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.
Highlights
The delayed ventricular repolarization (QT prolongation) is a dangerous event for the heart
Clinicians are well aware that when they face a patient affected by thyroid dysfunctions his/her heart may suffer potential negative effects of the altered thyroid status as well as of an inappropriate treatment
Atrial fibrillation and arrhythmias are frequently observed in patients with thyroid dysfunctions and are considered hallmarks of the hyperthyroid s tate[3,4]
Summary
The delayed ventricular repolarization (QT prolongation) is a dangerous event for the heart. Conflicting results have been reported in the literature regarding the role of THs dysfunctions on changes in ventricular repolarization Both hyperthyroidism and hypothyroidism, have been reported to be responsible for changes in QT interval duration, with hypothyroidism associated with a prolongation of the QTc interval and hyperthyroidism associated with both decreased and increased repolarization times[8,9,10,11,12,13,14,15,16,17,18,19]. The human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent an excellent model to analyze, directly at the single cell level, specific compound cardiotoxicity This model gives the possibility to study the hormonal effects on QT interval duration directly in a human context and in a controlled. The deep characterization of these THs-responsive genes could help to better understand the mechanisms involved in cardiac repolarization and provides new diagnostic and potential therapeutic tools for patients affected by cardiac diseases due to QT interval alterations
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