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Abstract
Prolongation of cardiac repolarization (QT interval) represents a dangerous and potentially life-threatening electrical event affecting the heart. Thyroid hormones (THs) are critical for cardiac development and heart function. However, little is known about THs influence on ventricular repolarization and controversial effects on QT prolongation are reported. Human iPSC-derived cardiomyocytes (hiPSC-CMs) and multielectrode array (MEA) systems were used to investigate the influence of 3,3′,5-triiodo-l-Thyronine (T3) and 3,3′,5,5′-tetraiodo-l-Thyronine (T4) on corrected Field Potential Duration (FPDc), the in vitro analog of QT interval, and on local extracellular Action Potential Duration (APD). Treatment with high THs doses induces a significant prolongation of both FPDc and APD, with the strongest increase reached after 24 h exposure. Preincubation with reverse T3 (rT3), a specific antagonist for nuclear TH receptor binding, significantly reduces T3 effects on FPDc, suggesting a TRs-mediated transcriptional mechanism. RNA-seq analysis showed significant deregulation in genes involved in cardiac repolarization pathways, including several QT-interval related genes. In conclusion, long-time administration of high THs doses induces FPDc prolongation in hiPSC-CMs probably through the modulation of genes linked to QT-interval regulation. These results open the way to investigate new potential diagnostic biomarkers and specific targeted therapies for cardiac repolarization dysfunctions.
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Details
1 Niccolò Cusano University Foundation, Laboratory of Biomedical Research, Rome, Italy (GRID:grid.460091.a) (ISNI:0000 0004 4681 734X)
2 Policlinico Casilino, Department of Cardiology, Rome, Italy (GRID:grid.452730.7) (ISNI:0000 0004 1768 3469)
3 Niccolò Cusano University Foundation, Laboratory of Biomedical Research, Rome, Italy (GRID:grid.460091.a) (ISNI:0000 0004 4681 734X); PTV, Tor Vergata University Hospital, Medical Genetics Units, Rome, Italy (GRID:grid.413009.f)
4 Niccolò Cusano University Foundation, Laboratory of Biomedical Research, Rome, Italy (GRID:grid.460091.a) (ISNI:0000 0004 4681 734X); Sapienza University, Department of Clinical and Molecular Medicine, Rome, Italy (GRID:grid.7841.a)