Ibrutinib, a Bruton's tyrosine kinase inhibitor, regulates ventricular electromechanical activities and enhances arrhythmogenesis.

Autor: Liu CM; Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan., Lin FJ; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan., Chhay C; Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Cardiovascular Department, Faculty of Medicine, University of Health Sciences, Phnom Penh, Cambodia., Chen YC; Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan., Lin YK; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan., Lu YY; Division of Cardiology, Sijhih Cathay General Hospital, New Taipei City, Taiwan., Chan CS; Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan., Higa S; Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa, Japan., Chen SA; Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan; National Chung Hsing University, Taichung, Taiwan., Chen YJ; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: yjchen@tmu.edu.tw.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Aug 15; Vol. 977, pp. 176675. Date of Electronic Publication: 2024 May 31.
DOI: 10.1016/j.ejphar.2024.176675
Abstrakt: Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor used in cancer therapy, exerts ventricular proarrhythmic effects; however, the underlying mechanisms remain unclear. Excitation-contraction coupling (E-C) disorders are pivotal for the genesis of ventricular arrhythmias (VAs), which arise mainly from the right ventricular outflow tract (RVOT). In this study, we aimed to comprehensively investigate whether ibrutinib regulates the electromechanical activities of the RVOT, leading to enhanced arrhythmogenesis, and explore the underlying mechanisms.
Methods: We utilized conventional microelectrodes to synchronously record electrical and mechanical responses in rabbit RVOT tissue preparations before and after treatment with ibrutinib (10, 50, and 100 nM) and investigated their electromechanical interactions and arrhythmogenesis during programmed electrical stimulation. The fluorometric ratio technique was used to measure intracellular calcium concentration in isolated RVOT myocytes.
Results: Ibrutinib (10-100 nM) shortened the action potential duration. Ibrutinib at 100 nM significantly increased pacing-induced ventricular tachycardia (VT) (from 0% to 62.5%, n = 8, p = 0.025). Comparisons between pacing-induced VT and non-VT episodes demonstrated that VT episodes had a greater increase in contractility than that of non-VT episodes (402.1 ± 41.4% vs. 232.4 ± 29.2%, p = 0.003). The pretreatment of ranolazine (10 μM, a late sodium current blocker) prevented the occurrence of ibrutinib-induced VAs. Ibrutinib (100 nM) increased late sodium current, reduced intracellular calcium transients, and enhanced calcium leakage in RVOT myocytes.
Conclusion: Ibrutinib increased the risk of VAs in the RVOT due to dysregulated electromechanical responses, which can be attenuated by ranolazine or apamin.
Competing Interests: Declaration of competing interest None.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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