Hyperthermia Influences the Effects of Sodium Channel Blocking Drugs in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

IntroductionFever can increase the susceptibility to supraventricular and ventricular arrhythmias, in which sodium channel dysfunction has been implicated. Whether fever influences the efficacy of sodium channel blocking drugs is unknown. The current study was designed to investigate the temperature dependent effects of distinct sodium channel blocking drugs on the sodium currents in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).Methods and ResultshiPSC-CMs were generated from human skin fibroblasts of a healthy donor. The peak and late sodium currents (INa), steady-state activation, inactivation and recovery from inactivation of INa in hiPSC-CMs were analyzed using the whole-cell patch clamp technique. The effects of different concentrations of the antiarrhythmic drugs flecainide, lidocaine, ajmaline and the antianginal drug ranolazine on INa were tested at 36°C and 40°C. Increasing the temperature of the bath solution from 36°C to 40°C enhanced the inhibition of peak INa but reduced the inhibition of late INa by flecainide and lidocaine. By contrast, increasing the temperature reduced the effect of ajmaline and ranolazine on the peak INa but not late INa. None of the tested drugs showed temperature-dependent effects on the steady-state activation and inactivation as well as on the recovery from inactivation of INa in hiPSC-CMs.ConclusionsTemperature variation from the physiological to the febrile range apparently influences the effects of sodium channel blockers on the sodium currents. This may influence their antiarrhythmic efficacy in patients suffering from fever.

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Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

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“…This animal model is not ideal, either, because the differences between animals and humans—as well as the differences between the drug‐induced SQTS and disease‐induced SQTS—may influence the results of drug testing. Our group has successfully used human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) to model some key features of different diseases, including SQTS1 . We have demonstrated that the hiPSC‐CMs from an SQTS1 patient (SQTS1 hiPSC‐CMs) are able to recapitulate the single‐cell phenotypic features of SQTS (APD‐shortening and arrhythmic calcium transients) and provide novel opportunities to further elucidate the disease mechanism and test drug effects …”