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

Abstract

Background Accidental 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. Methods Using 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. Results Milrinone 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. Conclusions Levosimendan 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.

In silico study of the mechanisms of hypoxia and contractile dysfunction during ischemia and reperfusion of hiPSC cardiomyocytes

“…LEVO had a marginal prolonging effect on the AP repolarization phase ( Fig. 3A ; Table S4 ), in accord with a recent in vitro hiPSC-CM experiment ( Selli et al, 2023 ), and reported dose-dependent LEVO association with the prolongation of QT interval in healthy individuals and patients with heart failure ( Ng, 2004 ). At 0.3 and 2 µM concentrations, LEVO did not significantly alter the CaT values ( Fig.…”

“…2B ) for the studied doses of LEVO based on data from Yokoshiki et al (1997a) . We selected 0.3, 2 and 10 µM doses of LEVO in the simulations, to be consistent with the LEVO animal experiment research ( Edes et al, 1995 ; Yokoshiki et al, 1997a ) and hiPSC-CM research ( Selli et al, 2023 ). For the f KATP activation, we followed data presented in fig.…”

“…Overcoming these hurdles, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer promising opportunities for investigating the pathogenesis and mechanisms of action of pharmaceutical compounds in a human-based model ( Forouzandehmehr et al, 2022 ; Gaballah et al, 2022 ). Of importance, hiPSC-CMs have been shown to be a dependable approach for identifying the pro-arrhythmic effects of medications ( Selli et al, 2023 ). Furthermore, organ-on-chip approaches offer novel measurement modalities and robust ways to control the measurement conditions, such as precise local regulation of oxygen levels ( Gaballah et al, 2022 ).…”