Pharmacological treatment of hypothermia-induced cardiac dysfunction


Cardiovascular dysfunction is a potentially lethal complication of hypothermia. Due to a knowledge gap, pharmacological interventions are not recommended at core temperatures below 30°C. Yet, further cooling is induced in surgical procedures and survival of accidental hypothermia is reported after rewarming from below 15°C, advocating a need for evidence-based treatment guidelines. In vivo studies proposed a combination of positive inotropic effects through intracellular cAMP-elevation and afterload reduction through arteriole smooth muscle cAMP and/or cGMP-elevation as a favorable strategy to prevent cardiovascular dysfunction in hypothermia. Further development of treatment guidelines demand information about temperature-dependent changes in pharmacological effects of clinically relevant vasodilators.

In our recent papers, we found PDE3- and PDE5-inhibitors were able to inhibit elimination of cGMP and cAMP down to 20°C. As the cellular effects of these drugs can provide increased inotropy and afterload reduction, they show potential in treating cardiovascular dysfunction during hypothermia.

Different in vitro models for studying the temperature-dependent effects of phosphodiesterase-enzymes and transporter proteins were utilized to evaluate how PDE-inhibitors sildenafil, vardenafil, milrinone, amrinone, levosimendan and pentoxifylline affected cellular efflux and enzymatic breakdown of cAMP and cGMP at 37°C-20°C. We also assessed the electrophysiological effects of levosimendan, milrinone and isoprenaline in hiPSC-derived cardiomyocytes. Recordings of cellular action potential waveforms and contraction were recorded from monolayers of cultured cells during cooling to 26°C and after rewarming.

Publications:

Proarrhythmic changes in human cardiomyocytes during hypothermia by milrinone and isoprenaline, but not levosimendan: an experimental in vitro study (2023)

Moderate but not severe hypothermia increases intracellular cyclic AMP through preserved production and reduced elimination (2023)

Pharmacodynamic properties for inhibition of cAMP- and cGMP elimination by pentoxifylline remain unaltered in vitro during hypothermia (2022)

Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate (2022)

Treatment of Cardiovascular Dysfunction With PDE5-Inhibitors – Temperature Dependent Effects on Transport and Metabolism of cAMP and cGMP (2021)



Members:

Ole Martin Fuskevåg
Georg Sager
Roy Andre Lyså
Aina Westrheim Ravna
Natalia Smaglyukova