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A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart

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Abstract

Tamoxifen, a selective estrogen receptor modulator, was initially used to treat cancer in women and more recently to induce conditional gene editing in rodent hearts. However, little is known about the baseline biological effects of tamoxifen on the myocardium. In order to clarify the short-term effects of tamoxifen on cardiac electrophysiology of myocardium, we applied a single-chest-lead quantitative method and analyzed the short-term electrocardiographic phenotypes induced by tamoxifen in the heart of adult female mice. We found that tamoxifen prolonged the PP interval and caused a decreased heartbeat, and further induced atrioventricular block by gradually prolonging the PR interval. Further correlation analysis suggested that tamoxifen had a synergistic and dose-independent inhibition on the time course of the PP interval and PR interval. This prolongation of the critical time course may represent a tamoxifen-specific ECG excitatory-inhibitory mechanism, leading to a reduction in the number of supraventricular action potentials and thus bradycardia. Segmental reconstructions showed that tamoxifen induced a decrease in the conduction velocity of action potentials throughout the atria and parts of the ventricles, resulting in a flattening of the P wave and R wave. In addition, we detected the previously reported prolongation of the QT interval, which may be due to a prolonged duration of the ventricular repolarizing T wave rather than the depolarizing QRS complex. Our study highlights that tamoxifen can produce patterning alternations in the cardiac conduction system, including the formation of inhibitory electrical signals with reduced conduction velocity, implying its involvement in the regulation of myocardial ion transport and the mediation of arrhythmias.

Graphical abstract

A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart（Figure 9）. A working model of tamoxifen producing acute electrical disturbances in the myocardium. SN, sinus node; AVN, atrioventricular node; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle

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Acknowledgements

We thank the other managers, staff, and participants in the authors’ institutions who have supported this study.

Funding

This research was funded by the National Key Research and Development Program of China (2018YFA0108700), the National Natural Science Foundation of China (81974019, 82100275, 82070484), the Guangdong Provincial Special Support Program for Prominent Talents(2021JC06Y656), the Science and Technology Planning Project of Guangdong Province (2020B1111170011, 2022B1212010010), the Guangdong Special Funds for Science and Technology Innovation Strategy, China (Stability support for scientific research institutions affiliated to Guangdong Province (GDCI 2021)), the Guangzhou Science and Technology Plan Project (202201000006), and the Special Project of Dengfeng Program of Guangdong Provincial People’s Hospital (DFJH201812; KJ012019119; KJ012019423).

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Author notes

  1. Ming Xie, Shuoji Zhu, Gang Liu and Yijin Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiac Surgery, School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China

    Ming Xie, Ge Li, Nanbo Liu & Ping Zhu

  2. Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510100, Guangdong, China

    Ming Xie, Shuoji Zhu, Yijin Wu, Wenkai Zhou, Dingdang Yu, Lin Gan, Ge Li, Nanbo Liu & Ping Zhu

  3. Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, and Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, 510100, Guangdong, China

    Ming Xie, Shuoji Zhu, Yijin Wu, Wenkai Zhou, Dingdang Yu, Lin Gan, Ge Li, Nanbo Liu & Ping Zhu

  4. University of Tokyo, Tokyo, 113-8666, Japan

    Shuoji Zhu

  5. Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Gang Liu & Hao Lai

  6. Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Jinkai Wan, Shenghui Xing & Siqing Wang

  7. University of Tokyo Hospital Department of Cell Therapy in Regenerative Medicine, Tokyo, 113-8666, Japan

    Dehua Chang

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Contributions

P. Z., N. L., H. L., and D. C. designed and monitored the experiments. M. X., N. L., and G. L. (Gang Liu) performed and analyzed experiments. Y. W., W. Z., D. Y., J. W., S. X., and S. W. analyzed and interpreted experiments. M. X., S. Z., G. L. (Gang Liu), Y. W., N. L., and P. Z. wrote the manuscript. N. L., M. X., L. G., G. L. (Ge Li), D. C., H. L., and P. Z. edited the manuscript.

Corresponding authors

Correspondence to Dehua Chang, Hao Lai, Nanbo Liu or Ping Zhu.

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Xie, M., Zhu, S., Liu, G. et al. A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart. J. of Cardiovasc. Trans. Res. 16, 1232–1248 (2023). https://doi.org/10.1007/s12265-023-10395-5

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