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

Data de publicação: 01/01/2024 Data Ahead of Print: 23/01/2024

Autores da FMUP

Joaquim Adelino Correia Ferreira Leite Moreira

Autor

Participantes de fora da FMUP

Moreira-Costa L.
Tavares-Silva M.
Almeida-Coelho J.
Gonçalves A.
Trindade F.
Vasques-Nóvoa F.
Sousa-Mendes C.
Leite S.
Vitorino R.
Falcão-Pires I.
Lourenço A.P.

Unidades de investigação

Cirurgia e Fisiologia
Laboratório Associado RISE- Rede de Investigação em Saúde

Investigador

Fernando Carlos De Landér Schmitt
RISE-Health

Investigador

Fernando Carlos De Landér Schmitt

Abstract

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. © 2024 The Authors

Dados da publicação

ISSN/ISSNe:: 0014-2999, 1879-0712
Tipo:: Article
Páginas:: 176336-176336
DOI:: 10.1016/j.ejphar.2024.176336
Link para outro recurso:: www.scopus.com

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Métricas

Filiações

Moreira-Costa L.:: Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
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 A.F.:: 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 A.P.:: 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

Keywords

Animals; Fibrosis; Heart Failure; Humans; Hypertrophy; Male; Mammals; Obesity; Rats; Rats, Inbred WKY; Simendan; Stroke Volume; levosimendan; mammalian target of rapamycin; phospholamban; simendan; animal cell; animal experiment; animal model; animal tissue; arterial pressure; Article; calcium blood level; cardiac index; cardiac muscle cell; clinical effectiveness; controlled study; echocardiography; fibrosing alveolitis; heart failure with preserved ejection fraction; heart left atrium; heart left ventricle mass; hemodynamic parameters; histopathology; in vitro study; male; nonhuman; obesity; oxygen consumption; protein phosphorylation; randomized controlled trial; rat; sarcomere length; treatment outcome; treatment response; ventricular end diastolic pressure; Western blotting; Wistar Kyoto rat; animal; complication; fibrosis; heart failure; heart stroke volume; human; hypertrophy; mammal; obesity

Campos de estudo

Financiamento

Faculty of Medicine of University Porto ((LCF/PR/HP17/52190002)

Faculty of Medicine of University Porto (PTDC/DTP-PIC/4104/2014)

Faculty of Medicine of University Porto (SFRH/BD/145216/2019))

Fundação para a Ciência e a Tecnologia