KEY TAKEAWAYS
- The study aimed to understand the precise mechanism behind ibrutinib-induced atrial fibrillation in patients with CLL.
- The results revealed that the ibrutinib’s off-target effect on PI3K-AKT-mTOR causes connexin degradation, promoting autophagy and atrial arrhythmia.
Ibrutinib has been associated with an increased risk of atrial fibrillation (AF) in patients with chronic lymphocytic leukemia (CLL). However, the precise mechanism behind this effect is not yet fully understood.
Huiyuan Qin and the team aimed to determine the incidence of new-onset atrial fibrillation (AF) in patients with CLL receiving ibrutinib and elucidate its underlying mechanism.
Researchers investigated the prevalence of new-onset AF in patients with CLL undergoing treatment with ibrutinib. They utilized optical mapping to elucidate the proarrhythmic effects of ibrutinib on HL-1 cells.
Furthermore, fluorescence staining and western blot analysis were employed to compare the expression levels of connexins 43 and 40 between the ibrutinib-treated group and the control group. To characterize autophagy phenotypes, they utilized western blotting to assess the levels of autophagy-related proteins.
The study employed transmission electron microscopy (TEM) to visualize autophagosomes and used a transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes. Additionally, hydroxychloroquine, an autophagy inhibitor, was administered to counteract ibrutinib-induced degradation of Cx43 and Cx40.
About 2.67% of patients experienced atrial arrhythmias following the administration of ibrutinib. HL-1 cells subjected to ibrutinib treatment displayed decreased conduction velocity and a heightened occurrence of reentry-like arrhythmias compared to the control group.
Furthermore, the expression of connexins 43 and 40 was reduced, accompanied by an increase in autophagy markers in HL-1 cells treated with ibrutinib. The inhibition of autophagy led to the upregulation of connexins 43 and 40.
The off-target impact of ibrutinib on the PI3K-AKT-mTOR signaling pathway resulted in the degradation of connexins and the onset of atrial arrhythmia by inducing autophagy.
Funding was provided by the National Nature Science Foundation of China.
Source: https://pubmed.ncbi.nlm.nih.gov/38812314/
Qin H, Zheng B, Lin Z, et al. (2024). “Ibrutinib Contributes to Atrial Arrhythmia through the Autophagic Degradation of Connexins by Inhibiting the PI3K-AKT-mTOR Signaling Pathway.” Front Biosci (Landmark Ed). 2024 May 22;29(5):201. doi: 10.31083/j.fbl2905201. PMID: 38812314.
