RESUMEN
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.
Asunto(s)
Hipertensión Pulmonar , MicroARNs , Ratas Sprague-Dawley , Simendán , Regulación hacia Arriba , MicroARNs/metabolismo , MicroARNs/genética , Animales , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/patología , Ratas , Regulación hacia Arriba/efectos de los fármacos , Simendán/farmacología , Masculino , Células Cultivadas , Proteínas Smad/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Proliferación Celular/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Apoptosis/efectos de los fármacosRESUMEN
BACKGROUND: Levosimendan (Levo) is a drug commonly used to treat heart failure. Recent studies have suggested that Levo may have neuroprotective effects, but it is still unknown how exactly it contributes to hypoxia-induced brain damage. Thus, the aim of this study was to investigate how Levo affects hypoxia-induced brain damage and to clarify any possible underlying mechanisms. METHODS: One group of rats (Levo group) was pretreated with Levo via oral force-feeding for four weeks. Another group (Ferrostatin-1 (Fer-1) group) was pretreated with intraperitoneal injections of Fer-1 for four weeks. A rat model of chronic hypoxia was created by treating rats with 13% O2 for 14 days in a closed hypoxia chamber. For each group (Control, Model, Levo, Fer-1), we evaluated learning and memory capacity and the morphology and structure of neurons in the rats' brain tissue. Other measurements included tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6); malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px); Fe2+; apoptosis; cleaved caspase-3, caspase-3; phosphatase and tensin homolog (PTEN), protein kinase B (Akt), phosphorylated Akt (p-Akt); and ferroptosis-related proteins Nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). RESULTS: The Model group rats had considerably fewer neurons than the Control group, with loosely arranged cells, and markedly impaired learning and memory abilities (p < 0.05). Oxidative damage and inflammation in brain tissues of the Model group were significantly intensified, accompanied by a substantial increase in neuronal apoptosis (p < 0.05). PTEN protein, Fe2+ concentration, and cleaved caspase-3 expression were all significantly upregulated, whereas p-Akt, Nrf2, GPX4, and SLC7A11 proteins were dramatically downregulated (p < 0.05). Both the Levo and Fer-1 groups demonstrated significantly more neurons and closely arranged cells than the Model group, along with a notable improvement in learning and memory abilities (p < 0.05). Oxidative damage and inflammation in brain tissues of the Levo and Fer-1 groups were markedly alleviated, and neuronal apoptosis was suppressed (p < 0.05). p-Akt, Nrf2, GPX4, and SLC7A11 proteins were dramatically upregulated, whereas the expression of cleaved caspase-3, PTEN protein, and Fe2+ content was considerably downregulated (p < 0.05). CONCLUSIONS: Levo effectively mitigates brain injury in rats with chronic hypoxia, likely by regulating ferroptosis via the PTEN/Akt signaling pathway.
Asunto(s)
Ferroptosis , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Simendán , Animales , Fosfohidrolasa PTEN/metabolismo , Ratas , Ferroptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Simendán/farmacología , Simendán/uso terapéutico , Ratas Sprague-Dawley , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/etiología , Lesiones Encefálicas/patología , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Ciclohexilaminas , FenilendiaminasRESUMEN
OBJECTIVE: To explore the therapeutic effect of levosimendan in patients with prolonged ventilator weaning and cardiac dysfunction. METHOD: Patients with prolonged ventilator weaning and cardiac dysfunction were randomly allocated to receive conventional treatment (control group) or intravenous infusion of levosimendan for 24 h based on conventional treatment (levosimendan group). Weaning success rates were then compared between the two groups. The study was retrospectively registered with Research Registry (ID No. researchregistry10304). RESULTS: A total of 40 patients were included (20 per group). Within 3 days after initiation of treatment, significantly more cases were successfully weaned in the levosimendan group versus control group (eight versus four cases, respectively). Among the eight patients who underwent pulse indicator continuous cardiac output monitoring in the levosimendan group, the global ejection fraction increased 24 h after treatment, and the cardiac function index and cardiac index increased 72 h after treatment. CONCLUSION: For patients requiring prolonged mechanical ventilation who have concomitant cardiac dysfunction, levosimendan may be considered to increase the probability of weaning success.
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Simendán , Desconexión del Ventilador , Humanos , Simendán/uso terapéutico , Masculino , Femenino , Desconexión del Ventilador/métodos , Persona de Mediana Edad , Anciano , Cardiotónicos/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Respiración Artificial , Cardiopatías/tratamiento farmacológico , Cardiopatías/fisiopatología , Piridazinas/uso terapéuticoRESUMEN
OBJECTIVE: The objective of this study was to assess the effectiveness and safety of levosimendan as an alternative treatment for pediatric patients with decompensated heart failure unresponsive to conventional inotropes and to emphasize its role in enhancing cardiovascular stability. METHODS: A total of 15 pediatric patients with decompensated heart failure, stemming from acute fulminant myocarditis (53.3%) and post-congenital heart disease surgery complications (46.7%), received levosimendan. The evaluation focused on adverse effects, respiratory support requirements, and concurrent inotropic medication use during levosimendan treatment. Key cardiovascular parameters were assessed at 0, 6, 12, and 24 h post-levosimendan infusion. RESULTS: Levosimendan administration significantly improved key cardiovascular metrics. Left ventricular ejection fraction increased notably from 45±14.8% to 58±15.6% at 24 h (p<0.001). Systolic and diastolic blood pressures rose significantly, with systolic increasing from 79 (68-90) to 98 (89-109) mmHg and diastolic from 47 (40-57) to 66 (54-76) mmHg by 24 h (p<0.001). Heart rate decreased from 162 (111-175) to 132 (99-148) bpm (p=0.02), and lactate levels significantly decreased from 4.15 (2.3-6.5) to 1.85 (0.8-2.6) mmol/L within 6 h (p<0.001). CONCLUSION: Levosimendan demonstrates its significance in managing pediatric heart failure, indicating its safety and potential to enhance cardiac outcomes by reducing reliance on traditional inotropes.
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Cardiotónicos , Insuficiencia Cardíaca , Hidrazonas , Piridazinas , Simendán , Humanos , Simendán/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Cardiotónicos/uso terapéutico , Piridazinas/uso terapéutico , Piridazinas/efectos adversos , Masculino , Femenino , Hidrazonas/uso terapéutico , Preescolar , Niño , Resultado del Tratamiento , Lactante , Adolescente , Presión Sanguínea/efectos de los fármacos , Miocarditis/tratamiento farmacológico , Factores de Tiempo , Frecuencia Cardíaca/efectos de los fármacos , Volumen Sistólico/efectos de los fármacosRESUMEN
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.
Asunto(s)
Calcio , Fibras Musculares de Contracción Rápida , Simendán , Simendán/farmacología , Animales , Ratones , Calcio/metabolismo , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Rápida/metabolismo , Contracción Muscular/efectos de los fármacos , Sarcómeros/metabolismo , Sarcómeros/efectos de los fármacos , Masculino , Miofibrillas/metabolismo , Miofibrillas/efectos de los fármacosRESUMEN
PURPOSE: Pulmonary hypertension (PH) is a common cause of postoperative mortality in cardiac surgery that is commonly treated with conventional inhaled therapies, specifically nitric oxide and prostacyclin. Alternative therapies include inhaled milrinone and levosimendan, which are receiving more research interest and are increasing in clinical use as they may cut costs while allowing for easier administration. We sought to conduct a scoping review to appraise the evidence base for the use of these two novel inhaled vasodilators as an intervention for PH in cardiac surgery. SOURCE: We searched Embase and MEDLINE for relevant articles from 1947 to 2022. PRINCIPAL FINDINGS: We identified 17 studies including 969 patients. The included studies show that inhaled milrinone and levosimendan are selective pulmonary vasodilators with potential benefits ranging from ease of weaning from cardiopulmonary bypass to reduction in ventricular dysfunction. Nevertheless, high-quality data are limited, and study design and comparators are extremely heterogeneous, limiting the potential validity and generalizability of findings. CONCLUSION: The findings of this scoping review suggest that milrinone and levosimendan may be effective alternatives to current inhaled therapies for cardiac dysfunction in the setting of PH. Nevertheless, randomized trials have focused on specific agents and consistent outcome measures are needed to better validate the early-stage promise of these agents. STUDY REGISTRATION: Open Science Framework ( https://osf.io/z3k6f/ ); first posted 21 July 2022.
RéSUMé: OBJECTIF: L'hypertension pulmonaire (HTP) est une cause fréquente de mortalité postopératoire en chirurgie cardiaque généralement traitée par des thérapies inhalées conventionnelles, en particulier le monoxyde d'azote et la prostacycline. Les thérapies alternatives comprennent la milrinone et le lévosimendan inhalés, qui suscitent de plus en plus d'intérêt dans la recherche et sont de plus en plus utilisés en clinique car ils peuvent réduire les coûts tout en permettant une administration plus facile. Nous avons cherché à réaliser une étude de portée afin d'évaluer la base de données probantes concernant l'utilisation de ces deux nouveaux vasodilatateurs inhalés comme intervention pour l'HTP en chirurgie cardiaque. SOURCES: Nous avons cherché des articles pertinents dans Embase et MEDLINE de 1947 à 2022. CONSTATATIONS PRINCIPALES: Nous avons identifié 17 études incluant 969 patient·es. Les études incluses montrent que la milrinone et le lévosimendan inhalés sont des vasodilatateurs pulmonaires sélectifs possédant des avantages potentiels allant de la facilité de sevrage de la circulation extracorporelle à la réduction de la dysfonction ventriculaire. Néanmoins, les données de haute qualité sont limitées, et la conception des études et les comparateurs sont extrêmement hétérogènes, ce qui limite la validité potentielle et la généralisabilité des résultats. CONCLUSION: Les résultats de cette étude de portée suggèrent que la milrinone et le lévosimendan pourraient être des solutions de rechange efficaces aux traitements inhalés actuels pour le dysfonctionnement cardiaque dans un contexte d'HTP. Néanmoins, les études randomisées se sont concentrées sur des agents spécifiques et des mesures cohérentes des résultats sont nécessaires pour mieux valider les promesses de ces agents à un stade précoce. ENREGISTREMENT DE L'éTUDE: Open Science Framework ( https://osf.io/z3k6f/ ); première publication le 21 juillet 2022.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Hipertensión Pulmonar , Milrinona , Simendán , Vasodilatadores , Humanos , Vasodilatadores/administración & dosificación , Vasodilatadores/uso terapéutico , Administración por Inhalación , Procedimientos Quirúrgicos Cardíacos/métodos , Milrinona/administración & dosificación , Milrinona/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Simendán/administración & dosificación , Simendán/uso terapéutico , Simendán/farmacología , Adulto , Complicaciones Posoperatorias/tratamiento farmacológicoAsunto(s)
Cardiotónicos , Hidrazonas , Válvula Mitral , Piridazinas , Simendán , Disfunción Ventricular Derecha , Humanos , Simendán/uso terapéutico , Disfunción Ventricular Derecha/tratamiento farmacológico , Piridazinas/uso terapéutico , Hidrazonas/uso terapéutico , Válvula Mitral/cirugía , Cardiotónicos/uso terapéuticoRESUMEN
ABSTRACT: Objective: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. Methods: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBTs) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 µg/kg for 10 min, followed by a continuous infusion at 0.2 µg/kg/min. The control group received an equivalent dose of a placebo. The preadministration and postadministration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). Results: Forty-four patients were enrolled in the study. We found that postadministration of levosimendan, the patients' tidal volume (GCSMV) increased, whereas the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO 2 ) decreased when compared to the preadministration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively) and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant ( P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the postadministration levels of DE, TFdi, and D-RSBI as compared to the preadministration period ( P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning ( P = 0.545). Conclusion: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.
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Diafragma , Hidrazonas , Piridazinas , Sepsis , Simendán , Humanos , Simendán/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/fisiopatología , Diafragma/efectos de los fármacos , Diafragma/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Piridazinas/uso terapéutico , Hidrazonas/uso terapéutico , Anciano , Método Simple Ciego , Adulto , Análisis de los Gases de la SangreAsunto(s)
Cardiotónicos , Insuficiencia Cardíaca , Contracción Miocárdica , Simendán , Humanos , Simendán/uso terapéutico , Simendán/farmacología , Proyectos Piloto , Contracción Miocárdica/fisiología , Contracción Miocárdica/efectos de los fármacos , Masculino , Femenino , Cardiotónicos/uso terapéutico , Cardiotónicos/farmacología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/terapia , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Piridazinas/uso terapéuticoRESUMEN
ABSTRACT: The aim of this study was to synthesize the available evidence regarding differences in the long-term safety and efficacy of intermittent, repeated, or continuous palliative inotropic therapy among patients with advanced heart failure. We systematically searched the PubMed, Embase, and Cochrane Library electronic databases, with a cutoff date of November 23, 2023, for studies reporting outcomes in adult patients with advanced heart failure treated with intermittent, repeated, or continuous levosimendan, milrinone, or dobutamine. Forty-one studies (18 randomized controlled trials and 23 cohort studies) comprising 5137 patients met the inclusion criteria. The results of the network meta-analysis of randomized controlled trials showed that levosimendan had significant advantages over milrinone or dobutamine in reducing mortality and improving left ventricular ejection fraction. A single-arm meta-analysis also indicated that levosimendan had the lowest mortality and significantly improved B-type brain natriuretic peptide and left ventricular ejection fraction. Regarding safety, hypotension events were observed more frequently in the levosimendan and milrinone groups. However, the current evidence is limited by the heterogeneity and relatively small sample size of the studies.
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Cardiotónicos , Dobutamina , Insuficiencia Cardíaca , Milrinona , Metaanálisis en Red , Simendán , Función Ventricular Izquierda , Humanos , Simendán/uso terapéutico , Simendán/efectos adversos , Simendán/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Milrinona/efectos adversos , Milrinona/uso terapéutico , Milrinona/administración & dosificación , Cardiotónicos/efectos adversos , Cardiotónicos/uso terapéutico , Cardiotónicos/administración & dosificación , Dobutamina/administración & dosificación , Dobutamina/efectos adversos , Dobutamina/uso terapéutico , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Masculino , Volumen Sistólico/efectos de los fármacos , Recuperación de la Función , Esquema de Medicación , Femenino , Factores de Tiempo , Anciano , Persona de Mediana Edad , Factores de Riesgo , Cuidados PaliativosRESUMEN
BACKGROUND: Patients with cardiac amyloidosis (CA) often experience heart failure (HF) episodes. No evidence is available on inotropic therapy. This study aims to fill this gap by examining the safety and efficacy of levosimendan. METHODS: We retrieved all HF patients receiving ≥1 levosimendan infusion from 2013 to 2023. CA patients were matched with HF patients without CA (controls) based on sex, age, and left ventricular ejection fraction (LVEF). The response to levosimendan was measured as changes in daily urinary output, body weight, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR). RESULTS: CA patients (median age 77 years, 73% men, 59% with ATTR-CA) and controls were compared. Levosimendan infusion was stopped because of hypotension in 2 cases with CA and (in 1 case) worsening renal function, and in 2 controls because of ventricular tachycardia episodes and (in 1 case) hypotension. CA patients showed a trend toward increased daily urinary output (p = 0.078) and a significant decrease in body weight (p < 0.001), without significant changes in NT-proBNP (p = 0.497) and eGFR (p = 0.732). Both CA patients and controls displayed similar changes in urinary output, weight, and eGFR, but NT-proBNP decreased more significantly among controls (p < 0.001). No differences were noted in rehospitalization rates, but CA patients experienced higher mortality at 6 and 12 months (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Levosimendan appears safe for CA patients needing inotropic support. The diuretic response and weight decrease during hospitalization were comparable between CA patients and matched HF patients, despite the greater mortality of CA patients after discharge.
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Amiloidosis , Cardiomiopatías , Cardiotónicos , Simendán , Humanos , Simendán/uso terapéutico , Simendán/administración & dosificación , Masculino , Femenino , Anciano , Amiloidosis/tratamiento farmacológico , Amiloidosis/complicaciones , Amiloidosis/mortalidad , Resultado del Tratamiento , Anciano de 80 o más Años , Cardiotónicos/uso terapéutico , Cardiotónicos/efectos adversos , Cardiotónicos/administración & dosificación , Cardiomiopatías/tratamiento farmacológico , Estudios Retrospectivos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Persona de Mediana EdadRESUMEN
Interconnected mechanisms of ischemia and reperfusion (IR) has increased the interest in IR in vitro experiments using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We developed a whole-cell computational model of hiPSC-CMs including the electromechanics, a metabolite-sensitive sarcoplasmic reticulum Ca2+-ATPase (SERCA) and an oxygen dynamics formulation to investigate IR mechanisms. Moreover, we simulated the effect and action mechanism of levosimendan, which recently showed promising anti-arrhythmic effects in hiPSC-CMs in hypoxia. The model was validated using hiPSC-CM and in vitro animal data. The role of SERCA in causing relaxation dysfunction in IR was anticipated to be comparable to its function in sepsis-induced heart failure. Drug simulations showed that levosimendan counteracts the relaxation dysfunction by utilizing a particular Ca2+-sensitizing mechanism involving Ca2+-bound troponin C and Ca2+ flux to the myofilament, rather than inhibiting SERCA phosphorylation. The model demonstrates extensive characterization and promise for drug development, making it suitable for evaluating IR therapy strategies based on the changing levels of cardiac metabolites, oxygen and molecular pathways.
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Calcio , Simulación por Computador , Células Madre Pluripotentes Inducidas , Contracción Miocárdica , Miocitos Cardíacos , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Simendán , Humanos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Simendán/farmacología , Simendán/uso terapéutico , Contracción Miocárdica/efectos de los fármacos , Calcio/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Oxígeno/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/metabolismo , Animales , Modelos BiológicosRESUMEN
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.
Asunto(s)
Simendán , Disfunción Ventricular Izquierda , Remodelación Ventricular , Simendán/uso terapéutico , Simendán/farmacología , Simendán/administración & dosificación , Humanos , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/fisiopatología , Remodelación Ventricular/efectos de los fármacos , Función Ventricular Izquierda/fisiología , Función Ventricular Izquierda/efectos de los fármacos , Volumen Sistólico/fisiología , Volumen Sistólico/efectos de los fármacos , Cardiotónicos/uso terapéutico , SístoleRESUMEN
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.
Asunto(s)
Circulación Cerebrovascular , Simendán , Hemorragia Subaracnoidea , Vasoespasmo Intracraneal , Humanos , Simendán/farmacología , Simendán/uso terapéutico , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/fisiopatología , Hemorragia Subaracnoidea/diagnóstico por imagen , Vasoespasmo Intracraneal/tratamiento farmacológico , Vasoespasmo Intracraneal/diagnóstico por imagen , Vasoespasmo Intracraneal/etiología , Vasoespasmo Intracraneal/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Circulación Cerebrovascular/efectos de los fármacos , Imagen de Perfusión , Tomografía Computarizada por Rayos X , Hemodinámica/efectos de los fármacos , Adulto , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
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.
Asunto(s)
Inhibidores de Agregación Plaquetaria , Agregación Plaquetaria , Humanos , Simendán/farmacología , Simendán/uso terapéutico , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Proyectos Piloto , Activación Plaquetaria , PlaquetasRESUMEN
OBJECTIVE: To verify the impact of preoperative levosimendan on patients with severe left ventricular dysfunction (ejection fraction <35%) undergoing isolated coronary artery bypass grafting. DESIGN: A meta-analysis. SETTING: Hospitals. PARTICIPANTS: The authors included 1,225 patients from 6 randomized controlled trials. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 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; I2 = 0%), postoperative acute kidney injury (RR 0.44; 95% CI 0.25-0.77; p < 0.01; I2 = 0%), low-cardiac-output syndrome (RR 0.45; 95% CI 0.30-0.66; p < 0.001; I2 = 0%), and postoperative atrial fibrillation (RR 0.49; 95% CI 0.25-0.98; p = 0.04; I2 = 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. CONCLUSION: 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.
Asunto(s)
Lesión Renal Aguda , Fibrilación Atrial , Simendán , Disfunción Ventricular Izquierda , Humanos , Lesión Renal Aguda/etiología , Fibrilación Atrial/etiología , Gasto Cardíaco Bajo/tratamiento farmacológico , Gasto Cardíaco Bajo/etiología , Cardiotónicos/uso terapéutico , Puente de Arteria Coronaria/efectos adversos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Simendán/uso terapéuticoRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 µg/kg + 0.1 µg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca2+ levels and enhanced Ca2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients.
Asunto(s)
Insuficiencia Cardíaca , Humanos , Ratas , Masculino , Animales , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Volumen Sistólico , Simendán/farmacología , Ratas Endogámicas WKY , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Fibrosis , Hipertrofia , MamíferosRESUMEN
BACKGROUND: Levosimendan is increasingly being used in patients with sepsis or septic shock because of its potential to improve organ function and reduce mortality. We aimed to determine if levosimendan can reduce mortality in patients with sepsis or septic shock via meta-analysis. EVIDENCE SOURCES AND STUDY SELECTION: We comprehensively searched the PubMed, Embase, Web of Science, and Cochrane Library databases from inception through 1 October 2022. Literature evaluating the efficacy of levosimendan in patients with sepsis or septic shock was included. DATA EXTRACTION AND OUTCOME MEASUREMENTS: Two reviewers extracted data and assessed study quality. A meta-analysis was performed to calculate an odds ratio (OR), 95% confidence intervals (CI), and P -values for 28-day mortality (primary outcome). Secondary outcomes included changes in indexes reflecting cardiac function before and after treatment, changes in serum lactate levels in the first 24â h of treatment, and the mean SOFA score during the study period. Safety outcomes included rates of tachyarrhythmias and total adverse reactions encountered with levosimendan. RESULTS: Eleven randomized controlled trials were identified, encompassing a total of 1044 patients. After using levosimendan, there was no statistical difference between groups for 28-day mortality (34.9% and 36.2%; OR: 0.93; 95% CI [0.72-1.2]; P â =â 0.57; I 2 â =â 0%; trial sequential analysis-adjusted CI [0.6-1.42]) and sequential organ failure assessment (SOFA) score, and more adverse reactions seemed to occur in the levosimendan group, although the septic shock patient's heart function and serum lactate level improved. CONCLUSION: There was no association between the use of levosimendan and 28-day mortality and SOFA scores in patients with septic shock, though there was statistically significant improvement in cardiac function and serum lactate.
Asunto(s)
Sepsis , Choque Séptico , Humanos , Simendán/uso terapéutico , Choque Séptico/tratamiento farmacológico , Puntuaciones en la Disfunción de Órganos , LactatosRESUMEN
ABSTRACT: In the latest years, several studies described the impact of repetitive/intermittent i.v. levosimendan treatment in the management of advanced heart failure. For this updated review, we systematically searched the literature for clinical trials, registries , and real-world data and identified 31 studies that we commented in a narrative review: 3814 patients were described, of whom 1744 were treated repetitively with levosimendan. On the basis of the nature of the study protocols and of the end points, out of those studies, we further selected 9 that had characteristics, making them suitable for a meta-analysis on mortality. This short list describes data from 680 patients (of whom 399 received repeated doses of levosimendan) and 110 death events (of which 50 occurred in the levosimendan cohort). In the meta-analysis, repetitive/intermittent therapy with i.v. levosimendan was associated with a significant reduction in mortality at the longest time point available: 50 of 399 (12.5%) versus 60 of 281 (21.4%) in the control arms, with a risk ratio of 0.62 (95% confidence interval, 0.42-0.90; P < 0.01). In a sensitivity analysis, removing each trial and reanalyzing the remaining data set did not change the trend, magnitude, or significance of the results. A visual inspection of the funnel plot did not suggest publication bias. The results provide a very strong rationale for continuing to investigate the repetitive use of levosimendan in patients with advanced heart failure by properly powered regulatory clinical trials. Meanwhile, it seems that the use of repetitive/intermittent i.v. levosimendan infusions has become one of the few effective options for preserving the hemodynamic and symptomatic balance in such patients.