Endocrine Abstracts

Thyroid hormones (TH)s have as a major target the heart, where they regulate many different functions, including the modulation of the heart rate and myocyte contractility. Their effects on ventricular repolarization are controversial and QT prolongation was reported both in patients with hypothyroidism and hyperthyroidism, in their overt or subclinical forms. We analyzed the effects of 3.3',5.5'-tetraiodo-L-Thyronine (T4), 3.3',5-triiodo-L-Thyronine (T3) and of 3.3',5'-triiodo-L-thyronine reverse T3 (rT3) on Field Potential Duration (FPD), the in vitro analog of QT interval, and on induction of arrhythmiausing a human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cell line, namely the human iCell Cardiomyocytes (Cellular Dynamics International, Inc. Madison, WI, USA, clone 01434)and the very sensitive Maestro Pro Multielectrode Array (MEA) platform (Axion Biosystem, Atlanta, GA, USA). Treatment with T3, at slightly supraphysiological doses (1 nM), induces a significant prolongation of the FPD while, at highly supraphysiological doses (up to 100 nM), T3 is able to induce arrhythmia in our cell system. The maximum effect on FPD was a 25% increase of the FPD, corrected by Fridericia (fFPDc), observed with T3 at the dose of 1 nM, while the major effect on induction of arrythmia was observed with the dose of 100 nM. T3 induces a clear dose-dependent prolongation effect on FPD and is responsible for a dose-dependent induction of arrhythmia. Both effectsare visible long time after exposure of cells to T3, up to 24 hours for the effect on FPD and up to 4 days for those on induction of arrhythmia, suggesting that both effects are mediated by genomic actions. To test this hypothesis, FPD prolongation and induction of arrhythmia were evaluated after preincubation with rT3, the specific antagonist of T3 at the thyroid hormone receptor (TR). Preincubation with rT3 significantly reduced both effects, indicating that interaction with TR is necessary for T3-induced FPD prolongation and arrhythmia. In conclusion, we demonstrated the direct impact of THs treatment on hiPSC-CMselectrophysiology and, in particular, on FPD duration and on the induction of arrhythmia. The present study gives useful insight on the mechanism of T3-induced arrhythmias and open the way to identify new potential diagnostic biomarkers and to develop specific targeted therapies.