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  3. Enzastaurin cardiotoxicity: QT interval prolongation, negative inotropic responses and negative chronotropic action

Enzastaurin cardiotoxicity: QT interval prolongation, negative inotropic responses and negative chronotropic action

  • Biochem Pharmacol. 2023 Jan 28;115443. doi: 10.1016/j.bcp.2023.115443.
He-Qiang Zhang 1,  Jia-le Lin 1,  Lei Pan 1,  Liang Mao 2,  Jing-Long Pang 1,  Qian Yuan 1,  Gui-Yang Li 3,  Gang-Si Yi 1,  Yang-Bin Lin 1,  Bao-Long Feng 1,  Yun-da Li 1,  Yan Wang 4,  Ling-Jun Jie 5,  Yanhui Zhang 6
Affiliations

Affiliations

  • 1 Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 2 Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China; Key Laboratory of Medical Electrophysiology, Southwest Medical University, Luzhou, Sichuan, China.
  • 3 Department of Cardiology, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 4 Department of Cardiology, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. Electronic address: [email protected].
  • 5 Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China; Department of Cardiology, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. Electronic address: [email protected].
  • 6 Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. Electronic address: [email protected].
PMID: 36720353 DOI: 10.1016/j.bcp.2023.115443
Abstract

Several clinical trials observed that enzastaurin prolonged QT interval in Cancer patients. However, the mechanism of enzastaurin is unclear. Therefore, this study aimed to assess the effect and mechanism of enzastaurin on QT interval and cardiac function. The Langendorff and Ion-Optix MyoCam systems were used to assess the effects of enzastaurin on QT interval, cardiac systolic function and intracellular Ca2+ transient in guinea pig hearts and ventricular myocytes. The effects of enzastaurin on the rapid delayed rectifier (IKr), the slow delayed rectifier K+ current (IKs), transient outward potassium current (Ito), action potentials, Ryanodine Receptor 2 (RyR2) and The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) expression and activity in HEK 293 cell system and primary cardiomyocytes were investigated using whole-cell recording technique and western blotting. We found that enzastaurin significantly prolonged QT interval in guinea pig hearts and increased the action potential duration (APD) in guinea pig cardiomyocytes in a dose-dependent manner. Enzastaurin potently inhibited IKr by binding to the human Ether-à-go-go-Related gene (hERG) channel in both open and closed states and hERG mutant channels including S636A, S631A, and F656V attenuated the inhibitory effect of enzastaurin. Enzastaurin also moderately decreased IKs. Additionally, enzastaurin also induced negative chronotropic action. Moreover, enzastaurin impaired cardiac systolic function and reduced intracellular Ca2+ transient via inhibition of RyR2 phosphorylation. Taken together, we found that enzastaurin prolongs QT, reduces heart rate and impairs cardiac systolic function. Therefore, we recommend that electrocardiogram (ECG) and cardiac function should be continuously monitored when enzastaurin is administered to Cancer patients.

Keywords

Enzastaurin; QT interval prolongation; cardiac systolic function; cardiotoxicity; ryanodine receptor type 2.

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