1149 - Ibrutinib induces cardiac arrhythmia by targeting CaV1.2 calcium channel

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor that has shown significant efficacy against chronic lymphocytic leukemia (CLL). Clinical studies have found that ibrutinib increases the risk of cardiac arrhythmia, but the underlying molecular mechanisms are still unclear. CaV1.2 calcium channel is indispensable for the cardiac excitations, its dysregulations indeed lead to arrhythmia. However, the associations between ibrutinib and cardiac CaV1.2 channel and calcium-dependent signaling remain unknown.

Methods: We collected clinical history of the CLL patients treated with ibrutinib to analyze possible factors which might associated with cardiac arrhythmia. Electrophysiological experiments were conducted in the hearts from mouse model and neonatal rat ventricular myocytes (NRVMs) to assess ibrutinib induced arrhythmia. mRNA transcriptomic of cardiac tissue was performed to screen the potential target genes of ibrutinib-induced arrhythmia. The pathogenesis of arrhythmia was further studied at mouse models and cellular experiments.

Results: Clinical data showed that the incidence of cardiac arrhythmia of CLL patients treated with ibrutinib is ~19.2%. At animal model, the mouse treated with ibrutinib (25 mg/kg/d) for 28 days were more likely to develop spontaneous ventricular arrhythmias (46.2%, 6/13) in comparison to the control mice (8.3%, 1/12), and M-mode echocardiography indicated ibrutinib treatment induces systolic dysfunction. The expression levels of CaV1.2 1C protein and the phosphorylated CaMKII, which were identified by RNA-seq, in mouse hearts and ibrutinib-treated NRVMs were significantly increased. Whole-cell patch clamp showed that the activation kinetics of cardiac CaV1.2 channel of ibrutinib-treated NRVMs shifts towards hyperpolarization, and its current size is also increased. Furthermore, the intracellular calcium concentration that detected with Fluo-4 AM was found to be increased after application with ibrutinib in NRVMs.

Conclusions: These findings suggest that ibrutinib could increase CaV1.2 expression of myocardial cells, and enhance the functions of CaV1.2 channels. Thus, this causes intracellular calcium signaling disturbance and triggering cardiac arrhythmia.