ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1613438
Abnormal Ca²⁺ handling and reduced I to contribute to citalopram-induced QT prolongation and cardiac arrhythmias
Provisionally accepted
Yangpeng Li1Yuqing Zheng1Jiamin Xie1Jianhong Li1Min Zhao1Li Liu1Hongping Shen1
Ming Lei2
Xiaoqiu Tan1Juan Xiao1*Xueru Liu1*
Tangting Chen1*- 1Southwest Medical University, Luzhou, China
- 2University of Oxford, Oxford, England, United Kingdom
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Background: Citalopram (CIT) is widely used for anti-depression and reported to be associated with QT prolongation and torsades de pointes (TdP), while the underlying mechanism remains unclear.Objective: Determine the proarrhythmic properties and underlying mechanisms of CIT.Methods: Mice were intraperitoneally injected with CIT or saline (SAL) for 4 weeks.Echocardiograms and electrocardiograms were performed to evaluate the cardiac electrophysiological and hemodynamic properties. Proarrhythmic mechanisms of CIT was then explored by optical mapping. Finally, transcriptomics array, RT-qPCR, and whole-cell patch-clamp were conducted to explore and validate potential ionic mechanisms of CIT related electrical abnormalities.Results: CIT treatment induced QT prolongation and increased vulnerability of cardiac arrhythmias in the absence of structural or hemodynamic changes. Optical mapping showed that action potential duration (APD) and Ca 2+ transient duration (CaTD) was prolonged, but the degree of prolongation was heterogeneous, resulting in impaired Vm-Ca 2+ coupling in CIT treated hearts. Meanwhile, CaT alternans exhibited a regional preference for initiating ventricular tachyarrhythmias in hearts treated with CIT. Transcriptomics array showed that multiple potassium channels were downregulated in hearts treated with CIT, which were confirmed with RT-qPCR.Prolonged APD and downregulated I to and I CaL were recorded in isolated single cardiomyocytes with patch-clamp after CIT treatment.CIT treatment resulted in QT prolongation and higher susceptibility of ventricular arrhythmia. Regions with serious cardiac alternans were mainly responsible for initiation of CIT related arrhythmias. Abnormal Ca²⁺ handling and decreased I to related genes expression likely underlie the ionic mechanism and may be a novel target for CIT related arrhythmias.
Keywords: Citalopram, selective serotonin reuptake inhibitor, cardiac arrhythmia, action potential, alternans
Received: 17 Apr 2025; Accepted: 28 Jul 2025.
Copyright: © 2025 Li, Zheng, Xie, Li, Zhao, Liu, Shen, Lei, Tan, Xiao, Liu and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Juan Xiao, Southwest Medical University, Luzhou, China
Xueru Liu, Southwest Medical University, Luzhou, China
Tangting Chen, Southwest Medical University, Luzhou, China
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