Acute and chronic effects of levosimendan in the ZSF1 obese rat model of heart failure with preserved ejection fraction.

Autor: Moreira-Costa L; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal. Electronic address: up201908621@med.up.pt., Tavares-Silva M; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Cardiology, Centro Hospitalar Universitário São João, Porto, Portugal., Almeida-Coelho J; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal., Gonçalves A; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal., Trindade F; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal., Vasques-Nóvoa F; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Medicine, Centro Hospitalar Universitário São João, Porto, Portugal., Sousa-Mendes C; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal., Leite S; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal., Vitorino R; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal., Falcão-Pires I; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal., Leite-Moreira AF; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Cardiothoracic Surgery, Centro Hospitalar Universitário São João, Porto, Portugal., Lourenço AP; Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Anaesthesiology, Centro Hospitalar Universitário São João, Porto, Portugal.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Mar 05; Vol. 966, pp. 176336. Date of Electronic Publication: 2024 Jan 23.
DOI: 10.1016/j.ejphar.2024.176336
Abstrakt: Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 μg/kg + 0.1 μg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O 2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca 2+ levels and enhanced Ca 2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients.
Competing Interests: Declaration of competing interest None.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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