Proarrhythmic changes in human cardiomyocytes during hypothermia by milrinone and isoprenaline, but not levosimendan: an experimental in vitro study

Selli, A. L., Ghasemi, M., Watters, T., Burton, F., Smith, G. and Dietrichs, E. S. (2023) Proarrhythmic changes in human cardiomyocytes during hypothermia by milrinone and isoprenaline, but not levosimendan: an experimental in vitro study. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 31(1), 61. (doi: 10.1186/s13049-023-01134-5) (PMID:37880801) (PMCID:PMC10601188)

Abstract

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

• Item Type: Articles
• Additional Information: Open access funding provided by UiT The Arctic University of Norway (incl University Hospital of North Norway). The study was funded by grant awarded ESD from the Northern Norwegian Health Authority [HNF1337-17].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Godfrey and Burton, Dr Francis and Dietrichs, Mr Erik
• Authors: Selli, A. L., Ghasemi, M., Watters, T., Burton, F., Smith, G., and Dietrichs, E. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine
• Publisher: BioMed Central
• ISSN: 1757-7241
• ISSN (Online): 1757-7241
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 31:61
• Publisher Policy: Reproduced under a Creative Commons licence