a unique calcium (Ca 2+ ) enhancer with inotropic activity, has been introduced into clinical usage for heart failure treatment. Human-induced pluripotent cell-derived cardiomyocytes (hiPSC-CMs) offer an opportunity to better understand the pathophysiological mechanisms of the disease as well as to serve as a platform for drug screening. Here, we developed an in vitro IHD model using hiPSC-CMs in hypoxic conditions and defined the effects of the subsequent hypoxic stress on CMs functionality. Furthermore, the effect of levosimendan on hiPSC-CMs functionality was evaluated during and after hypoxic stress. The morphology, contractile, Ca 2+ -handling, and gene expression properties of hiPSC-CMs were investigated in response to hypoxia. Hypoxia resulted in significant cardiac arrhythmia and decreased Ca 2+ transient amplitude. In addition, disorganization of sarcomere structure was observed after hypoxia induction. Interestingly, levosimendan presented significant antiarrhythmic properties, as the arrhythmia was abolished or markedly reduced with levosimendan treatment either during or after the hypoxic stress. Moreover, levosimendan presented significant protection from the sarcomere alterations induced by hypoxia. In conclusion, this chip model appears to be a suitable preclinical representation of IHD. With this hypoxia platform, detailed knowledge of the disease pathophysiology can be obtained. The antiarrhythmic effect of levosimendan was clearly observed, suggesting a possible new clinical use for the drug.

Background: Levosimendan preconditioning has been shown to attenuate myocardial apoptosis in animal models. However, protective effects of levosimendan postconditioning against myocardial apoptosis following myocardial infarction (MI) have not been evaluated. Therefore, we investigated the effects of levosimendan postconditioning on myocardial apoptosis in MI rat models., Methods: In an anoxia/reoxygenation (A/R) model, H9c2 cells were pretreated with or without levosimendan postconditioning after which their apoptosis rates were assessed by flow cytometry, RT-qPCR, and western blot analyses. Then, postconditioning was performed with or without levosimendan in MI rat models. Myocardiocyte apoptosis was evaluated by echocardiography, TTC staining, TUNEL staining, immunohistochemical staining, RT-qPCR, and western blot analysis., Results: Levosimendan postconditioning inhibited H9c2 cell apoptosis in A/R models by elevating Bcl-2 while suppressing Caspase-3 and Bax at both mRNA and protein levels. Moreover, it improved cardiac functions and reduced the left ventricle infarction area in MI rat models. Compared to the MI control group, cardiomyocyte apoptosis rates in the levosimendan postconditioning group were low. The reduced cardiomyocyte apoptosis rates were associated with downregulation of Bax and Caspase-3 as well as with upregulation of Bcl-2 at mRNA and protein levels., Conclusions: Levosimendan postconditioning of MI rat models protected against cardiomyocyte apoptosis, implying that it is a potential strategy for preventing cardiomyocyte apoptosis in the treatment of cardiac dysfunction following MI., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Ying Xie et al.)

Levosimendan exerts positive inotropic and vasodilatory effects. Currently, its effects on right heart function remain uncertain. This systematic review and meta-analysis is intended to illustrate the impacts of levosimendan on systolic function of the right heart in patients with heart dysfunction. We systematically searched electronic databases (PubMed, the Cochrane Library, Embase and Web of Science) up to November 30, 2020, and filtered eligible studies that reported the impacts of levosimendan on right heart function. Of these, only studies whose patients suffered from heart dysfunction or pulmonary hypertension were included. Additionally, patients were divided into two groups (given levosimendan or not) in the initial research. Then, RevMan5.3 was used to conduct further analysis. A total of 8 studies comprising 390 patients were included. The results showed that after 24 h of levosimendan, patients' right ventricular fractional area change [3.17, 95% CI (2.03, 4.32), P < 0.00001], tricuspid annular plane systolic excursion [1.26, 95% CI (0.35, 2.16), P = 0.007] and tricuspid annular peak systolic velocity [0.86, 95% CI (0.41, 1.32), P = 0.0002] were significantly increased compared to the control group. And there is an increasing trend of cardiac output in levosimendan group [1.06, 95% CI (- 0.16, 2.29), P = 0.09 ] .Furthermore, patients' systolic pulmonary arterial pressure [- 5.57, 95% CI (- 7.60, - 3.54), P < 0.00001] and mean pulmonary arterial pressure [- 1.01, 95% CI (- 1.64, - 0.37), P = 0.002] were both significantly decreased, whereas changes in pulmonary vascular resistance [- 55.88, 95% CI (- 206.57, 94.82), P = 0.47] were not significant. Our study shows that in patients with heart dysfunction, levosimendan improves systolic function of the right heart and decreases the pressure of the pulmonary artery., (© 2021. The Author(s).)

Background: We investigated whether levosimendan prevents contrast medium nephrotoxicity with glycerol aggravation in rats., Methods: Forty-eight Wistar albino rats were assigned to eight groups (n = 6 × 8). No medication was administered to group I (controls); glycerol (intramuscular injection of 25% glycerol, 10 mL/kg) group II; intravenous iohexol 10 mL/kg to group III; glycerol and iohexol to group IV; iohexol and intraperitoneal levosimendan 0.25 mg/kg to group V; glycerol, iohexol, and levosimendan 0.25 mg/kg to group VI; iohexol and levosimendan 0.5 mg/kg to group VII; and glycerol, iohexol, and levosimendan 0.5 mg/kg to group VIII. One-day water withdrawal and glycerol injection prompted renal damage; iohexol encouraged nephrotoxicity; levosimendan was administered 30 min after glycerol injection and continued on days 2, 3, and 4. The experiment was completed on day 5. Serum blood urea nitrogen (BUN) and creatinine levels, superoxide dismutase (SOD) activity, glutathione (GSH), malondialdehyde (MDA) levels, tumour necrosis factor-α (TNF-α), nuclear factor kappa ß (NFK-ß), interleukin 6 (IL-6), and histopathological marks were assessed. One-way analysis of variance and Duncan's multiple comparison tests were used., Results: Levosimendan changed serum BUN (p = 0.012) and creatinine (p = 0.018), SOD (p = 0.026), GSH (p = 0.012), and MDA (p = 0.011). Levosimendan significantly downregulated TNF-α (p = 0.022), NFK-ß (p = 0.008), and IL-6 (p = 0.033). Histopathological marks of hyaline and haemorrhagic cast were improved in levosimendan-injected groups., Conclusion: Levosimendan showed nephroprotective properties due to its vasodilator, oxidative distress decreasing and inflammatory cytokine preventing belongings., (© 2021. The Author(s).)

Objective: Levosimendan, an inotrope, is widely used in the management of heart failure (HF) and cardiac surgery, but it remains uncertain whether levosimendan can improve renal function in patients with left ventricular dysfunction (LVD)., Methods: PubMed, Embase, and Cochrane CENTRAL from the inception to June 2020 were systematically screened for randomized controlled trials (RCTs) to investigate whether levosimendan offers kidney-related advantages in cardiovascular patients with LVD. We pooled the effects using a random-effect model., Results: Twenty-eight studies enrolling 5069 patients were included. Levosimendan reduced the sCr (SMD -0.28, 95% CI (-0.48, -0.09), P = 0.005, I 2  = 52.5%, high quality) and the risk of ARF (relative risk 0.75, 95%CI (0.60, 0.95), P = 0.017, I 2  = 11.3%, moderate-quality) in patients with LVD compared with control group. The reduction of sCr was more pronounced in patients with a relatively higher baseline sCr level. For secondary outcomes, levosimendan therapy was associated with the improvement of GFR (SMD 0.32, 95%CI (-0.05, 0.68), P = 0.092, I 2  = 55.1%, low-quality) and urine output (SMD 0.42, 95%CI (0.06, 0.79), P = 0.024, I 2  = 50.0%, very low-quality), but there was no significant reduction in BUN (SMD -0.14, 95%CI (-0.97, 0.70), P = 0.774, I 2  = 77.9%, very low-quality)., Conclusions: Levosimendan might improve renal function of patients with LVD.

BACKGROUND The aim of this study was to explore the effect of levosimendan in patients after heart valve replacement and its influence on postoperative recovery. MATERIAL AND METHODS This prospective study included 185 patients with valvular diseases undergoing conventional valve replacement. Patients were divided into 2 groups using a random number table before surgery. Patients in the levosimendan group were administrated levosimendan intravenous infusion immediately after entering the Intensive Care Unit (ICU). The left ventricular ejection fraction (LVEF), cardiac output, and heart failure-related index, such as B-type natriuretic peptide (BNP) level, were recorded at 1, 3, and 7 days after surgery. The dosage and administration time of dopamine and epinephrine, mechanical ventilation time, ICU length of stay, and postoperative adverse events were recorded. RESULTS Cardiac output and LVEF of patients in the levosimendan group were significantly higher than those in the control group at different time points (P<0.05), and BNP level was lower than that of the control group (P<0.0001). Dosage and administration time of dopamine and epinephrine in the levosimendan group were lower than those of the control group (P<0.0001, P<0.0001, respectively). ICU length of stay and total incidence of postoperative adverse events were lower than those of the control group (P<0.0001, P=0.002, respectively). CONCLUSIONS Levosimendan administration immediately after heart valve replacement effectively improved the heart function of patients, reduced administration of vasoactive drugs, shortened length of ICU stay, reduced incidence of postoperative adverse events, and promoted recovery of patients after surgery.

Rare pediatric non-compaction and restrictive cardiomyopathy are usually associated with a rapid and severe disease progression. While the non-compaction phenotype is characterized by structural defects and is correlated with systolic dysfunction, the restrictive phenotype exhibits diastolic dysfunction. The molecular mechanisms are poorly understood. Target genes encode among others, the cardiac troponin subunits forming the main regulatory protein complex of the thin filament for muscle contraction. Here, we compare the molecular effects of two infantile de novo point mutations in TNNC1 (p.cTnC-G34S) and TNNI3 (p.cTnI-D127Y) leading to severe non-compaction and restrictive phenotypes, respectively. We used skinned cardiomyocytes, skinned fibers, and reconstituted thin filaments to measure the impact of the mutations on contractile function. We investigated the interaction of these troponin variants with actin and their inter-subunit interactions, as well as the structural integrity of reconstituted thin filaments. Both mutations exhibited similar functional and structural impairments, though the patients developed different phenotypes. Furthermore, the protein quality control system was affected, as shown for TnC-G34S using patient's myocardial tissue samples. The two troponin targeting agents levosimendan and green tea extract (-)-epigallocatechin-3-gallate (EGCg) stabilized the structural integrity of reconstituted thin filaments and ameliorated contractile function in vitro in some, but not all, aspects to a similar degree for both mutations.

Levosimendan is a distinctive inodilator combing calcium sensitization, phosphodiesterase inhibition and vasodilating properties through the opening of adenosine triphosphate-dependent potassium channels. It was first approved in Sweden in 2000 for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. After more than 20 years, clinical applications have considerably expanded across critical care and emergency medicine, and levosimendan is now under investigation in different cardiac settings (eg, septic shock, pulmonary hypertension) and for non-cardiac applications (eg, amyotrophic lateral sclerosis). This narrative review outlines key milestones in levosimendan history, by addressing regulatory issues, pharmacological peculiarities and clinical aspects (efficacy and safety) of a drug that did not receive great attention in the heart failure guidelines. A brief outlook to the ongoing clinical trials is also offered., Competing Interests: Professor Emanuel Raschi reports personal fees from Novartis for Consultancy, outside the submitted work. Prof. Dr. Luciano Potena reports personal fees from Novartis, personal fees from Biotest, personal fees from AstraZeneca, personal fees from Abbott, personal fees from Sandoz, outside the submitted work. The author reports no other conflicts of interest relevant to this work., (© 2021 Conti et al.)

Background: Splanchnic vasodilation by inodilators is an argument for their use in critical cardiac dysfunction. To isolate peripheral vasoactivity from inotropy, such drugs were investigated, and contrasted to vasopressors, in a fixed low cardiac output (CO) model resembling acute cardiac dysfunction effects on the gastrointestinal tract. We hypothesized that inodilators would vasodilate and preserve the aerobic metabolism in the splanchnic circulation in low CO., Methods: In anesthetized pigs, CO was lowered to 60% of baseline by partial inferior caval vein balloon inflation. The animals were randomized to placebo (n = 8), levosimendan (24 μg kg-1 bolus, 0.2 μg kg-1 min-1, n = 7), milrinone (50 μg kg-1 bolus, 0.5 μg kg-1 min-1, n = 7), vasopressin (0.001, 0.002 and 0.006 U kg-1 min-1, 1 h each, n = 7) or norepinephrine (0.04, 0.12, and 0.36 μg kg-1 min-1, 1 h each, n = 7). Hemodynamic variables including mesenteric blood flow were collected. Systemic, mixed-venous, mesenteric-venous, and intraperitoneal metabolites were analyzed., Results: Cardiac output was stable at 60% in all groups, which resulted in systemic hypotension, low superior mesenteric artery blood flow, lactic acidosis, and increased intraperitoneal concentrations of lactate. Levosimendan and milrinone did not change any circulatory variables, but levosimendan increased blood lactate concentrations. Vasopressin and norepinephrine increased systemic and mesenteric vascular resistances at the highest dose. Vasopressin increased mesenteric resistance more than systemic, and the intraperitoneal lactate concentration and lactate/pyruvate ratio., Conclusion: Splanchnic vasodilation by levosimendan and milrinone may be negligible in low CO, thus rejecting the hypothesis. High-dose vasopressors may have side effects in the splanchnic circulation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Background: Ischemia-reperfusion injury (IRI) is cellular damage that emerges from re-oxygenation of a hypoxic organ. In the present study, we aimed to examine the effects of a combination of levosimendan, an inotropic agent, and N-Acetylcysteine, the precursor of antioxidants and glutathione, in an experimental liver IRI model., Methods: In this study, 38 rats were randomly divided into five groups. Before the ischemia, study arms were given physiological saline solution, N-Acetylcysteine (NAS), levosimendan or a combination of NAS+levosimendan in a predetermined amount and duration, and the infusion was continued until the end of this study. The hepatic pedicle was occluded using an atraumatic vein clamp, and 60 minutes of ischemia was achieved. The clamp was then opened and 60 minutes of reperfusion was ensured. Liver tissue samples were obtained after sacrifice, and tissue malondialdehyde (MDA) and myeloperoxidase (MPO) levels were determined. Serum Tumor Necrosis Factor (TNF)-α, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and MPO levels of blood samples were also measured., Results: Among the histopathological changes in the liver tissue after IRI, differences between groups were statistically significant in the injury scoring system based on congestion, vacuolization and necrosis levels. Histopathological injury score, plasma MPO, AST, ALT, tissue MPO and tissue MDA values were statistically significantly lower in the treatment groups, prominently in the levosimendan and NAS combination group concerning liver histopathological damage., Conclusion: The use of a levosimendan plus NAS combination in liver IRI markedly suppressed inflammation and oxidative stress and significantly reduced liver ischemia-reperfusion injury and can be recommended for decreasing IRI instead of single agent use of levosimendan or NAS.

Background: Acute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support., Methods: In this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvO 2 ) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70-80 mmHg. Intra-group differences were tested by Mann-Whitney U-tests, and a linear mixed model was used to test time and group interaction., Results: Twenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, p = 0.030), and the estimated GFR was lower (46 ± 12 vs 57 ± 11 ml/min/1.73 m 2 , p = 0.025). Levosimendan induced a significantly (p = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance (- 18% vs. - 4%, respectively, p = 0.043). There was a trend for a minor increase in glomerular filtration rate with levosimendan (4.5%, p = 0.079), which did differ significantly from the placebo group (p = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group (p = 0.012)., Conclusions: In hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation. Trial registration NCT02531724, prospectly registered on 08/20/2015. https://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1.

Abstract: Levosimendan, a calcium sensitizer, exerts inotropic action through improving left ventricular ejection fraction. We noticed that only few clinical studies are published in which the effects of levosimendan on cardiac function are studied by echocardiography. When screening the literature (PubMed, Embase, and CENTRAL, from inception to August 2020), we found 29 randomized controlled trials on levosimendan containing echocardiographic data. We included those studies, describing a total of 574 heart failure patients, in our meta-analysis and extracted 14 ultrasonic parameters, pooling the effect estimates using a random-effect model. Our analysis of the diastolic parameters of the left ventricle shows that levosimendan reduce the early/late transmitral diastolic peak flow velocity ratio [standardized mean difference (SMD) -0.45 to 95% confidence interval (CI) (-0.87 to -0.03), P = 0.037] and E/e' (e': mitral annulus peak early diastolic wave velocity using tissue-doppler imaging) [SMD -0.59, 95% CI (-0.8 to -0.39), P < 0.001]. As it regards the systolic parameters of the right ventricle, levosimendan increased tricuspid annular plane systolic excursion [SMD 0.62, 95% CI (0.28 to 0.95), P < 0.001] and tricuspid annular peak systolic velocity [SMD 0.75, 95% CI (0.35 to 1.16), P < 0.001], and reduced systolic pulmonary artery pressure [SMD -1.02, 95% CI (-1.32, -0.73), P < 0.001]. As it regards the diastolic parameters of the right ventricle, levosimendan was associated with the decrease of Aa (peak late diastolic tricuspid annular velocity using tissue-doppler imaging) [SMD -0.38, 95% CI (-0.76 to 0), P = 0.047] and increase of Ea (peak early diastolic tricuspid annular velocity using tissue-doppler imaging) [SMD 1.03, 95% CI (0.63 to 1.42), P < 0.001] and Ea/Aa [SMD 0.86, 95% CI (0.18 to 1.54), P = 0.013]. We show that levosimendan is associated with an amelioration in the diastolic and systolic functions of both ventricles in heart failure patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Levosimendan is an effective calcium sensitizer with complementary mechanisms of action: calcium sensitization and opening of adenosine triphosphate-dependent potassium channels, both on the sarcolemma of the smooth muscle cells in the vasculature and on the mitochondria of cardiomyocytes. Levosimendan has a long-acting metabolite with a half-life of approximately 80 h. There have been a few small studies on this drug regarding right ventricular function. In view of this, we investigated the effect of levosimendan on right ventricular function in patients with coronary artery disease., Methods: This was a prospective, randomized, double-blind study on 50 patients with coronary artery disease and severe left ventricular dysfunction (left ventricular ejection fraction ≤35%) undergoing elective off-pump coronary artery bypass., Results: Levosimendan had an inotropic effect on right ventricular myocardium and a vasodilatory effect on blood vessels. It caused a decline in pulmonary vascular resistance ( p  < 0.018), right ventricular systolic pressure ( p  < 0.001), and pulmonary artery systolic pressure ( p  < 0.001), and improved right ventricular diastolic function as shown by the decrease in right ventricular Tei index ( p  < 0.001), right ventricular end-diastolic pressure, and the ratio of early diastolic tricuspid inflow to tricuspid lateral annular velocity ( p  < 0.006). However, we found no beneficial effects on intensive care unit or hospital stay ( p  = 0.164, p  = 0.349, respectively) nor a mortality benefit., Conclusions: Levosimendan has salutary effects on right ventricular function in patients with severe left ventricular dysfunction undergoing coronary artery bypass, in terms of improved hemodynamic parameters.

Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3-10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration-response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; p < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA.

Background: Levosimendan is a cardiac inotrope that augments myocardial contractility without increasing myocyte oxygen consumption. Additionally, levosimendan has been shown to exhibit anti-inflammatory, antioxidative, and other cardioprotective properties and is approved for treatment of heart failure. Recent studies indicated that these beneficial effects can be achieved with doses lower than the standard dose of 12.5 mg. Patients with preoperatively diagnosed left ventricular ejection fraction (LVEF) ≤40% received 1.25 mg levosimendan after induction of anesthesia. After surgery, administration of low-dose levosimendan was repeated until cardiovascular stability was achieved., Objective: This study aimed to evaluate if pharmacological preconditioning with 1.25 mg levosimendan in patients with LVEF ≤40% altered the postoperative need for inotropic agents, the incidence of newly occurring atrial fibrillation, renal replacement therapy, mechanical circulatory support and 30-day mortality. The cumulative dosage of levosimendan was recorded to assess the required dosage in the context of individualized treatment., Material and Methods: This retrospective study included patients with preoperatively diagnosed LVEF ≤40% who underwent cardiac surgery at this institution between January 2015 and December 2018 and who received 1.25 mg levosimendan after induction of anesthesia to prevent postoperative low cardiac output syndrome. Based on echocardiography results, invasive hemodynamic monitoring, and central venous or mixed venous oxygen saturation and lactate clearance, repetitive doses of levosimendan in 1.25 mg increments could be postoperatively administered until cardiovascular stability was achieved. The results were compared to the current literature., Results: We identified 183 patients with LVEF <40% who received pharmacological preconditioning with 1.25 mg levosimendan. Maximum doses of epinephrine, incidence of atrial fibrillation, need for renal replacement therapy and 30-day mortality were found to be below the published rates of comparable patient collectives. In 73.2% of patients, a cumulative dosage of 5 mg levosimendan or less was considered sufficient., Conclusion: The presented concept of pharmacological preconditioning with 1.25 mg levosimendan followed by individualized additional dosing in cardiac surgery patients with preoperative LVEF ≤40% suggests that this concept is safe, with possible advantages regarding the need of inotropic agents, renal replacement therapy, and 30-day mortality, compared to the current literature. Individualized treatment with levosimendan to support hemodynamics and a timely reduction of inotropic agents needs further confirmation in randomized trials.

Abstract: The calcium sensitizer levosimendan is indicated for the hemodynamic stabilization of patients with acutely decompensated heart failure and has been shown to be protective against reperfusion injury after myocardial infarction. However, affected forms of cell death and underlying signaling pathways remain controversial. Therefore, the aim of this study was to examine the influence of levosimendan preconditioning and postconditioning on anoxia/reoxygenation-induced apoptosis, necrosis, and autophagy in H9c2 myoblasts. To mimic conditions of myocardial ischemia/reperfusion, rat cardiac H9c2 myoblasts were exposed to anoxia/starvation, followed by reoxygenation/refeeding. Apoptosis, necrosis, autophagy, cell viability, survival signaling, and mitochondrial permeability transition pore (mPTP) opening were measured. Both, pharmacological preconditioning and postconditioning with levosimendan were capable to reduce apoptosis as well as necrosis in stressed H9c2 cells. However, preconditioning showed to have the stronger impact compared with postconditioning. Moreover, levosimendan preconditioning increased autophagy, suggesting enhanced repair processes initiated by the early presence of the drug. Underlying mechanisms differ between both interventions: Although both are associated with PI3/Akt activation and reduced mPTP opening, only postconditioning but not preconditioning depended on mKATP activation. This variation might indicate that a pharmacological treatment after the onset of reoxygenation at least in part directly addresses mitochondrial structures for protection. In conclusion, we demonstrate that both pharmacological preconditioning and postconditioning with levosimendan protect anoxia/reoxygenation-stressed cells but differ in the underlying mechanisms. These results are decisive to obtain more insights into the beneficial effects of levosimendan in the treatment of reperfusion-mediated damage., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim was to test the hypothesis that preoperative infusion of levosimendan would decrease patients' cardiac biomarker profiles during the immediate postoperative stage (troponin I and B-type natriuretic peptide levels) more efficiently than placebo after cardiopulmonary bypass., Methods: In a randomised, placebo-controlled, double-blinded study, 30 paediatric patients were scheduled for congenital heart disease surgery. 15 patients (50%) received prophylactic levosimendan and 15 patients (50%) received placebo from 12 h before cardiopulmonary bypass to 24 h after surgery., Results: Troponin I levels were higher in the placebo group at 0, 12, and 24 h after cardiopulmonary bypass, although the mean differences between the study groups and the 95% confidence intervals (CIs) for troponin I levels did not present statistically significant differences at any of the three time points considered (mean differences [95% CIs] - 3.32 pg/ml [- 19.34 to 12.70], - 2.42 pg/ml [- 19.78 to 13.95], and - 79.94 pg/ml [- 266.99 to 16.39] at 0, 12, and 24 h, respectively). A similar lack of statistically significant difference was observed for B-type natriuretic peptide (mean differences [95% CIs] 36.86 pg/dl [- 134.16 to 225.64], - 350.79 pg/dl [- 1459.67 to 557.45], and - 310.35 pg/dl [- 1505.76 to 509.82]). Lactic acid levels were significantly lower with levosimendan; the mean differences between the study groups and the 95% CIs for lactate levels present statistically significant differences at 0 h (- 1.52 mmol/l [- 3.19 to - 0.25]) and 12 h (- 1.20 mmol/l [- 2.53 to - 0.10]) after cardiopulmonary bypass. Oxygen delivery (DO 2 ) was significantly higher at 12 h and 24 h after surgery (mean difference [95% CI] 627.70 ml/min/m 2 [122.34-1162.67] and 832.35 ml/min/m 2 [58.15 to 1651.38], respectively)., Conclusions: Levosimendan does not significantly improve patients' postoperative troponin I and B-type natriuretic peptide profiles during the immediate postoperative stage in comparison with placebo, although both were numerically higher with placebo. Levosimendan, however, significantly reduced lactic acid levels and improved patients' DO 2 profiles. These results highlight the importance of this new drug and its possible benefit with regard to myocardial injury; however, evaluation in larger, adequately powered trials is needed to determine the efficacy of levosimendan. Trial registry number: EudraCT 2012-005310-19.

The more recent studies of human pathologies have essentially revealed the complexity of the interactions involved at the different levels of integration in organ physiology. Integrated organ thus reveals functional properties not predictable by underlying molecular events. It is therefore obvious that current fine molecular analyses of pathologies should be fruitfully combined with integrative approaches of whole organ function. It follows that an important issue in the comprehension of the link between molecular events in pathologies and whole organ function/dysfunction is the development of new experimental strategies aimed at the study of the integrated organ physiology. Cardiovascular diseases are a good example as heart submitted to ischemic conditions has to cope both with a decreased supply of nutrients and oxygen, and the necessary increased activity required to sustain whole body-including the heart itself-oxygenation.By combining the principles of control analysis with noninvasive 31 P NMR measurement of the energetic intermediates and simultaneous measurement of heart contractile activity, we developed MoCA (for Modular Control and regulation Analysis), an integrative approach designed to study in situ control and regulation of cardiac energetics during contraction in intact beating perfused isolated heart (Diolez et al., Am J Physiol Regul Integr Comp Physiol 293(1):R13-R19, 2007). Because it gives real access to integrated organ function, MoCA brings out a new type of information-the "elasticities," referring to integrated internal responses to metabolic changes-that may be a key to the understanding of the processes involved in pathologies. MoCA can potentially be used not only to detect the origin of the defects associated with the pathology, but also to provide the quantitative description of the routes by which these defects-or also drugs-modulate global heart function, therefore opening therapeutic perspectives. This review presents selected examples of the applications to isolated intact beating heart that evidence different modes of energetic regulation of cardiac contraction. We also discuss the clinical application by using noninvasive 31 P cardiac energetics examination under clinical conditions for detection of heart pathologies.

Background and Aims: Levosimendan, a calcium (Ca 2+ )-sensitizing cardiotonic agent, is mainly used in patients with advanced heart failure. However, no research could explain how levosimendan reduces the mortality in advanced heart failure patients. We aim to illustrate the efficacy of levosimendan through clinical indexes., Methods: We searched PubMed, Embase, and CENTRAL from 1994 to August 2019 to compare the efficacy of levosimendan infusion for the treatment of advanced heart failure with that of other agents (placebo, dobutamine, furosemide, and prostaglandin E1). Levels of B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP), and left ventricular ejection fraction (LVEF) and heart rate (HR) were analyzed. The count data were analyzed by the standardized mean difference (SMD) and its 95% confidence interval (CI) to determine the effect size. We chose the random effect model or the fixed effect model according to the heterogeneity., Results: Nine randomized controlled trials with 413 patients were ultimately enrolled. Compared with other agents (placebo, dobutamine, furosemide, and prostaglandin E1), levosimendan significantly reduced the BNP level (SMD - 0.91; 95% CI - 1.44 to - 0.39; p = 0.001; I 2  = 74.3%) and improved the LVEF (SMD 0.74; 95% CI 0.22-1.25; p = 0.005; I 2  = 79.7%). However, levosimendan did not significantly change the HR (SMD 0.09; 95% CI - 0.24 to 0.42; p = 0.592; I 2  = 51.5%). Meanwhile, we found that the main source of heterogeneity was the use of loaded or unloaded levosimendan., Conclusion: Our meta-analysis suggests that intravenous levosimendan can reduce BNP level and increase LVEF in patients with advanced heart failure to reduce the mortality at the shortest follow-up available.

Background: Advanced heart failure (AdvHF) is associated with high morbidity and mortality. Patients with this clinical condition are potential candidates for heart transplantation or mechanical circulatory support. Initially, however, they are usually supported with inotropic drugs. Recent studies have suggested that levosimendan, independently of hemodynamic improvements, may lead to outcome benefits., Objectives: To present clinical experiences concerning the indications, effectiveness, tolerance, and safety of levosimendan in the real-life therapy of patients with decompensated AdvHF in 3 cardiac centers in Poland., Material and Methods: This is a prospective, observational, three-center study. Forty-nine patients with AdvHF admitted with decompensation were included (88% men, mean age 58 years, 65% ischemic etiology, left ventricular ejection fraction (LVEF) in median 20%) and followed up for an early (3 months) and prolonged period (1 year) after infusion of levosimendan. Patients were analyzed in relation to death., Results: Levosimendan therapy was associated with reduced HF symptoms and signs, New York Heart Association (NYHA) class and level of B-type natriuretic peptide (BNP) at discharge. Five patients died during hospitalization, a further 10 during the three-month follow-up and 3 died during the next nine-month follow-up. During the three-month follow-up, 22 patients were re-hospitalized due to HF and in the next nine-month follow-up 8 were re-hospitalized. A multivariate analysis indicated the QRS duration at discharge (hazard ratio (HR) = 1.02; 95% confidence interval (95% CI) = 1.003-1.03; p = 0.018), high-sensitivity C-reactive protein (hsCRP) (HR = 1.01; 95% CI = 1.004-1.02; p = 0.002), and simultaneous dobutamine infusion (HR = 6.54; 95% CI = 1.4-30.5; p = 0.017) were independent risk factors for death in the one-year follow-up. There were no side effects leading to the interruption of the levosimendan infusion., Conclusions: The use of levosimendan was safe and associated with clinical improvement and reduction in BNP level in AdvHF patients hospitalized due to HF decompensation, although the mortality and re-hospitalization rate during the one-year follow-up remains high.

Introduction: Veno-arterial extracorporeal membrane oxygenation may be used to support patients with refractory cardiogenic shock. Many patients can be successfully weaned, the ability of some medications to facilitate weaning from veno-arterial extracorporeal membrane oxygenation were reported. To date, there are limited studies investigating the impact of levosimendan on veno-arterial extracorporeal membrane oxygenation weaning. The objective of this systematic review and meta-analysis was to assess the effects of levosimendan on successful weaning from veno-arterial extracorporeal membrane oxygenation and survival in adult patients with cardiogenic shock., Methods: We performed a systematic review and meta-analysis (PubMed, the Cochrane Library, and the International Clinical Trials Registry Platform published from the year 2000 onwards) investigating whether levosimendan offers advantages compared to standard therapy or placebo, in cardiogenic shock adult patients treated with veno-arterial extracorporeal membrane oxygenation. The primary outcome was veno-arterial extracorporeal membrane oxygenation successful weaning, whereas secondary outcome was all-cause mortality at the longest follow-up available. We pooled risk ratio and 95% confidence interval using fixed and random effects models according to the heterogeneity., Results: A total of five non-randomized clinical trials comprising 557 patients were included, 299 patients for levosimendan and 258 patients for control groups. The pooled prevalence of veno-arterial extracorporeal membrane oxygenation successful weaning was 61.4% (95% confidence interval 39.8-82.9%), and all-cause mortality was 36% (95% confidence interval 29.6-48.8%). There was a significant increase in veno-arterial extracorporeal membrane oxygenation successful weaning with levosimendan compared to the controls (risk ratio = 1.42 (95% confidence interval 1.12-1.8), p for effect = 0.004, I 2  = 71%). A decrease risk of all-cause mortality in the levosimendan group was also observed, risk ratio = 0.62 (95% confidence interval 0.44-0.88), p for effect = 0.007, I 2  = 36%., Conclusion: The use of levosimendan on adult patients with cardiogenic shock may facilitate the veno-arterial extracorporeal membrane oxygenation weaning and reduce all-cause mortality. Few articles of this topic are available, and prospective, randomized multi-center trials are warranted to conclude decisively on the benefits of levosimendan in this setting.

Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used over the last decade in patients with refractory cardiogenic shock. ECMO weaning can, however, be challenging and lead to circulatory failure and death. Recent data suggest a potential benefit of levosimendan for ECMO weaning. We sought to further investigate whether the use of levosimendan could decrease the rate of ECMO weaning failure in adult patients with refractory cardiogenic shock., Methods: We performed an observational single-center cohort study. All patients undergoing VA-ECMO from January 2012 to December 2018 were eligible and divided into two groups: group levosimendan and group control (without levosimendan). The primary endpoint was VA-ECMO weaning failure defined as death during VA-ECMO treatment or within 24 h after VA-ECMO removal. Secondary outcomes were mortality at day 28 and at 6 months. The two groups were compared after propensity score matching. P < 0.05 was considered statistically significant., Results: Two hundred patients were analyzed (levosimendan group: n = 53 and control group: n = 147). No significant difference was found between groups on baseline characteristics except for ECMO duration, which was longer in the levosimendan group (10.6 ± 4.8 vs. 6.5 ± 4.7 days, p < 0.001). Levosimendan administration started 6.6 ± 5.4 days on average following ECMO implantation. After matching of 48 levosimendan patients to 78 control patients, the duration of ECMO was similar in both groups. The rate of weaning failure was 29.1% and 35.4% in levosimendan and control groups, respectively (OR: 0.69, 95%CI: 0.25-1.88). No significant difference was found between groups for all secondary outcomes., Conclusion: Levosimendan did not improve the rate of successful VA-ECMO weaning in patients with refractory cardiogenic shock., Trial Registration: ClinicalTrials.gov, NCT04323709 .

Background This study investigated whether levosimendan, an inotropic calcium sensitizer, when combined with moderate therapeutic hypothermia, may exert synergistic benefits on post-cardiac arrest myocardial dysfunction and improve outcomes. Methods and Results After 9.5-minute asphyxia-induced cardiac arrest and resuscitation, 48 rats were randomized equally into 4 groups following return of spontaneous circulation (ROSC), including normothermia, hypothermia, normothermia-levosimendan, and hypothermia-levosimendan groups. For the normothermia group, the target temperature was 37°C while for the hypothermia group, the target temperature was 32°C, both of which were to be maintained for 4 hours after ROSC. Levosimendan was administered after ROSC with a loading dose of 10 μg/kg and then infused at 0.1 μg/kg per min for 4 hours. In the hypothermia-levosimendan group, left ventricular systolic function and cardiac output increased significantly, whereas the heart rate and systemic vascular resistance decreased significantly compared with the normothermia group. Also, the concentrations of interleukin 1β at 4 hours post-ROSC and the production of NO between 1 hour and 4 hours post-ROSC were reduced significantly in the hypothermia-levosimendan group compared with the normothermia group. The 72-hour post-ROSC survival and neurological recovery were also significantly better in the hypothermia-levosimendan group compared with the normothermia group (survival, 100% versus 50%, χ 2 test, P =0.006). Conclusions Compared with normothermia, only combined moderate therapeutic hypothermia and levosimendan treatment could consistently improve post-cardiac arrest myocardial dysfunction and decrease the release of pro-inflammatory molecules, thereby improving survival and neurological outcomes. These findings suggest synergistic benefits between moderate therapeutic hypothermia and levosimendan.