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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. [ABSTRACT FROM AUTHOR]

Background: Acute Decompensated Heart Failure (ADHF) is a prevalent reason for hospital admissions globally each year, yet the ideal treatment approach for these patients remains undefined. Levosimendan has been shown to positively impact cardiac performance, alleviate symptoms, reduce hospital stays, and improve survival rates in patients with ADHF. The current study aimed to analyze the short- and long-term effects of levosimendan in patients with acute decompensated heart failure. Methods: This is a single-center, non-randomized, quasi-experimental, parallel-group study that assessed the outcome of acutely decompensated heart failure patients treated at Kurnool General Hospital (GGH, Kurnool). The sample size was based on determining differences in clinical status, morbidity, and mortality between the Levosimendan and placebo groups at 180 days. Results: One hundred and twenty-five (125) patients were included in the study, of which 25 patients lost follow-up. Among 100 patients who have been included in the study. In both trials, patients in the levosimendan group were discharged from the hospital earlier than those in the placebo group. Brief hospital stays (5 days) were more common in the levosimendan group than in the placebo group (46% vs. 37%), whereas long hospital stays (>10 days) were more common in the placebo group than in the levosimendan group (23% vs. 16%, P- 0.009). The Change of Mean EF which has been (calculated by the Simpson method), the improvement in ejection fraction for the first 3 months post-Levosimendan group from 30.94 SD 5.1 to 32.48 SD 5.2 with a P-value of 0.10 which is not statistically significant, but the change of EF from 30.94 to 33.08 at 6 months was statistically significant with P-value of 0.02. Conclusion: Despite the challenges inherent in the evaluation of acutely ill patients with ADHF who are receiving rapidly changing background treatments, the current study demonstrates that levosimendan can produce meaningful symptomatic benefits, improved left ventricular performance indices, reduced re-hospitalization rates and mortality benefits both in short-term and long-term in patients with acute decompensated heart failure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

Objective: To study Effects of levosimendan on myocardial perfusion and electrocardiogram indexes in patients with acute myocardial infarction after Percutaneous coronary intervention (PCI). Methods: 113 patients with acute myocardial infarction who received PCI treatment in our hospital from January 2020 to December 2022 were selected and divided into experimental group (n=57) and control group (n=56) by random number table method. The control group was treated with clopidogrel after PCI, and the experimental group was treated with levosimendan. The clinical efficacy, myocardial perfusion grade, ST segment retreat within 2 h, Tp-e/QT, CI, LVEF, LVESD, LVEDD and the incidence of complications were compared between the two groups. Results: The total effective rate of the experimental group was 89.13%, higher than that of the control group 71.11%(P<0.05). After treatment, the myocardial perfusion grade level of both groups was increased, and the increase of experimental group was more obvious(P<0.05). The ST segment in test group was better than that in control group within 2 h(P<0.05). After treatment, the Tp-e/QT level in both groups was decreased, and the decrease in test group was more obvious (P<0.05). After treatment, CI and LVEF levels were increased in both groups, more significantly in experimental group(P<0.05); LVESD and LVEDD levels were decreased in both groups, more significantly in experimental group (P<0.05); During treatment, the main adverse reactions were nausea, fever, recurrent angina pectoris and arrhythmia, and the incidence rate was compared between the two groups (P>0.05). Conclusion: Levosimendan has a good effect in PCI treatment of patients with acute myocardial infarction, which can effectively improve the level of myocardial perfusion and electrocardiogram. [ABSTRACT FROM AUTHOR]

This phase I thorough QTc, double‐blind, randomized, placebo‐ and positive‐controlled, parallel group, multiple‐dose study evaluated avacopan's effect on cardiac repolarization using concentration‐QTc (C‐QTc) as the primary analysis. Avacopan 30 mg b.i.d. (therapeutic dose) was administered orally on days 1 through 7 followed by avacopan 100 mg b.i.d. (supratherapeutic dose) on days 8 through 14 in 29 healthy participants. Moxifloxacin 400 mg and placebo were administered on days 1 and 15 in a nested crossover design for assay sensitivity in separate cohorts to 28 participants. Time‐matched plasma concentrations and up to 10 replicate ECGs were obtained on prespecified days at baseline and postdose on days 1, 7, 14, and 15. The mean change from baseline on QTcF for avacopan (−5.5 to 3.5 ms) was similar to placebo (−6.9 to 1.4 ms) across days 1, 7, and 14. The mean effect on ΔΔQTcF (90% CI) was estimated as 1.5 ms (−0.17 to 3.09) and 0.8 ms (−2.41 to 4.05) for 30 and 100 mg avacopan b.i.d. treatments, respectively. Based on the C‐QTc analysis, avacopan's effect on ΔΔQTcF >10 ms can be excluded within the observed plasma concentration range of up to ~1220 and ~335 ng/mL for avacopan and active major metabolite, M1, respectively. The estimated population slopes showed a shallow relationship, which was not statistically significant. There was no clinically meaningful effect of avacopan on heart rate or cardiac conduction (PR and QRS intervals). Avacopan appeared to be generally well tolerated in this study population. [ABSTRACT FROM AUTHOR]

Abstract 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.

Background: Patients with poor left ventricular function undergoing cardiac surgery frequently require inotropic drug support immediately after cardiopulmonary bypass. Levosimendan is an effective agent that acts via two complementary mechanisms. It enhances cardiac contractility and reduces cardiac workload. Aim: to assess the effect of histidine-tryptophan-ketoglutarate cardioplegia (HTK cardioplegia) alone or combined with preoperative infusion of levosimendan on the vasoactive inotropic score in patients with poor left ventricular function undergoing coronary artery bypass grafting. Material and method: this double-blinded randomized controlled trial was carried on 100 patients, divided into two groups; Levosimendan group (n = 49): patients received 0.1ug/kg/min levosimendan without loading, 12 hours preoperatively and continued for a total of 24 hours. Control group (n = 51): patients received a placebo 12 hours before surgery and continued for a total 24 hours. Both groups received HTK cardioplegia after cross-clamping of the aorta approximately 20 ml/kg into the ascending aorta over 6–8 minutes at a temperature of 4−10°C. Results: Levosimendan group was superior to control group with statistical significance regarding the need of intraaortic balloon pump (IABP), vasoactive inotropic score over the first 24 hours, troponin levels over the first 72 hours, ICU stays, hospital stay, and cumulative hospital costs. Although the incidence of postoperative low Cardiac output syndrome (LCOS), atrial fibrillation (AF), acute kidney injury (AKI), and overall mortality was lower in levosimendan group, but all were not statistically significant. Conclusion: Preoperative infusion of levosimendan combined with HTK cardioplegia in patients with poor cardiac function decreased vasoactive inotropic score and lowered the costs of hospital stay. [ABSTRACT FROM AUTHOR]

Cervical cancer presents a significant challenge to the global health of women. Despite substantial advances in human papillomavirus (HPV)-related cervical cancer vaccines, non-HPV-related cervical cancer is still waiting novel therapeutic options. Drug repurposing has provided a promising approach to improve cancer therapy in recent years. Our study aimed to explore the potential in vitro antineoplastic effects of levosimendan on cervical cancer cells. The antiproliferative effects of levosimendan were investigated on cervical cancer cells using a standard MTT assay. Fluorescent double staining was performed to identify its ability to induce apoptosis and necrosis. The possible mechanism of action of levosimendan was explored using cell-cycle analysis. Furthermore, antimetastatic effects were investigated using a wound-healing assay and a Boyden chamber assay. Our results revealed that levosimendan exhibited the highest growth-inhibitory effect in the HPV-negative C33A cell line. However, the effects were modest compared to the standard agent, cisplatin. Cell-cycle analysis detected that levosimendan can induce cell-cycle arrest in C33A cells by increasing the G1 and G2/M phases, decreasing the S phase, and enhancing the hypodiploid subG1 population. Levosimendan inhibited cell migration and invasion in a concentration-dependent manner. As levosimendan showed antimetastatic efficacy, it could be considered for repurposing to contribute to overcoming resistance to therapy in cervical cancer.

Abstract 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

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. [ABSTRACT FROM AUTHOR]

Despite the reduction in perioperative mortality observed over the past two decades, the risk of performing cardiac surgery in patients with coronary artery disease and severe left ventricular dysfunction remains high, these risks have led to the appearance of several ways to provide better outcomes. These ways are either mechanical like intraaortic balloon pump (IABP) or using medical inotropic drugs either adrenergic (epinephrine, norepinephrine &dobutamine) or non-adrenergic (levosimendan) drugs. It is indicated for the short-term treatment of acutely. Patients and Method:Patients had collected, evaluated thorough the preoperative, intra-operative, postoperative period withpoor left ventricular function ejection less than or equal to 40%. Cases had allocated into two gatherings of 50 cases.cases had admitted to the cardiovascular intensive care unit (ICU) 24h before surgery, a peri-operative dose of continuous levosimendan infusion over a total of 24h in the other gathering, cases will be submitted to conventional inotropes only (non levosimendan gathering) according to their medical requirements. Objective: the aim of this study had to detect the outcome of clinical use of preioperative Levosemindan for cases undergoing coronary artery bypass grafting with poor left ventricular function, also comparing it with the conventional medications as catecholamines. Results: Gathering A included 38 cases received levosimendan as perioperative cardiac support Gathering B included 40 cases received conventional cardiac support. A critical difference between both gatherings regarding total operative time, total bypass time, failure of weaning from cardiobypass (C.P.B), the use of intraoperative I.A.B.P. There had a statistically critical difference between both gatherings in which C.V. P had lower in levosimendan. There had statistically critical difference regarding base critical in the levosimendan gathering. with high statistical difference for medical support, no difference for support. Conclusion: the use of levosimendan perioperatively decrease the operative time, cross clamp time, facilitate the weaning from cardiomachine decrease the need of conventional inotropic support, decrease the duration of postoperative ventilation, improve the tissue perfusion, cardiac output parameters, length of I.C.U, hospital stay with decreasing early postoperative mortality, it had high degree of drug safety, tolerability. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hypovolemic shock is a circulatory failure, due to a loss in the effective circulating blood volume, that causes tissue hypoperfusion and hypoxia. This condition stimulates reactive oxygen species (ROS) and pro-inflammatory cytokine production in different organs and also in the central nervous system (CNS). Levosimendan, a cardioprotective inodilator, and dobutamine, a β1-adrenergic agonist, are commonly used for the treatment of hypovolemic shock, thanks to their anti-inflammatory and antioxidant effects. For this reason, we aimed at investigating levosimendan and dobutamine's neuroprotective effects in an "in vitro" model of lipopolysaccharide (LPS)-induced neuroinflammation. Human microglial cells (HMC3) were challenged with LPS (0.1 µg/mL) to induce an inflammatory phenotype and then treated with levosimendan (10 µM) or dobutamine (50 µM) for 24 h. Levosimendan and dobutamine significantly reduced the ROS levels and markedly increased Nrf2 and HO-1 protein expression in LPS-challenged cells. Levosimendan and dobutamine also decreased p-NF-κB expression and turned off the NLRP3 inflammasome together with its downstream signals, caspase-1 and IL-1β. Moreover, a reduction in TNF-α and IL-6 expression and an increase in IL-10 levels in LPS-stimulated HMC3 cells was observed following treatment. In conclusion, levosimendan and dobutamine attenuated LPS-induced neuroinflammation through NF-κB pathway inhibition and NLRP3 inflammasome activation via Nrf2/HO-1 signalling, suggesting that these drugs could represent a promising therapeutic approach for the treatment of neuroinflammation consequent to hypovolemic shock. [ABSTRACT FROM AUTHOR]

Background: The management of cardiogenic shock (CS) after ACS has evolved over time, and the development of a multidisciplinary team-based approach has been shown to improve outcomes, although mortality remains high. Methods: All consecutive patients with ACS-CS admitted at our CICU from March 2012 to July 2021 were included in this single-center retrospective study. In 2019, we established a "shock team" consisting of a cardiac intensivist, an interventional cardiologist, an anesthetist, and a cardiac surgeon. The primary outcome was in-hospital mortality. Results: We included 167 patients [males 67%; age 71 (61–80) years] with ischemic CS. The proportion of SCAI shock stages from A to E were 3.6%, 6.6%, 69.4%, 9.6%, and 10.8%, respectively, with a mean baseline serum lactate of 5.2 (3.1–8.8) mmol/L. Sixty-six percent of patients had severe LV dysfunction, and 76.1% needed ≥ 1 inotropic drug. Mechanical cardiac support (MCS) was pursued in 91.1% [65% IABP, 23% Impella CP, 4% VA-ECMO]. From March 2012 to July 2021, we observed a significative temporal trend in mortality reduction from 57% to 29% (OR = 0.90, p = 0.0015). Over time, CS management has changed, with a significant increase in Impella catheter use (p = 0.0005) and a greater use of dobutamine and levosimendan (p = 0.015 and p = 0.0001) as inotropic support. In-hospital mortality varied across SCAI shock stages, and the SCAI E profile was associated with a poor prognosis regardless of patient age (OR 28.50, p = 0.039). Conclusions: The temporal trend mortality reduction in CS patients is multifactorial, and it could be explained by the multidisciplinary care developed over the years. [ABSTRACT FROM AUTHOR]

Objectives: For patients with severe cardiopulmonary failure, such as cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is primarily utilized to preserve their life by providing continuous extracorporeal respiration and circulation. However, because of the complexity of patients' underlying diseases and serious complications, successful weaning from ECMO is often difficult. At present, there have been limited studies on ECMO weaning strategies, so the principal purpose of this meta-analysis is to examine how levosimendan contributes to the weaning of extracorporeal membrane oxygenation. Methods: The Cochrane Library, Embase, Web of Science, and PubMed were browsed for all potentially related research about clinical benefits of levosimendan in weaning patients receiving VA-ECMO and included 15 of them. The main outcome is success of weaning from extracorporeal membrane oxygenation, with the secondary outcomes of 1-month mortality (28 or 30 days), ECMO duration, hospital or intensive care unit (ICU) length of stay, and use of vasoactive drugs. Results: 1772 patients altogether from 15 publications were incorporated in our meta-analysis. We used fixed and random-effect models to combine odds ratio (OR) and 95% confidence interval (CI) for dichotomous outcomes and standardized mean difference (SMD) for continuous outcomes. The weaning success rate in the levosimendan group was considerably higher in contrast to the comparison (OR = 2.78, 95% CI 1.80–4.30; P < 0.00001; I2 = 65%), and subgroup analysis showed that there was less heterogeneity in patients after cardiac surgery (OR = 2.06, 95% CI, 1.35–3.12; P = 0.0007; I2 = 17%). In addition, the effect of levosimendan on improving weaning success rate was statistically significant only at 0.2 mcg/kg/min (OR = 2.45, 95% CI, 1.11–5.40; P = 0.03; I2 = 38%). At the same time, the 28-day or 30-day proportion of deaths in the sample receiving levosimendan also decreased (OR = 0.47, 95% CI, 0.28–0.79; P = 0.004; I2 = 73%), and the difference was statistically significant. In terms of secondary outcomes, we found that individuals undergoing levosimendan treatment had a longer duration of VA-ECMO support. Conclusions: In patients receiving VA-ECMO, levosimendan treatment considerably raised the weaning success rate and helped lower mortality. Since most of the evidence comes from retrospective studies, more randomized multicenter trials are required to verify the conclusion. [ABSTRACT FROM AUTHOR]

Objective: We conducted a systematic review to assess the advantages and disadvantages of levosimendan in patients with sepsis compared with placebo, milrinone, and dobutamine and to explore the clinical efficacy of different concentrations of levosimendan. Methods: PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wanfang data, VIP, and CBM databases were searched using such keywords as simendan, levosimendan, and sepsis. The search time was from the establishment of the database to July 2023. Two researchers were responsible for literature screening and data collection respectively. After the risk of bias in the included studies was evaluated, network meta-analysis was performed using R software gemtc and rjags package. Results: Thirty-two randomized controlled trials (RCTs) were included in the network meta-analysis. Meta-analysis results showed that while levosimendan significantly improved CI levels at either 0.1 µg/kg/min (mean difference [MD] [95%CrI] = 0.41 [-0.43, 1.4]) or 0.2 µg/kg/min (MD [95%CrI] =0.54 [0.12, 0.99]). Levosimendan, at either 0.075 µg/kg/min (MD [95% CrI] =0.033 [-0.75, 0.82]) or 0.2 µg/kg/min (MD [95% CrI] = -0.014 [-0.26, 0.23]), had no significant advantage in improving Lac levels. Levosimendan, at either 0.1 µg/kg/min (RR [95% CrI] = 0.99 [0.73, 1.3]) or 0.2 µg/kg/min (RR [95% CrI] = 1.0 [0.88, 1.2]), did not have a significant advantage in reducing mortality. Conclusion: The existing evidence suggests that levosimendan can significantly improve CI and lactate levels in patients with sepsis, and levosimendan at 0.1 µg/kg/min might be the optimal dose. Unfortunately, all interventions in this study failed to reduce the 28-day mortality. [ABSTRACT FROM AUTHOR]

To verify the impact of preoperative levosimendan on patients with severe left ventricular dysfunction (ejection fraction <35%) undergoing isolated coronary artery bypass grafting. A meta-analysis. Hospitals. The authors included 1,225 patients from 6 randomized controlled trials. None. The authors performed a meta-analysis of trials that compared preoperative levosimendan with placebo or no therapy, reporting efficacy and safety endpoints. Statistical analyses used mean differences and risk ratios (RR), with a random effects model. Six studies were included, comprising 1,225 patients, of whom 615 (50.2%) received preoperative levosimendan, and 610 (49.8%) received placebo/no therapy. Preoperative levosimendan showed a lower risk of all-cause mortality (RR 0.31; 95% CI 0.16-0.60; p < 0.01; I 2 = 0%), postoperative acute kidney injury (RR 0.44; 95% CI 0.25-0.77; p < 0.01; I 2 = 0%), low-cardiac-output syndrome (RR 0.45; 95% CI 0.30-0.66; p < 0.001; I 2 = 0%), and postoperative atrial fibrillation (RR 0.49; 95% CI 0.25-0.98; p = 0.04; I 2 = 85%) compared to control. Moreover, levosimendan significantly reduced the need for postoperative inotropes and increased the cardiac index at 24 hours postoperatively. There were no differences between groups for perioperative myocardial infarction, hypotension, or any adverse events. Preoperative levosimendan in patients with severe left ventricular dysfunction undergoing isolated coronary artery bypass grafting was associated with reduced all-cause mortality, low-cardiac-output syndrome, acute kidney injury, postoperative atrial fibrillation, and the need for circulatory support without compromising safety. [Display omitted] [ABSTRACT FROM AUTHOR]

• The primary adverse effects of levosimendan administration are hypotension and cardiac arrhythmias, particularly tachycardia. • The overall benefits of levosimendan in enhancing cardiac activity likely outweigh the magnitude of its side effects. The potential risks associated with the use of levosimendan in the pediatric population has not been systematically evaluated. This study aimed to review the available evidence regarding the safety of this treatment. Bio Med Central, PubMed, Embase, and the Cochrane Central Register of clinical trials were searched for studies describing levosimendan administration in the pediatric population in any setting. Relevant studies were independently screened, selected, and their data extracted by two investigators. The authors excluded: reviews, meta-analyses, as well as basic research and trials involving patients >18 years old. The primary outcome was the number and the type of adverse side effects reported during levosimendan administration. The updated systematic review included 48 studies, enrolling a total of 1,271 pediatric patients who received levosimendan as treatment (790 patients in the 11 studies that reported side effects). The primary adverse effects of levosimendan administration were hypotension and cardiac arrhythmias, particularly tachycardia. Hypotension occurred in approximately 28.9% of patients, while arrhythmia occurred in about 12.3% of patients. Meta analysis of RCTs revealed a rate of all-cause mortality of 2.0% (8 out of 385) in the levosimendan group compared to 3.9% (15 out of 378) in the control group (dobutamine, milrinone or placebo) (risk ratio [RR] = 0.55; 95% confidence interval [CI] = 0.25-1.21; P = 0.14; I2 = 0%) Hypotension and cardiac arrhythmia are the most reported side effects of levosimendan in pediatric patients. However, adverse events remain underreported, especially in randomized trials. [ABSTRACT FROM AUTHOR]

Inotropes are a group of drugs that alter myocardial contractility by increasing intracellular calcium or enhancing sensitivity to it. However, they may result in suboptimal myocardial oxygen supply demand ratios with impaired diastolic filling and greater arrhythmia risk. As shock is frequently encountered perioperatively and in the intensive care unit (ICU), an understanding of its pathophysiology and the pharmacology of inotropes and vasopressors is essential for their rational use. Until resolution of the primary issue, this heterogeneous group of drugs may be used in combination. However, knowing their mechanisms of action is necessary to minimize complications. With advances in our understanding of heart failure pathophysiology novel agents aim to enhance benefit with minimal harm. However, to date, none is in widespread use. Measurement of cardiac output is recommended to guide inotrope administration. This is frequently achieved with devices using pulse contour analysis or ultrasound. As mechanical support devices are more widely available current trends favour their earlier use. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Worsening heart failure (WHF) is a severe and dynamic condition characterized by significant clinical and hemodynamic deterioration. It is characterized by worsening HF signs, symptoms and biomarkers, despite the achievement of an optimized medical therapy. It remains a significant challenge in cardiology, as it evolves into advanced and end-stage HF. The hyperactivation of the neurohormonal, adrenergic and renin-angiotensin-aldosterone system are well known pathophysiological pathways involved in HF. Several drugs have been developed to inhibit the latter, resulting in an improvement in life expectancy. Nevertheless, patients are exposed to a residual risk of adverse events, and the exploration of new molecular pathways and therapeutic targets is required. This review explores the current landscape of WHF, highlighting the complexities and factors contributing to this critical condition. Most recent medical advances have introduced cutting-edge pharmacological agents, such as guanylate cyclase stimulators and myosin activators. Regarding device-based therapies, invasive pulmonary pressure measurement and cardiac contractility modulation have emerged as promising tools to increase the quality of life and reduce hospitalizations due to HF exacerbations. Recent innovations in terms of WHF management emphasize the need for a multifaceted and patient-centric approach to address the complex HF syndrome. [ABSTRACT FROM AUTHOR]

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Objective To observe the efficacy of ivabradine combined with levosimendan in patients with acute myocardial infarction complicated with heart failure. Methods A total of 78 patients with acute myocardial infarction complicated with heart failure admitted to the hospital from May 1, 2020 to December 31, 2022 were selected and divided into control group (n = 39) and study group (n = 39) by random number table method. In addition to basic treatment, the control group received levosimendan, and the study group ivabradine and levosimendan. The treatment period of both groups was 4 weeks. Compare two groups of patients' vital signs, clinical curative effect and heart function index, serological indexes, inflammatory factors and security. Results Compared with before treatment, the systolic blood pressure, diastolic blood pressure and heart rate of the two groups were decreased after treatment (P < 0.05), and the systolic blood pressure, heart rate, diastolic blood pressure and heart rate of the study group were significantly decreased compared with the control group (P < 0.05). Compared with the control group, the total effective rate of the study group was significantly higher (P < 0.05). Compared with before treatment, the levels of CO and LVEF were increased (P < 0.05), while the levels of LVEDV and LVESV were decreased (P < 0.05). Compared with the control group, the levels of CO and LVEF in the study group were higher (P < 0.05), and the levels of LVEDV and LVESV in the study group were lower (P < 0.05). Compared with before treatment, the levels of cTnI, sST2 and NT-proBNP in both groups were decreased after treatment (P < 0.05), and the serum levels of cTnI, sST2 and NT-proBNP in the study group were significantly decreased compared with the control group (P < 0.05). Tumor necrosis factor α (TNF-α), myeloperoxidase (MPO) and highly sensitive C-reactive protein (hs-CRP) were all decreased after treatment in the two groups (P < 0.05), and those in the study group were much lower (P < 0.05 ) No difference between the incidence of adverse reactions to the total contrast the two groups (P > 0.05). Conclusion Levosimendan combined with ivabadinehave a definite effect on patients with acute myocardial infarction complicated with heart failure for the improved cardiac function, reduced inflammation, regulated serum sST2, cTnI, and NT-proBNP level. It is also safe and reliable [ABSTRACT FROM AUTHOR]

Oxidative stress plays a key role in the development of heart failure. The study is a phase III, single-centre, randomized, double-blind, clinical trial that assesses the influence of early intravenous levosimendan administration in patients with decompensated CHF on oxidative stress parameters and the function of enzymatic antioxidative mechanisms. A total of 50 patients with diagnosed CHF with reduced ejection fraction, LVEF = 35% are randomized in a 1:1 ratio to receive either levosimendan or dobutamine. The hypothesis is that levosimendan in patients with decompensated heart failure may reduce ROS production and/or enhance antioxidant protection. MDA and LPO concentrations and the activity of antioxidant enzymes SOD, GPX, GR, and CAT will be measured in plasma samples. [ABSTRACT FROM AUTHOR]

BackgroundThe inotropic drug levosimendan is often used off-label perioperatively in cardiac surgery patients with cardiopulmonary bypass (CPB). Data regarding serum concentrations of levosimendan and its metabolites within this context is lacking.MethodsTotal serum concentrations (TSC) and unbound fractions (UF) of levosimendan and its metabolites OR-1896 and OR-1855 in cardiac surgery patients with CPB were retrospectively measured using LC-ESI-MS/MS. Simulation of expected levosimendan TSC was performed using Pharkin 4.0. Serum NT-proBNP was assessed with ELISA.ResultsAfter prolonged levosimendan infusion (1.25 mg or 2.5 mg, respectively) after induction of anaesthesia, a median TSC of 1.9 ng/ml and 10.4 ng/ml was determined in samples taken directly after surgery (T1). Median TSC of 7.6 ng/ml and 22.0 ng/ml, respectively, were simulated at T1. Whereas 1.1 ng/ml and 1.6 ng/ml TSC of OR-1896, respectively, was quantified the day after surgery (T2), TSC of the intermediate metabolite OR-1855 was mostly below the lower limit of quantification (LLOQ). The UF was 0.5% and 1.1% for levosimendan and 64.1% and 52.1% for OR-1896, respectively, with over half the samples being below LLOQ. No difference in NT-proBNP concentrations before surgery and T2 was detected.DiscussionThe low TSC, UF and unchanged NT-proBNP levels suggest a need for dose adjustments of levosimendan in this off-label range. In addition, the differences between the measured and estimated concentrations may suggest a possible influence of a CPB on levosimendan serum concentrations. Due to high variation of serum levels between patients, an optimized dosing regimen combined with therapeutic drug monitoring may be advisable.

Torsades de Pointes (TdP) is a malignant polymorphic ventricular tachycardia with heart rate corrected QT interval (QTc) prolongation, which may be attributed to congenital and acquired factors. Although various acquired factors for TdP have been summarized, levosimendan administration in complex postoperative settings is relatively uncommon. Timely identification of potential causes and appropriate management may improve the outcome. Herein, we describe the postoperative case of a 56-year-old female with initial normal QTc who accepted the administration of levosimendan for heart failure, suffered TdP, cardiac arrest, and possible Takotsubo cardiomyopathy, further genetically confirmed as long QT syndrome type 1 (LQT1). The patient was successfully treated with magnesium sulfate, atenolol, and implantable cardioverter defibrillator implantation. There should be a careful evaluation of the at-risk populations and close monitoring of the electrocardiograms, particularly the QT interval, to reduce the risk of near-fatal arrhythmias during the use of levosimendan.

ABSTRACTBackground Post cardiac surgery acute kidney injury (AKI) secondary to postoperative low cardiac output syndrome (LCOS), is a serious complication. Positive inotropic agents are the main line of treatment for LCOS with different degrees of improvement of cardiac function & nephroprotective efficacy Levosimendan is a calcium sensitizer in cardiac muscles, which has a comparable positive inotropic and nephroprotective effects to that of classic beta2 agonists.Objective To evaluate the possible nephroprotective effect of levosimendan as compared to beta agonists in cardiac surgery patients with LCOS.Patients and Methods It is a prospective, randomized and comparative study conducted at Ain Shams University Hospitals over the period from December 2020 to May 2021. A total of 60 patients with post cardiac surgery low cardiac output syndrome were divided into two groups of 30 patients each. Group A (control) received beta-agonists (dobutamine or adrenaline) and Group B (study) received levosimendan. The incidence of AKI at the diagnosis of LCOS & its progression to renal failure in both groups were assessed.Results The incidence of AKI at diagnosis of LCOS postoperative was 30% (n = 9) in each group; 44% of them in the control group (n = 4) developed renal failure at discharge from ICU and none of the study group patients developed renal failure at discharge. At the time of discharge from ICU, the incidence of renal failure in beta-agonist group was 13.3%, while the incidence in the levosimendan group was 0% with statistically significant P value of 0.038.Conclusion In comparison to beta-agonists, Levosimendan may have a better nephroprotective effect that plays a role in decreasing the incidence of kidney failure in patients with post cardiac surgery LCOS. A larger randomized, controlled trials are recommended to prove such a beneficial nephroprotective effect and its exact mechanism.

Abstract Background Accidental hypothermia, recognized by core temperature below 35 °C, is a lethal condition with a mortality rate up to 25%. Hypothermia-induced cardiac dysfunction causing increased total peripheral resistance and reduced cardiac output contributes to the high mortality rate in this patient group. Recent studies, in vivo and in vitro, have suggested levosimendan, milrinone and isoprenaline as inotropic treatment strategies in this patient group. However, these drugs may pose increased risk of ventricular arrhythmias during hypothermia. Our aim was therefore to describe the effects of levosimendan, milrinone and isoprenaline on the action potential in human cardiomyocytes during hypothermia. Methods Using an experimental in vitro-design, levosimendan, milrinone and isoprenaline were incubated with iCell2 hiPSC-derived cardiomyocytes and cellular action potential waveforms and contraction were recorded from monolayers of cultured cells. Experiments were conducted at temperatures from 37 °C down to 26 °C. One-way repeated measures ANOVA was performed to evaluate differences from baseline recordings and one-way ANOVA was performed to evaluate differences between drugs, untreated control and between drug concentrations at the specific temperatures. Results Milrinone and isoprenaline both significantly increases action potential triangulation during hypothermia, and thereby the risk of ventricular arrhythmias. Levosimendan, however, does not increase triangulation and the contractile properties also remain preserved during hypothermia down to 26 °C. Conclusions Levosimendan remains a promising candidate drug for inotropic treatment of hypothermic patients as it possesses ability to treat hypothermia-induced cardiac dysfunction and no increased risk of ventricular arrhythmias is detected. Milrinone and isoprenaline, on the other hand, appears more dangerous in the hypothermic setting.

Key Clinical Message: In an adolescent patient with severe yew intoxication and consecutive cardiac arrest, non‐responsive to conventional resuscitation necessitating extracorporeal life support, Levosimendan has been implemented in the early acute phase of hemodynamic stabilization, without obvious side effects. However, the additive value of this treatment in severe yew intoxication remains speculative. [ABSTRACT FROM AUTHOR]

Background and Objective: Spinal cord ischemia with subsequent paraplegia secondary to aortic coarctation repair procedures is rare, but it has serious consequences that can affect quality of life. Infrared spectroscopy (NIRS) is used for non invasive spinal cord oxygenation monitoring to estimate cord perfusion and detect early cord ischemic changes. Several pharmacological agents have been used to improve cord perfusion, the main action of these agents is to improve regional/systemic perfusion and decrease ICP. In the current study, we studied magnesium sulphate and levosimendan for their vasodilating effect that might improve spinal cord perfusion as part of spinal cord protection. Methods: Forty two infants undergoing aortic coarctectomy under general anaesthesia were registered in double blinded randomized controlled study, three groups were included; group C received i.v. saline, group L received levosimendan in loading dose 6ug/kg i.v. for 15 minutes then maintenance dose 0.1 ug/kg/min till end of surgery and group M received levosimendan in loading dose 6 ug/kg i.v. for 15 minutes then maintenance dose 0.1 ug/kg/min in combination with magnesium sulphate in loading dose 25 mg/kg i.v. for 15 minutes then maintenance dose 10 mg/kg/hr till the end of surgery. The vital signs and NIRS values assessed before, during and after clamping of aorta. Results: All baseline demographic data were comparable among all groups except for height (cm), which was significantly lower in Group L compared to Group C (p = 0.013). NIRS values were comparable among the three groups throughout experimental protocol except after cross clamp at 20 minutes, where Group M was significantly higher compared to group C (P = 0.007). Heart rate, mean arterial blood pressure, total fluid intake, urine output, aortic cross clamp time and surgical time was comparable among all groups, were comparable among 3 studied groups. Conclusion: Adding magnesium sulphate to levosimendan has showed improvement in spinal cord perfusion during cross clamping as monitored by NIRS when compared to use of levosimendan alone or placebo in coarctectomy operations without affecting hemodynamics. [ABSTRACT FROM AUTHOR]

Background: Post cardiac surgery acute kidney injury (AKI) secondary to postoperative low cardiac output syndrome (LCOS), is a serious complication. Positive inotropic agents are the main line of treatment for LCOS with different degrees of improvement of cardiac function & nephroprotective efficacy Levosimendan is a calcium sensitizer in cardiac muscles, which has a comparable positive inotropic and nephroprotective effects to that of classic beta2 agonists. Objective: To evaluate the possible nephroprotective effect of levosimendan as compared to beta agonists in cardiac surgery patients with LCOS. Patients and Methods: It is a prospective, randomized and comparative study conducted at Ain Shams University Hospitals over the period from December 2020 to May 2021. A total of 60 patients with post cardiac surgery low cardiac output syndrome were divided into two groups of 30 patients each. Group A (control) received beta-agonists (dobutamine or adrenaline) and Group B (study) received levosimendan. The incidence of AKI at the diagnosis of LCOS & its progression to renal failure in both groups were assessed. Results: The incidence of AKI at diagnosis of LCOS postoperative was 30% (n = 9) in each group; 44% of them in the control group (n = 4) developed renal failure at discharge from ICU and none of the study group patients developed renal failure at discharge. At the time of discharge from ICU, the incidence of renal failure in beta-agonist group was 13.3%, while the incidence in the levosimendan group was 0% with statistically significant P value of 0.038. Conclusion: In comparison to beta-agonists, Levosimendan may have a better nephroprotective effect that plays a role in decreasing the incidence of kidney failure in patients with post cardiac surgery LCOS. A larger randomized, controlled trials are recommended to prove such a beneficial nephroprotective effect and its exact mechanism. [ABSTRACT FROM AUTHOR]

OR-1896 ((R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide) is the main active metabolite of levosimendan. However, nobody has reported a positive inotropic effect of OR-1896 in isolated human cardiac preparations. The mechanism of action of OR-1896 remains controversial. Hence, we wanted to know whether OR-1896 exerts a positive inotropic effect in humans and what might be the underlying mechanism. Therefore, we measured the contractile effects of OR-1896 (0.01–10 µM cumulatively applied) in isolated electrically stimulated (1 Hz) human right atrial preparations (HAP) obtained during cardiac surgery. OR-1896, given alone, exerted time- and concentration-dependent positive inotropic effects; 1-µM OR-1896 increased force by 72 ± 14.7% (p < 0.05, n = 6) and shortened the time of relaxation by 10.6 ± 3.6% (p < 0.05, n = 11) in HAP started at 0.1 µM, plateaued at 1-µM OR-1896, and was antagonized by 1-µM propranolol. The maximum positive inotropic effect of OR-1896 in human right atrial preparations was less than that of 10-µM isoprenaline. EMD 57033 (10 µM), a calcium sensitizer, enhanced the force of contraction further in the additional presence of 1-µM OR-1896 by 109 ± 19% (p < 0.05, n = 4). Cilostamide (10 µM), an inhibitor of phosphodiesterase III given before OR-1896 (1 µM), blocked the positive inotropic effect of OR-1896 in HAP. Our data suggest that OR-1896 is, indeed, a positive inotropic agent in the human heart. OR-1896 acts as a PDE III inhibitor. OR-1896 is unlikely to act as a calcium sensitizer in the human heart. [ABSTRACT FROM AUTHOR]

Aim: The LeoDOR trial explored the efficacy and safety of intermittent levosimendan therapy in the vulnerable phase following a hospitalization for acute heart failure (HF). Methods and results: In this prospective multicentre, double‐blind, two‐armed trial, patients with advanced HF were randomized 2:1 at the end of an index hospitalization for acute HF to intermittent levosimendan therapy or matching placebo for 12 weeks. All patients had left ventricular ejection fraction (LVEF) ≤30% during index hospitalization. Levosimendan was administered according to centre preference either as 6 h infusion at a rate of 0.2 μg/kg/min every 2 weeks, or as 24 h infusion at a rate of 0.1 μg/kg/min every 3 weeks. The primary efficacy assessment after 14 weeks was based on a global rank score consisting of three hierarchical groups. Secondary clinical endpoints included the composite risk of tiers 1 and 2 at 14 and 26 weeks, respectively. Due to the COVID‐19 pandemic, the planned number of patients could not be recruited. The final modified intention‐to‐treat analysis included 145 patients (93 in the combined levosimendan arm, 52 in the placebo arm), which reduced the statistical power to detect a 20% risk reduction in the primary endpoint to 60%. Compared with placebo, intermittent levosimendan had no significant effect on the primary endpoint: the mean rank score was 72.55 for the levosimendan group versus 73.81 for the placebo group (p = 0.863). However, there was a signal towards a higher incidence of the individual clinical components of the primary endpoint in the levosimendan group versus the placebo group both after 14 weeks (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.12–7.68; p = 0.021) and 26 weeks (HR 1.64, 95% CI 0.87–3.11; p = 0.122). Conclusions: Among patients recently hospitalized with HF and reduced LVEF, intermittent levosimendan therapy did not improve post‐hospitalization clinical stability. [ABSTRACT FROM AUTHOR]

Objective • To systematically evaluate the effect of levosimendan on cardiac function and outcomes in patients with sepsis. Method • We searched multiple databases including CNKI, VIP, WanFang Data, WOS, PubMed, EMbase, and The Cochrane Library up to February 2023. We targeted RCTs comparing levosimendan with dobutamine as a control for treating sepsis. After a rigorous screening and quality evaluation, 18 studies were selected for metaanalysis using Review Manager 5.4. Results • Out of 18 studies involving 980 sepsis patients, the meta-analysis revealed the following for the levosimendan group compared to dobutamine: (1) A significant reduction in mortality rate (OR = 0.63, 95% CI (0.42,0.95), P = .03). (2) Shortened ICU stay (MD = -2.55, 95% CI (-3.12, -1.98), P < .00001). (3) Increased left ventricular ejection fraction (LVEF) (MD = 6.05, 95%CI (5.28, 6.81), P < .00001) and cardiac index (CI) (MD = 0.47, 95%CI (0.35, 0.59), P < .00001). (4) Decreased blood lactate (Lac) (MD = -1.31, 95%CI (-1.73, -0.90), P < .00001) and troponin I (TnI) levels (MD = -0.43, 95%CI (-0.66, -0.21), P = .0002). (5) Reduced incidence of adverse events (OR = 0.43, 95% CI (0.23,0.81), P = .008). Conclusions • Compared to dobutamine, levosimendan substantially enhances cardiac function in sepsis patients, leading to improved outcomes and fewer adverse events. [ABSTRACT FROM AUTHOR]

Background: Accidental hypothermia, recognized by core temperature below 35 °C, is a lethal condition with a mortality rate up to 25%. Hypothermia-induced cardiac dysfunction causing increased total peripheral resistance and reduced cardiac output contributes to the high mortality rate in this patient group. Recent studies, in vivo and in vitro, have suggested levosimendan, milrinone and isoprenaline as inotropic treatment strategies in this patient group. However, these drugs may pose increased risk of ventricular arrhythmias during hypothermia. Our aim was therefore to describe the effects of levosimendan, milrinone and isoprenaline on the action potential in human cardiomyocytes during hypothermia. Methods: Using an experimental in vitro-design, levosimendan, milrinone and isoprenaline were incubated with iCell2 hiPSC-derived cardiomyocytes and cellular action potential waveforms and contraction were recorded from monolayers of cultured cells. Experiments were conducted at temperatures from 37 °C down to 26 °C. One-way repeated measures ANOVA was performed to evaluate differences from baseline recordings and one-way ANOVA was performed to evaluate differences between drugs, untreated control and between drug concentrations at the specific temperatures. Results: Milrinone and isoprenaline both significantly increases action potential triangulation during hypothermia, and thereby the risk of ventricular arrhythmias. Levosimendan, however, does not increase triangulation and the contractile properties also remain preserved during hypothermia down to 26 °C. Conclusions: Levosimendan remains a promising candidate drug for inotropic treatment of hypothermic patients as it possesses ability to treat hypothermia-induced cardiac dysfunction and no increased risk of ventricular arrhythmias is detected. Milrinone and isoprenaline, on the other hand, appears more dangerous in the hypothermic setting. [ABSTRACT FROM AUTHOR]

Background: Patients with acute myocardial infarction are at greater risk for chronic heart failure and mortality. Currently, there is limited evidence supporting the beneficial effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular outcomes in non-diabetic patients with reduced left ventricular ejection fraction following acute myocardial infarction. Furthermore, the clinical effects of the combination of standard-dose sodium-glucose cotransporter-2 inhibitors with colchicine and high-dose sodium-glucose cotransporter-2 inhibitors in this setting have not been evaluated yet. Methods: A prospective, double-blinded, parallel-group, placebo control randomized trial will be carried out at Shahid Madani Heart Center, the largest teaching referral hospital for cardiovascular diseases, affiliated with Tabriz University of Medical Sciences. A total of 105 patients with reduced left ventricular ejection fraction (≤ 40%) following the first episode of ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention with stent insertion will be randomized 1:1:1 to receive empagliflozin 10 mg daily, a combination of empagliflozin 10 mg daily and colchicine 0.5 mg twice daily, or empagliflozin 25 mg daily for 12 weeks. The primary outcomes are changes in the New York Heart Association functional classification and high-sensitivity C-reactive protein from the randomization through week 4 and week 12. Discussion: The present study will be the first trial to evaluate the efficacy and safety of early treatment with the combination of standard-dose empagliflozin and colchicine as well as high-dose empagliflozin in non-diabetic patients with reduced left ventricular ejection fraction following ST-elevation myocardial infarction. The results of this research will represent a significant step forward in the treatment of patients with acute myocardial infarction. Trial registration: Clinical trial ID: IRCT20111206008307N39. Registration date: 27 October 2022. [ABSTRACT FROM AUTHOR]

Objective • This study aims to investigate the effectiveness of levosimendan in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection complicated by cardiac insufficiency and myocardial injury. Methods • A total of 22 patients with SARS-CoV-2 infection and myocardial injury, admitted to the Cardiology Department of our hospital between December 2022 and February 2023, are randomly divided into two groups: a dobutamine general treatment group and a levosimendan observation treatment group. The treatment outcomes of the two groups are compared and analyzed. Results • The overall improvement rate in the general treatment group is 80%, while the levosimendan treatment group shows a 100% improvement rate. There is a statistically significant difference between the two groups (P<.05). Posttreatment, the left ventricular ejection fraction for the general treatment group and the levosimendan treatment group are (48 ± 7)% and (54 ± 6)%, respectively. Additionally, the left ventricular end-diastolic diameter is (55.0 ± 3.0) mm in the general treatment group and (51 ± 5.0) mm in the levosimendan group, with a statistically significant difference (P<.05). After active treatment, the plasma levels of B-type natriuretic peptide (Brain Natriuretic Peptide, NT-proBNP) are significantly lower in the levosimendan treatment group than in the general treatment group (P<.05). Moreover, the plasma levels of interleukin-6 (IL-6) and C-reactive protein (CRP) in the levosimendan group decrease slightly faster than those in the general treatment group, with a statistically significant difference (P<.05). The length of hospital stay in the levosimendan group is (12±3) days, significantly lower than the general treatment group (16±5) days, with a statistically different result (P<.05). Conclusions • Levosimendan demonstrates significant efficacy in patients with novel coronavirus infection complicated by myocardial injury, resulting in improved clinical symptoms, enhanced cardiac function, shorter hospital stays, early discharge, and cost savings. [ABSTRACT FROM AUTHOR]

Objective • This meta-analysis aims to evaluate the effects of levosimendan on B-type natriuretic peptide (BNP) levels in patients with decompensated heart failure and assess the efficacy and safety of levosimendan in treating left heart failure. Methods • Randomized controlled trials (RCTs) were identified through searches in the Chinese Biomedical Literature Database (CBM), Chinese Academic Journal Full Text Database (CNKI), Wanfang Database (CECDB), VIP Chinese Scientific, PubMed, Cochrane Library, and Web of Science. Quality assessment and data extraction were performed for the included studies, and meta-analysis was conducted using Review Manager 5.2 software. Results • The meta-analysis revealed a statistically significant difference in the regulatory effect of levosimendan on BNP levels in patients with stage III heart failure compared to the control group [OR = 2.12, 95% CI (1.22, 3.67), P = .008, I2 = 37%, Z = 2.67]. Additionally, leosimendan showed a significant effect on BNP levels in patients with stage IV heart failure [OR = 1.88, 95% CI (1.27, 2.79), P = .002, I2 = 0%, Z = 3.14], compensatory heart failure [OR=2.97, 95% CI (1.81, 4.86), P < .0001, I2 = 55%, Z = 4.32], and decompensated heart failure [OR=1.98, 95% CI (1.59, 2.47), P<.00001, I2=76%, Z=6.07]. Conclusions • Levosimendan administration demonstrated improved cardiac function and a significant reduction in plasma BNP levels in patients with decompensated heart failure. [ABSTRACT FROM AUTHOR]

Background: Maintaining a low left atrial pressure (LAP) in off-pump coronary artery bypass grafting (OPCAB) is desirable. This study was done to compare the effects of intravenous levosimendan or milrinone on LAP at different stages of OPCAB. Materials and Methods: After institutional ethics committee clearance, this two-arm double-blind randomized control trial was done in 44 adult patients with triple vessel coronary artery disease undergoing OPCAB at cardiac OT of IPGME&R, Kolkata. The patients were randomly allocated into two groups receiving intraoperative either levosimendan or milrinone. Pulmonary capillary wedge pressure (PCWP) was compared as the primary outcome parameter, whereas other echocardiographic and hemodynamic parameters were also assessed during six stages of OPCAB, that is, after sternotomy, proximal(s), left anterior descending artery (LAD), obtuse marginal (OM), posterior descending artery (PDA) grafting, and before sternal closure. Numerical parameters were compared using Student's unpaired two-tailed t-test. Results: PCWP was found to be significantly lower (P < 0.05) in the levosimendan group during proximal (P = 0.047), LAD (P = 0.018), OM (P < 0.0001), PDA grafting (P = 0.028), and before sternal closure (P = 0.015). Other parameters indicate LAP, that is, from mitral early diastolic inflow velocity to mitral annular early diastolic velocity ratio (E/e'), which indicated significantly lower LAP in levosimendan group during LAD, OM, and PDA grafting and before sternal closure. Conclusion: Levosimendan may be used as a primary inotrope in terms of better reduction in left atrial pressure during different stages of OPCAB, translating to a decrease in left ventricular end-diastolic pressure, therefore maintaining optimum coronary perfusion pressure, which is the primary goal of the surgery. [ABSTRACT FROM AUTHOR]