Mechanism of levosimendan in treating hypoxic pulmonary hypertension based on network pharmacology and molecular docking technology / 中国药理学通报

Aim To explore the efficacy of levosimendan on hypoxia pulmonary hypertension through animal experiments, and to further explore the potential mechanism of action using network pharmacological methods and molecular docking technique. Methods The rat model of hypoxia pulmonary hypertension was constructed to detect right heart systolic pressure and right heart remodeling index. HE , Masson, and VG staining were core targets were screened out. GO and KEGG pathway enrichment analysis were performed using the DAVID database. Molecular docking of the core targets was performed with the AutoDock software. Results The results of animal experiments showed that levosimendan had obvious therapeutic effect on hypoxia pulmonary hypertension. The network pharmacology results showed that SRC, HSP90AA1, MAPK1, PIK3R1, AKT1, HRAS, MAPK14, LCK, EGFR and ESR1 used to analyze the changes of rat lung histopathology. Search the Swiss Target Prediction, DrugBank Online, BatMan, Targetnet, SEA, and PharmMapper databases were used to screen for drug targets. Disease targets were retrieved from the GeneCards, OMIM databases. The "drug-target-disease" network was constructed after identification of the two intersection targets. The protein interaction network was constructed and the were the key targets to play a therapeutic role. Molecular docking showed good docking of levosimendan with all the top five core targets with degree values. Conclusions Levosimendan may exert a therapeutic effect on hypoxia-induced pulmonary hypertension through multiple targets.

The effect of levosimendan on the right ventricular function in patients with right ventricular dysfunction undergoing mitral valve surgery

Background: Right ventricular (RV) dysfunction is an important predictor of both immediate and long-term outcomes in valve surgeries. Levosimendan has proven beneficial in improving RV function. Aims: The objective was to study the effect of the addition of levosimendan to the conventional treatment on RV function in patients with RV dysfunction undergoing mitral valve (MV) surgeries. Setting and Design: Prospective randomized double-blinded controlled study at a tertiary care institution. Materials and Methods: Sixty adult patients aged 15� years, with preoperative transthoracic echocardiography (TTE) findings of RV dysfunction posted for elective MV surgery, were randomized into levosimendan (L) group and placebo (P) group. Patients in the L group were administered levosimendan at a rate of 0.1 mcg/kg/min after induction for 24 hrs, whereas patients in the P group were given multivitamin infusion at the same rate. Both the groups received standard inotropic therapy. The hemodynamic and echocardiographic parameters of RV function (RV size, Inferior vena cava (IVC) diameter, RV fractional area change (RVFAC) Tricuspid annular plane systolic excursion (TAPSE), and Systolic Pulmonary Artery Pressure (SPAP) were compared between the groups at 6 hrs, 24 hrs, and 7th day postoperatively. Results: All hemodynamic and echocardiographic parameters of RV function like RV size, IVC diameter, RVFAC, TAPSE, and SPAP improved from baseline to 24 hrs in both groups. Levosimendan caused a significant improvement in RV function compared to the P group at 24 hrs and 7th day postoperatively. Conclusions: The present study concludes that levosimendan is a promising option in patients with RV dysfunction undergoing MV surgeries.

Safety and efficacy of levosimendan in patients with acute heart failure: a prospective, multicenter, and observational study / 中华急诊医学杂志

Objective:To investigate the indication, effectiveness, tolerance, and safety of levosimendan in patients with acute heart failure (AHF) in 20 hospitals in Beijing, China.Methods:This prospective, observational, and multicenter study consecutively enrolled AHF patients who were treated with levosimendan at 20 hospitals in Beijing from April 2020 to March 2022. Baseline demographics, laboratory parameters, clinical presentation, concomitant diseases and medications were collected. After initiation of levosimendan, levosimendan administration, laboratory parameter pre- and post-administration, symptoms improvement, and adverse events were also collected.Results:Totally 800 AHF patients were included, 67% of whom were male, aged (65 ±17) years, 50% of whom had ischemic heart disease, and the left ventricular ejection fraction (LVEF) was (36±11)%. The dose of levosimendan was (11.84 ±2.11) mg and the mean infusion time was (1 450±307) min. Dyspnea was improved in 83.4% of AHF patients at 24 h after treatment. The level of B-type natriuretic peptide (BNP) significantly decreased from 689 (406-1509) pg/mL to 410 (156-697) pg/mL in all patients at 24-72 h after treatment ( P<0.001), and the level of N-terminal pro-brain natriuretic peptide (NT-pro BNP) decreased from 6910 (3 715-13 914) pg/mL to 2 851 (1 288-6 191) pg/mL ( P<0.001). Meanwhile, LVEF level also improved significantly [(40±11)% vs. (36±11)%, P<0.001]. During levosimendan administration, adverse events occurred in 74 (9.3%) patients, including hypotension (5.9%), arrhythmia (1.9%), and other symptoms (1.1%). Among them, 7 patients ( 2 patients with hypotension and 5 patients with ventricular tachycardia) interrupted levosimendan administration. Conclusions:The use of levosimendan is safe, and can improve symptoms reduce BNP or NT-pro BNP levels and increase LVEF level in AHF patients.

Measures to Improve In?Hospital Outcomes of Patients Undergoing Surgical Repair for Anomalous Origin of Left Coronary Artery from Pulmonary Artery

Background:Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly leading to progressive left ventricular dysfunction and mitral regurgitation. We conducted this study to investigate various measures to optimize the outcomes of surgical correction for ALCAPA. Materials And Methods: This was a single?centre, retrospective, observational study including consecutive patients operated for ALCAPA. The main outcomes evaluated were in?hospital mortality, duration of mechanical ventilation, and duration of intensive care unit (ICU) stay. Independent sample t? test and Fisher’s exact test were used for the analysis of continuous and categorical variables respectively. Results: 31 patients underwent surgical correction for ALCAPA during the study duration. The median age was 7.3 months with a range of 21 days to 25 months. All patients underwent coronary re?implantation with the coronary button transfer technique. There was no in?hospital mortality, the mean duration of mechanical ventilation and ICU stay was 117.6 hours and 10.7 days respectively. Age at admission, development of acute kidney injury after surgery, lactate levels at 12? and 24?hours post?surgery, and heart rate at ICU admission and 12?hours post?surgery were significantly associated with mechanical ventilation duration longer than 48 hours. Use of a combination of levosimendan and milrinone and elective intermittent nasal continuous positive airway pressure ventilation after extubation in all patients with severe left ventricular dysfunction were helpful in preventing low cardiac output and need for reintubation post?surgery respectively. Conclusion: Surgical correction for ALCAPA by coronary re?implantation has an excellent short?term outcome. Optimal postoperative management is of utmost importance for achieving the best results.

Levosimendan: evolution over last two decades

Levosimendan was maiden agent at the time of its emergence, promoting inotropy mainly through calcium sensitization of cardiac troponin C(cTnC). Levosimendan seems a lucrative option but has not demonstrated a clear superiority to other inotropes in well-designed trials. We searched the PubMed database and reviewed the pertinent studies published till 2021 and summarized various trials/studies to come to a consensus regarding its indications in cardiac patients.Patients with decompensated heart failure requiring inotropic support and receiving beta-blockers represent most widely accepted indication. Levosimendan infusions are increasingly used to facilitate extracorporeal membrane oxygenation (ECMO) weaning and avoiding hospitalizations in patients with end-stage heart failure. Levosimendan doesn抰 seem to have long term survival benefit in ventricular dysfunction patients undergoing surgery. The evidence supporting therole in right ventricular failure is not well-established.These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.

Effects of levosimendan on the hypoxic / reoxygenated cardiomyocyte fibrosis by regulating long chain noncoding RNA / microRNA-641 / 解剖学报

[Abstract] Objective To investigate whether levosimendan (Lev) affects hypoxia / reoxygenation (H / R) - induced cardiomyocyte proliferation, apoptosis and fibrosis by regulating the molecular axis of long chain noncoding RNA (LncRNA) eosinophil granule ontogeny transcript (EGOT) / microRNA (miR) -641. Methods Rat cardiomyocytes H9C2 were cultured in vitro, and H / R-treated cells were used to establish cell damage models, which were randomly divided into control group, H / R group, H / R + Lev 1 μmol / L (H / R + Lev-L) group, H / R + Lev 5 μmol / L (H / R + Lev-M) group, and H / R + Lev 10 μmol / L (H / R + Lev-H) group, 9 samples per group. MTT method was used to detect cell proliferation. Flow cytometry was used to detect the apoptosis rate. Real-time P CR was used to detect the expression levels of EGOT and miR-641 mRNA. P cDNA-EGOT and EGOT small interfering RNA (si-EGOT) were transfected into H9 C2 cells respectively, and the cell proliferation and apoptosis rates were detected by the above method. The dual luciferase report experiment verified the targeting relationship between EGOT and miR-641. Western blotting was used to detect the expression levels of Bax, Bcl-2, collagen I (colI), collagen Ⅲ (col Ⅲ), tissue inhibitor of matrix metalloproteinase 2 (TIMP 2), matrix metalloproteinase-2 (MMP -2) . Results Compared with the control group, the cell survival rate of the H / R group reduced significantly (P < 0. 05), the apoptosis rate increased significantly (P < 0. 05), and the protein levels of Bax, c I, col Ⅲ, TIMP 2, and MMP -2 increased significantly (P < 0. 05), the level of Bcl-2 protein reduced significantly (P < 0. 05), the expression level of EGOT reduced significantly (P < 0. 05), the expression level of miR-641 increased significantly (P < 0. 05) . Compared with the H / R group, the cell survival rate of the H / R + Lev-L group, H / R + Lev-M group, and H / R + Lev-H group increased significantly (P < 0. 05), and the apoptosis rate decreased significant (P < 0. 05), the protein levels of Bax, colI, colⅢ, TIMP 2, MMP -2 reduced significantly (P < 0. 05), the level of Bcl-2 protein increased significantly (P < 0. 05), the expression level of EGOT increased significantly (P < 0. 05), the expression level of miR-641 reduced significantly (P < 0. 05), and each index of H / R + Lev-L group, H / R + Lev-M group, H / R + Lev-H group, the difference was statistically significant (P < 0. 05) . The dual luciferase report experiment confirmed that EGOT ccould target and bind to miR-641. The effect of transfecting pcDNA-EGOT and Lev was similar. Transfection of si-EGOT could reduce the effect of Lev on H / R-induced proliferation, apoptosis and fibrosis of H9 C2 cells. Conclusion Levosimendan may promote H / R-induced H9 C2 cell proliferation and inhibit apoptosis and fibrosis by up-regulating EGOT expression and down-regulating miR-641 expression.

Clinical observation of intermittently repeated application of levosimendan in the treatment of right heart failure of pulmonary hypertension / 中国药房

OBJECTIVE To observe th e efficacy and safety of intermittently repeated application of levosimendan in the treatment of right heart failure of pulmonary hypertension. METHODS A total of 70 cases of right heart failure of pulmonary hypertension were collected from the First Affiliated Hospital of Guangxi Medical University during Jan. 2019-May 2021，and then randomly divided into control group and observation group ，with 35 cases in each group.In control group ，the patients with moderate risk of classification of pulmonary hypertension were given Tadalafil tablets and Ambrisentan tablets ，while the patients with high risk were given Tadalafil tablets ，Ambrisentan tablets and Treprostinil injection ；both were given anti-right heart failure drugs at the same time. On the basis of treatment in the control group ，patients in the observation group were additionally intravenously pumped with levosimendan injection 12.5 mg，once a month ，at a rate of 0.05-0.1 μg/（kg·min），3 months in total. Response rate of therapy ，improvement of risk stratification of pulmonary hypertension after treatment ，and average pulmonary artery pressure ，six-minute walk distance （6MWD），serum level of N-terminal pro brain natriuretic peptide （NT-proBNP），right atrial pressure （RAP），oxygen saturation in mixed venous blood （SvO2），cardiac index （CI），right ventricular ejection fraction （RVEF），early diastolic tricuspid inflow velocity/early diastolic tricuspid annular velocity （E/Ea），tricuspid annular plane systolic excursion（TAPSE），right ventricular end-diastolic diameter （RVEDD），right ventricular end-systolic diameter （RVESD）before and after treatment ，and the occurrence of adverse reactions were observed in 2 groups. RESULTS The total response rate of observation group was significantly higher than control group after treatment （P＜0.05）. After treatment ，average pulmonary artery pressure，NT-proBNP level ，RAP，E/Ea，RVEDD and RVESD of 2 groups were significantly lower than before treatment ，while 6MWD，SvO2， CI， TAPSE and RVEF were significantly higher than before treatment ；NT-proBNP level and E/Ea of observation group were significantly lower than control group ， while 6MWD，CI，TAPSE and RVEF were significantly higher than control group （P＜0.05 or P＜0.01）. There was no significant difference in average pulmonary artery pressure ， risk stratification improvement cases of pulmonary hypertension ， RAP， SvO2， RVEDD， RVESD and the incidence of asymptomatic hypotension between 2 groups（P＞0.05）. CONCLUSIONS Intermittently repeated application of levosimendan can improve the function of right heart of pulmonary hypertension complicated with right heart failure and has good safety.

Mechanism of levosimendan on acute kidney injury after cardiopulmonary resuscitation in rats / 中华急诊医学杂志

Objective:To investigate the mechanism of levosimendan on acute kidney injury after cardiopulmonary resuscitation (CPR) in rats.Methods:Twenty-five healthy adult male SD rats were randomly divided into three groups: control group ( n=5), levosimendan group ( n=10) and experimental group ( n=10). A cardiac arrest-cardiopulmonary resuscitation model was established using smothering method in the experimental group and levosimendan group. The levosimendan group was treated with levosimandan during and after resuscitation, while the experimental group was given equivalent volume of saline solution during and after resuscitation, and the control group was only given equivalent volume of saline without performance of CPR. The rats in the three groups were sacrificed at 6 h after resuscitation. The serum and kidney tissue samples were collected. Serum biochemical indicators [serum creatinine (Scr), blood urea nitrogen (Bun), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)] were measured. HE staining and Paller score were used to identify the degree of kidney damage. Apoptosis was estimated by TUNEL staining. Western blot was used to detect the expression levels of phosphorylation of extracellular regulated protein kinases (p-ERK). One-way analysis of variance was used to compare the mean values of normally distributed measurement data between groups. Comparisons between groups were performed using the least significant difference t-test. Results:Scr (85.02±1.31) μmol/L, Bun (7.36±0.13) mmol/L, Paller score (7.3±0.2), IL-1β (302.20±17.35) pg/mL, IL-6 (564.60±23.24) pg/mL and TNF-α (1346±83.73) pg/mL in the experimental group were significantly higher than those of the control group [(15.94±0.96) μmol/L, (2.95±0.18) mmol/L, (0.7±0.2), (7.27±0.44) pg/mL, (51.30±2.87) pg/mL, and (10.39±0.52) pg/mL] (all P<0.01). Compared with the experimental group, Scr (63.88±2.01) μmol/L, Bun (5.45±0.47) mmol/L, paller score (4.8±0.2), IL-1β (78.61±3.66) pg/mL, IL-6 (297.90±13.64) pg/mL and TNF-α (276.2±20.18) pg/mL were significantly decreased in the levosimendan group (all P<0.01). TUNEL staining showed that levosimendan could improve the apoptosis of renal cells ( P<0.01). The expression of p-ERK protein in the levosimendan group was significantly higher than that in the experimental group ( P<0.01). Conclusions:Lovosimendan could attenuate acute kidney injury following cardiac arrest and cardiopulmonary resuscitation via suppression apoptosis. The mechanism of levosimendan protective effect might be associated with activation of ERK signaling pathway.

Levosimendan combined with Shengmai injection for the treatment of pump failure in 55 patients with acute myocardial infarction / 中国基层医药

Objective:To investigate the effects of levosimendan combined with Shengmai injection on pump failure in patients with acute myocardial infarction and its effects on tissue perfusion and oxygen metabolism. Methods:A total of 110 patients with acute myocardial infarction and pump failure who received treatment in Jiaozhou People's Hospital (South Branch) from July 2019 to December 2020 were included in this study. They were randomly assigned to receive either routine treatments including electrocardiography monitoring, oxygen saturation monitoring, oxygen therapy, dual antiplatelet therapy, statins, vasoactive drugs, and nitrates (control group, n = 55) or levosimendan combined with Shengmai injection based on routine treatments (observation group, n = 55) for 10 successive days. Curative efficacy, cardiac function, tissue perfusion, and oxygen metabolism capacity were compared between the control and observation groups. The 1-month mortality rate was compared between the two groups. Results:Total effective rate was significantly higher in the observation group than in the control group [58.18% (32/55) vs. 38.18% (21/55), χ2 = 4.41, P < 0.05]. After treatment, left ventricular end-diastolic diameter, left ventricular ejection fraction, and stroke volume were superior in the observation group to in the control group ( t = 2.12, –5.85, –7.33, all P < 0.05). Oxygen partial pressure, oxygenation index, central venous oxygen saturation, lactate, lactate clearance rate, and urine volume in the observation group were (103.53 ± 9.85) mmHg, (247.69 ± 18.95) mmHg, (77.56 ± 3.59)%, (3.02 ± 0.45) mmol/L, (42.89 ± 5.22)%, (40.88 ± 1.64) mL/hour, respectively, and they were (95.47 ± 11.98) mmHg, (194.69 ± 16.52) mmHg, (70.88 ± 2.13)%, (3.58 ± 0.51) mmol/L, (36.89 ± 5.14)%, and (36.55 ± 2.23) mL/hour, respectively in the observation group. There were significant differences in these indices between the control and observation groups ( t = –3.85, –15.64, –11.87, 3.11, –6.07, –11.27, all P < 0.001). At 1 month of follow-up, mortality rate was significantly lower in the observation group than in the control group [3.64% (2/55) vs. 16.36% (9/55), χ2 = 4.95, P < 0.05]. Conclusion:Levosimendan combined with Shengmai injection is a highly effective treatment for pump failure in acute myocardial infarction. It can improve cardiac function and tissue perfusion, increase oxygen metabolism capacity, and decrease mortality.

The clinical efficacy of levosimendan in the treatment of patients with acute myocardial infarction combined with cardiogenic shock and its effects on monitoring hemodynamic parameters of pulse index continuous cardiac output / 中国医师进修杂志

Objective:To observe the clinical efficacy of levosimendan in the treatment of patients with acute myocardial infarction (AMI) combined with cardiogenic shock (CS) and its effects on monitoring hemodynamic parameters of pulse index continuous cardiac output (PICCO).Methods:One hundred and six patients with AMI combined with CS admitted and treated in Jiaxing Second Hospital from June 2017 to December 2019 were divided into the control group and observation group according to the random number table method , with 53 cases in each group. The control group received routine comprehensive intervention, while the observation group received levosimendan treatment based on the control group. In observation group, 12 μg/kg of levosimendan was administered intravenously within 10 min, then, 0.1 μg/(kg·min) was administered intravenously and continued for 24 h. In control group, 5% glucose injection was administered intravenously, and the intravenous infusion rate and time was same as that in observation group. Both groups were treated for 24 h. PICCO was used to monitor the hemodynamic parameters , including heart rate (HR), central venous pressure (CVP), cardiac index (CI), global end-diastolic volume index (GEDVI) and extravascular lung water index (EVLWI) before and after the treatment; the neurohumoral indexes including norepinephrine (NE), angiotensinⅡ(AngⅡ); cardiac function indexes including stroke volume (SV), left ventricular ejection fraction (LVEF), and the efficacy and complications were observed and compared between two groups.Results:After 24 h of treatment, the levels of HR, CVP, GEDVI, EVLWI in two groups were decreased, and the levels of above index in the observation group were lower than those in the control group: (90.26 ± 12.61) beats/min vs. (97.82 ± 12.58) beats/min, (9.85 ± 1.14) cmH 2O (1 cmH 2O = 0.098 kPa) vs. (11.63 ± 1.37) cmH 2O, (759.53 ± 62.47) ml/m 2 vs. (867.21 ± 63.24) ml/m 2, (7.95 ± 1.56) ml/kg vs. (9.01 ± 1.78) ml/kg; after treatment the level of CI in the observation group was higher than that in the control group: (3.58 ± 0.74) L/(min·m 2) vs. (2.37 ± 0.86) L/(min·m 2), and the differences were statistically significant ( P<0.05). After 24 h of treatment, the levels of NE and AngⅡ in two groups was decreased, and the levels of NE and AngⅡ in the observation were lower than those in the control group: (60.42 ± 5.93) ml vs. (54.42 ± 6.14) ml, (41.62 ± 4.19)% vs. (36.87 ± 4.36)%, and the differences were statistically significant ( P<0.05). After 24 h of treatment, the time of intra-aortic balloon counterpulsation (IABP) in the observation was shorter than that in the control group: (61.52 ± 15.41) h vs. (89.56 ± 17.63) h; the injury rate of renal functions in the observation was lower than that in the control group: 3.77%(2/53) vs. 18.87%(10/53), and the differences were statistically significant ( P<0.05). There was no significant difference in mortality and other complications after 30 d of follow-up between two groups ( P>0.05). Conclusions:Levosimengdan can significantly improve the PICCO hemodynamics, neurohumoral indexes and cardiac function indexes of patients with AMI and CS. It has a protective effect on the kidneys of patients, but it cannot significantly improve the 30-day mortality rate of patients.

Levosimendan alleviates coronary microembolization-induced myocardial injury through LOX-1/p38 MAPK pathway / 中华急诊医学杂志

Objective:To study the effect of levosimendan on coronary microembolization (CME)-induced myocardial injury and LOX-1/p38MAPK pathway.Methods:Microspheres were injected into coronary anterior descending branch to construct swine CME model, swine was given levosimendan by continuous intravenous drip for 24 h before modeling, and myocardial-specific overexpression of lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) was achieved through coronary artery injection of adeno-associated virus (AAVs) at 2 weeks before modeling. Then, echocardiography was used to measure cardiac function; HE staining and HBFP staining were used to observe the pathological changes of myocardium and myocardial microinfarction area, respectively; ELISA was used to detect the serum level of cTnI; TUNLE staining was used to detect cardiomyocyte apoptotic index; the LOX-1, Bax, caspase-3 p12, Bcl-2, and p-p38 MAPK protein in myocardial tissue was observed by immunofluorescence method.Results:Compared to the sham group, the LVEF, LVFS, and CO value in the CME group were decreased, while the LVEDd value was increased significantly (all P<0.05); the area of myocardial micro-infarction, serum cTnI level and cardiomyocyte apoptotic rate in the CME group were increased significantly (all P<0.05); the protein levels of Bax, caspase-3 p12, LOX-1, and p-p38 MAPK were increased significantly, while the Bcl-2 level was decreased significantly ( P<0.05). Levosimendan pretreatment significantly improved cardiac dysfunction, reduced the area of myocardial micro-infarction and serum cTnI level, alleviated cardiomyocyte apoptosis, and significantly reduced the LOX-1 and p-p38 MAPK protein expression levels following CME (all P<0.05); while pretreatment with levosimendan and LOX-1 overexpression AAVs simultaneously abolished the effects of pretreatment with levosimendan alone (all P<0.05). Conclusion:Levosimendan alleviates CME-induced myocardial injury through inhibiting cardiomyocyte apoptosis mediated by LOX-1/p38 MAPK signaling pathway.

Clinical study of Perioperative Use of Levosimendan in Patients Undergoing Heart Valve Replacement

Objective To investigate the clinical effect of levosimendan in perioperative aortic and/or mitral valvereplacement. Methods Patients undergoing open heart aortic and/or mitral valve replacement in our hospitalfrom January 2018 to December 2019 were enrolled. 45 patients in the control group received routineperioperative treatment based on dopamine, while 45 patients in the research group received continuousperioperative administration of levosimendan injection for 24h on the basis of routine treatment. The leftventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd) and left ventricular end-systolicdiameter (LVDs) were evaluated by color doppler echocardiography before and one week after surgery.Postoperative mechanical ventilation weaning time, length of ICU stays, number of vasoactive drugs used andwithdrawal time; indexes of liver and kidney function before and on the day after surgery to 10 days after surgery;use of in vitro support techniques such as aortic balloon pulsation (IABP), continuous renal replacement therapy(CRRT) and extracorporeal membrane oxygenation (ECMO) within 5 days of perioperative period. Results Theimprovement of LVDs and LVEF in the study group using levosimendan one week after the operation wassignificantly better than that in the control group (P value was 0.013 and 0.001, respectively), and fewer kinds ofvasoactive drugs were needed (P<0.001), and the risk of postoperative AKI in the study group was significantlylower than that in the control group (P=0.047). Conclusion The perioperative use of levosimendan can effectivelypromote the recovery of cardiac systolic function and reduce the risk of postoperative AKI.

Analysis of Clinical Efficacy of Recombinant Human Brain Natriuretic Peptide Combined with Levosimendan in the Treatment of Acute Decompensated Heart Failure Complicated with Renal Insufficiency / 中国药房

OBJECTIVE：To observe the clinical effect and safety of recombinant human brain natriuretic peptide （rhBNP） combined with levosimendan in the treatment of acute decompensated heart failure （ADHF）complicated with renal insufficiency. METHODS：A total of 156 patients with ADHF complicated with renal insufficiency admitted to the Dept. of Cardiology in the Affiliated Hospital of Southwest Medical University during Jan.-Dec. 2019 were randomly divided into rhBNP group ，levosimendan group and combination group ，with 52 patients in each group. All patients received rountine treatment. On this basis ，rhBNP group was given rhBNP for injection [after 1.5 μg/kg intravenous pulse injection，intravenous dripping for 24 h with 0.007 5 μg（/ kg· min）]；leosimendan group was given Leosimendan injection 12.5 mg [intravenous dripping for 1 h with 6-12 μg（/ kg·min），then intravenous dripping for 23 h with 0.1 μg（/ kg·min）]. Combination group received drug combination according to the administration method of single drug group. Three groups received treatment for consecutive 7 d. Cardiac function indexes [heart rate （HR），left ventricular ejection fraction （LVEF），left ventricular end-diastolic diameter （LVEDD）]，mean arterial pressure （MAP），pulmonary capillary pressure （PCWP），renal function indexes [estimated glomerular filtration rate （eGFR），serum creatinine （Scr）]，serum levels of cystatin C （Cys-c）and amino-terminal brain natriuretic peptide precursor （NT-proBNP）were observed in 3 groups before and after treatment. Clinical efficacy and the occurrence of ADR were recorded. RESULTS ：Three cases withdrew from the study in rhBNP group and 1 case in levosimendan group ；152 cases completed the study. Before treatment ，there was no statistical significance in cardiac function indexes ，MAP，PCMP，renal function indexes or serum levels of Cys-C and NT-proBNP among 3 groups（P＞0.05）. After treatment ，the HP ，MAP，PCWP and serum level of NT-proBNP in 3 group as well as serum level of Cys-C in combination group were decreased significantly （P＜0.05）；the LVEF in 3 group as well as the eGFR and Scr level in levosimendan group and combination group were significantly increased （P＜0.05），compared with before treatment ；above indexes of combination group were significantly better than those of rhBNP group and levosimendan group （P＜0.05）. Total effective rate of combination group was 94.23％ ，which was significantly higher than those of rhBNP group （77.55％）and levosimendan group （76.47％）（P＜0.05）. There was no significant difference in the incidence of ADR among 3 groups（P＞ 0.05）. CONCLUSIONS ：rhBNP combined with levosimendan in the treatment of ADHF complicated with renal insufficiency can significantly increase the clinical efficacy ，and improve cardiac and renal function but don ’t increase the incidence of ADR.

Application of levosimendan in severe patients after cardiac surgery / 中国临床药理学与治疗学

AIM: To explore the influence of levosimendan on cardiac function, pulmonary hypertensions, renal function of the patients after severe heart surgery. METHODS: A total of 320 cases of patients with severe disease who underwent surgery in cardiac surgery department in our hospital from January 2014 to June 2019 were selected and divided into experiment group and control group using random number table method, 160 cases in each group. The prosthetic heart valve replacement or non-extracorporeal bypass surgery were underwent based on the specific condition of patient, the experiment group received levosimendan during the perioperation at the same time. The changes of cardiac, renal function parameters and pulmonary artery systolic pressure (PASP) at different times before and after operation were compared between the 2 groups. RESULTS: There was no significant difference in HR, MAP and CVP between the two groups 24 h after operation. LAC of the experimental group was significantly lower than that of the control group 12 h and 24 h after operation (P0.05), the levels of serum BUN, 24Upro and Scr increased first and then decreased in the control group, and the experiment group was significantly lower than the control group at the same time point (P<0.05 or P<0.01). Compared with the control group, the postoperative mortality, ICU stay, ventilator and IABP support time in the experimental group were significantly lower than those in the control group (P<0.05). CONCLUSION: Levosimendan after cardiac surgery can effectively improve the postoperative cardiac function of severe patients, protect renal injury caused by low perfusion, and reduce the incidence of early postoperative pulmonary hypertension, which is worthy of clinical reference.

Efficacy of Levosimendan on postoperative low cardiac output syndrome of infants with congenital heart disease / 中华实用儿科临床杂志

Objective To investigate the efficacy of Levosimendan in the treatment of postoperative low cadiac output syndrome (LCOS) in infants with congenital heart disease (CHD).Methods Clinical data of patients with CHD developed postoperative LCOS in the Children Heart Center of Fuwai Central China Cardiovascular Hospital from January to December 2018 was collected.In patients that traditional vasoactive drugs failed to alleviate LCOS,the efficacy of continuous infusion of O.1 μg/(kg · min) Levosimendan was observed.Besides,the mechanical ventilation time,ICU stay time,mortality,the changes of ejection fraction (EF) and central venous oxygen saturation (ScvO2) at the infusion of Levosimendan and 48 h after infusion,as well as the changes of heart rate (HR),systolic blood pressure (SBP),vasoactive drugs score (VIS) and lactic acid at the infusion of Levosimendan and 3 h,6 h,12 h,24 h and 48 h after infusion were recorded.Results There were 29 cases,including 17 males (58.6％) and 12 females (41.4％),with median age of 2 (0.5,40.0) months,median body mass of 4.7 (2.6,13.5) kg,median mechanical ventilation time of 109.5 (42.5,367.0) h,ICU stay time of 187.5 (83,446) h,and 1 case died (3.4％).EF (48％ vs.52％)and ScvO2 (53％ vs.58％) increased 48 h after infusion,and the differences were statistically significant (all P ＜0.01).HR level (173 times/min,176 times/min,175 times/min,173 times/min,170 times/min,170 times/min) and lactic acid level (4.72 mmol/L,4.65 mmol/L,4.34 mmol/L,3.79 mmol/L,3.28 mmol/L,2.74 mmol/L) gradually decreased after infusion,and the differences of both between the beginning of infusion and 48 h after infusion were statistically significant (P =0.029);SBP decreased and then increased (74 mmHg,70 mmHg,71 mmHg,73 mmHg,74 mmHg,75 mmHg,1 mmHg =0.133 kPa),and VIS increased and then decreased (26 scores,27 scores,27 scores,26 scores,25 scores,25 scores) at different time points after infusion,however,the data of both between the beginning of infusion and 48 h after infusion had no significant differences (P =0.294,0.151).Conclusions Levosimendan can increase EF,enhance myocardial contractility and systemic tissue perfusion,thus improving the prognosis,when Levosimendan was applied for the treatment of postoperative LCOS of infants with CHD.

Efficacy of Levosimendan on postoperative low cardiac output syndrome of infants with congenital heart disease / 中华实用儿科临床杂志

Objective@#To investigate the efficacy of Levosimendan in the treatment of postoperative low cadiac output syndrome (LCOS) in infants with congenital heart disease (CHD).@*Methods@#Clinical data of patients with CHD developed postoperative LCOS in the Children Heart Center of Fuwai Central China Cardiovascular Hospital from January to December 2018 was collected.In patients that traditional vasoactive drugs failed to alleviate LCOS, the efficacy of continuous infusion of 0.1 μg/(kg·min) Levosimendan was observed.Besides, the mechanical ventilation time, ICU stay time, mortality, the changes of ejection fraction (EF) and central venous oxygen saturation (ScvO2) at the infusion of Levosimendan and 48 h after infusion, as well as the changes of heart rate (HR), systolic blood pressure (SBP), vasoactive drugs score (VIS) and lactic acid at the infusion of Levosimendan and 3 h, 6 h, 12 h, 24 h and 48 h after infusion were recorded.@*Results@#There were 29 cases, including 17 males (58.6%) and 12 females (41.4%), with median age of 2 (0.5, 40.0) months, median body mass of 4.7 (2.6, 13.5) kg, median mechanical ventilation time of 109.5 (42.5, 367.0) h, ICU stay time of 187.5 (83, 446) h, and 1 case died (3.4%). EF (48% vs.52%) and ScvO2 (53% vs.58%) increased 48 h after infusion, and the differences were statistically significant (all P<0.01). HR level (173 times/min, 176 times/min, 175 times/min, 173 times/min, 170 times/min, 170 times/min) and lactic acid level (4.72 mmol/L, 4.65 mmol/L, 4.34 mmol/L, 3.79 mmol/L, 3.28 mmol/L, 2.74 mmol/L) gradually decreased after infusion, and the differences of both between the beginning of infusion and 48 h after infusion were statistically significant (P=0.029); SBP decreased and then increased (74 mmHg, 70 mmHg, 71 mmHg, 73 mmHg, 74 mmHg, 75 mmHg, 1 mmHg=0.133 kPa), and VIS increased and then decreased (26 scores, 27 scores, 27 scores, 26 scores, 25 scores, 25 scores) at different time points after infusion, however, the data of both between the beginning of infusion and 48 h after infusion had no significant differences (P=0.294, 0.151).@*Conclusions@#Levosimendan can increase EF, enhance myocardial contractility and systemic tissue perfusion, thus improving the prognosis, when Levosimendan was applied for the treatment of postoperative LCOS of infants with CHD.

Preoperative uses of levosimendan in patients with low LVEF undergoing OPCABG / 中华胸心血管外科杂志

To investigate the effect of preoperative uses of levosimendan in patients with low LVEF(≤0. 40) undergoing off-pump coronary artery bypass grafting(OPCABG). Methods 63 patients with low LVEF coronary artery diseases were prospectively enrolled during June 2015 to May 2018, randomized to levosimendan-treated group(n =32) and control group(n =31)preoperatively. Patients in levosimendan-treated group underwent levosimendan intravenous infusion 24 h before OPCABG. All patients underwent OPCABG at normal temperature. Internal mammary artery and great saphenous vein were used as bypass materials. Hemodynamics and cardiac function were compared between the two groups after OPCABG. Results Compared to control group, the systemic vascular resistance(SVR) and central venous pressure(CVP) of levosimendan- treated group were decreased significantly and the CO and LVEF increased significantly at 12h and 24h after surgery(P < 0. 05). The heart rate and mean artery pressure had no statistical difference between the two groups(P >0. 05). The dosage and administration time of vasoactive agents in levosimendan-treated group were significantly smaller than those in control group (P <0. 05). The time of mechanical ventilation, the ICU stay length, the BNP level in the first two days after operation, and the incidence of new atrial fibrillation were less than those of the control group(P <0. 05). The perioperative intra-aortic balloon pump implantation rate in levosimendan-treated group was significantly lower than that of the control group(P < 0. 05). Conclusion Preoperative use of levosimendan can significantly improve the hemodynamic and cardiac function status of patients with low LVEF after OPCABG, shorten the time of ventilator assisted and ICU hospitalization, and reduce the incidence of adverse events.

Effect of Levosimendan on the prognosis in severe coronary disease patients undergoing coronary artery bypass grafting / 中华老年医学杂志

Objective To evaluate the effect of Levosimendan on the prognosis in patients with severe coronary heart disease after operation.Methods A total of 485 severe coronary disease patients undergoing coronary artery bypass grafting from Teda International Cardiovascular Hospital and the Cardiac Surgery Department of the First Affiliated Hospital of China Medical University from May 2014 to June 2016 were enrolled.Of them,45 cases receiving Levosimendan postoperatively were assigned to the Levosimendan group,and according to propensity score matching,another 45 cases were selected as the control group in this study.Clinical data before treatment had no difference between the groups (P ＞ 0.1).Postoperative prognosis was compared between the two groups.Results There were significant differences in heart rate,mean arterial pressure,central venous pressure,cardiac output and other hemodynamic parameters between the two groups 48h after operation.The heart ultrasound results showed that the left ventricular ejection fraction(IVEF) was increased [(0.53±0.12) ％vs.(0.46±0.09)％,t =2.594,P=0.002],the postoperative ventilation time was reduced [(46.8±11.3) h vs.(58.5±16.3) h,t=-2.031,P=0.045]and the onset of bowel sounds became early [(16.5±5.9) h vs.(18.7±10.1) h,t =1.592,P=0.039]in the levosimendan group than in the control group 48h after operation.The incidences of new-onset acute kidney injury(20 ％ and 40 ％,x2 =6.702,P =0.018),new-onset postoperative atrial fibrillation (15.6％ and 44.4％,x2 =6.156,P =0.023) and perioperative myocardial infarction(11.1 ％ and 33.3％,x2 =6.429,P =0.021) had significant differences between the two groups(P＜0.05),but there was no difference in ICU retention time,1-month mortality after operation,malignant arrhythmia incidence and auxiliary equipment use (P ＞ 0.05).Conclusions Levosimendan can improve the early prognosis of severe coronary disease patients undergoing coronary artery bypass grafting and reduce the occurrence of postoperative organ dysfunction.

Levosimendan confers perioperative renoprotection in severe patients undergoing cardiac surgery: A systematic review and meta-analysis / 中国胸心血管外科临床杂志

@#Objective    To evaluate the effect of levosimendan on acute kidney injury (AKI) in patients with left ventricular dysfunction (preoperative left ventricular ejection fraction≤40.0%) undergoing cardiac surgery. Methods    A systematic review and meta-analysis was conducted based on a comprehensive search of the randomized controlled trial (RCT) from PubMed, EMbase and The Cochrane Library (up to Jan 2018). The clinical endpoints included the incidence of AKI and need for renal replacement therapy (RRT), mortality, mechanic ventilation (MV) duration and intensive care unit (ICU) stay. Random-effect model was used for the potential clinical inconsistency. All analyses were performed by RevMan 5.3 and Stata 12.0. Results    Thirteen trials with a total of 2 046 patients were selected. Compared with controls, levosimendan significantly reduced the incidence of postoperative AKI (OR=0.44, P=0.000 1, I2=0%), the risk of RRT (OR=0.63, P=0.02, I2=0%) and the mortality (OR=0.49, P<0.000 1, I2=0%). Levosimendan also shortened the postoperative MV duration (WMD=–5.62, P=0.07, I2=93%) and ICU stay (WMD=–1.50, P=0.005, I2=98%). Conclusion    The present meta-analysis suggests that perioperative levosimendan for patients with left ventricular ejection fraction≤40.0%undergoing cardiac surgery reduces the incidence of AKI, RRT and death, as well as shortens MV duration and ICU stay.