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

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.